WO2003084524A1 - Combination therapy for the treatment of conditions with pathogenic inflammatory components - Google Patents

Combination therapy for the treatment of conditions with pathogenic inflammatory components Download PDF

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Publication number
WO2003084524A1
WO2003084524A1 PCT/US2003/009424 US0309424W WO03084524A1 WO 2003084524 A1 WO2003084524 A1 WO 2003084524A1 US 0309424 W US0309424 W US 0309424W WO 03084524 A1 WO03084524 A1 WO 03084524A1
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Prior art keywords
butyl
phenyl
methyl
imidazol
alkyl
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PCT/US2003/009424
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French (fr)
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James Krause
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Neurogen Corporation
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Priority to EP03716867A priority Critical patent/EP1490044A4/en
Priority to JP2003581764A priority patent/JP2005530719A/en
Priority to AU2003220553A priority patent/AU2003220553A1/en
Priority to CA002480082A priority patent/CA2480082A1/en
Publication of WO2003084524A1 publication Critical patent/WO2003084524A1/en

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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Definitions

  • This invention relates generally to compositions and methods for treating diseases that are associated with inflammation.
  • the invention relates more specifically to compositions comprising a C5a antagonist and a C5a receptor-inactive therapeutic agent, and to therapeutic methods in which a C5a antagonist and a C5a receptor-inactive therapeutic agent are administered to a patient.
  • Inflammation is a localized defense mechanism that is elicited by tissue damage or injury, and serves to destroy, dilute or wall off both injurious agents and injured tissues.
  • Individuals suffering from inflammation typically experience redness, heat, swelling, pain and loss of function in the afflicted area.
  • inflammatory responses cause or exacerbate the harmful effects of many diseases. Inhibition of inflammatory responses in patients afflicted with such diseases can decrease symptom severity and improve treatment outcome.
  • Harmful inflammation typically involves the pathogenic activation of the complement system, and in particular the C5a anaphylatoxin.
  • C5a a 74 amino acid peptide, is a complement component generated early in the terminal phase of the complement cascade by the proteolytic cleavage (by C5 convertase) of the complement component plasma protein C5, and is itself a plasma protein and a key mediator of inflammation.
  • C5a promotes both vascular and cellular inflammatory responses; it has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and chemotactic effects.
  • C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of inflammation and/or cellular injury and is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also primes neutrophils for various antibacterial functions (e.g., phagocytosis).
  • C5a stimulates the release of various inflammatory mediators (e.g., activated oxygen radicals, histamines, TNF-alpha, DJ-1, IL-6, IL-8, prostaglandins, and leukotrienes) from various cell types and the release of lysosomal enzymes and other cytotoxic components from granulocytes.
  • the anaphylatoxic actions of C5a result from its stimulation of smooth muscle contraction. Both the anaphylatoxic and chemotactic effects of C5a are believed to be mediated through its interaction with the C5a receptor (CD88 antigen), a 52 kD membrane- bound cell surface G-protein coupled receptor (GPCR).
  • a wide variety of diseases and medical procedures can result in harmful inflammation, and inhibition of C5a-mediated inflammatory responses in patients afflicted with diseases or undergoing procedures that are associated with such inflammation can be beneficial.
  • Diseases associated with harmful inflammation include, for example, diseases of the joints, lungs, kidneys, heart, skin, liver, and digestive system, and as well as more generally, trauma and auto-immune and infectious diseases.
  • C5a receptor activity was found to improve survival rates for sepsis (Riedemann et al. (2002) J. Clin. Invest. 770:101-108).
  • Medical procedures associated with harmful inflammation include, for example, organ transplantation, tissue grafts, cardiopulmonary bypass and hemodialysis.
  • ASTHMA organ transplantation, tissue grafts, cardiopulmonary bypass and hemodialysis.
  • Asthma is a lung disease characterized by a usually reversible airway obstruction, airway inflammation and increased airway responsiveness to stimuli.
  • the airway obstruction in an asthma attack is thought to be due to the combination of bronchospasm of the smooth muscles of the bronchial tree, increased mucous section, edema of airway mucosa due to increased vascular permeability, cellular infiltration of the airway walls, and injury to airway epithelium.
  • Studies in animal models have implicated both IgE and the complement system (and C5a in particular) in airway hyperresponsiveness and asthma pathogenesis.
  • Asthma may be triggered by a variety of causes such as allergic reactions, a secondary response to infections, industrial or occupational exposures, ingestion of certain chemicals or drugs, exercise, and vasculitis. Regardless of the trigger, many of the pathological features of asthma can be attributed to mast cell degranulation. Such responses are, at least in part, mediated by IgE antibodies, which trigger mast cell degranulation in the lung interstitium.
  • the mast cell degranulation releases, among other factors, histamine, bradykinin, and slow- reacting substance of anaphylaxis (SRS-A) which includes the leukotrienes C, D and E, prostaglandins including PGF 2 , PGF 2 ⁇ and PGD 2 , and thromboxane A 2 .
  • SRS-A anaphylaxis
  • the histamine then attaches to receptor sites in the larger bronchi, causing irritation, inflammation and edema.
  • the SRS-A attaches to receptor sites in the smaller bronchi, causing edema and attracting prostaglandins, which enhance the effects of histamine in the lungs.
  • histamine also stimulates excessive mucous secretion, further narrowing the bronchial lumen.
  • the narrowed bronchial lumen still expands slightly, allowing air to reach the alveoli.
  • the increased thoracic pressure closes the bronchial lumen completely.
  • air can enter, but not exit the lungs.
  • Mucous then fills the lung bases, inhibiting alveolar ventilation.
  • blood is shunted to other alveoli. Without adequate compensation, hypoxia, and in extreme cases, respiratory acidosis may result.
  • the early phase includes the immediate inflammatory response including the reactions caused by the release of cellular mediators from mast cells.
  • Late phase reactions develop over a period of hours and are characterized histologically by an early influx of polymorphonuclear leukocytes and fibrin deposition followed later by infiltration of eosinophils. Late phase reactions increase airway reactivity and lead to prolonged asthmatic exacerbations that may last from hours to days to months in some subjects.
  • Asthma is most commonly treated with oral and inhaled bronchodilators. Such agents alleviate the symptoms of asthma, but have no effect on the underlying inflammation. Corticosteroids are also used to treat the inflammation, but these drugs can have serious side effects and many patients continue to suffer from incompletely controlled asthma.
  • the complement system is an important skin defense mechanism, and complement activation (particularly C5a) is involved in the pathogenesis of a variety of skin conditions such as bullous pemphigoid, lichen planas, herpes gestationis and psoriasis.
  • Psoriasis is one of the most common dermatologic diseases, affecting about 2 percent of the population. This condition presents as elevated lesions that vary in size from one to several centimeters, and results from an overproduction of epidermal cells.
  • the increased production of epidermal cells is due to a shortened cell cycle time, an increase in the absolute number of cells capable of proliferating and an increased rate of division.
  • the thickened epidermis, overgrowth of blood vessels, and infiltration of neutrophils and lymphocytes account for the psoriatic lesions being raised and easily palpable.
  • T cell mediated immune responses appear to be responsible for the inflammation and hyperproliferation of epidermal cells. Neutrophils are found in psoriatic lesions, associated with increased levels of plasminogen activator.
  • Psoriatic fibroblasts have increased levels of enzymes involved in collagen synthesis, secondary to expansion of the papillary dermis.
  • Psoriatic plaques comprise HLA-DR positive keratinocytes and Langerhans cells, as well as activated T cells expressing elevated levels of IL-2 receptors and secreting cytokines including TNF and interleukin-6, which stimulate skin cell growth.
  • RHEUMATOID ARTHRITIS Rheumatoid arthritis is a chronic disease characterized by persistent joint inflammation (inflammatory synovitis). Early clinical manifestations of the disease include pain, swelling and tenderness of the joints that is initially poorly localized. Many patients exhibit general fatigue, weakness, loss of appetite, low-grade fever and musculoskeletal symptoms before joint pain becomes localized. As the disease progresses, joint pain, swelling and stiffness become more evident. Movement, particularly after periods of inactivity, becomes painful and difficult. The persistent inflammation caused by rheumatoid arthritis often leads to destruction or weakening of ligaments and tendons, and destruction of cartilage and bone.
  • RA rheumatoid arthritis
  • Current treatments of RA can be divided into two types - therapies which act to alleviate the symptoms of the disease, such as pain medications, and disease-modifying therapies which act on some underlying cause of the disease and slow its progression, such as steroids.
  • Inhibitors of cyclooxygenase (COX) enzymes which inhibit prostaglandin production and thereby reduce inflammation are commonly used to treat rheumatoid arthritis.
  • COX enzymes non-specifically (e.g., the salicylates), or may specifically inhibit COX-2.
  • Injections of gold sodium thiomalate and oral administration of gold compounds have also been shown to suppress the synovitis of active rheumatoid arthritis. In some case, surgery may be performed.
  • autoimmune disorders and pathologic autoimmune responses are known to have an inflammatory component, such as multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, lupus erythematosus and irritable bowel syndrome.
  • inflammatory component such as multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, lupus erythematosus and irritable bowel syndrome.
  • anti-C5 antibodies also been used to treat glomerulonephritis, a disease characterized by inflammation of the kidney (see US Patent No. 6,355,245).
  • a variety of medical procedures involve the introduction of foreign matter into the patient's body. Such procedures generally trigger, and are complicated by, inflammation. For example, inflammation may result from cardiopulmonary bypass surgery or hemodialysis. Rejection of transplanted organs and tissue grafts also has an inflammatory component. In some cases, for example, the blood supply to the transplant becomes blocked due to inflammation of the blood vessels leading to the transplanted organ.
  • Current therapy for transplant rejection involves a regimen of immunosuppressants, including cyclosporin A, tacrolimus, and rapamycin (sirolimus).
  • immunosuppressants including cyclosporin A, tacrolimus, and rapamycin (sirolimus).
  • patients continue to have a 20 to 50 percent risk of rejecting a donated organ during the first three years following transplantation, and less than 50 percent of patients have functioning transplants after 10 years. Additionally, chronic use of immunosuppressants can lead to impairment of the recipients' immune system.
  • ISCHEMIA-REPERFUSION INJURY Ischemia is a condition in which blood flow (and thus oxygen) is restricted to a part of the body and may occur, for example, due to thrombosis or surgery.
  • Reperfusion injury occurs when a blood flow is restored to a blood vessel that has been previously occluded.
  • Reperfusion injury has also been found to occur during surgeries in which blood vessels are not occluded but in which a heart bypass pump is employed.
  • the hypoxic conditions in occluded blood vessels induces the production of a number of pro-inflammatory cytokines. While prompt restoration of blood flow is necessary to restore normal function, reperfusion also causes the destruction of additional cells and an intense inflammatory reaction that involves C5a activation.
  • the pro-inflammatory cytokines produced while the vessel was occluded causes leads leukocyte recruitment and subsequent destruction of the endothelium. Additional damage may occur due to obstruction of microcapillaries by leukocytes.
  • inhibition of C5a receptor activity has been found to improve survival rates for ischemia- reperfusion injury (De Vries et al. (2003) Transplantation 75:375-82).
  • a small molecule C5a receptor antagonist also was shown to protect kidneys from ischemia-reperfusion injury in rats (Arumugam et al. (2003) Kidney Int. 63:134-42).
  • the invention provides compositions useful for the treatment of diseases with inflammatory components, such as arthritis (particularly rheumatoid arthritis) and other autoimmune disorders, asthma, cardio- and cerebrovascular disease, psoriasis, reperfusion injury, and traumatic CNS and spinal cord injury.
  • Such compositions comprise at least one C5a receptor antagonist (hereinafter a "C5a antagonist”) and at least one C5a receptor-inactive therapeutic agent (Le., a therapeutic agent that is not a C5a antagonist).
  • Preferred properties for C5a antagonists for use in the practice of the invention are one or preferably 2 or most preferably all 3 of: 1) having a molecular mass less than 700 a.m.u. 2) being nonpeptidic (i.e., do not contain amino acids joined by a peptide bond; preferably do not contain any amino acid moiety) and 3) having minimal agonist activity (i.e., induce an increase in the basal activity of the C5a receptor in the absence of C5a that is less than 5% of the increase that would be induced by C5a, preferably inducing no statistically significant increase).
  • Preferred C5a antagonists for used in the practice of the invention include neutral antagonists and inverse agonists of the C5a receptor.
  • the C5a receptor-inactive therapeutic agent is an NSAID, a cyclo-oxygenase enzyme inhibitor, a gold compound, a salicylate, a steroid such as a corticosteroid, methotrexate, lefunomide, a TNF antagonist, a cholesterol lowering agent, an HMG-CoA reductase inhibitor, a platelet aggregation inhibitor, or an anti-hypertensive agent.
  • the present invention provides pharmaceutical compositions, comprising a C5a antagonist in combination with a C5a receptor-inactive therapeutic agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutical formulations such as tablets, pills and capsules, containing a C5a antagonist and a C5a receptor-inactive therapeutic agent are included in the invention.
  • Pharmaceutical formulations of the invention may include additional active or inert ingredients. Processes for preparing such pharmaceutical compositions and pharmaceutical formulations are included in the invention.
  • packages comprising such a pharmaceutical composition and instructions for use to treat a patient suffering from arthritis or another autoimmune disorder, asthma, cardio- and cerebrovascular disease, psoriasis, reperfusion injury, or traumatic CNS or spinal cord injury.
  • the C5a antagonist and a C5a receptor-inactive therapeutic agent may be provided each in a separate container within the package or - where both are to be given by the same route of administration - preferably combined in a single formulation.
  • Methods are further provided, within other aspects for treating a patient suffering from arthritis or another autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burns, or traumatic CNS or spinal cord injury, comprising administering to the patient a therapeutically effective amount of a C5a receptor antagonist in combination with a therapeutically effective amount of a C5a receptor-inactive therapeutic agent.
  • the combination therapy provided herein encompasses either or both of 1) the administration of a C5a antagonist and a C5a receptor-inactive therapeutic agent together, preferably in a single pharmaceutical formulation, and 2) the administration of a C5a antagonist in a first formulation and the separate administration of a C5a receptor-inactive therapeutic agent in a second pharmaceutical formulation.
  • a “C5a antagonist” or “C5a receptor antagonist” is any compound that exhibits C5a antagonist activity within the a C5a receptor-mediated chemotaxis, radioligand binding assay, or calcium mobilization assay as provided herein.
  • a compound in a calcium mobilization assay, a compound is a C5a antagonist if incubation of cells with 1 uM of C5a antagonist results in at least a 2-fold increase in the fluorescence response relative to that measured in the presence of C5a alone.
  • a compound is a C5a antagonist if it displays an affinity constant or IC 50 of 1 uM or less.
  • a C5a antagonist displays an
  • C5a antagonists provided herein inhibit activation and/or activity of a primate C5a receptor, such as human C5a receptor, which may be a cloned, recombinantly expressed receptor or a naturally expressed receptor.
  • a primate C5a receptor such as human C5a receptor, which may be a cloned, recombinantly expressed receptor or a naturally expressed receptor.
  • a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.
  • therapeutic agent refers to a compound which has been shown to exhibit clinical efficacy in reducing the symptoms of one or more of arthritis (preferably rheumatoid arthritis) or another autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burns, or traumatic CNS or spinal cord injury.
  • a "C5a receptor-inactive therapeutic agent” is such an agent that does not satisfy the criteria (above) for a C5a antagonist.
  • active agent refers to either or both of the C5a antagonist and the
  • C5a receptor-inactive therapeutic agent This term is intended to encompass all salt, ester and prodrug forms of C5a antagonists and C5a receptor-inactive therapeutic agents, even where the prodrug is not active itself but is converted to the active form after administration to the patient.
  • An active agent is said to be "administered” if it is caused to be contacted with a patient so as to provide a detectable therapeutic effect. Administration may be oral, intranasal, topical, rectal or parenteral.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.
  • a "condition with a pathogenic inflammatory component” is any disease, disorder or injury that is caused, prolonged or exacerbated by C5a-mediated inflammation.
  • Such conditions include, but are not limited to, arthritis (such as rheumatoid arthritis) and other autoimmune disorders (e.g., multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, Guillain-Barre Syndrome, lupus erythematosus and irritable bowel syndrome); asthma and other lung disorders, including respiratory distress syndrome; skin conditions and injuries such as psoriasis, bullous pemphigoid, lichen planas, burns and wounds; cardio- and cerebrovascular disease, including restenosis; ischemia- reperfusion injury; trauma (e.g., CNS); sepsis and other infections; hemorrhagic shock; and multiple organ system failure.
  • Such conditions also include medical procedures such as organ transplantation (e.g., lung
  • C5a antagonists used in the compositions and methods provided herein are generally described using standard nomenclature.
  • Certain compounds described herein contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like (e.g., asymmetric carbon atoms) so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • these compounds can additionally be mixtures of diastereomers. Unless otherwise specified all optical isomers and mixtures thereof are encompassed for compounds having asymmetric centers.
  • compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified.
  • the invention is not limited to any one of the specific tautomers, but rather encompasses all tautomeric forms.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ⁇ C, I3 C, and 14 C.
  • a "ring substituent” may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound (i.e., a compound that can be isolated, characterized and tested for biological activity).
  • 2 hydrogens on the atom are replaced.
  • aromatic moieties are substituted by an oxo group
  • the aromatic ring is replaced by the corresponding partially unsaturated ring.
  • a pyridyl group substituted by oxo is a tetrahydropyridone.
  • Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, -COOH, SO 2 NH 2 , alkyl (e.g., C ⁇ -C 8 alkyl), alkenyl (e.g., C -C 8 alkenyl), alkynyl (e.g., C 2 -C 8 alkynyl), alkoxy (e.g., C ⁇ -C 8 alkoxy), alkyl ether (e.g., C 2 -C 8 alkyl ether), alkylthio (e.g., C ⁇ -C 8 alkylthio), mono- or di-(C 1 -C 8 alkyl)amino, haloalkyl (e.g., Ci- C 6 haloalkyl), hydroxyalkyl (e.g., C !
  • -C 6 hydroxyalkyl aminoalkyl (e.g., C ⁇ -C 6 aminoalkyl), haloalkoxy (e.g., Ci-C 6 haloalkoxy), alkanoyl (e.g., C ⁇ -C 8 alkanoyl), alkanone (e.g., - C 8 alkanone), alkanoyloxy (e.g., C ⁇ -C 8 alkanoyloxy), alkoxycarbonyl (e.g., Ci- C 8 alkoxycarbonyl), mono- and di-(C ⁇ -C 8 alkyl)amino, mono- and di-(C ⁇ -C 8 alkyl)aminoC ⁇ - C 8 alkyl, mono- and di-(C ⁇ -C 8 alkyl)carboxamido, mono- and di-(C ⁇ -C 8 alkyl)sulfonamido, alkylsulfinyl (e.g., C ⁇ -C 8 alkylsulf
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, and where specified, having the specified number of carbon atoms.
  • Ci-C ⁇ alkyl indicates an alkyl group having from 1 to 6 carbon atoms.
  • Co-C 4 alkyl refers to a bond or a - alkyl group.
  • Alkyl groups include groups having from 1 to 8 carbon atoms (C ⁇ -C 8 alkyl), from 1 to 6 carbon atoms ( - C 6 alkyl) and from 1 to 4 carbon atoms (C ⁇ -C 4 alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • Aminalkyl is an alkyl group as defined herein substituted with one or more -NH 2 groups.
  • Hydroxyalkyl is a hydroxy group as defined herein substituted with one or more -OH groups.
  • Alkenyl refers to a straight or branched hydrocarbon chain comprising one or more unsaturated carbon-carbon bonds, such as ethenyl and propenyl.
  • Alkenyl groups include C 2 - C 8 alkenyl, C2-C6alkenyl and C2-C4alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively), such as ethenyl, allyl or isopropenyl.
  • Alkynyl refers to straight or branched hydrocarbon chains comprising one or more triple carbon-carbon bonds.
  • Alkynyl groups include C 2 -C 8 alkynyl, C2-C6alkynyl and ⁇ 2- C4alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • Alkynyl groups include for example groups such as ethynyl and propynyl.
  • Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy.
  • alkanoyl refers to an acyl group in a linear or branched arrangement (e.g.,
  • Alkanoyl groups include C 2 -C 8 alkanoyl, C2-C6alkanoyl and C2-C4alkanoyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.
  • alkyl ether refers to a linear or branched ether substituent linked via a carbon-carbon bond.
  • Alkyl ether groups include C 2 -C 8 alkyl ether, C 2 -C 6 alkyl ether and C 2 -
  • C 6 alkyl ether groups which have 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.
  • a C 2 alkyl ether group has the structure -CH 2 -O-CH 3 .
  • Alkoxycarbonyl groups include C 2 -C 8 ,
  • C 2 -C 6 and C 2 -C 4 alkoxycarbonyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.
  • Alkanoyloxy groups include C 2 -C 8 , C 2 -C 6 , and C 2 -C alkanoyloxy groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.
  • alkylthio refers to an alkyl group attached via a thioether linkage. Alkylthio groups include C ⁇ -C 8 alkylthio, C ⁇ -C 6 alkylthio and C ⁇ -C 4 alkylthio, which have from 1 to 8, 1 to 6 or 1 to 4 carbon atoms, respectively.
  • Alkylsulfinyl refers to an alkyl group attached via a sulfinyl linkage.
  • Alkylsulfinyl groups include Ci-Csalkylsulfinyl, C ⁇ -C 6 alkylsulfinyl, and - alkylsulfinyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.
  • alkylsulfonyl is meant an alkyl group attached via a sulfonyl linkage.
  • Alkylsulfonyl groups include C ⁇ -C 8 alkylsulfonyl, C ⁇ -C 6 alkylsulfonyl, and Ci-
  • C 4 alkylsulfonyl which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.
  • Alkylamino refers to a secondary or tertiary amine having the general structure - NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl may be the same or different.
  • groups include, for example, mono- and di-(C ⁇ -C 8 alkyl)amino groups, in which each alkyl may be the same or different and may contain from 1 to 8 carbon atoms, as well as mono- and di-(C ⁇ - C 6 alkyl)amino groups and mono- and di-(C ⁇ -C alkyl)amino groups.
  • Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group (i.e., a group having the general structure - alkyl-NH-alkyl or -alkyl-N(alkyl)(a ⁇ kyl)).
  • alkyl group i.e., a group having the general structure - alkyl-NH-alkyl or -alkyl-N(alkyl)(a ⁇ kyl)).
  • alkyl group i.e., a group having the general structure - alkyl-NH-alkyl or -alkyl-N(alkyl)(a ⁇ kyl)).
  • alkyl group i.e., a group having the general structure - alkyl-NH-alkyl or -alkyl-N(alkyl)(a ⁇ kyl)
  • Such groups include, for example, mono- and di-( - C 8 alkyl)aminoC ⁇ -C 8 alkyl, mono
  • cycloalkyl refers to hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from. Cycloalkyl groups include C 3 -C 8 , and C 3 -C 7 cycloalkyl groups, which have from 3 to 8 and 3 to 7 carbon atoms, respectively.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, as well as bridged and caged saturated ring groups such as norbornane or adamantane and the like.
  • (cycloalkyl)alkyl is as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylethyl.
  • halogen indicates fluorine, chlorine, bromine, or iodine.
  • Haloalkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Haloalkoxy indicates a haloalkyl group as defined above attached through an oxygen bridge.
  • aryl indicates aromatic groups containing only carbon in the aromatic ring(s). Such aromatic groups may be further substituted with carbon or non- carbon atoms or groups. Typical aryl groups contain 1 to 3 separate or fused rings, at least one of which is aromatic, and from 6 to about 18 ring atoms, without heteroatoms as ring members. Specifically preferred carbocyclic aryl groups include phenyl and napthyl, including 1 -naphthyl and 2-naphthyl. When indicated, carbon atoms present within a carbocyclic ring may be optionally substituted with any of variety of ring substituents, as described above, or with specifically listed substituents.
  • arylalkyl refers to an aryl group is linked via an alkyl group.
  • Certain arylalkyl groups are (C ⁇ -Cisaryr -Csalkyl groups (i.e., groups in which a 6- to 18- membered aryl group is linked via a C ⁇ -C 8 alkyl group).
  • Such groups include, for example, groups in which phenyl or naphthyl is linked via a bond or C ⁇ -C 8 alkyl, preferably via - C 4 alkyl, such as benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl.
  • Biphenyl as used herein indicates, for example, a group of the formula:
  • heteroaryl is intended to indicate a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4 heteroatoms selected from N, O, and S, with remaining ring atoms being carbon.
  • the total number of S and 0 atoms in the heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1, 2, or 3, more typically 1 or 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl. isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7, 8-tetrahydroisoquinoline.
  • heterocyclic group or “heterocycle” is used to indicate saturated, partially unsaturated, or aromatic groups having 1 or 2 rings, 3 to 8 atoms in each ring and in at least one ring between 1 and 3 heteroatoms selected from N, O, and S. Any nitrogen or sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized.
  • heteroaryl groups and heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, l ⁇ -indazolyl, indoleny
  • C5a at the C5a receptor reduces the activity of the C5a receptor below its basal activity level in the absence of added C5a.
  • Inverse agonists of the C5a receptor may also inhibit binding of C5a to the C5a receptor.
  • the ability of a compound to inhibit the binding of C5a to the C5a receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 5.
  • the basal activity of the C5a receptor may be determined from a GTP binding assay, such as the assay of Example 6.
  • the reduction of C5a activity may also be determined from a GTP binding assay such as the assay of Example 6 or a calcium mobilization assay such as the assay of Example 7.
  • a "neutral antagonist of the C5a receptor is a compound which inhibits the activity of C5a at the C5a receptor, but does not significantly change the basal activity of the C5a receptor.
  • Neutral antagonists of the C5a receptor may inhibit the binding of C5a to the C5a receptor.
  • a "partial agonist" of the C5a receptor elevates the activity of the C5a receptor above the basal activity level of the receptor in the absence of C5a, but does not elevate the activity of the C5a receptor to the level brought about by saturating levels of the natural agonist, C5a.
  • Partial agonist compounds may inhibit the binding of C5a to the C5a receptor.
  • Partial agonists of the C5a receptor usually elevate the active of the C5a receptor from 5% to 90% of the activity level brought about by saturated concentrations of the natural agonist, C5a.
  • a "pharmaceutically acceptable salt” is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH 2 ) n -COOH where n is 0-4 and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfur
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • pharmaceutically acceptable salts include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). Accordingly, the present disclosure should be construed to include all pharmaceutically acceptable salts of the compounds specifically recited.
  • a wide variety of synthetic procedures is available for the preparation of pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • a C5a receptor is a G-coupled protein receptor that specifically binds C5a protein.
  • the C5a receptor is a human C5a receptor such as the protein product of the sequence of the resulting PCR product described by Gerard and Gerard, (1991) Nature 549:614-17.
  • the human C5a receptor may also be that described by Boulay (1991) Biochemistry, 30(12): 2993-9 (GENBANK Accession No. M62505).
  • Non-primate C5a receptors may be a rat C5a receptor such as a rat C5a receptor, GENBANK Accession Nos. X65862, Y09613, and AB003042, a canine C5a receptor, GENBANK Accession No.
  • a "C5a receptor modulatory amount" of a compound is an amount that is sufficient to yield a plasma concentration of the compound (or its active metabolite, if a prodrug) high enough to detectably alter (modulate) C5a receptor activity and/or ligand binding, when that concentration is used in an in vitro assay.
  • Suitable in vitro assays include the standard in vitro C5 receptor-mediated chemotaxis assay (described in Example 8 herein); C5a receptor- mediated calcium mobilization assay (described in Example 7 herein); and/or radioligand binding assay such as the assay provided in Example 5.
  • a "therapeutically effective amount" of a drug or pharmaceutical agent that elicits a detectable and desirable biological or medical response in a patient may take place in a tissue, a system, a non-human animal or a human and is generally sought by a researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount may reduce symptom severity or frequency.
  • a therapeutically effective amount may improve patient outcome and/or prevent or delay disease or symptom onset.
  • the dosage regimen utilizing an C5a antagonist in combination with a C5a receptor-inactive therapeutic agent is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the enhanced effects achieved by combining them together (if any) must also be taken into account in determining a therapeutically effective amount.
  • One marker of pathogenic inflammation is C reactive protein (CRP). Decreased plasma levels of CRP after treatment (as compared to levels before treatment) is an indication of an effective anti-inflammatory treatment of a disease with an inflammatory component.
  • a “patient” is any individual treated with a C5a antagonist as provided herein.
  • Patients include humans, as well as other animals such as companion animals (e.g., dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to C5a receptor modulation, or may be free of such symptom(s) (i.e., treatment may be prophylactic).
  • the patient is a human.
  • a "patient at risk for myocardial infarction or stroke” is any patient determined to have one or more of the known risk factors for such vascular events.
  • Known risk factors for myocardial infarction and stroke include, but are not limited to obesity, an elevated cholesterol level, hypertension, elevated low density lipoprotein (LDL) levels, congenital heart defects, smoking, previous history of myocardial infarction or stroke, and sedentary lifestyle.
  • a “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a substituted tetrahydroisoquinoline.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Preferred prodrugs include acylated derivatives.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved to the parent compounds. Those of ordinary skill in the art will recognize various synthetic methods that may be employed to prepare prodrugs of the compounds provided herein. C5A ANTAGONISTS
  • Any C5a antagonist including neutral antagonists and inverse agonists, may be used in the compositions and methods provided herein.
  • the synthesis of certain C5a antagonists listed herein has been described in PCT International Application WO 02/49993 and US Patent Application No. 09/672,701 at pages 161-201 which is hereby incorporated by reference for its teachings regarding the synthesis of C5a antagonists. Additional C5a antagonists have been described in PCT International Application WO 02/14265, published February 21, 2002.
  • compounds that act as C5a antagonists may be readily identified by assays for C5a receptor antagonist activity such as the assays provided in Examples 7 and 8, herein.
  • the C5a antagonist may also be chosen from the compounds given in Table I and their pharmaceutically acceptable salts.
  • Certain C5a antagonists have a molecular mass of less than 700 a.m.u. and exhibit a three dimensional structure that is described by Formula I.
  • ARl and AR2 are independently carbocyclic aryl or heteroaryl;
  • LIP represents an alkyl, carbocyclic aryl, heteroaryl, or arylalkyl;
  • A is oxygen or nitrogen;
  • di represents the distance between A and the geometric center of ARl and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound;
  • d 2 represents the distance between A and the geometric center of AR2 and is between 7 and 10 angstroms in at least one energetically accessible conformer of the compound;
  • d 3 represents the distance between A and the nearest atom of LIP and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound.
  • Preferred C5a antagonists of Formula I are non-peptidic and contain one or more heteroaryl rings.
  • the C5a antagonist is a compound of Formula II:
  • a 5-membered heteroaryl ring system in which x is 0; A is m carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or (ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms.
  • R and Ri in Formula II independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, -CHO, -CONH 2 , C ⁇ -C 6 haloalkyl, or C ⁇ -C 6 haloalkoxy; ii) C ⁇ -C 6 alkyl, - C 6 alkenyl, C ⁇ -C 6 alkynyl, C ⁇ -C 6 alkoxy, C 3 -C cycloalkyl, (C 3 -C 7 cycloalkyl)C ⁇ -C 4 alkyl, mono- or di-(C ⁇ -C 6 alkyl)amino, mono- or di-(C ⁇ -C 6 alkyl)aminoC ⁇ -C 6 alkyl, mono- or di-(C ⁇ - C 6 alkyl)carboxamide, C ⁇ -C 6 alkoxycarbonyl, -NHSO n C ⁇ -C 6 alkyl, -SO n N(C ⁇ -C 6 alkyl)(C ⁇
  • R is chosen from C ⁇ -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 - C 7 cycloalkyl(C ⁇ -C alkyl), benzyl and Ci-C ⁇ haloalkyl.
  • R 2 is chosen from halogen, hydroxy, C ⁇ -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C ⁇ -C 7 alkoxy, C ⁇ -C alkylamino, C 3 -C 7 cycloalkyl(C ⁇ -C 4 alkyl), benzyl, -Cehaloalkyl, and C ⁇ -C 6 haloalkoxy.
  • R 3 is hydrogen, C t -C ⁇ alkyl, C 2 -C 6 alkenyl, hydroxyC ⁇ -C 6 alkyl, C ! -C 6 haloalkyl, C 3 - C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C ⁇ -C 4 alkyl, or phenyl(Ci-C 4 alkyl), or when x is 0, Ri and R 3 may be joined to form a C 3 -C 7 cycloalkyl ring, which may be optionally substituted, y is and integer ranging from 1 to 6; in certain embodiments y is 1 or 2.
  • R represents i) hydrogen; ii) C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - cycloalkyl, C 3 -C 7 cycloalkenyl, (C 3 -C 7 cycloalkyl)C ⁇ -C 4 alkyl, (C 3 -C cycloalkenyl)C ⁇ - C 4 alkyl, or hexahydro-l,3-benzodioxolylmethyl, each of which may be optionally substituted; iii) optionally substituted arylCi- alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylC ⁇ -C 4 alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon; v)
  • R 5 and R 6 are independently chosen from hydrogen and C ⁇ -C 6 alkyl, and z is 1, 2, or 3.
  • Ari is optionally substituted aryl having 1 or 2 fused or pendant rings, optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having
  • ring atoms chosen from N, O, and S with remaining ring atoms being carbon, or optionally substituted heteroaryl, having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S.
  • Ar 2 is optionally substituted C 3 -C 7 cycloalkyl, C 3 -C cycloalkyl(C ⁇ -C 4 alkyl), C 3 - C 7 cycloalkenyl, C 3 -C 7 cycloalkenyl(C ⁇ -C 4 alkyl), or hexahydro-l,3-benzodioxolyl, optionally substituted aryl having 1 or 2 fused or pendant rings, optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, or optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms selected from the group consisting of N, O, and S.
  • Certain compounds and salts of Formula II are imidazoles in which A and G are carbon, E is nitrogen, X is 0 and Ri and R 3 do not form a ring. Such compounds satisfy Formula Ila:
  • Formula lie Additional compounds and salts of Formula II are triazoles in which in which A and E are nitrogen, G is carbon, x is 0, and Ri and R 3 are not joined to form a cycloalkyl ring. Such compounds satisfy Formula Ed:
  • Formula ⁇ d Further compounds and salts of Formula II are isothiazoles or isoxazoles in which x is 0, A is sulfur or oxygen, G and E are carbon; and Ri and R 3 are not joined to form a cycloalkyl ring.
  • Such compounds satisfy Formula He or Il :
  • Additional compounds and salts of Formula II are pyridines in which x is 1, A, B, E, and G are carbon, and Ri and R 3 are not joined to form a cycloalkyl ring. Such compounds satisfy Formula Ilg:
  • Still further compounds and salts of Formula ⁇ are pyrimidines or pyridizines in which x is 1, either A or B is nitrogen, and E and G are carbon. Such compounds satisfy Formula Ilh or Iii.
  • Formula Ilh Formula ffi Compounds and salts of Formula II also include those in which Ri and R 3 are joined to form a cycloalkyl ring. Certain such compounds are illustrated by Formula Uj, in which x is 0; y is 1, A and G are carbon, and E is nitrogen.
  • X, in Formula IIj represents from 1 to 4 optional substituents independently chosen from hydroxy, halogen, cyano, C ⁇ -C 2 alkyl, - C 2 alkoxy, and C ⁇ -C 2 haloalkoxy, and a is 1, 2 or 3
  • compounds and salts of Formula II and subformulas thereof satisfy one or more of the following:
  • R 5 is hydrogen
  • R 6 is hydrogen, methyl, or ethyl.
  • R 5 is hydrogen
  • R 6 is hydrogen, methyl, or ethyl
  • Ari is phenyl, pyrazolyl, or thienyl, each of which is optionally substituted with 1 or 2 groups independently chosen from halogen, hydroxy, C ⁇ -C 2 alkyl, C ⁇ -C 2 alkoxy, C ⁇ -C 2 haloalkyl, and -
  • R 5 and R 6 are hydrogen; and Ari is unsubstituted phenyl, unsubstituted pyrazolyl, or unsubstituted thienyl.
  • Ri groups include phenyl substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH 2 , -
  • Ci-C ⁇ haloalkyl Ci-C ⁇ haloalkyl, C ⁇ -C 6 haloalkoxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, l,3-dioxol-5-yl, Ci-
  • Ri may be phenyl substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH 2 , -
  • Ri is unsubstituted phenyl.
  • Additional representative Ri groups include thienyl and pyridyl, each of which is substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH 2 , -SO 2 NH 2 , C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 alkyl, and C ⁇ -C 2 alkoxy.
  • Ri is hydrogen, halogen, Ci-C 4 alkyl, C ⁇ -C alkoxy, cyano, trifluoromethyl, pentafluoroethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, C ⁇ -C 2 alkylaminoC ! - C 2 alkyl, hydroxymethyl, and hydroxyethyl.
  • R 2 groups include hydrogen, propyl, butyl, pentyl and 3-methylbutyl
  • R 2 is preferably hydrogen when Ari is alkyl-substituted phenyl, pyrazolyl or phenyl, and E is carbon.
  • R groups include hydrogen and C t -Csalkyl.
  • R 4 within certain embodiments, is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • R groups are unsubstituted, such as cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexylmethyl, cyclohexenylmethyl, cyclhexenyl, or hexahydro-l,3-benzodioxolylmethyl.
  • R 4 is: a) aryl or aryl(Co-C 2 )alkyl having 1 or 2 fused or pendant rings, b) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, c) saturated or partially unsaturated heterocycle(Co- C alkyl) having 1 or 2 fused or pendant rings, from 5- to 7-members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S or d) heteroaryl or heteroaryl(C ⁇ - C 2 alkyl) having 1 or 2 fused or pendant rings, from 5- to 7-members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, wherein each of a), b), c), and d) are substituted with from 0 to 4 groups independently chosen from hydroxy,
  • R 4 may be optionally substituted benzyl.
  • R 4 may be pyridylmethyl, pyrimidylmethyl, thienylmethyl, napthylmethyl, indolylmethyl, benzoxadiazolylmethyl (e.g., benzoxadiazol-5-ylmethyl), benzooxazolylmethyl, benzothiazolyl, quinazolinylmethyl, or benzimidazolylmethyl, each of which is substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, C ⁇ -C 2 haloalkyl, CpC 2 haloalkoxy, -C 2 alkyl, mono- or di-(C ⁇ -C 2 )alkylamino, and C ⁇ -C 2 alkoxy.
  • the heteroaryl group is pyridyl, pyrimidyl, thienyl, naphthyl, indolyl, benzoxadiazolyl, benzoxazolyl, quinazolinyl, or benzimidazolyl, each optionally substituted with from 1 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 alkyl, and - C 2 alkoxy.
  • Ar groups include C 3 -C 7 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3 -C 7 cycloalkenyl (e.g., cyclohexenyl), (C 3 -C 7 cycloalkyl) C ⁇ -C 4 alkyl, (C 3 - C 7 cycloalkenyl)C ⁇ -C 4 alkyl, and hexahydro-l,3-benzodioxolyl, each of which is optionally substituted with from 0 to 3 groups independently chosen from hydrogen, hydroxy, halogen, amino, cyano, C ⁇ -C 2 alkyl, C ⁇ -C 2 alkoxy, or C ⁇ -C 2 alkoxycarbonyl.
  • C 3 -C 7 cycloalkyl e.g., cyclopentyl or cyclohexyl
  • C 3 -C 7 cycloalkenyl e.g., cycl
  • Ar 2 groups include phenyl substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH 2 , -SO 2 NH 2 , oxo, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, Q- C 6 alkyl, -Cealkoxy, mono- and di-(C ⁇ -C 6 alkyl)amino, C ⁇ -C 6 alkanoyl, C ⁇ -C 6 alkylsulfonyl, C !
  • Ar 2 groups include pyridyl, pyrimidyl, thienyl, naphthyl, indolyl, benzoxadiazolyl (e.g., benzoxadiazol-5-yl), benzoxazolyl, quinazolinyl, and benzimidazolyl, each of which is substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 alkyl, mono- or di-(C 1 -C 2 alkyl)amino, C ⁇ -C 2 alkoxy, and C 2 -C6cycloalkylamino.
  • Additional representative Ar 2 groups include phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, or a heteroaryl or heteroaryl(C ⁇ -C 2 alkyl) group, having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, each of which is substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH 2 , -SO 2 NH 2 , oxo, Ci- C 6 haloalkyl, Ci-C ⁇ haloalkoxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkanoyl, C ⁇ -C 6 sulfonate, - C 6 alkylsulfon
  • the phenyl group fused to a 5- to 7-membered saturated or partially unsaturated ring may be 1,3- benzodioxol-5-yl, 2,3-dihydro-l-benzofuran-6-yl, 2,3-dihydro-l-benzofuran-5-yl, 2,3- dihydro-l,4-benzodioxin-6-yl, chroman-6-yl, chroman-7-yl, 1,3-benzothiazolyl, or 2,3- dihydroindol-5-yl, each of which is substituted with from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 alkyl, and C ⁇ -C 2 alkoxy.
  • Formulas Ilk-IIp represent additional subformulas of compounds within the scope of Formula II.
  • R is C 3 -C 5 alkyl;
  • R 3 is hydrogen or methyl;
  • R 5 is hydrogen or methyl;
  • R 7 represents from 0 to 3 substituents independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy;
  • R and Rio may occur at any position on the benzo[l,3]dioxole or 2,3-Dihydro-benzo[l,4]dioxine group available for substitution and represent from 0 to 3 substituents
  • the present invention further comprises combinations in which the C5a receptor antagonist is a compound of Formula III:
  • Formula III or a pharmaceutically acceptable salt thereof, wherein: x is 1, 2, or 3.
  • R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyano, amino, nitro, -COOH, carboxamide, optionally substituted mono or di-alkyl amino, optionally substituted haloalkyl, and optionally substituted haloalkoxy.
  • R 1 for compounds of Formula I is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, and optionally substituted indanyl.
  • R , R , and R are independently selected at each occurrence from the group consisting of hydrogen, optionally substituted alkyl, halogen, and optionally substituted alkoxy.
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, hydroxy, amino, mono or dialkyl amino, and cyano.
  • R 7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or optionally substituted arylalkyl.
  • Ar 1 is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted biphenyl, optionally substituted heterocyclic group, or and optionally substituted phenyl group fused to a 5 to 7 membered saturated or partially unsaturated ring, said saturated or partially unsaturated ring having from 5 to 7 ring atoms, with 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon.
  • Ar 1 is taken in combination with CR 7 (CR 7 Ar 1 ), to form an optionally substituted group of the formula:
  • p is an integer from 1 to about 3.
  • Ar is optionally substituted aryl or optionally substituted heteroaryl having about 5 to
  • C5a antagonists for use in the combination provided by the invention include compounds of Formula IV:
  • Ar 1 is, in Formula IV: i) optionally substituted phenyl having at least one optionally substituted phenyl or optionally substituted heterocyclic substituent attached thereto; ii) optionally substituted carbocycle having from 2 to about 4 partially unsaturated or aromatic rings, 3 to 8 members in each ring, or iii) optionally substituted heteroaryl.
  • R 1 in formula IV is optionally substituted cycloalkyl, optionally substituted
  • (aryl)alkyl wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 2 substituents independently chosen from halogen, alkyl and alkoxy.
  • R 2 in Formula IV is alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, or indanyl, each of which is optionally substituted, or R 2 is optionally substituted phenyl(Co-C 2 alkyl), wherein the phenyl portion is fused to a 5 to 7 membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.
  • R 2 is indanyl, (aryl)alkyl, or cycloalkyl, each of which is optionally substituted.
  • R 2 is selected from C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C ⁇ -C alkyl, (heteroaryl)C ⁇ -C 4 alkyl,
  • (aryl)C ⁇ -C alkyl, and indanyl; each of which is substituted with from 0 to 5 substituents independently selected from halogen, hydroxy, C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, C ⁇ -C alkylthio, -NC( O)C ⁇ -C 2 alkyl, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, thienyl, and phenyl.
  • Ar 3 is phenyl, pyridyl, furanyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, naphthyl, thiazolyl, or pyrimidinyl, each of which is substituted with from 0 to 3 substituents independently selected from halogen, hydroxy, amino, cyano, C ⁇ -C 4 alkyl,
  • Z 1 is carbon or nitrogen
  • Z 2 , Z 3 , and each occurrence of Z 4 are independently selected from CR 7 , NR 8 , S, and O such that each S or O ring atom, if any, is disposed between two CR 7 groups
  • p is an integer ranging from 1 to about 3
  • R 7 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, Ci- C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6
  • Formula IVe wherein R 2 is as described for Formula IV; R 3 , R 4 and Ar 2 are as described for Formula IVa; and Z 1 , Z 2 , Z 3 , Z 4 , p, and R 6 are as described for Formula IVc;
  • R is: (i) halogen, hydroxy, C ⁇ -C 3 haloalkyl, or C ⁇ -C 3 haloalkoxy;
  • C 6 alkyl)amino or C 3 -C cycloalkyl(Co-C 4 alkyl), each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, and mono- and di(C ⁇ -C )alkylamino;
  • (iv) a heterocyclic ring, having from 4 to 8 ring atoms, and 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of (iii) and (iv) is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, mono- and di-C ⁇ -C 6 alkylamino, mono- and di-C ⁇ -C 6 alkylaminoC ⁇ -C 6 alkyl, C ⁇ -C 6 haloalkyl, - C 6 haloalkoxy, -C 2 alkylthio, and -NHC( O)C ! -C2 alkyl; and
  • Other compounds and salts for use in the combinations provided herein are compounds of Formula V:
  • m represents a carbon chain that may be substituted with hydrogen, halogen, cyano, nitro amino, mono or dialkyl amino, alkenyl, alkynyl, alkoxy, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, or cycloalkyl. and n is 1, 2, or 3.
  • Ar 2 , and Ar 3 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
  • Ri represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH 2 ), mono or dialkylaminocarbonyl, sulfonamido, and mono or dialkylsulfonamido.
  • the invention includes combinations in which the C5a receptor is a compound of Formula VI:
  • Formula VI or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • n represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydroxy, halogen, or amino.
  • Ri represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, and(cycloalkyl)alkyl.
  • R 2 is i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl) alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, mono- or dialkylamino.
  • Ari is ethylenedioxyphenyl, methylenedioxyphenyl, or optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
  • Ar 2 is carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
  • Preferred compounds for use in the combinations provided herein exhibit an IC 50 of about 500 nM or less in such a standard C5a receptor-mediated chemotaxis, radioligand binding, and/or calcium mobilization assay, more preferably an IC 5 0 of about 250 nM or less in such an assay, still more preferably an IC 50 of about 200, 150, 100, 50, 25, 10, or 5 nM or less in such an assay.
  • IC 50 of about 500 nM or less in such a standard C5a receptor-mediated chemotaxis, radioligand binding, and/or calcium mobilization assay, more preferably an IC 5 0 of about 250 nM or less in such an assay, still more preferably an IC 50 of about 200, 150, 100, 50, 25, 10, or 5 nM or less in such an assay.
  • Such assays are provided in Examples 5, 7 and 8.
  • Certain preferred compounds further have favorable pharmacological properties, including oral bioavailability (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose, preferably less than 2 grams, more preferably of less than or equal to one gram, can provide a detectable in vivo effect such as a reduction of C5a-induced neutropenia), ability to inhibit leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations, low toxicity (a preferred compound is nontoxic when a C5a receptor-modulatory amount is administered to a subject), minimal side effects (a preferred compound produces side effects comparable to placebo when a C5a receptor- modulatory amount of the compound is administered to a subject), low serum protein binding, and a suitable in vitro and in vivo half -life (a preferred compound exhibits an in vitro half-life that is equal to an in vivo half-life allowing for Q.I.D.
  • oral bioavailability such that a sub-lethal or preferably a pharmaceutically
  • dosing preferably T.I.D. dosing, more preferably B.I.D. dosing, and most preferably once-a-day dosing). Distribution in the body to sites of complement activity is also desirable (e.g., compounds used to treat CNS disorders will preferably penetrate the blood brain barrier, while low brain levels of compounds used to treat periphereal disorders are typically preferred).
  • Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use.
  • assays used to predict bioavailability include transport across human intestinal cell monolayers, such as Caco-2 cell monolayers.
  • Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously).
  • Serum protein binding may be predicted from albumin binding assays, such as those described by Oravcova, et al. (1996) Journal of Chromatography B 677:1-21.
  • Compound half-life is inversely proportional to the frequency of dosage of a compound required to achieve an effective amount.
  • In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition 26: 1120-27.
  • Toxicity and side effects may be assessed using any standard method.
  • nontoxic as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration (“FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans).
  • Toxicity may be also evaluated using the assay detecting an effect on cellular ATP production.
  • Other assays that may be used include bacterial reverse mutation assays, such as an Ames test, as well as standard teratogenicity and tumorogenicity assays.
  • administering does not result in prolongation of heart QT intervals (i.e., as determined by electrocardiography in guinea pigs, minipigs or dogs).
  • doses When administered daily for five or preferably ten days, such doses also do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 100%, preferably not more than 75%, and more preferably not more than 50% over matched controls in laboratory rodents (e.g., mice or rats).
  • Such doses also preferably do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls in dogs or other non-rodent mammals.
  • liver enzymes e.g., ALT, LDH or AST
  • the above doses do not elevate serum levels of such enzymes by more than 100%, preferably not by more than 75%, and more preferably not by more than 50% over matched untreated controls in vivo in laboratory rodents.
  • concentrations (in culture media or other such solutions that are contacted and incubated with cells in vitro) equivalent to two-fold, preferably five-fold, and most preferably ten-fold the minimum in vivo therapeutic concentration do not cause detectable release of any of such liver enzymes from hepatocytes in vitro into culture medium above baseline levels seen in media from untreated cells.
  • preferred compounds exert their receptor-modulatory effects with high specificity. This means that they only bind to, activate, or inhibit the activity of certain receptors other than C5a receptors with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar.
  • the invention also includes highly specific C5a receptor modulatory compounds that exhibit 200-fold greater affinity for the C5a receptor that for other cellular receptors.
  • Such receptors include neurotransmitter receptors such as alpha- or beta-adrenergic receptors, muscarinic receptors (particularly ml, m2 or m3 receptors), dopamine receptors, and metabotropic glutamate receptors; as well as histamine receptors and cytokine receptors (e.g., interleukin receptors, particularly IL-8 receptors).
  • neurotransmitter receptors such as alpha- or beta-adrenergic receptors, muscarinic receptors (particularly ml, m2 or m3 receptors), dopamine receptors, and metabotropic glutamate receptors
  • histamine receptors and cytokine receptors e.g., interleukin receptors, particularly IL-8 receptors.
  • Such receptors may also include GABAA receptors, bioactive peptide receptors (other than C5a receptors and C3a receptors, including NPY or VIP receptors), neurokinin receptors, bradykinin receptors, and hormone receptors (e.g., CRF receptors, thyrotropin releasing hormone receptors or melanin-concentrating hormone receptors).
  • GABAA receptors include GABAA receptors, bioactive peptide receptors (other than C5a receptors and C3a receptors, including NPY or VIP receptors), neurokinin receptors, bradykinin receptors, and hormone receptors (e.g., CRF receptors, thyrotropin releasing hormone receptors or melanin-concentrating hormone receptors).
  • Compounds that act with high specificity generally exhibit fewer undesirable side effects.
  • modulators provided herein do not bind detectably to receptors that do not mediate inflammatory responses, such as GABA receptors, MCH receptors, NPY receptors, dopamine receptors, serotonin receptors and VRl receptors, with high or even moderate affinity.
  • certain preferred C5a receptor modulators exhibit an affinity for C5a receptor that is substantially higher than for receptors that do not mediate inflammatory responses (e.g., at least five times higher, at least ten times higher or at least 100 times higher).
  • Assays for evaluating binding to receptors that do not mediate inflammatory responses include, for example, those described in US patent 6,310,212, which is incorporated herein by reference for its disclosure of a GABAA receptor binding assays in Examples 14, columns 16-17, in US patent application no.
  • Certain preferred compounds are C5a receptor antagonists that do not possess significant (e.g., greater than 5%) agonist activity in any of the C5a receptor-mediated functional assays discussed herein. Specifically, this undesired agonist activity can be evaluated, for example, in the GTP binding assay of Example 6, by measuring small molecule mediated GTP binding in the absence of the natural agonist, C5a. Similarly, in a calcium mobilization assay (e.g., that of Example 6) a small molecule compound can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist, C5a.
  • the preferred extent of C5a agonist activity exhibited by compounds provided herein is less than 10%, 5% or 2% of the response elicited by the natural agonist, C5a.
  • preferred C5a receptor modulators do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity.
  • Preferred C5a receptor modulators also do not exhibit cytotoxicity in vitro or in vivo, are not clastogenic (e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) and do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells).
  • C5a receptor modulators that inhibit the occurrence of C5a-induced oxidative burst (OB) in inflammatory cells (e.g., neutrophil) as can be conveniently determined using an in vitro neutrophil OB assay.
  • OB
  • At least one therapeutic compound that is not a C5a antagonist i.e., a C5a receptor-inactive therapeutic agent
  • a C5a receptor-inactive therapeutic agent is administered in combination with at least one C5a antagonist in order to provide a therapeutic effect to a patient suffering from a condition (e.g., disease, disorder or injury) associated with pathogenic inflammation.
  • the C5a antagonist(s) and C5a receptor-inactive agent(s) may be present in the same composition during administration, or may be administered separately, either essentially simultaneously or sequentially in either order.
  • the C5a receptor-inactive therapeutic agent(s) are packaged in combination with the C5a antagonist(s). The precise formulation of combinations described herein will vary depending on the disease to be treated, as discussed in more detail below.
  • the present invention provides combinations useful for the treatment of arthritis, particularly rheumatoid arthritis, comprising a C5a antagonist and a C5a receptor- inactive therapeutic agent that is an anti-arthritic agent (i.e., a C5a receptor-inactive anti- arthritic agent).
  • C5a receptor-inactive therapeutic agents useful in such combinations include, but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and modulators of other enzymes and receptors associated with arthritis.
  • a C5 antagonist is combined with methotrexate for treatment of rheumatoid arthritis.
  • the C5a receptor-inactive therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID).
  • NSAIDs include, but are not limited to ibuprofen (e.g., ADVILTM, MOTRINTM), flurbiprofen (ANSAIDTM), naproxen or naproxen sodium (e.g., NAPROXYN, ANAPROX, ALEVETM), diclofenac (e.g., CATAFLAMTM, VOLTARENTM), combinations of diclofenac sodium and misoprostol (e.g., ARTHROTECTM), sulindac (CLINORILTM), oxaprozin (DAYPROTM), diflunisal (DOLOBIDTM), piroxicam (FELDENETM), indomethacin (INDOCINTM), etodolac (LODBSfETM), fenoprofen calcium (NALFONTM), ketoprofen (e.g., ORUDISTM
  • the C5a receptor-inactive therapeutic agent(s) comprise one or more NSAIDS combined with one or more anti-ulcer agents such as misoprostol (CYTOTECTM).
  • CYTOTECTM misoprostol
  • the invention comprises the use of a preparation of diclofenac and misoprostol (e.g., as marketed under the brand name ARTHROTECTM) as the C5a receptor-inactive therapeutic agents.
  • At least one C5a receptor-inactive therapeutic agent is a COX-2 specific inhibitor (i.e., a compound that inhibits COX-2 with an IC 50 that is at least 50-fold lower than the IC 50 for COX-1).
  • a COX-2 inhibitor such as celecoxib (CELEBREXTM), valdecoxib (BEXTRATM), lumiracoxib (PREXIGETM), etoricoxib (ARCOXIATM) and/or rofecoxib (VIOXXTM).
  • at least one C5a receptor-inactive therapeutic agent is a salicylate.
  • Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, choline and magnesium salicylates (TRILISATETM), and salsalate (DISALCIDTM).
  • the C5a receptor-inactive therapeutic agent may also be a corticosteroid.
  • the corticosteroid may be cortisone (CORTONETM acetate), dexamethasone (e.g., DECADRONTM), methylprednisolone (MEDROLTM) prednisolone (PRELONETM), prednisolone sodium phosphate (PEDIAPREDTM), and prednisone (e.g., PREDNICEN-MTM, DELTASONETM, STERAPREDTM). Additional coriticosteroids are listed herein in the description of combinations for the treatment of asthma.
  • At least one C5a receptor-inactive therapeutic agent is a gold compound such as gold sodium thiomalate (MYOCHRYSINETM) or auranofin (RID AURATM).
  • the C5a receptor- inactive therapeutic agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate (e.g., RHEUMATREXTM, TREXALLTM) or a dihydroorotate dehydrogenase inhibitor, such as leflunomide (ARAVATM).
  • a dihydrofolate reductase inhibitor such as methotrexate (e.g., RHEUMATREXTM, TREXALLTM) or a dihydroorotate dehydrogenase inhibitor, such as leflunomide (ARAVATM).
  • At least one C5a receptor-inactive therapeutic agent is a joint lubricant such as sodium hyaluronate (HYALGANTM or SYNVISCTM).
  • a joint lubricant such as sodium hyaluronate (HYALGANTM or SYNVISCTM).
  • an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine (NEORALTM, SAND MUNETM), tacrolimus (PROGRAFTM), azathioprine (EVIURANTM), or mycophenolate mofetil (CellCeptTM).
  • Still other embodiments of the invention are directed to combinations in which at least one C5a receptor-inactive therapeutic agent is:
  • an anti-C5 monoclonal antibody such as eculizumab or pexelizumab
  • a TNF antagonist such as entanercept (ENBRELTM), which is an injectible fusion protein consisting of the extracellular domain of the TNF receptor and the Fc portion of human IgGl, adalimumab (MUNTRATM), the humanized antibody CDP-571 (HUMICADETM; WO 92/11383), the anti-TNF humanized antibody fragment CDP-870 (WO 01/94585), or infliximab (REMICADETM), which is an anti-TNF alpha monoclonal antibody;
  • ENBRELTM entanercept
  • MUNTRATM humanized antibody CDP-571
  • CDP-870 WO 01/94585
  • REMICADETM infliximab
  • TNF-alpha induced inflammatory genes such as AGIX-4207
  • an IL-1 receptor antagonist such as anakinra (KINERETTM) or AMG-719
  • IL-1 receptor type I or type II, such as SIL-lr2 (Amgen); • an IL-1 trap, such as Regeneron's IL-1 trap;
  • an IL-6 receptor antagonist such as the humanized anti-IL-6 receptor monoclonal antibody Altizumab (WO 92/19759);
  • an anti IL-12 antibody such as the human anti-DL-12 monoclonal antibody J695 (Abbott Laboratories);
  • an IL-15 antagonist such as the human anti-IL-15 monoclonal antibody HuMax
  • a B-cell targeted chimeric monoclonal antibody such as Rituximab
  • MAP mitogen-activated protein
  • BIRB-796 VX-702, VX-850, VX-745, SCIO-469, SCIO-323, or GXK- 681323; • an integrin antagonist such as GSK-683699;
  • TACE TNF alpha converting enzyme
  • IKK IKappaB kinase
  • phospholipase A2 phospholipase A2
  • LCK-selective tyrosine kinase an inhibitor of IKappaB kinase (IKK), phospholipase A2 or an LCK-selective tyrosine kinase
  • a CCR3 receptor antagonist such as DPC-168 or GXK-766994
  • an ICE inhibitor such as VX-740.
  • compositions and methods provided herein are useful for the treatment of respiratory diseases, such as respiratory distress syndrome and asthma.
  • respiratory diseases such as respiratory distress syndrome and asthma.
  • combinations provided herein may be used to prevent or decrease the severity of both acute early phase asthma attack and the late phase reactions that follow such an asthma attack.
  • C5a receptor-inactive therapeutic agents useful for the treatment of asthma include anti-thrombin agents, which reduce bronchoconstriction by inhibiting the release of calcium and proliferation of smooth muscle cells, adrenergic receptor agonists, particularly Beta adrenergic receptor agonists; methylxanthines such as theophylline (e.g., AEROLATE SRTM, AEROLATE JRTM THEO-DURTM, UNI-DURTM or UNIPHYLTM); corticosteroids; leukotriene modifiers such as zafirlukast (e.g., ACCOLATETM) and zileuton (e.g., ZYFLOTM, or FILMTABTM); anti
  • corticosteroids include, but are not limited to betamethasone (e.g., CelestoneTM), beclomethasone dipropionate (e.g., VANCERILTM, QVARTM), budesonide (e.g., PULMICORTTM), cortisone (e.g., CORTONE ACETATETM), dexamethasone (e.g., DEXASONETM), fluticasone propionate, (e.g., ADVAIRTM, FLOVENTTM) hydrocortisone, ethylprednisolone (e.g., MEDROLTM), flunisolide (AEROBIDTM), prednisolone (e.g., PREDALONETM, PRELONETM), prednisone (e.g., CORDROLTM, DELTASONETM, STERAPREDTM, STERAPRED DSTM ), and triamcinolone (AZMACORTTM). Additional coriticosteroids are listed here
  • Beta agonist may be a long or short acting Beta adrenergic receptor agonist.
  • Beta adrenergic receptor agonists include, but are not limited to, albuterol (e.g PROVENTILTM, VENTELINTM), bitolterol, epinephrine (e.g., PR ATENETM ADRENALIN CHLORIDE, BRONCAID MIST), fenoterol (e.g., FORADILTM), formoterol isoetharine, isoproterenol, metaproterenol sulfate (e.g., ALUPENTTM), pirbuterol (e.g.
  • MAXAIR MAXAIR
  • procaterol racepinephrine
  • salmeterol xinafoate e.g., ADVAIR DISKUSTM SEREVENT DISKUSTM
  • terbutaline e.g., BRETHINETM
  • the present invention further provides combinations useful for the treatment of T cell- mediated inflammatory diseases such as psoriasis.
  • the C5a receptor-inactive therapeutic agent(s) may inhibit the hyperfunctional proliferation of epidermal cells; inhibit the inflammatory response; promote immunomodulation; and/or inhibit infection by bacteria and fungi.
  • the C5a receptor-inactive therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID), such as the non-specific nonsteroidal anti-inflammatory agents, COX-2 specific and salicylates listed above.
  • NSAID non-steroidal anti-inflammatory drug
  • the present invention includes combinations in which the C5a receptor-inactive therapeutic agent is a steroid (e.g., corticosteroid such as clobetasol propionate (e.g., TEMOVATETM), coal tar, a moisturizer, calendula plant extract, theophylline (which arrests the proliferation of cells during the metaphase stage of cell division; e.g., SLO-PHYLLINTM or THEO-DUR SPRINKLETM), anthralin (a synthetic derivative of a tree bark extract; e.g., DRITHOCREMETM, DRITHO-SCALPTM or MICANOLTM), calcipotriene (a synthetic vitamin D-3 analog that regulates skin cell production; e.g., CALCIOPTRIOLTM or DOVONEXTM), dithranol, an angiogenesis inhibitor such as ganglioside GM3 or a GM3 analog, a phospholipase A2 inhibitor such as an n-deacety
  • C5a receptor-inactive therapeutic agent that is an immunomodulator.
  • agents may be included to control the abnormal cornification of epidermal cells and the hyperfunction of leukocyte migration, and include methotrexate (a folic acid antagonist that inhibits DNA synthesis in tissues with high rates of turnover and is immunosuppressive to mononuclear cells), cyclosporine (which inhibits production of interleukin-2, the cytokine responsible for inducing T-cell proliferation), tacrolimus (FK506; e.g., PROGRAFTM or PROTOPICTM), TNF-alpha modulators such as etanercept (e.g., ENBRELTM) and infliximab (e.g., REMICADETM), antileukotriene agents, and retinoid Vitamin A derivatives such as tazarotene (e.g., TAZORACTM), etretinate, isotretinoin (e.g., ACCUTANETM), bexa
  • the C5a receptor-inactive agent may be, for example, a steroid such as prednisone, an antibiotic such as tetracycline or dapsone, an immunosuppressant such as azothioprine, or methotrexate.
  • compositions are generally formulated for topical administration to a wound or burn site. Any agent that facilitates healing of such conditions may be used as the C5a receptor- inactive therapeutic agent(s) including, for example, antibiotics and growth factors.
  • the present invention also provides combinations useful for treating autoimmune disorders and pathologic autoimmune responses known to have an inflammatory component including, but not limited to multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, Guillain-Barre Syndrome, lupus erythematosus and irritable bowel syndrome.
  • a C5a receptor-antagonist may be combined with another anti- inflammatory agent to increase the effectiveness the anti-inflammatory agent, or may be combined with a C5a receptor-inactive therapeutic agent suitable for the disease of interest that is not an anti-inflammatory agent.
  • Suitable C5a receptor-inactive therapeutic agents include, for example, steroids as discussed above.
  • drug-resistant bacterial infections such as pneumococcal bacteremia, pneumococcal meningitis, nosocomial (hospital-acquired) infections (e.g., Staphylococcus aureus and Enterococcus faecium), Group A streptococci infections, multiple
  • Suitable C5a receptor-inactive therapeutic agents for use in such combinations include, for example, antibiotic agents.
  • Representative anti-bacterial antibiotic agents include, for example, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides (e.g., vancomycin), quinolones, tetracyclines, macrolides, and fluoroquinolones.
  • Combinations may be administered after a patient has acquired an infection, or may be administered to a patient considered at risk for such an infection (e.g., post-surgically).
  • Certain combinations are provided herein are suitable for use in medical procedures in which foreign material is introduced into a patient. For example, such combinations may be used to prevent or decrease rejection of transplanted organs and tissue grafts, or in hemodialysis or cardiopulmonary bypass surgery. Certain compositions may be used in the treatment of lung inflammation associated with transplantation. C5a receptor-antagonists may be combined with another anti-inflammatory agent to increase the effectiveness the anti- inflammatory agent or combined with a C5a receptor-inactive therapeutic agent that is not an anti-inflammatory agent in order to decrease complications and improve outcome for the patient undergoing the medical procedure. Combinations may also be used to prevent activation of platelets during storage, and thereby decreasing the loss of function and viability known as "platelet storage lesion.” Such combinations are typically added to platelets prior to storage.
  • Combinations provided herein are useful for preventing or reducing the risk of formation of thrombi and thromboemboli, for preventing or reducing the risk of thrombotic occlusions and reocclusions, for treating, preventing or reducing the risk of a first or subsequent myocardial infarction, for preventing or reducing the risk of restenosis, for treating, preventing or reducing the risk of acute cerebrovascular ischemic events such as a first or subsequent thrombotic stroke or transient ischemic attack, and for halting or slowing the progression of atherosclerotic disease.
  • C5a receptor-inactive therapeutic agents useful in the combinations provided herein for the treatment or cardio- and cerebrovascular disease include, but are not limited to, anti-inflammatories (e.g., non-steroidal anti-inflammatory drugs (NSAIDs) such as the non-specific nonsteroidal anti-inflammatory agents, COX-2 specific and salicylates listed above), antihypertensive agents, platelet inhibitors such as aspirin, ticlopidine, and GP lib/ Ilia antagonists, antihypertensive agents, including adrenergic receptor agonists, alpha/beta adrenergic receptor antagonists, beta adrenergic receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics and periphereal vasodilators, anti-coagulants, thrombolytics, and cholesterol lowering agents such as HMG-CoA reductase inhibitors.
  • NSAIDs non-steroidal anti
  • the C5a receptor-inactive therapeutic agent is a cholesterol lowering drug.
  • the cholesterol lowering drug is a 3-hydroxy- methyl-glutaryl coenzyme A reductase inhibitor (HMG-CoA RI).
  • HMG-CoA RI 3-hydroxy- methyl-glutaryl coenzyme A reductase inhibitor
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well- known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACORTM; see U.S. Pat. No. 4,231,938), simvastatin (ZOCORTM; see U.S. Pat. No. 4,444,784), pravastatin (PRAVACHOLTM; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOLTM; see U.S. Pat. No. 5,354,772), atorvastatin (LIPITORTM.; see U.S. Pat. No. 6,273,995) and cerivastatin (also known as rivastatin; see U.S. Pat. No. 5,177,080).
  • lovastatin MVACORTM
  • simvastatin ZOCORTM
  • ZOCORTM see U.S. Pat. No. 4,444,784
  • pravastatin PRAVACHOLTM
  • fluvastatin see U.S. Pat. No. 5,354,77
  • HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (Feb. 5, 1996).
  • HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters and lactone forms is included within the scope of this invention.
  • the C5a receptor-inactive therapeutic agent is a platelet aggregation inhibitor such as a salicylate as described above; a glycoprotein (GP) ⁇ b/IIIa inhibitor, such as tirofiban hydrochloride (AGGRASTATTM), abciximab (REOPROTM), or eptifibatide (INTEGRILINTM); a phosphodiesterase (PDE) inhibitor, such as dipyridimole (PERSANTINETM) or cilostazol (PLETALTM); a compound that reduces megakaryocyte hypermaturation, (e.g., anagrelide, AGRYLINTM); or ADP receptor inhibitor such as clopidogrel bisulfate (PLAVIXTM) or ticlopidine hydrochloride (TICLIDTM).
  • the C5a receptor-inactive therapeutic agent is an anti- hypertensive agent.
  • the anti-hypertensive agent is an alpha adrenergic receptor antagonist such as phenoxybenzamine hydrochloride (DIBENZYLINETM), doxazosin mesylate (CARDURATM), terazosin hydrochloride (HYTRINTM), or prazosin hydrochloride (MINIPRESSTM).
  • the antihypertensive agent is an adrenergic receptor stimulator.
  • adrenergic receptor stimulators that may be used in' the combinations provided herein include, but are not limited to, methyldopa (ALDOMETTM), clonidine hydrochloride (CATAPRESTM), and guanfacine hydrochloride (TENEXTM).
  • the antihypertensive agent is a non-specific alpha/beta adrenergic receptor antagonist such as carvedilol (COREGTM) or labetalol hydrochloride (NORMODYNETM).
  • the antihypertensive agent is an angiotensin converting enzyme (ACE) inhibitor.
  • Suitable angiotensin converting enzyme (ACE) inhibitors include, but are not limited to enalaprilat (VASOTECTM for injection), enalapril maleate (VASOTECTM), catopril, benazepril hydrochloride (LOTRELTM, LOTENSINTM), fosinopril sodium (MONOPRILTM), lisinopril (PRINIVILTM and ZESTRILTM), quinapril (ACCUPRILTM), perindopril erbumine (ACEONTM), ramipril (ACEONTM), moexipril hydrochloride (UNIVASCTM), and trandolapril (MAVIKTM).
  • the antihypertensive agent is an angiotensin ⁇ receptor antagonist such as candesartan cilexetil (ATACANDTM), irbesartan (AVAPROTM), losartan potassium (COZAARTM), valsartan (DIOVANTM), telmisartan (MICARDISTM), or eprosartan mesylate (TEVETENTM).
  • angiotensin ⁇ receptor antagonist such as candesartan cilexetil (ATACANDTM), irbesartan (AVAPROTM), losartan potassium (COZAARTM), valsartan (DIOVANTM), telmisartan (MICARDISTM), or eprosartan mesylate (TEVETENTM).
  • the antihypertensive agent is a beta-adrenergic receptor blocker, including combinations in which the antihypertensive agent is a beta- adrenergic receptor antagonist.
  • Beta-adrenergic receptor blockers include, but are not limited to chlorthalidone, sotalol hydrochloride (BETAPACETM and BETAPACE AFTM), timolol maleate (BLOCADRENTM), nadolol (CORGARDTM), propranolol hydrochloride (INDERALTM), acebutolol hydrochloride (SECTRALTM), atenolol (TENORMINTM), metoprolol succinate (TOPROL-XLTM), and bisoprolol fumarate (ZEBETATM).
  • the antihypertensive agent is a calcium channel blocker, such as felodipine (PLENDILTM), nifedipine (ADALATTM, PROCARDIATM, PROCARDIATM), nicardipine hydrochloride (CARDENETM), nimodipine (NIMOTOPTM), amlodipine besylate
  • NORVASCTM diltiazem hydrochloride
  • CARDIZEMTM verapamil hydrochloride
  • COVERA-HSTM ISOPTINTM, VERELANTM, VERELAN PMTM
  • isradipine DYNACIRCTM, DYNACIRC CRTM
  • nisoldipine SULARTM
  • TIAZICTM diltiazem hydrochloride
  • VASCORTM bepridil hydrochloride
  • the C5a receptor-inactive therapeutic agent is a diuretic such as ionized potassium, chlorothiazide (DIURILTM), chlorthalidone, hydrochlorothiazide (HYDRODIURILTM, MICROZIDETM), polythiazide (RENESETM), bendroflumethiazide, atenolol, dichlorphenamide (DARANIDETM), torsemide (DEMADEXTM), ethacrynic acid (EDECRINTM), furosemide, triamterene (DYRENIUMTM) amioride (MIDAMORTM), hydroflumethiazide (DIUCARDINTM), indapamide, or metolazone (MYKROXTM, ZAROXOLYNTM).
  • a diuretic such as ionized potassium, chlorothiazide (DIURILTM), chlorthalidone, hydrochlorothiazide (HYDRODIURILTM, MIC
  • the C5a receptor-inactive therapeutic agent is blood modifier, such as an anticoagulant.
  • Anticoagulants useful in the combinations provided herein include, but are not limited to, thrombin inhibitors such as argatroban, inhibitors of thrombin and Factor X, such as dalteparin sodium injection (FRAGMINTM), heparin (e.g., TUBEXTM Heparin Sodium Injection, INNOHEPTM), enoxaparin sodium a low molecular weight heparin (LOVENOXTM), danaparoid sodium (ORGARANTM) inhibitors of vitamin K dependent coagulation, such as coumarin and warfarin, and hirudin.
  • thrombin inhibitors such as argatroban
  • inhibitors of thrombin and Factor X such as dalteparin sodium injection (FRAGMINTM), heparin (e.g., TUBEXTM Heparin Sodium Injection, INNOHEPTM), enoxaparin sodium
  • the present invention provides, in an additional embodiment, a combination comprising a C5a antagonist and a C5a receptor-inactive therapeutic agent that is a thrombolytic.
  • thrombolytics include, but are not limited to recombinant alteplase (ACTIVASETM), anistreplase (EMINASETM), recombinant reteplase (RETAVASETM), streptokinase (STREPTASETM), and urokinase (ABBOKINASETM).
  • the C5a receptor-inactive therapeutic agent is a prescribed combination, such as AGGRENOXTM, a tablet comprised of dypridimole and aspirin or MINIZiDETM, a marketed combination of polythiazide (RENESETM) and prazosin hydrochloride (MINIPRESSTM), MICARDISTM HCT (telmisartan and hydrochlorothiazide), ATACANDTM HCT (candesartan cilexetil and hydrochlorothiazide), AVALIDETM (irbesartan and hydrochlorothiazide), DIOVANTM HCT (valsartan and hydrochlorothiazide), HYZAARTM (losartan potassium-hydrochlorothiazide tablets), CORZIDETM (nadolol and bendroflumethiazide), INDERIDETM (propranolol hydrochloride and hydrochlorothiazide), TENORETICTM (
  • TAREXTM a combination of trandolapril and verapamil hydrochloride, and ALDORILTM (methyldopa and hydrochlorothiazide).
  • Certain combinations provided herein are useful for treating or preventing reperfusion injury due to thrombosis or surgery.
  • the invention particularly provides combinations for preventing or reducing reperfusion injury during surgeries in which blood vessels are occluded, or in which a heart bypass pump is employed.
  • the C5a receptor-inactive agent(s) used in the combination may be one or more or an anticoagulant or thrombolyitc agent, as described above in the discussion of combinations for the treatment of cardio- and cerebrovascular disease, and/or a surgical anesthetic.
  • the present invention includes combinations useful for the treatment of CNS trauma
  • C5a receptor-inactive therapeutic agent(s) may further inhibit such inflammation, or may mediate pain or damage resulting form other aspects of CNS trauma.
  • Suitable anti-inflammatory agents include those described elsewhere herein (e.g., steroids such as methylprednisone), as well as agents (e.g., antibodies) that inhibit proinflammatory cytokine responses, such as IL-1, IL-6, IL-8 and TNF.
  • Other suitable C5a receptor-inactive therapeutic agents include, for example, diazepam (to control seizures).
  • C5a receptor antagonists are surgery to control bleeding and ensure adequate blood flow to the brain, as well as therapies that promote nerve growth, reduce scar tissue barriers, repair damaged myelin and promote compensatory growth of intact nerve fibers. Combinations provided herein may also be used in the treatment of hemorrhagic shock, multiple organ system failure or sepsis.
  • C5a antagonist(s) and C5a receptor-inactive therapeutic agent(s) are preferred for use in the compositions and methods of the present invention.
  • Dosages and methods of administration of therapeutic agents that are not C5a receptor antagonists are known to those skilled in the medical and pharmaceutical arts and can be found, for example, in the manufacturer's instructions set forth in the package insert for the agent, conveniently recorded in the Physician's Desk Reference.
  • NSAIDS certain therapeutic compounds, such as NSAIDS, are suitable for oral administration while others, such as antibody-based drugs, are typically only suitable for non-oral administration.
  • the combination administration of at least one C5a receptor antagonist with at least one C5a receptor-inactive therapeutic agent results in a reduction of the dosage of the C5a receptor-inactive therapeutic agent required to produce a therapeutic effect.
  • the dosage of a C5a receptor-inactive therapeutic agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the C5a receptor- inactive therapeutic agent without combination administration of a C5a receptor antagonist.
  • this dosage is less than %, even more preferably less than V2, and highly preferably, less than l A of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the C5a receptor- inactive therapeutic agent(s) when administered without combination administration of a C5a receptor antagonist. It will be apparent that the dosage amount of C5a antagonist component of the combination needed to achieve the desired effect may similarly be affected by the dosage amount and potency of the C5a receptor-inactive therapeutic agent component of the combination.
  • dosage of a C5a receptor antagonist administered as part of a combination in as described herein is preferably adjusted to achieve specific levels of the C5a receptor antagonist in a body fluid that is in contact with the site of disease or injury (a target body fluid) in the patient being treated.
  • target body fluids include, for example one or more of 1) in arthritis, synovial fluid, 2) in, e.g., septicemia, myocardial infarction and conditions involving a potential for reperfusion injury, blood, plasma, or preferably serum, 3) in, e.g., traumatic spinal or brain injury, cerebrospinal fluid, 4) in, e.g., retinopathy, aqueous humor, and 5) in various conditions including the foregoing, cellular interstitial fluid or lymphatic fluid.
  • preferred levels to be achieved in a target body fluid range from about 5 ng /mL to about 10 ug/mL, preferably from about 20 ng/mL to about 1 ug/mL, more preferably from about 30 ng/mL to about 500 ng/ml, and most preferably from about 50 ng/ml to about 100 ng/ml. Dosages and routes of administration are preferably adjusted to achieve such preferred levels.
  • Oral dosage amount of the C5a antagonist component of the combination preferably ranges from about 0.001 mg per kg of body weight per day (mg/kg/day) to about 50.0 mg/kg/day, more preferably 0.005-20.0 mg/kg/day and most preferably 0.005-10.0 mg/kg/day.
  • Suitable oral tablets and capsules for human patients contain between about 0.1 mg and 5.0 g, preferably between about 0.5 mg and 2.0 g, most preferably between about 0.5 mg and 1.0 g, for example, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 150 mg, 250 mg, or 500 mg of C5a antagonist receptor antagonist.
  • Oral administration may be in one or divided doses of two, three, or four times daily.
  • the oral dosage amount of the C5a antagonist component of the combination is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day.
  • dosage amounts will vary depending on the potency, solubility and bioavailability of the specific C5a antagonist used as well as other factors noted above.
  • the most preferred doses for the C5a antagonist component of the combination will range from about 0.5 pg to about 5 mg/kg/minute during a constant rate infusion, to achieve a plasma level concentration during the period of time of administration of between 0.1 ng/ml and 1.0 mg/ml.
  • the combination therapy methods of the invention include administration of a single pharmaceutical dosage formulation which contains both the C5a antagonist and the C5a receptor-inactive therapeutic agent, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
  • the C5a receptor antagonist can be administered by a number of methods, for example orally, parenterally, transdermally, intravenously, intranasally, intra-articularly, or by any other known method for pharmaceutical administration. Oral, intranasal or topical dosing is generally preferred.
  • all active agents of the instant combination therapy are administered orally, and the active agents are combined in a single oral dosage formulation.
  • a C5a antagonist and the C5a receptor-inactive therapeutic agent can be administered to the patient together in one oral composition such as a tablet or capsule.
  • the combination therapy may comprise administration of an oral preparation of a C5a antagonist with a separate oral preparation of a C5a receptor-inactive therapeutic agent, or with a separate intravenous, transdermal, intraocular, intranasal, or intra-articular preparation of a C5a receptor-inactive therapeutic agent.
  • combination administration and combination therapy include all such regimens that result in both the C5a antagonist and the C5a receptor-inactive therapeutic agent providing therapeutic effects that overlap in time with each other.
  • combination treatments where one or more of the therapeutic agents are administered by direct application to an affected area (e.g., by topical administration or injection), such effect is generally achieved when target blood level concentrations of each active agent occur at substantially the same time.
  • combination indicates both composition of matter and method of treatment.
  • the dosage regimen utilizing a C5a antagonist and a C5a receptor-inactive therapeutic agent is selected in accordance with a variety of factors including species, age, weight, sex, medical condition of the patient, and other pharmaceutical agents that are being administered to the patient during treatment in accordance with the present invention. These factors further include the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compounds (including any salts or prodrugs thereof) employed. In some cases, the therapy may be administered on a long-term chronic basis, such as a period of several months or years, for as long as deemed medically appropriate for the patient.
  • kits comprising at least one C5a antagonist and at least one C5a receptor-inactive therapeutic agent together with indicia comprising instructions for using the contents of the kit to treat a patient suffering from a condition with a pathogenic inflammatory component.
  • pathogenic inflammatory component include those described above, such as arthritis, asthma, psoriasis, reperfusion, traumatic brain and spinal cord injury, and cardio- and cerebrovascular disease.
  • the active agents in a pharmaceutical kit i.e., the C5a antagonist(s) and the C5a receptor-inactive therapeutic agent(s)
  • one or more of the active agents of the pharmaceutical kit may be formulated for separate administration, for example by different routes of administration.
  • a pharmaceutical kit for oral administration of the active agents comprise a blister package containing rows of a C5a antagonist tablet and a tablet containing a C5a receptor- inactive therapeutic agent (e.g., COX-2 inhibitor or methotrexate), placed side by side on the same blister card, one each of the two types of tablets in its own blister bubble (or one each of the two types of tablets in a single blister bubble with no other tablets), with indicia on the card directing that one "pair" of tablets (i.e., one C5a antagonist tablet and one C5a receptor- inactive therapeutic agent ) is to be ingested per day.
  • a C5a receptor- inactive therapeutic agent e.g., COX-2 inhibitor or methotrexate
  • the pharmaceutical kit is comprised of a C5a receptor-inactive therapeutic agent selected from non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase enzyme inhibitors, such as salicylates, and particularly including cyclooxygenase-2 enzyme specific inhibitors, such as rofecoxib or celecoxib; corticosteroids, such as cortisone, prednisolone and prednisone; gold compounds including injectible gold sodium thiomalate and gold compounds formulated for oral administration; methotrexate; dihydroorotate dehydrogenase inhibitors, such as leflunomide; anti-C5 monoclonal antibodies; TNF alpha antagonists, such as entanercept or infliximab; and IL-1 receptor antagonists, such as anakinra.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • cyclooxygenase enzyme inhibitors such as salicylate
  • One example of this embodiment is a pharmaceutical kit comprised of an oral dosage formulation of a C5a antagonist and an oral dosage formulation of aspirin and instructions for using the contents of the pharmaceutical kit to treat rheumatoid arthritis.
  • Another example of this embodiment is a pharmaceutical kit comprised of a C5a antagonist and a COX-2 inhibitor formulated for either single or separate oral administration together with instructions for using the contents of the pharmaceutical kit to treat rheumatoid arthritis.
  • the pharmaceutical kit provided is comprised of a C5a receptor antagonist and a C5a receptor-inactive therapeutic agent for the treatment of asthma.
  • the C5a receptor-inactive therapeutic agent for the treatment of asthma may be a corticosteroid, such as fluticasone propionate or triamcinolone.
  • the C5a receptor-inactive therapeutic agent may also be cromolyn sodium, a long- or short- acting Beta adrenergic receptor agonist, particularly a Beta-2-receptor agonist, a leukotriene modifier, and anticholinergic, or a methylxanthine, for example, theophylline.
  • kits of the invention for the treatment of asthma may also comprise inhaled formulations of both the C5a receptor antagonist and the C5a receptor-inactive therapeutic agent for the treatment of asthma, prepared as separate formulations or as a single formulation.
  • an inhaler, nebulizer, or other device for inhalation may be provided in the kit.
  • kits for the treatment of psoriasis comprised of a C5a-antagonist and a C5a receptor-inactive therapeutic agent for the treatment of psoriasis which is preferably selected from therapeutic agents the inhibit the hyperfunctional proliferation of epidermal cells; inhibit the inflammatory response; promote immunomodulation; and/or inhibit infection by bacteria and fungi.
  • the C5a receptor-inactive therapeutic agent of the kit is a non-steroidal anti-inflammatory drug (NSAID), a steroid, coal tar, a moisturizer, calendula plant extract, an agents that arrests the proliferation of cells during the metaphase stage of cell division; e.g., SLO-PHYLLINTM or THEO-DUR SPRINKLETM), an angiogenesis inhibitor such as ganglioside GM3 or a GM3 analog, a phospholipase A2 inhibitor or an imidazole antifungal.
  • NSAID non-steroidal anti-inflammatory drug
  • a steroid steroid
  • coal tar e.g., a moisturizer, calendula plant extract
  • an agents that arrests the proliferation of cells during the metaphase stage of cell division e.g., SLO-PHYLLINTM or THEO-DUR SPRINKLETM
  • an angiogenesis inhibitor such as ganglioside GM3 or a GM3 analog, a
  • a C5a receptor-inactive therapeutic agent included in a kit for the treatment of psoriasis may also be an immunomodulator, such as a folic acid antagonist, an inhibitor of interleukin-2 production, an immunosuppressant, a TNF-alpha modulators, and antileukotriene agents, or a Vitamin A derivatives.
  • an immunomodulator such as a folic acid antagonist, an inhibitor of interleukin-2 production, an immunosuppressant, a TNF-alpha modulators, and antileukotriene agents, or a Vitamin A derivatives.
  • the invention particularly includes kits for the treatment of psoriasis in which one or both or the C5a antagonist and C5a receptor-inactive therapeutic agent is formulated for topical administration.
  • kits for the treatment of cardio- and cerbrovascular disease comprised of a C5a receptor-inactive therapeutic agent selected from the group that includes non- steroidal anti-inflammatory drugs (NSAIDs), cholesterol lowering drugs, particularly 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoA RI) such as lovastatin, pravastatin, or simvastatin, anti-hypertensive agents, including adrenergic receptor stimulators, including agonists, alpha/ beta adrenergic receptor antagonists, beta adrenergic receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics and periphereal vasodilators, and platelet aggregation inhibitors, particularly GP Ilb/IIIa inhibitors, PDE inhibitors, particularly PDE III inhibitors, inhibitors of megakaryocyte hypermaturation, and ADP receptor
  • An example of this embodiment is a pharmaceutical kit comprising an oral dosage formulation of a C5a antagonist and an oral dosage formulation of simvastatin (ZOCORTM) and instructions for using the contents of the pharmaceutical kit to reduce the risk of myocardial infarction and/ or stroke.
  • ZOCORTM simvastatin
  • the compounds for use in the described combination therapy may be administered orally, topically, transdermally, parenterally, by inhalation or spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal and like types of injection or infusion techniques.
  • One or more compounds of the combination may be present in association with one or more non- toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of the combination may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non- toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • Compounds for use in the described combination therapy may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • Compounds used in the described combination therapy may be prepared as a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectible preparation may also be sterile injectible solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectibles.
  • Compounds of for use in the combination therapy may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • one or more adjuvants such as preservatives, buffering agents, or local anesthetics can also be present in the vehicle.
  • the compounds of the present invention may be delivered via any inhalation methods known to those skilled in the art.
  • inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or
  • HFA or propellants that are physiologically and environmentally acceptable.
  • Other included devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Formulation suitable for administration by inhalation includes formulations of the active ingredient in a form that can be dispensed by such inhalation devices known to those in the art. Such formulations may include carriers such as powders and aerosols.
  • the inhalant compositions used in the present invention may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptable for intrabronchial administration.
  • the powder compositions can be administered via an aerosol dispenser or encased in a breakable capsule which may be inserted by the patient into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
  • Aerosol formulations for use in the subject method would typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
  • Formulations suitable for nasal administration include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions provided herein are formulated for topical administration.
  • Such formulations typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
  • Topical formulations are useful, for example, in the treatment of psoriasis and sunburn.
  • Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin
  • glycols e.g., butylene, isoprene or
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • the topical formulations provided herein may be prepared in a variety of physical forms.
  • solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions are all contemplated by the present invention.
  • the physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifiers and viscosity adjusters present in the formulation.
  • Particular topical formulations can often be prepared in a variety of these forms.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity.
  • These formulations may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers.
  • Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, behentirmonium methosulfate, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 sterate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
  • Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate.
  • a gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
  • Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • nonionic, amphoteric, ionic and anionic surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • dimethicone copolyol polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
  • Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • Suitable fragrances and colors for use in the formulations of the present invention include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
  • Other suitable additional ingredients that may be included a topical formulation include, but are not limited to, abrasives, absorbents, anti- caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
  • a suitable topical vehicle for formulation of a gel is: hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%); propylene glycol
  • a suitable topical vehicle for formulation as a foam is: cetyl alcohol (1.1%); stearyl alcohol (0.5%; Quaternium 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.
  • Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing.
  • Controlled release vehicles can also be used to administer the compounds of the present invention.
  • the technology and products in this art are variably referred to as controlled release, sustained release, prolonged action, depot, repository, delayed action, retarded release and timed release; the words "controlled release” as used herein is intended to incorporate each of the foregoing technologies.
  • Controlled release drug delivery devices include creams, lotions, tablets, capsules, gels, microspheres and liposomes.
  • Transdermal formulations, from which active ingredients are slowly released are also well known and can be used in the present invention. Controlled release preparations can be achieved by the use of polymers to complex or absorb the active agent(s).
  • the controlled delivery can be exercised by selecting appropriate macromolecule such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylenevinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate, and the concentration of these macromolecule as well as the methods of incorporation are selected in order to control release of active compound.
  • appropriate macromolecule such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylenevinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate
  • Hydrogels wherein the active agent(s) are dissolved in an aqueous constituent to gradually release over time, can be prepared by copolymerization of hydrophilic mono- olefinic monomers such as ethylene glycol methacrylate.
  • Matrix devices wherein the active agent(s) are dispersed in a matrix of carrier material, can be used.
  • the carrier can be porous, non-porous, solid, semi-solid, permeable or impermeable.
  • a device comprising a central reservoir of active agent(s) surrounded by a rate controlling membrane can be used to control the release of active agent(s).
  • Rate controlling membranes include, for example, ethylene-vinyl acetate copolymer and butylene terephthalate/polytetramethylene ether terephthalate.
  • a human C5a receptor cDNA is obtained by PCR using 1) a forward primer adding a Kozak ribosome binding site and 2) a reverse primer that added no additional sequence, and
  • the PCR product is subcloned into the cloning vector pCR-Script AMP (STRATAGENE, La
  • the recombinant virus- containing supernatant is serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Lenexa, KS) supplemented Grace's salts and with 4.1mM L-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter "insect medium”) and plaque assayed for recombinant plaques. After four days, recombinant plaques are selected and harvested into 1 ml of insect medium for amplification.
  • Each 1 ml volume of recombinant baculovirus (at passage 0) is used to infect a separate T25 flask containing 2 x 10 6 S 9 cells in 5 mis of insect medium. After five days of incubation at 27°C, supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum.
  • Two of seven recombinant baculoviral clones are then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect 1 x 10 cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eight hours post infection, passage 2 medium from each 100 ml prep is harvested and plaque assayed for titer. The cell pellets from the second round of amplification are assayed by affinity binding as described below to verify recombinant receptor expression. A third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect a liter of S 9 cells. Forty hours post-infection the supernatant medium is harvested to yield passage 3 baculoviral stock.
  • the remaining cell pellet is assayed for affinity binding using the "Binding Assays" essentially as described by DeMartino et al. (1994) J. Biol. Chem. 269:14446-50 at page 14447, adapted as follows.
  • Radioligand is 0.005-0.500nM [125 ⁇ jC5a (human recombinant; New England Nuclear Corp., Boston, MA); the hC5a receptor-expressing baculoviral cells are used instead of 293 cells; the assay buffer contains 50 mM Hepes pH.
  • Titer of the passage 3 baculoviral stock is determined by plaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression.
  • EXAMPLE 3 BACULOVIRAL INFECTIONS
  • Log-phase S/9 cells (INVITROGEN Corp., Carlsbad CA) are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27°C.
  • Infections are carried out either only with virus directing the expression of the hC5a receptor or with this virus in combination with three G-protein subunit-expression virus stocks: 1) rat GDi2 G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2) bovine bl G-protein- encoding virus stock (BIOSIGNAL #V5H012), and 3) human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), all of which may be obtained from BIOSIGNAL Inc.
  • the infections are conveniently carried out at a multiplicity of infection of
  • S/9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 ug/ml leupeptin, 2 ug/ml Aprotinin, 200 uM PMSF, and 2.5 mM EDTA, pH 8.
  • the homogenate is centrifuged (536 x g/ 10 minutes/4°C) to pellet the nuclei.
  • the supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000 X g/ 30 minutes, 4°C) and the resulting pellet resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice.
  • the final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at -80°C until needed.
  • P2 membranes The protein concentration of the resulting membrane preparation (hereinafter "P2 membranes") is conveniently measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, CA). By this measure, a 1-liter culture of cells typically yields 100- 150 mg of total membrane protein.
  • Purified P2 membranes prepared by the method given above, are resuspended by
  • membranes (5-50 ⁇ g) are added to polypropylene tubes containing 0.005-0.500 nM [ 125 I]C5a (human (recombinant), New England Nuclear
  • Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St. Louis, MO) and accounts for less than 10 % of total binding.
  • GTP ⁇ S is added to duplicate tubes at the final concentration of 50 ⁇ M.
  • membranes (5-50 ⁇ g) are added to polypropylene tubes containing 0.030 nM [ 125 I]C5a (human).
  • Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10 "10 M to 10 "5 M to yield a final volume of 0.250 mL.
  • Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St.
  • EXAMPLE 6 AGONIST-INDUCED GTP BINDING Agonist-stimulated GTP-gamma 35 S binding (“GTP binding") activity can be used to identify agonist and antagonist compounds and to differentiate neutral antagonist compounds from those that possess inverse agonist activity. This activity can also be used to detect partial agonism mediated by antagonist compounds. A compound being analyzed in this assay is referred to herein as a "test compound.” Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of the hC5a receptor and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of S/9 cells as described in Example 3.
  • Agonist-stimulated GTP binding on purified membranes is assessed using hC5a (Sigma Chemical Co., St. Louis, MO) as agonist in order to ascertain that the receptor/G-protein-alpha-beta-gamma combination(s) yield a functional response as measured by GTP binding.
  • hC5a Sigma Chemical Co., St. Louis, MO
  • P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgC12, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, lOOKIU/mL aprotinin, 5 ⁇ M GDP) and added to reaction tubes at a concentration of 30 ⁇ g protein/reaction tube. After adding increasing doses of the agonist hC5a at concentrations ranging from 10 "12 M to 10 "6 M, reactions are initiated by the addition of 100 pM GTP-gamma S.
  • GTP binding assay buffer 50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgC12, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, lOOKIU/mL aprotinin, 5 ⁇ M GDP
  • Neutral antagonists are those test compounds that reduce the C5a-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added C5a or other agonist and in the further absence of any test compound).
  • certain preferred compounds will reduce the GTP binding activity of the receptor-containing membranes below baseline, and are thus characterized as inverse agonists. If a test compound that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the C5a agonist, it is characterized as a neutral antagonist.
  • An antagonist test compound that elevates GTP binding activity above baseline in the absence of added hC5a in this GTP binding assay is characterized as having partial agonist activity.
  • Preferred antagonist compounds do not elevate GTP binding activity under such conditions more than 10%, 5% or 2% above baseline.
  • U937 cells are grown in differentiation media (1 mM dibutyrl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37°C then reseeded onto 96-well plates suitable for use in a FLIPRTM Plate Reader (Molecular Devices Corp., Sunnyvale CA). Cells are grown an additional 24 hours (to 70-90% confluence) before the assay. The cells are then washed once with Krebs Ringer solution. FLUO-3 calcium sensitive dye (Molecular Probes, Inc. Eugene, OR) is added to 10 ⁇ g/mL and incubated with the cells at room temperature for 1 to 2 hours. The 96 well plates are then washed to remove excess dye.
  • differentiation media (1 mM dibutyrl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37°C then reseeded onto 96-well plates suitable for use in a FLIPRTM Plate Reader (Molecular Devices Corp., Sunnyvale CA
  • Fluorescence responses measured by excitation at 480 nM and emission at 530 nM, are monitored upon the addition of human C5a to the cells to a final concentration of 0.01-30.0 nM, using the FLIPRTM device (Molecular Devices).
  • Differentiated U937 cells typically exhibit signals of 5,000-50,000 Arbitrary Fluorescent Light Units in response to agonist stimulation.
  • Differentiated U937 cells (prepared and tested as described above under "A. Response to C5a") are stimulated by the addition of ATP (rather than C5a) to a final concentration of 0.01 to 30 ⁇ M.
  • This stimulation typically triggers a signal of 1,000 to 12,000 arbitrary fluorescence light units.
  • Certain preferred compounds produce less than a 10%, less than a 5%, or less than a 2% alteration of this calcium mobilization signal when this control assay is carried out in the presence of the compound, as compared to the signal when the assay is performed in the absence of the compound.
  • the calcium mobilization assay described above may be readily adapted for identifying test compounds that have agonist or antagonist activity at the human C5a receptor.
  • differentiated U937 cells are washed and incubated with Fluo-3 dye as described above.
  • Fluo-3 dye as described above.
  • a subset of the cells is incubated with 1 ⁇ M of at least one compound to be tested.
  • the fluorescence response upon the subsequent addition of 0.3 nM (final concentration) human recombinant C5a is monitored using the FLIPRTM plate reader.
  • Antagonist compounds elicit at least a 2-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone.
  • Preferred antagonist compounds elicit at least a 5-fold, preferably at least a 10-fold, and more preferably at least a 20-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone.
  • Agonist compounds elicit an increase in fluorescence without the addition of C5a, which increase will be at least partially blocked by a known C5a receptor antagonist.
  • This assay is a standard assay of C5a receptor mediated chemotaxis.
  • Human promonocytic U937 cells or purified human or non-human neutrophilis are treated with dibutyryl cAMP for 48 hours prior to performing the assay.
  • Human neutrophils or those from another mammalian species are used directly after isolation.
  • the cells are pelleted and resuspended in culture media containing 0.1% fetal bovine serum (FBS) and 10 ug/ml calcein AM (a fluorescent dye). This suspension is then incubated at 37 °C for 30 minutes such that the cells take up the fluorescent dye.
  • FBS fetal bovine serum
  • 10 ug/ml calcein AM a fluorescent dye
  • the suspension is then centrifuged briefly to pellet the cells, which are then resuspended in culture media containing 0.1% FBS at a concentration of approximately 3 x 10 6 cells/mL. Aliquots of this cell suspension are transferred to clean test tubes, which contain vehicle (1% DMSO) or varying concentrations of a compound of interest, and incubated at room temperature for at least 30 minutes.
  • the chemotaxis assay is performed in CHEMO TX 101-8, 96 well plates (Neuro Probe, Inc. Gaithersburg, MD).
  • the bottom wells of the plate are filled with medium containing 0-10 nM of C5a, preferably derived from the same species of mammal as are the neutrophils or other cells (e.g., human C5a for the human U937 cells).
  • the top wells of the plate are filled with cell suspensions (compound or vehicle-treated).
  • the plate is then placed in a tissue culture incubator for 60 minutes.
  • the top surface of the plate is washed with PBS to remove excess cell suspension.
  • the number of cells that have migrated into the bottom well is then determined using a fluorescence reader. Chemotaxis index (the ratio of migrated cells to total number of cells loaded) is then calculated for each compound concentration to determine an IC 50 value.
  • the bottom wells of the plate may be filled with varying concentrations chemo-attractants that do not mediate chemotaxis via the C5a receptor (e.g., zymosan- activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4 (LTB4)), rather than C5a, under which conditions the compounds provided herein preferably do not inhibit chemotaxis.
  • chemo-attractants that do not mediate chemotaxis via the C5a receptor
  • C5a receptor e.g., zymosan- activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4 (LTB4)
  • Preferred compounds exhibit IC 5 0 values of less than 1 ⁇ M in the above assay for C5a receptor mediated chemotaxis.
  • EXAMPLE 9 PHARMACEUTICAL PREPARATIONS OF ORAL AND INTRAVENOUS ADMINISTRATION
  • Tablets containing a C5a antagonist and an anti-arthritic agent which is not a C5a antagonist can be prepared as illustrated below:
  • C5a receptor-inactive therapeutic agent 1 mg -500 mg diluent, binder, distigrant, lubricant, excipients q.s. 200-400 mg.
  • Tablets containing a C5a antagonist as the only active ingredient can be prepared as illustrated below: Ingredient mg mg C5a antagonist 10 50 Microcrystalline Cellulose 70.4 352 Granular Mannitol 15.1 75.5 Croscarmellose Sodium 3.0 15.0 Colloidal Silicon Dioxide 0.5 2.5 Magnesium Stearate (Impalpable Powder) 1.0 5.0 Total (mg) 100 500
  • Tablets containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:
  • Intravenous formulations containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:
  • E. Oral suspensions containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:

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Abstract

Compositions and methods for treating diseases that are associated with inflammation are provided. Such diseases include arthritis (particularly rheumatoid arthritis) and other autoimmune disorders, asthma, cardio-and cerebrovascular disease, burns, psoriasis, reperfusion injury, and traumatic CNS and spinal cord injury. The compositions generally comprise at least one C5a antagonist and at least one C5a receptor-inactive therapeutic agent. The methods involve co-administration of at least one C5a antagonist and at least one C5a receptor-inactive therapeutic agent to a patient. The C5a antagonist and C5a receptor-inactive therapeutic agent may be present within the same composition, or may be administered separately to the patient.

Description

COMBINATION THERAPY FOR THE TREATMENT OF CONDITIONS WITH PATHOGENIC INFLAMMATORY COMPONENTS
FIELD OF THE INVENTION
This invention relates generally to compositions and methods for treating diseases that are associated with inflammation. The invention relates more specifically to compositions comprising a C5a antagonist and a C5a receptor-inactive therapeutic agent, and to therapeutic methods in which a C5a antagonist and a C5a receptor-inactive therapeutic agent are administered to a patient.
BACKGROUND
Inflammation is a localized defense mechanism that is elicited by tissue damage or injury, and serves to destroy, dilute or wall off both injurious agents and injured tissues. Individuals suffering from inflammation typically experience redness, heat, swelling, pain and loss of function in the afflicted area. In addition, inflammatory responses cause or exacerbate the harmful effects of many diseases. Inhibition of inflammatory responses in patients afflicted with such diseases can decrease symptom severity and improve treatment outcome.
Harmful inflammation typically involves the pathogenic activation of the complement system, and in particular the C5a anaphylatoxin. C5a, a 74 amino acid peptide, is a complement component generated early in the terminal phase of the complement cascade by the proteolytic cleavage (by C5 convertase) of the complement component plasma protein C5, and is itself a plasma protein and a key mediator of inflammation. C5a promotes both vascular and cellular inflammatory responses; it has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and chemotactic effects. C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of inflammation and/or cellular injury and is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also primes neutrophils for various antibacterial functions (e.g., phagocytosis). Additionally, C5a stimulates the release of various inflammatory mediators (e.g., activated oxygen radicals, histamines, TNF-alpha, DJ-1, IL-6, IL-8, prostaglandins, and leukotrienes) from various cell types and the release of lysosomal enzymes and other cytotoxic components from granulocytes. The anaphylatoxic actions of C5a result from its stimulation of smooth muscle contraction. Both the anaphylatoxic and chemotactic effects of C5a are believed to be mediated through its interaction with the C5a receptor (CD88 antigen), a 52 kD membrane- bound cell surface G-protein coupled receptor (GPCR).
A wide variety of diseases and medical procedures can result in harmful inflammation, and inhibition of C5a-mediated inflammatory responses in patients afflicted with diseases or undergoing procedures that are associated with such inflammation can be beneficial. Diseases associated with harmful inflammation include, for example, diseases of the joints, lungs, kidneys, heart, skin, liver, and digestive system, and as well as more generally, trauma and auto-immune and infectious diseases. For example, in mice, inhibition of C5a receptor activity was found to improve survival rates for sepsis (Riedemann et al. (2002) J. Clin. Invest. 770:101-108). Medical procedures associated with harmful inflammation include, for example, organ transplantation, tissue grafts, cardiopulmonary bypass and hemodialysis. ASTHMA
Asthma is a lung disease characterized by a usually reversible airway obstruction, airway inflammation and increased airway responsiveness to stimuli. The airway obstruction in an asthma attack is thought to be due to the combination of bronchospasm of the smooth muscles of the bronchial tree, increased mucous section, edema of airway mucosa due to increased vascular permeability, cellular infiltration of the airway walls, and injury to airway epithelium. Studies in animal models have implicated both IgE and the complement system (and C5a in particular) in airway hyperresponsiveness and asthma pathogenesis.
Asthma may be triggered by a variety of causes such as allergic reactions, a secondary response to infections, industrial or occupational exposures, ingestion of certain chemicals or drugs, exercise, and vasculitis. Regardless of the trigger, many of the pathological features of asthma can be attributed to mast cell degranulation. Such responses are, at least in part, mediated by IgE antibodies, which trigger mast cell degranulation in the lung interstitium. The mast cell degranulation releases, among other factors, histamine, bradykinin, and slow- reacting substance of anaphylaxis (SRS-A) which includes the leukotrienes C, D and E, prostaglandins including PGF2, PGF2α and PGD2, and thromboxane A2. The histamine then attaches to receptor sites in the larger bronchi, causing irritation, inflammation and edema. The SRS-A attaches to receptor sites in the smaller bronchi, causing edema and attracting prostaglandins, which enhance the effects of histamine in the lungs. With the help of the prostaglandins, histamine also stimulates excessive mucous secretion, further narrowing the bronchial lumen. When the asthmatic inhales, the narrowed bronchial lumen still expands slightly, allowing air to reach the alveoli. However, upon exertion to exhale, the increased thoracic pressure closes the bronchial lumen completely. Thus, in an asthma attack, air can enter, but not exit the lungs. Mucous then fills the lung bases, inhibiting alveolar ventilation. In an effort to compensate for lowered alveolar ventilation, blood is shunted to other alveoli. Without adequate compensation, hypoxia, and in extreme cases, respiratory acidosis may result.
In many cases, there are two phases to an allergic asthma attack, an early phase and a late phase which follows 4-6 hours after bronchial stimulation. The early phase includes the immediate inflammatory response including the reactions caused by the release of cellular mediators from mast cells. Late phase reactions develop over a period of hours and are characterized histologically by an early influx of polymorphonuclear leukocytes and fibrin deposition followed later by infiltration of eosinophils. Late phase reactions increase airway reactivity and lead to prolonged asthmatic exacerbations that may last from hours to days to months in some subjects. Asthma is most commonly treated with oral and inhaled bronchodilators. Such agents alleviate the symptoms of asthma, but have no effect on the underlying inflammation. Corticosteroids are also used to treat the inflammation, but these drugs can have serious side effects and many patients continue to suffer from incompletely controlled asthma.
SKIN DISORDERS ASSOCIATED WITH INFLAMMATION
The complement system is an important skin defense mechanism, and complement activation (particularly C5a) is involved in the pathogenesis of a variety of skin conditions such as bullous pemphigoid, lichen planas, herpes gestationis and psoriasis.
Psoriasis is one of the most common dermatologic diseases, affecting about 2 percent of the population. This condition presents as elevated lesions that vary in size from one to several centimeters, and results from an overproduction of epidermal cells. The increased production of epidermal cells is due to a shortened cell cycle time, an increase in the absolute number of cells capable of proliferating and an increased rate of division. The thickened epidermis, overgrowth of blood vessels, and infiltration of neutrophils and lymphocytes account for the psoriatic lesions being raised and easily palpable. T cell mediated immune responses appear to be responsible for the inflammation and hyperproliferation of epidermal cells. Neutrophils are found in psoriatic lesions, associated with increased levels of plasminogen activator. Psoriatic fibroblasts have increased levels of enzymes involved in collagen synthesis, secondary to expansion of the papillary dermis. Psoriatic plaques comprise HLA-DR positive keratinocytes and Langerhans cells, as well as activated T cells expressing elevated levels of IL-2 receptors and secreting cytokines including TNF and interleukin-6, which stimulate skin cell growth.
It is not known what causes psoriasis, although there is evidence of a genetic predisposition and an autoimmune etiology. Onset may be triggered by systemic infections such as strep throat infection, skin injury, vaccinations, and certain oral medications such as steroids, which induce inflammation and excessive skin cell reproduction. Psoriasis can be exacerbated by additional factors such as stress and diet. Regardless of the trigger, C5a activation appears to play a direct role in the pathogenesis of the disease.
RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is a chronic disease characterized by persistent joint inflammation (inflammatory synovitis). Early clinical manifestations of the disease include pain, swelling and tenderness of the joints that is initially poorly localized. Many patients exhibit general fatigue, weakness, loss of appetite, low-grade fever and musculoskeletal symptoms before joint pain becomes localized. As the disease progresses, joint pain, swelling and stiffness become more evident. Movement, particularly after periods of inactivity, becomes painful and difficult. The persistent inflammation caused by rheumatoid arthritis often leads to destruction or weakening of ligaments and tendons, and destruction of cartilage and bone. Deformities of the hands and feet, due to fibrous or bony ankylosis or soft tissue contracture, are often present in advanced disease. Current treatments of RA can be divided into two types - therapies which act to alleviate the symptoms of the disease, such as pain medications, and disease-modifying therapies which act on some underlying cause of the disease and slow its progression, such as steroids. Inhibitors of cyclooxygenase (COX) enzymes, which inhibit prostaglandin production and thereby reduce inflammation are commonly used to treat rheumatoid arthritis. Such compounds may inhibit COX enzymes non-specifically (e.g., the salicylates), or may specifically inhibit COX-2. Injections of gold sodium thiomalate and oral administration of gold compounds have also been shown to suppress the synovitis of active rheumatoid arthritis. In some case, surgery may be performed.
Considerable experimental evidence has demonstrated the presence of increased levels of C5a in rheumatoid arthritis. Antibodies that bind to C5 and inhibit the conversion of C5 to C5a (and C5b) by C5 convertase have been shown to be effective in reducing symptoms of rheumatoid arthritis in animal models of arthritis. A C5a receptor antagonist also showed activity as an anti-arthritic agent in a rat RA model (Woodruff et al. (2002) Arthritis Rheum 46: 2476-85). OTHER AUTOIMMUNE DISORDERS
A number of other autoimmune disorders and pathologic autoimmune responses are known to have an inflammatory component, such as multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, lupus erythematosus and irritable bowel syndrome. Considerable experimental evidence has demonstrated the presence of increased levels of C5a in a number of autoimmune diseases and inflammatory disorders. In addition, anti-C5 antibodies also been used to treat glomerulonephritis, a disease characterized by inflammation of the kidney (see US Patent No. 6,355,245).
MEDICAL PROCEDURES
A variety of medical procedures involve the introduction of foreign matter into the patient's body. Such procedures generally trigger, and are complicated by, inflammation. For example, inflammation may result from cardiopulmonary bypass surgery or hemodialysis. Rejection of transplanted organs and tissue grafts also has an inflammatory component. In some cases, for example, the blood supply to the transplant becomes blocked due to inflammation of the blood vessels leading to the transplanted organ. Current therapy for transplant rejection involves a regimen of immunosuppressants, including cyclosporin A, tacrolimus, and rapamycin (sirolimus). However, patients continue to have a 20 to 50 percent risk of rejecting a donated organ during the first three years following transplantation, and less than 50 percent of patients have functioning transplants after 10 years. Additionally, chronic use of immunosuppressants can lead to impairment of the recipients' immune system. CARDIO- AND CEREBROVASCULAR DISEASE
Low-level inflammation has been correlated to the incidence of heart attack and stroke. C-reactive protein, a marker for inflammation, has been shown to be associated with increased risk for cardiovascular events (Ridker et al. (2002) N. Engl. J. Med. 347:1551- 1565). In a study of men with levels of C-reactive protein considered to be within the normal range, the benefits of aspirin in the prevention of heart attack and stroke were more pronounced in individuals with higher levels of C-reactive protein, suggesting that aspirin's anti-inflammatory effects are responsible for the reduction in heart attacks and strokes (Ridker et al (1997) N. Eng. J. Med. 336:913019).
ISCHEMIA-REPERFUSION INJURY Ischemia is a condition in which blood flow (and thus oxygen) is restricted to a part of the body and may occur, for example, due to thrombosis or surgery. Reperfusion injury occurs when a blood flow is restored to a blood vessel that has been previously occluded. Reperfusion injury has also been found to occur during surgeries in which blood vessels are not occluded but in which a heart bypass pump is employed. The hypoxic conditions in occluded blood vessels induces the production of a number of pro-inflammatory cytokines. While prompt restoration of blood flow is necessary to restore normal function, reperfusion also causes the destruction of additional cells and an intense inflammatory reaction that involves C5a activation. The pro-inflammatory cytokines produced while the vessel was occluded causes leads leukocyte recruitment and subsequent destruction of the endothelium. Additional damage may occur due to obstruction of microcapillaries by leukocytes. In mice, inhibition of C5a receptor activity has been found to improve survival rates for ischemia- reperfusion injury (De Vries et al. (2003) Transplantation 75:375-82). A small molecule C5a receptor antagonist also was shown to protect kidneys from ischemia-reperfusion injury in rats (Arumugam et al. (2003) Kidney Int. 63:134-42).
While some treatments are presently available for both inflammatory and noninflammatory disease components, there remains a need in the art for improved anti- inflammatory medications and methods for using such improved medications in combination with currently available therapies. The present invention fulfills this need and provides further related advantages.
SUMMARY OF THE INVENTION
In a first aspect, the invention provides compositions useful for the treatment of diseases with inflammatory components, such as arthritis (particularly rheumatoid arthritis) and other autoimmune disorders, asthma, cardio- and cerebrovascular disease, psoriasis, reperfusion injury, and traumatic CNS and spinal cord injury. Such compositions comprise at least one C5a receptor antagonist (hereinafter a "C5a antagonist") and at least one C5a receptor-inactive therapeutic agent (Le., a therapeutic agent that is not a C5a antagonist).
Preferred properties for C5a antagonists for use in the practice of the invention are one or preferably 2 or most preferably all 3 of: 1) having a molecular mass less than 700 a.m.u. 2) being nonpeptidic (i.e., do not contain amino acids joined by a peptide bond; preferably do not contain any amino acid moiety) and 3) having minimal agonist activity (i.e., induce an increase in the basal activity of the C5a receptor in the absence of C5a that is less than 5% of the increase that would be induced by C5a, preferably inducing no statistically significant increase). Preferred C5a antagonists for used in the practice of the invention include neutral antagonists and inverse agonists of the C5a receptor.
Within certain embodiments, the C5a receptor-inactive therapeutic agent is an NSAID, a cyclo-oxygenase enzyme inhibitor, a gold compound, a salicylate, a steroid such as a corticosteroid, methotrexate, lefunomide, a TNF antagonist, a cholesterol lowering agent, an HMG-CoA reductase inhibitor, a platelet aggregation inhibitor, or an anti-hypertensive agent.
Within further aspects, the present invention provides pharmaceutical compositions, comprising a C5a antagonist in combination with a C5a receptor-inactive therapeutic agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutical formulations, such as tablets, pills and capsules, containing a C5a antagonist and a C5a receptor-inactive therapeutic agent are included in the invention. Pharmaceutical formulations of the invention may include additional active or inert ingredients. Processes for preparing such pharmaceutical compositions and pharmaceutical formulations are included in the invention.
Also provided are packages comprising such a pharmaceutical composition and instructions for use to treat a patient suffering from arthritis or another autoimmune disorder, asthma, cardio- and cerebrovascular disease, psoriasis, reperfusion injury, or traumatic CNS or spinal cord injury. The C5a antagonist and a C5a receptor-inactive therapeutic agent may be provided each in a separate container within the package or - where both are to be given by the same route of administration - preferably combined in a single formulation.
Methods are further provided, within other aspects for treating a patient suffering from arthritis or another autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burns, or traumatic CNS or spinal cord injury, comprising administering to the patient a therapeutically effective amount of a C5a receptor antagonist in combination with a therapeutically effective amount of a C5a receptor-inactive therapeutic agent. The combination therapy provided herein encompasses either or both of 1) the administration of a C5a antagonist and a C5a receptor-inactive therapeutic agent together, preferably in a single pharmaceutical formulation, and 2) the administration of a C5a antagonist in a first formulation and the separate administration of a C5a receptor-inactive therapeutic agent in a second pharmaceutical formulation.
These and other aspects of the present invention will become apparent upon reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION TERMINOLOGY
A "C5a antagonist" or "C5a receptor antagonist" is any compound that exhibits C5a antagonist activity within the a C5a receptor-mediated chemotaxis, radioligand binding assay, or calcium mobilization assay as provided herein. In other words, in a calcium mobilization assay, a compound is a C5a antagonist if incubation of cells with 1 uM of C5a antagonist results in at least a 2-fold increase in the fluorescence response relative to that measured in the presence of C5a alone. In a chemotaxis assay, a compound is a C5a antagonist if it displays an affinity constant or IC50 of 1 uM or less. Preferably, a C5a antagonist displays an
IC50 of less than 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM or 5 nM (in a chemotaxis and/or calcium mobilization assay) in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, or calcium mobilization assay. In certain embodiments, C5a antagonists provided herein inhibit activation and/or activity of a primate C5a receptor, such as human C5a receptor, which may be a cloned, recombinantly expressed receptor or a naturally expressed receptor. For treating non-human animals of any particular species, a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.
As used herein, "therapeutic agent" refers to a compound which has been shown to exhibit clinical efficacy in reducing the symptoms of one or more of arthritis (preferably rheumatoid arthritis) or another autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burns, or traumatic CNS or spinal cord injury. A "C5a receptor-inactive therapeutic agent" is such an agent that does not satisfy the criteria (above) for a C5a antagonist. As used herein, "active agent" refers to either or both of the C5a antagonist and the
C5a receptor-inactive therapeutic agent. This term is intended to encompass all salt, ester and prodrug forms of C5a antagonists and C5a receptor-inactive therapeutic agents, even where the prodrug is not active itself but is converted to the active form after administration to the patient. An active agent is said to be "administered" if it is caused to be contacted with a patient so as to provide a detectable therapeutic effect. Administration may be oral, intranasal, topical, rectal or parenteral. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.
A "condition with a pathogenic inflammatory component" is any disease, disorder or injury that is caused, prolonged or exacerbated by C5a-mediated inflammation. Such conditions include, but are not limited to, arthritis (such as rheumatoid arthritis) and other autoimmune disorders (e.g., multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, Guillain-Barre Syndrome, lupus erythematosus and irritable bowel syndrome); asthma and other lung disorders, including respiratory distress syndrome; skin conditions and injuries such as psoriasis, bullous pemphigoid, lichen planas, burns and wounds; cardio- and cerebrovascular disease, including restenosis; ischemia- reperfusion injury; trauma (e.g., CNS); sepsis and other infections; hemorrhagic shock; and multiple organ system failure. Such conditions also include medical procedures such as organ transplantation (e.g., lung), tissue grafts, hemodialysis, and cardiopulmonary bypass surgery, where recovery may be inhibited or delayed as a result of inflammation.
C5a antagonists used in the compositions and methods provided herein are generally described using standard nomenclature. Certain compounds described herein contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like (e.g., asymmetric carbon atoms) so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. Unless otherwise specified all optical isomers and mixtures thereof are encompassed for compounds having asymmetric centers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather encompasses all tautomeric forms.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include πC, I3C, and 14C.
Certain compounds are described herein using a general formula, such as Formula I, that includes variables, such as various R groups, Ar1, Ar2, and x. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, for example, if a group is shown to be substituted with 0-2 R , then said group may optionally be substituted with up to two R groups and R at each occurrence is selected independently from the definition of R . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound (i.e., a compound that can be isolated, characterized and tested for biological activity). When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example a pyridyl group substituted by oxo is a tetrahydropyridone.
The phrase "optionally substituted" indicates that a group may either be unsubstituted or substituted at one or more of any of the available positions, typically 1, 2, 3, 4, or 5 positions, by one or more suitable substituents such as those disclosed herein. Various groups within the compounds and formulae set forth herein are "optionally substituted" including, for example, R1, R2, and Ar1. Optional substitution may also be indicated by the phrase "substituted with from 0 to X substituents," in which X is the maximum number of substituents.
Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, -COOH, SO2NH2, alkyl (e.g., Cι-C8alkyl), alkenyl (e.g., C -C8alkenyl), alkynyl (e.g., C2-C8alkynyl), alkoxy (e.g., Cι-C8alkoxy), alkyl ether (e.g., C2-C8alkyl ether), alkylthio (e.g., Cι-C8alkylthio), mono- or di-(C1-C8alkyl)amino, haloalkyl (e.g., Ci- C6haloalkyl), hydroxyalkyl (e.g., C!-C6hydroxyalkyl), aminoalkyl (e.g., Cι-C6aminoalkyl), haloalkoxy (e.g., Ci-C6haloalkoxy), alkanoyl (e.g., Cι-C8alkanoyl), alkanone (e.g., - C8alkanone), alkanoyloxy (e.g., Cι-C8alkanoyloxy), alkoxycarbonyl (e.g., Ci- C8alkoxycarbonyl), mono- and di-(Cι-C8alkyl)amino, mono- and di-(Cι-C8alkyl)aminoCι- C8alkyl, mono- and di-(Cι-C8alkyl)carboxamido, mono- and di-(Cι-C8alkyl)sulfonamido, alkylsulfinyl (e.g., Cι-C8alkylsulfinyl), alkylsulfonyl (e.g., Cι-C8alkylsulfonyl), aryl (e.g., phenyl), arylalkyl (e.g., (C6-C18aryl)Cι-C8alkyl, such as benzyl and phenethyl), aryloxy (e.g., C6-C18aryloxy such as phenoxy), arylalkoxy (e.g., (C6-Cι8aryl)Cι-C8alkoxy) and/or 3- to 8- membered heterocyclic groups. Certain groups within the formulas provided herein are optionally substituted with from 1 to 3, 1 to 4 or 1 to 5 independently selected substituents.
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, and where specified, having the specified number of carbon atoms. Thus, the term Ci-Cβalkyl, as used herein, indicates an alkyl group having from 1 to 6 carbon atoms. "Co-C4alkyl" refers to a bond or a - alkyl group. Alkyl groups include groups having from 1 to 8 carbon atoms (Cι-C8alkyl), from 1 to 6 carbon atoms ( - C6alkyl) and from 1 to 4 carbon atoms (Cι-C4alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. "Aminoalkyl" is an alkyl group as defined herein substituted with one or more -NH2 groups. "Hydroxyalkyl" is a hydroxy group as defined herein substituted with one or more -OH groups.
"Alkenyl" refers to a straight or branched hydrocarbon chain comprising one or more unsaturated carbon-carbon bonds, such as ethenyl and propenyl. Alkenyl groups include C2- C8alkenyl, C2-C6alkenyl and C2-C4alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively), such as ethenyl, allyl or isopropenyl.
"Alkynyl" refers to straight or branched hydrocarbon chains comprising one or more triple carbon-carbon bonds. Alkynyl groups include C2-C8alkynyl, C2-C6alkynyl and θ2- C4alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively. Alkynyl groups include for example groups such as ethynyl and propynyl.
"Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy.
The term "alkanoyl" refers to an acyl group in a linear or branched arrangement (e.g.,
-(C=O)-alkyl). Alkanoyl groups include C2-C8alkanoyl, C2-C6alkanoyl and C2-C4alkanoyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. "Cialkanoyl" refers to -(C=O)-H, which (along with C2-C8alkanoyl) is encompassed by the term "Cι~
C8alkanoyl."
The term, "alkyl ether" refers to a linear or branched ether substituent linked via a carbon-carbon bond. Alkyl ether groups include C2-C8alkyl ether, C2-C6alkyl ether and C2-
C6alkyl ether groups, which have 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. By way of example, a C2alkyl ether group has the structure -CH2-O-CH3.
The term "alkoxycarbonyl" refers to an alkoxy group linked via a carbonyl (i.e., a group having the general structure ~C(=O)-O-alkyl). Alkoxycarbonyl groups include C2-C8,
C2-C6, and C2-C4alkoxycarbonyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. "Cialkoxycarbonyl" refers to -C(=O)OH, and is encompassed by "Ci- Csalkoxycarbonyl."
"Alkanoyloxy," as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure -O-C(=O)-alkyl). Alkanoyloxy groups include C2-C8, C2-C6, and C2-C alkanoyloxy groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. As used herein, the term "alkylthio" refers to an alkyl group attached via a thioether linkage. Alkylthio groups include Cι-C8alkylthio, Cι-C6alkylthio and Cι-C4alkylthio, which have from 1 to 8, 1 to 6 or 1 to 4 carbon atoms, respectively.
"Alkylsulfinyl," as used herein, refers to an alkyl group attached via a sulfinyl linkage. Alkylsulfinyl groups include Ci-Csalkylsulfinyl, Cι-C6alkylsulfinyl, and - alkylsulfinyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.
By "alkylsulfonyl," as used herein, is meant an alkyl group attached via a sulfonyl linkage. Alkylsulfonyl groups include Cι-C8alkylsulfonyl, Cι-C6alkylsulfonyl, and Ci-
C4alkylsulfonyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.
"Alkylamino" refers to a secondary or tertiary amine having the general structure - NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl may be the same or different. Such groups include, for example, mono- and di-(Cι-C8alkyl)amino groups, in which each alkyl may be the same or different and may contain from 1 to 8 carbon atoms, as well as mono- and di-(Cι- C6alkyl)amino groups and mono- and di-(Cι-C alkyl)amino groups. Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group (i.e., a group having the general structure - alkyl-NH-alkyl or -alkyl-N(alkyl)(aιkyl)). Such groups include, for example, mono- and di-( - C8alkyl)aminoCι-C8alkyl, mono- and di-(Cι-C6alkyl)aminoCι-C6alkyl, and mono- and di- (Cι-C4alkyl)aminoCι-C4alkyl, in which each alkyl may be the same or different.
The term "carboxamido" or "amido" refers to an amide group (i.e., -(C=O)NH2). "Alkylcarboxamido" refers to -NHC(=O)alkyl, preferably -NHC(=O)Cι-C2alkyl. The term "cycloalkyl" refers to hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from. Cycloalkyl groups include C3-C8, and C3-C7 cycloalkyl groups, which have from 3 to 8 and 3 to 7 carbon atoms, respectively. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, as well as bridged and caged saturated ring groups such as norbornane or adamantane and the like.
In the term "(cycloalkyl)alkyl," "cycloalkyl" and "alkyl" are as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylethyl.
The term "halogen" indicates fluorine, chlorine, bromine, or iodine. "Haloalkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
"Haloalkoxy" indicates a haloalkyl group as defined above attached through an oxygen bridge.
As used herein, the term "aryl" indicates aromatic groups containing only carbon in the aromatic ring(s). Such aromatic groups may be further substituted with carbon or non- carbon atoms or groups. Typical aryl groups contain 1 to 3 separate or fused rings, at least one of which is aromatic, and from 6 to about 18 ring atoms, without heteroatoms as ring members. Specifically preferred carbocyclic aryl groups include phenyl and napthyl, including 1 -naphthyl and 2-naphthyl. When indicated, carbon atoms present within a carbocyclic ring may be optionally substituted with any of variety of ring substituents, as described above, or with specifically listed substituents.
The term "arylalkyl" refers to an aryl group is linked via an alkyl group. Certain arylalkyl groups are (Cό-Cisaryr -Csalkyl groups (i.e., groups in which a 6- to 18- membered aryl group is linked via a Cι-C8alkyl group). Such groups include, for example, groups in which phenyl or naphthyl is linked via a bond or Cι-C8alkyl, preferably via - C4alkyl, such as benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl.
The term "aryloxy" refers to an aryl group linked via a carbonyl (i.e., a group having the general structure -C(=O)-O-aryl). Phenoxy is a representative aryloxy group. "Biphenyl" as used herein indicates, for example, a group of the formula:
^ — " ^ — v . 3-phenyl-phenyl and 2-phenyl-phenyl groups are also included in the definition of biphenyl. When indicated, the biphenyl group is substituted.
As used herein, the term "heteroaryl" is intended to indicate a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4 heteroatoms selected from N, O, and S, with remaining ring atoms being carbon. When the total number of S and 0 atoms in the heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1, 2, or 3, more typically 1 or 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl. isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7, 8-tetrahydroisoquinoline.
The term "heterocyclic group" or "heterocycle" is used to indicate saturated, partially unsaturated, or aromatic groups having 1 or 2 rings, 3 to 8 atoms in each ring and in at least one ring between 1 and 3 heteroatoms selected from N, O, and S. Any nitrogen or sulfur heteroatoms may optionally be oxidized. The heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. Representative examples of heteroaryl groups and heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lΗ-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- l,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4Η-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. An "inverse agonist" of the C5a receptor is a compound which inhibits the activity of
C5a at the C5a receptor, and reduces the activity of the C5a receptor below its basal activity level in the absence of added C5a. Inverse agonists of the C5a receptor may also inhibit binding of C5a to the C5a receptor. The ability of a compound to inhibit the binding of C5a to the C5a receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 5. The basal activity of the C5a receptor may be determined from a GTP binding assay, such as the assay of Example 6. The reduction of C5a activity may also be determined from a GTP binding assay such as the assay of Example 6 or a calcium mobilization assay such as the assay of Example 7.
A "neutral antagonist of the C5a receptor is a compound which inhibits the activity of C5a at the C5a receptor, but does not significantly change the basal activity of the C5a receptor. Neutral antagonists of the C5a receptor may inhibit the binding of C5a to the C5a receptor.
A "partial agonist" of the C5a receptor elevates the activity of the C5a receptor above the basal activity level of the receptor in the absence of C5a, but does not elevate the activity of the C5a receptor to the level brought about by saturating levels of the natural agonist, C5a.. Partial agonist compounds may inhibit the binding of C5a to the C5a receptor. Partial agonists of the C5a receptor usually elevate the active of the C5a receptor from 5% to 90% of the activity level brought about by saturated concentrations of the natural agonist, C5a.
As used herein, a "pharmaceutically acceptable salt" is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4 and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). Accordingly, the present disclosure should be construed to include all pharmaceutically acceptable salts of the compounds specifically recited. A wide variety of synthetic procedures is available for the preparation of pharmaceutically acceptable salts. In general, a pharmaceutically acceptable salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
"A C5a receptor" is a G-coupled protein receptor that specifically binds C5a protein. Preferably the C5a receptor is a human C5a receptor such as the protein product of the sequence of the resulting PCR product described by Gerard and Gerard, (1991) Nature 549:614-17. The human C5a receptor may also be that described by Boulay (1991) Biochemistry, 30(12): 2993-9 (GENBANK Accession No. M62505). Non-primate C5a receptors may be a rat C5a receptor such as a rat C5a receptor, GENBANK Accession Nos. X65862, Y09613, and AB003042, a canine C5a receptor, GENBANK Accession No. X65860, or a guinea pig C5a receptor, GENBANK Accession No. U86103. A "C5a receptor modulatory amount" of a compound is an amount that is sufficient to yield a plasma concentration of the compound (or its active metabolite, if a prodrug) high enough to detectably alter (modulate) C5a receptor activity and/or ligand binding, when that concentration is used in an in vitro assay. Suitable in vitro assays include the standard in vitro C5 receptor-mediated chemotaxis assay (described in Example 8 herein); C5a receptor- mediated calcium mobilization assay (described in Example 7 herein); and/or radioligand binding assay such as the assay provided in Example 5.
A "therapeutically effective amount" of a drug or pharmaceutical agent that elicits a detectable and desirable biological or medical response in a patient. Such a biological or medical response may take place in a tissue, a system, a non-human animal or a human and is generally sought by a researcher, veterinarian, medical doctor or other clinician. For example, a therapeutically effective amount may reduce symptom severity or frequency. Alternatively, or in addition, a therapeutically effective amount may improve patient outcome and/or prevent or delay disease or symptom onset. The dosage regimen utilizing an C5a antagonist in combination with a C5a receptor-inactive therapeutic agent is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the enhanced effects achieved by combining them together (if any) must also be taken into account in determining a therapeutically effective amount. One marker of pathogenic inflammation is C reactive protein (CRP). Decreased plasma levels of CRP after treatment (as compared to levels before treatment) is an indication of an effective anti-inflammatory treatment of a disease with an inflammatory component.
A "patient" is any individual treated with a C5a antagonist as provided herein. Patients include humans, as well as other animals such as companion animals (e.g., dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to C5a receptor modulation, or may be free of such symptom(s) (i.e., treatment may be prophylactic). In certain embodiments, the patient is a human.
As used herein a "patient at risk for myocardial infarction or stroke" is any patient determined to have one or more of the known risk factors for such vascular events. Known risk factors for myocardial infarction and stroke include, but are not limited to obesity, an elevated cholesterol level, hypertension, elevated low density lipoprotein (LDL) levels, congenital heart defects, smoking, previous history of myocardial infarction or stroke, and sedentary lifestyle. A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a substituted tetrahydroisoquinoline. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Preferred prodrugs include acylated derivatives. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved to the parent compounds. Those of ordinary skill in the art will recognize various synthetic methods that may be employed to prepare prodrugs of the compounds provided herein. C5A ANTAGONISTS
Any C5a antagonist, including neutral antagonists and inverse agonists, may be used in the compositions and methods provided herein. The synthesis of certain C5a antagonists listed herein has been described in PCT International Application WO 02/49993 and US Patent Application No. 09/672,701 at pages 161-201 which is hereby incorporated by reference for its teachings regarding the synthesis of C5a antagonists. Additional C5a antagonists have been described in PCT International Application WO 02/14265, published February 21, 2002. As noted above, compounds that act as C5a antagonists may be readily identified by assays for C5a receptor antagonist activity such as the assays provided in Examples 7 and 8, herein. The C5a antagonist may also be chosen from the compounds given in Table I and their pharmaceutically acceptable salts.
Certain C5a antagonists have a molecular mass of less than 700 a.m.u. and exhibit a three dimensional structure that is described by Formula I.
A
Figure imgf000018_0001
Formula I wherein:
ARl and AR2 are independently carbocyclic aryl or heteroaryl; LIP represents an alkyl, carbocyclic aryl, heteroaryl, or arylalkyl; A is oxygen or nitrogen; di represents the distance between A and the geometric center of ARl and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound; d2 represents the distance between A and the geometric center of AR2 and is between 7 and 10 angstroms in at least one energetically accessible conformer of the compound; and d3 represents the distance between A and the nearest atom of LIP and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound. Preferred C5a antagonists of Formula I are non-peptidic and contain one or more heteroaryl rings.
Within certain combinations provided herein, the C5a antagonist is a compound of Formula II:
R2 R3 Ar2 Formula II and the pharmaceutically acceptable salts thereof. The ring system in Formula II represented by
Figure imgf000019_0001
is (i) a 5-membered heteroaryl ring system, in which x is 0; A is m carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or (ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms.
R and Ri in Formula II independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, -CHO, -CONH2, Cι-C6haloalkyl, or Cι-C6haloalkoxy; ii) Cι-C6alkyl, - C6alkenyl, Cι-C6alkynyl, Cι-C6alkoxy, C3-C cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, mono- or di-(Cι-C6alkyl)amino, mono- or di-(Cι-C6alkyl)aminoCι-C6alkyl, mono- or di-(Cι- C6alkyl)carboxamide, Cι-C6alkoxycarbonyl, -NHSOnCι-C6alkyl, -SOnN(Cι-C6alkyl)(Cι- C6alkyl), or phenyl-SOn-, each of which is optionally substituted, and wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylCι-C4carbhydryl, a 5- or 6-membered heteroaryl group, or a 5- or 6-membered heteroarylCι-C4carbhydryl group, each of which is optionally substituted.
If E is nitrogen, R is chosen from Cι-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C3- C7cycloalkyl(Cι-C alkyl), benzyl and Ci-Cβhaloalkyl. If E is Carbon, R2 is chosen from halogen, hydroxy, Cι-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, Cι-C7alkoxy, Cι-C alkylamino, C3-C7cycloalkyl(Cι-C4alkyl), benzyl, -Cehaloalkyl, and Cι-C6haloalkoxy.
R3 is hydrogen, Ct-Cβalkyl, C2-C6alkenyl, hydroxyCι-C6alkyl, C!-C6haloalkyl, C3- C7cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, or phenyl(Ci-C4alkyl), or when x is 0, Ri and R3 may be joined to form a C3-C7cycloalkyl ring, which may be optionally substituted, y is and integer ranging from 1 to 6; in certain embodiments y is 1 or 2. R represents i) hydrogen; ii) Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- cycloalkyl, C3-C7cycloalkenyl, (C3-C7cycloalkyl)Cι-C4alkyl, (C3-C cycloalkenyl)Cι- C4alkyl, or hexahydro-l,3-benzodioxolylmethyl, each of which may be optionally substituted; iii) optionally substituted arylCi- alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylCι-C4alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(Co- C4alkyl); vi) optionally substituted heteroarylCι-C2alkyl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocycle(Co- C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon.
R5 and R6 are independently chosen from hydrogen and Cι-C6alkyl, and z is 1, 2, or 3.
Ari is optionally substituted aryl having 1 or 2 fused or pendant rings, optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having
0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, or optionally substituted heteroaryl, having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S.
Ar2 is optionally substituted C3-C7cycloalkyl, C3-C cycloalkyl(Cι-C4alkyl), C3- C7cycloalkenyl, C3-C7cycloalkenyl(Cι-C4alkyl), or hexahydro-l,3-benzodioxolyl, optionally substituted aryl having 1 or 2 fused or pendant rings, optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, or optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms selected from the group consisting of N, O, and S.
Certain compounds and salts of Formula II are imidazoles in which A and G are carbon, E is nitrogen, X is 0 and Ri and R3 do not form a ring. Such compounds satisfy Formula Ila:
Figure imgf000020_0001
Formula Ila
Other compounds and salts of Formula II are 5-aryl-pyrazoles or 1-aryl pyrazoles, in which E is carbon, one of A and G is nitrogen (with the other being carbon), x is 0, and Ri and R3 are not joined to form a cycloalkyl ring. Such compounds satisfy Formula IIB or lie:
Figure imgf000020_0002
Formula lie Additional compounds and salts of Formula II are triazoles in which in which A and E are nitrogen, G is carbon, x is 0, and Ri and R3 are not joined to form a cycloalkyl ring. Such compounds satisfy Formula Ed:
Figure imgf000020_0003
Formula πd Further compounds and salts of Formula II are isothiazoles or isoxazoles in which x is 0, A is sulfur or oxygen, G and E are carbon; and Ri and R3 are not joined to form a cycloalkyl ring. Such compounds satisfy Formula He or Il :
Figure imgf000021_0001
Formula Ilf
Additional compounds and salts of Formula II are pyridines in which x is 1, A, B, E, and G are carbon, and Ri and R3 are not joined to form a cycloalkyl ring. Such compounds satisfy Formula Ilg:
Figure imgf000021_0002
Formula Ilg
Still further compounds and salts of Formula π are pyrimidines or pyridizines in which x is 1, either A or B is nitrogen, and E and G are carbon. Such compounds satisfy Formula Ilh or Iii.
Figure imgf000021_0003
Formula Ilh
Figure imgf000021_0004
Formula ffi Compounds and salts of Formula II also include those in which Ri and R3 are joined to form a cycloalkyl ring. Certain such compounds are illustrated by Formula Uj, in which x is 0; y is 1, A and G are carbon, and E is nitrogen. X, in Formula IIj, represents from 1 to 4 optional substituents independently chosen from hydroxy, halogen, cyano, Cι-C2alkyl, - C2alkoxy,
Figure imgf000021_0005
and Cι-C2haloalkoxy, and a is 1, 2 or 3
Figure imgf000021_0006
Formula IIj
Within certain embodiments, compounds and salts of Formula II and subformulas thereof satisfy one or more of the following:
- z is 1 ; R5 is hydrogen; and R6 is hydrogen, methyl, or ethyl.
- z is 1; R5 is hydrogen; R6 is hydrogen, methyl, or ethyl; and Ari is phenyl, pyrazolyl, or thienyl, each of which is optionally substituted with 1 or 2 groups independently chosen from halogen, hydroxy, Cι-C2alkyl, Cι-C2alkoxy, Cι-C2haloalkyl, and -
C2haloalkoxy.
- z is 1; R5 and R6 are hydrogen; and Ari is unsubstituted phenyl, unsubstituted pyrazolyl, or unsubstituted thienyl.
Representative Ri groups include phenyl substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH2, -
SO2NH2, Ci-Cβ haloalkyl, Cι-C6 haloalkoxy, Cι-C6 alkyl, Cι-C6alkoxy, l,3-dioxol-5-yl, Ci-
C6alkanoyl, Cι-C6alkylsulfonyl, Cι-C6alkylsulfinyl, Cι-C6alkylthio, C2-C6alkanone; - C6alkanoyl; C2-C6alkyl ether; Cι-C6 alkanoyloxy; Cι-C6alkoxycarbonyl, and -
C6alkylcarboxamide. For example, Ri may be phenyl substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH2, -
SO2NH2, Cι-C2 haloalkyl, Cι-C2 haloalkoxy, Cι-C2alkyl, and Cι-C2alkoxy. In certain embodiments, Ri is unsubstituted phenyl. Additional representative Ri groups include thienyl and pyridyl, each of which is substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH2, -SO2NH2, Cι-C2 haloalkyl, Cι-C2 haloalkoxy, Cι-C2alkyl, and Cι-C2alkoxy. In other embodiments, Ri is hydrogen, halogen, Ci-C4alkyl, Cι-C alkoxy, cyano, trifluoromethyl, pentafluoroethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, Cι-C2alkylaminoC!- C2alkyl, hydroxymethyl, and hydroxyethyl.
Representative R2 groups include hydrogen, propyl, butyl, pentyl and 3-methylbutyl;
R2 is preferably hydrogen when Ari is alkyl-substituted phenyl, pyrazolyl or phenyl, and E is carbon.
Representative R groups include hydrogen and Ct-Csalkyl. R4, within certain embodiments, is Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-
C7cycloalkyl, C3-C7cycloalkenyl, (C3-C7cycloalkyl)Cι-C alkyl, (C3-C7cycloalkenyl)Cι-
C4alkyl, or hexahydro-l,3-benzodioxolylmethyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydrogen, hydroxy, halogen, amino, cyano, -
C2alkyl, Cι-C2alkoxy, and Cι-C2alkoxycarbonyl. Certain such R groups are unsubstituted, such as cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexylmethyl, cyclohexenylmethyl, cyclhexenyl, or hexahydro-l,3-benzodioxolylmethyl. In other embodiments, R4 is: a) aryl or aryl(Co-C2)alkyl having 1 or 2 fused or pendant rings, b) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, c) saturated or partially unsaturated heterocycle(Co- C alkyl) having 1 or 2 fused or pendant rings, from 5- to 7-members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S or d) heteroaryl or heteroaryl(Cι- C2alkyl) having 1 or 2 fused or pendant rings, from 5- to 7-members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, wherein each of a), b), c), and d) are substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH2, -SO2NH2, oxo, Cι-C6 haloalkyl, Cι-C6 haloalkoxy, Cι-C6 alkyl, Cι-C6alkoxy, Cι-C6alkanoyl, Cι-C6sulfonate, Cι-C6alkylsulfonyl, Cι-C6alkylsulfinyl, Cι-C6alkylthio, Cι-C6alkanone, C2-C6alkyl ether, Cι-C6 alkanoyloxy, Cι~C6alkoxycarbonyl, and Cι-C6alkylcarboxamide. For example, R4 may be optionally substituted benzyl. Alternatively, R4 may be pyridylmethyl, pyrimidylmethyl, thienylmethyl, napthylmethyl, indolylmethyl, benzoxadiazolylmethyl (e.g., benzoxadiazol-5-ylmethyl), benzooxazolylmethyl, benzothiazolyl, quinazolinylmethyl, or benzimidazolylmethyl, each of which is substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, Cι-C2haloalkyl, CpC2haloalkoxy, -C2 alkyl, mono- or di-(Cι-C2)alkylamino, and Cι-C2alkoxy. In further embodiments, is l,3-benzodioxol-5-ylmethyl, 2,3-dihydro-l- benzofuran-6-ylmethyl, 2,3-dihydro-l-benzofuran-5-ylmethyl, 2,3-dihydro-l,4-benzodioxin- 6-ylmethyl, chroman-6-ylmethyl, chroman-7-ylmethyl, 1,3-benzothiazolylmethyl, 2,3- dihydroindol-5-ylmethyl, each of which is substituted with from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, Cι-C2haloalkyl, - C2haloalkoxy, Cι-C2 alkyl, mono- or di-(Cι-C2)alkylamino, and Cι-C2alkoxy. In certain embodiments in which R4 is heteroaryl or heteroaryl(Cι-C2alkyl), the heteroaryl group is pyridyl, pyrimidyl, thienyl, naphthyl, indolyl, benzoxadiazolyl, benzoxazolyl, quinazolinyl, or benzimidazolyl, each optionally substituted with from 1 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, Cι-C2haloalkyl, Cι-C2haloalkoxy, Cι-C2 alkyl, and - C2alkoxy.
Representative Ar groups include C3-C7cycloalkyl (e.g., cyclopentyl or cyclohexyl), C3-C7cycloalkenyl (e.g., cyclohexenyl), (C3-C7cycloalkyl) Cι-C4alkyl, (C3- C7cycloalkenyl)Cι-C4alkyl, and hexahydro-l,3-benzodioxolyl, each of which is optionally substituted with from 0 to 3 groups independently chosen from hydrogen, hydroxy, halogen, amino, cyano, Cι-C2alkyl, Cι-C2alkoxy, or Cι-C2alkoxycarbonyl. Further Ar2 groups include phenyl substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH2, -SO2NH2, oxo, Cι-C6haloalkyl, Cι-C6haloalkoxy, Q- C6alkyl, -Cealkoxy, mono- and di-(Cι-C6alkyl)amino, Cι-C6alkanoyl, Cι-C6alkylsulfonyl, C!-C6alkylsulfinyl, Cι-C6alkylthio, C2-C6alkanone, C2-C6alkylether, Ci-Cδalkanoyloxy, - Cδalkoxycarbonyl, Ci-Cealkylcarboxamide, C2-C6cycloalkylamino, and C2- C6cycloalkylamino(Cι-C4alkyl). Still further Ar2 groups include pyridyl, pyrimidyl, thienyl, naphthyl, indolyl, benzoxadiazolyl (e.g., benzoxadiazol-5-yl), benzoxazolyl, quinazolinyl, and benzimidazolyl, each of which is substituted with from 0 to 2 groups independently chosen from hydroxy, halogen, amino, cyano, Cι-C2haloalkyl, Cι-C2haloalkoxy, Cι-C2alkyl, mono- or di-(C1-C2alkyl)amino, Cι-C2alkoxy, and C2-C6cycloalkylamino. Additional representative Ar2 groups include phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon, or a heteroaryl or heteroaryl(Cι-C2alkyl) group, having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, each of which is substituted with from 0 to 4 groups independently chosen from hydroxy, halogen, amino, cyano, nitro, -COOH, -CONH2, -SO2NH2, oxo, Ci- C6haloalkyl, Ci-Cβhaloalkoxy, Cι-C6alkyl, Cι-C6alkoxy, Cι-C6alkanoyl, Cι-C6sulfonate, - C6alkylsulfonyl, Ci-Cβalkylsulfinyl, Cι-C6alkylthio, C2-C6alkanone, C2-C6alkyl ether, Cι-C6 alkanoyloxy, Ci-Cealkoxycarbonyl, and Cι-C6alkylcarboxamide. For example, the phenyl group fused to a 5- to 7-membered saturated or partially unsaturated ring may be 1,3- benzodioxol-5-yl, 2,3-dihydro-l-benzofuran-6-yl, 2,3-dihydro-l-benzofuran-5-yl, 2,3- dihydro-l,4-benzodioxin-6-yl, chroman-6-yl, chroman-7-yl, 1,3-benzothiazolyl, or 2,3- dihydroindol-5-yl, each of which is substituted with from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, Cι-C2haloalkyl, Cι-C2haloalkoxy, Cι-C2 alkyl, and Cι-C2alkoxy.
Formulas Ilk-IIp represent additional subformulas of compounds within the scope of Formula II.
Formula III
Figure imgf000024_0001
Formula Hm Formula Iln
Figure imgf000025_0001
Formula Ho Formula up
Within Formulas Ilk-Hp, R is C3-C5 alkyl; R3 is hydrogen or methyl; R5 is hydrogen or methyl; R7 represents from 0 to 3 substituents independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy; R8 represents from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, -CONH2, - OC(=O)CH3, -COOH, methylthio, ethylthio, and -SO2CH3; R and Rio may occur at any position on the benzo[l,3]dioxole or 2,3-Dihydro-benzo[l,4]dioxine group available for substitution and represent from 0 to 3 substituents independently chosen from halogen, methyl, and methoxy; Ru and Rι2 independently represent from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, -CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, - OCF2CHF2, -CONH2, -C(=O)OCH3, -OC(=O)CH3, -COOH, methylthio, ethylthio, -SO2NH2, and -SO2CH3.
[REDO AND EXPAND THE FORMULA in SECTION AFTER COMPLETING 3003 CLAIMS]
The present invention further comprises combinations in which the C5a receptor antagonist is a compound of Formula III:
Figure imgf000025_0002
Formula III or a pharmaceutically acceptable salt thereof, wherein: x is 1, 2, or 3.
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyano, amino, nitro, -COOH, carboxamide, optionally substituted mono or di-alkyl amino, optionally substituted haloalkyl, and optionally substituted haloalkoxy. R1 for compounds of Formula I is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, and optionally substituted indanyl.
R , R , and R are independently selected at each occurrence from the group consisting of hydrogen, optionally substituted alkyl, halogen, and optionally substituted alkoxy.
R5 and R6 are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, hydroxy, amino, mono or dialkyl amino, and cyano.
R7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or optionally substituted arylalkyl. Ar1 is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted biphenyl, optionally substituted heterocyclic group, or and optionally substituted phenyl group fused to a 5 to 7 membered saturated or partially unsaturated ring, said saturated or partially unsaturated ring having from 5 to 7 ring atoms, with 0, 1, or 2 ring atoms chosen from N, O, and S with remaining ring atoms being carbon. Alternatively, Ar1 is taken in combination with CR7 (CR7Ar1), to form an optionally substituted group of the formula:
Figure imgf000026_0001
wherein p is an integer from 1 to about 3.
Ar" is optionally substituted aryl or optionally substituted heteroaryl having about 5 to
7 ring atoms and between 1 and 3 ring heteroatoms selected from N, O, and S. Other C5a antagonists for use in the combination provided by the invention include compounds of Formula IV:
O
Ar1^N'Rl
R Formula IV or a pharmaceutically acceptable salt thereof.
Ar1 is, in Formula IV: i) optionally substituted phenyl having at least one optionally substituted phenyl or optionally substituted heterocyclic substituent attached thereto; ii) optionally substituted carbocycle having from 2 to about 4 partially unsaturated or aromatic rings, 3 to 8 members in each ring, or iii) optionally substituted heteroaryl.
R1 in formula IV is optionally substituted cycloalkyl, optionally substituted
(cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted (aryl)alkyl, optionally substituted aryl, optionally substituted heteroaryl having about 5 to 7 ring atoms and between 1 and 3 ring heteroatoms selected from N, O, and S, or optionally substituted
(aryl)alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 2 substituents independently chosen from halogen, alkyl and alkoxy. R2 in Formula IV is alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, or indanyl, each of which is optionally substituted, or R2 is optionally substituted phenyl(Co-C2alkyl), wherein the phenyl portion is fused to a 5 to 7 membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy. For example, in certain embodiments R2 is indanyl, (aryl)alkyl, or cycloalkyl, each of which is optionally substituted.
In certain embodiments of compounds of Formula IV:
Ar1 is selected from: i) phenyl having at least one phenyl substituent or heterocyclic substituent attached thereto, wherein each phenyl, phenyl substituent, or heterocyclic substituent is substituted with from 0 to 4 substituents independently selected from halogen, amino, cyano, hydroxy, Cι-C alkyl, Cι-C4alkoxy, Cι-C2 haloalkyl, Cι-C2 haloalkoxy, mono- and di-Cι-C4alkylamino, Cι-C2 alkylthio, and -NHC(=O) Cι-C2 alkyl; ii) naphthyl substituted with from 1 to 3 substituents independently selected from halogen, amino, cyano, hydroxy, Cι-C4alkyl, Cι-C4alkoxy, Cι-C2 haloalkyl, Cι-C2 haloalkoxy, mono- and di-Cι-C4alkylamino, -C2 alkylthio, -NHC(=O) Cι-C2 alkyl, optionally substituted phenyl, and optionally substituted thienyl; and iii) 9h-fluorenyl susbstituted with from 0 to 3 substituents independently selected from halogen, amino, cyano, hydroxy, Cι-C4alkyl, Cι-C4alkoxy, Ci-C2 haloalkyl, Cι-C2 haloalkoxy, mono- and di-Cι-C4alkylamino, Cι-C2 alkylthio, -NHC(=O) Cι-C2 alkyl; and iv) heteroaryl substituted susbstituted with from 0 to 3 substituents independently selected from halogen, amino, cyano, hydroxy, Cι-C4alkyl, Cι-C alkoxy, Ci-C2 haloalkyl, Ci- C2 haloalkoxy, mono- and di-C1-C4alkylamino, Cι-C2 alkylthio, -NHC(=O) Cι-C2 alkyl; R s: i) (heteroaryl)Co-C alkyl or (aryl) Co-C4alkyl, each of which is substituted with from 0 to
3 substituents independently selected from halogen, hydroxy, nitro, cyano, Cι-C alkyl, C2-C4alkenyl, C2-C4alkynyl, Cι-C4alkoxy, Cι-C4alkylthio, -NC(=O)Cι-C2alkyl, mono- and di(Cι-C2alkyl)amino, C2-C3alkanoyloxy, Cι-C3alkoxycarbonyl, Cι-C2 haloalkyl, Cι-C2haloalkoxy, thienyl, and phenyl; or ii) (aryl)Cι-C4alkyl substituted with from 0 to 5 substituents independently chosen from halogen, hydroxy, Cι-C2 alkyl, Cι-C2 alkoxy, Cι-C haloalkyl, and Cι-C2haloalkoxy, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and
S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C alkyl and Cι-C alkoxy; and
R2 is selected from C3-C7 cycloalkyl, (C3-C7cycloalkyl)Cι-C alkyl, (heteroaryl)Cι-C4alkyl,
(aryl)Cι-C alkyl, and indanyl; each of which is substituted with from 0 to 5 substituents independently selected from halogen, hydroxy, Cι-C4 alkyl, Cι-C4 alkoxy, Cι-C alkylthio, -NC(=O)Cι-C2alkyl, Cι-C2haloalkyl, Cι-C2haloalkoxy, thienyl, and phenyl.
Certain compounds and salts of Formula IV satisfy Formula IVa:
Figure imgf000028_0001
Formula IVa wherein:
Ar1 is: i) phenyl substituted with from 0 to 4 substituents independently selected from halogen, hydroxy, Cι-C4alkyl, Cι-C4alkoxy, Cι-C2 haloalkyl, Cι-C haloalkoxy, Cι-C2alkylthio, and -NHC(=O) Cι-C2 alkyl, and substituted at the 2-position relative to the point of attachment with phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, naphthyl, thiazolyl, or pyrimidinyl, each of which is substituted with from 0 to 3 substituents independently selected from halogen, amino, cyano, hydroxy, - alkyl, Cι-C4alkoxy, Cι-C2 haloalkyl, Ci- C2haloalkoxy, mono- and di-Cι-C4alkylamino, Cι-C2 alkylthio, and -NHC(=O) Cι-C2 alkyl, or ii) naphthyl substituted with from 1 to 3 substituents independently selected from (a) halogen, amino, cyano, hydroxy, Cι-C4alkyl, Cι-C4alkoxy, Cι-C2haloalkyl, Cι-C2 haloalkoxy, mono- and di-Cι-C4alkylamino, Cι-C alkylthio, and -NHC(=O) Ci- C2 alkyl, and (b) phenyl and thienyl, each of which is substituted with from 0 to 3 substitutents indpendenlty chosen from halogen, Cι-C2alkyl, Cι-C2alkoxy, Ci- C2haloalkyl, and Cι-C2haloalkoxy; or iii) 9H-fluorenyl substituted with from 0 to 3 substituents independently selected from halogen, amino, cyano, hydroxy, Cι-C4alkyl, Cι-C4alkoxy, Cι~C2haloalkyl, Cι-C2 haloalkoxy, mono- and di-Cι-C4alkylamino, Cι-C2alkylthio, and
-NΗC(=O) Cι-C2 alkyl; or iv) heteroaryl substituted with from 0 to 3 substituents independently selected from halogen, amino, cyano, hydroxy, Cι-C4alkyl, Cι-C alkoxy, Cι-C2haloalkyl, Cι-C2 haloalkoxy, mono- and di-Cι-C4alkylamino, Cι-C2alkylthio, and -NHC(=O) Cι-C2 alkyl;
Ar2 is: i) phenyl, ii) naphthyl, iii) a heterocycle having 1 or 2 rings, 3 to 8 atoms in each ring, and 1 to 3 heteroatoms independently selected from N, O, and S; or iv) phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S, with remaining ring atoms being carbon; wherein each of i), ii), iii), and iv) is substituted with from 0 to 5 substituents independently selected from halogen, hydroxy, Cι-C4alkyl, Cι-C alkoxy, Cι-C2 haloalkyl, Cι-C2 haloalkoxy, CrC2 alkylthio, and-NHC(=O) Cι-C2 alkyl; R2 is selected from C3-C7 cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, (heteroaryl)Cι-C4alkyl, (aryl)C1-C4alkyl, and indanyl; each of which is substituted with from 0 to 3 substituents independently selected from halogen, hydroxy, -C4 alkyl, Cι-C4alkoxy,
Cι-C4alkylthio, -NC(=O)Cι-C2alkyl, Cι-C2 haloalkyl, Cι-C2haloalkoxy, thienyl, and phenyl; and R and R are independently selected from hydrogen, hydroxy, amino, cyano, halogen, C1-C4 alkyl, C2-C alkenyl, and C2-C alkynyl. Further compounds and salts of Formula IV satisfy Formula IVb:
Figure imgf000029_0001
Formula IVb wherein:
Ar3 is phenyl, pyridyl, furanyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, naphthyl, thiazolyl, or pyrimidinyl, each of which is substituted with from 0 to 3 substituents independently selected from halogen, hydroxy, amino, cyano, Cι-C4alkyl,
Cι-C4alkoxy, mono- and di-(Cι-C4alkyl)amino, Cι-C2 haloalkyl, Cι-C2haloalkoxy, -
C2 alkylthio, and -NHC(=O) -C2 alkyl;
R6 represents from 0 to 4 substituents independently selected from halogen, hydroxy, - C4alkyl, Cι-C4alkoxy, Cι-C2haloalkyl, Cι-C2haloalkoxy, Cι-C2alkylthio, and - NHC(=O) C1-C2 alkyl; and R1 and R2 are as described for Formula IV.
For example, certain such compounds satisfy Formula IVc:
Figure imgf000030_0001
Formula IVc wherein Z1 is carbon or nitrogen; Z2, Z3, and each occurrence of Z4 are independently selected from CR7, NR8, S, and O such that each S or O ring atom, if any, is disposed between two CR 7 groups; p is an integer ranging from 1 to about 3; R fι represents from 0 to 4 substituents independently selected from halogen, hydroxy, Cι-C4alkyl, Cι-C4alkoxy, Ci- C2haloalkyl, CrC2haloalkoxy, Cι-C2 alkylthio, and -NHC(=O)C!-C2 alkyl; R7 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, Ci- C6alkyl, Cι-C6alkoxy, Cι-C6haloalkyl, Cι-C6haloalkoxy, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, mono-and di-(Cι-C6alkyl)amino, cyano, nitro, and Cι-C6alkanoyl; and R8 is independently selected at each occurrence from hydrogen, amino, Cι-C6alkyl, Cι-C6alkoxy, Cι-C6haloalkyl, Cι-C6haloalkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, and Ci- C6alkanoyl.
Further such compounds satisfy Formula IVd or IVe:
Figure imgf000030_0002
Formula IVe wherein R2 is as described for Formula IV; R3, R4 and Ar2 are as described for Formula IVa; and Z1, Z2, Z3, Z4, p, and R6 are as described for Formula IVc;
R is: (i) halogen, hydroxy, Cι-C3haloalkyl, or Cι-C3haloalkoxy;
(ii) Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Cι-C6alkoxy, mono- or di-(Cι~
C6alkyl)amino, or C3-C cycloalkyl(Co-C4alkyl), each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, Cι-C4alkyl, Cι-C alkoxy, Cι-C2haloalkyl, Cι-C2haloalkoxy, and mono- and di(Cι-C )alkylamino;
(iii) phenyl;
(iv) a heterocyclic ring, having from 4 to 8 ring atoms, and 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of (iii) and (iv) is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, Cι-C6alkyl, Cι-C6alkoxy, mono- and di-Cι-C6alkylamino, mono- and di-Cι-C6alkylaminoCι-C6alkyl, Cι-C6haloalkyl, - C6haloalkoxy, -C2 alkylthio, and -NHC(=O)C!-C2 alkyl; and
R5 and R6 each represent 0 or more substituents independently chosen from halogen, hydroxy, cyano, nitro, amino, Cι-C6alkyl, C2-C6alkenyl, Cι-C6alkynyl, Cι-C6alkoxy, mono- and di-(Cι-C6)alkylamino, -Cshaloalkyl, Cι-C3haloalkoxy, Cι-C2alkylthio, and -NHC(=O) Cι-C2 alkyl. Other compounds and salts for use in the combinations provided herein are compounds of Formula V:
Figure imgf000031_0001
Formula V and the pharmaceutically acceptable salts thereof.
In Formula V, m represents a carbon chain that may be substituted with hydrogen, halogen, cyano, nitro amino, mono or dialkyl amino, alkenyl, alkynyl, alkoxy, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, or cycloalkyl. and n is 1, 2, or 3.
Ari, Ar2, and Ar3 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Ri represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH2), mono or dialkylaminocarbonyl, sulfonamido, and mono or dialkylsulfonamido. The invention includes combinations in which the C5a receptor is a compound of Formula VI:
Figure imgf000031_0002
Formula VI or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In Formula VI, m is 0, 1, 2, or 3, and m represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydroxy, halogen, or amino; n is
0, 1, 2, or 3, and n represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydroxy, halogen, or amino. Ri represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, and(cycloalkyl)alkyl.
R2 is i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl) alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, mono- or dialkylamino.
Ari is ethylenedioxyphenyl, methylenedioxyphenyl, or optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Ar2 is carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds for use in the combinations provided herein exhibit an IC50 of about 500 nM or less in such a standard C5a receptor-mediated chemotaxis, radioligand binding, and/or calcium mobilization assay, more preferably an IC50 of about 250 nM or less in such an assay, still more preferably an IC50 of about 200, 150, 100, 50, 25, 10, or 5 nM or less in such an assay. Such assays are provided in Examples 5, 7 and 8.
Certain preferred compounds further have favorable pharmacological properties, including oral bioavailability (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose, preferably less than 2 grams, more preferably of less than or equal to one gram, can provide a detectable in vivo effect such as a reduction of C5a-induced neutropenia), ability to inhibit leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations, low toxicity (a preferred compound is nontoxic when a C5a receptor-modulatory amount is administered to a subject), minimal side effects (a preferred compound produces side effects comparable to placebo when a C5a receptor- modulatory amount of the compound is administered to a subject), low serum protein binding, and a suitable in vitro and in vivo half -life (a preferred compound exhibits an in vitro half-life that is equal to an in vivo half-life allowing for Q.I.D. dosing, preferably T.I.D. dosing, more preferably B.I.D. dosing, and most preferably once-a-day dosing). Distribution in the body to sites of complement activity is also desirable (e.g., compounds used to treat CNS disorders will preferably penetrate the blood brain barrier, while low brain levels of compounds used to treat periphereal disorders are typically preferred).
Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, such as Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays, such as those described by Oravcova, et al. (1996) Journal of Chromatography B 677:1-21. Compound half-life is inversely proportional to the frequency of dosage of a compound required to achieve an effective amount. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition 26: 1120-27.
Toxicity and side effects may be assessed using any standard method. In general, the term "nontoxic" as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans). Toxicity may be also evaluated using the assay detecting an effect on cellular ATP production. Other assays that may be used include bacterial reverse mutation assays, such as an Ames test, as well as standard teratogenicity and tumorogenicity assays. Preferably, administration of compounds provided herein at certain doses (i.e., doses yielding effective in vivo concentrations) does not result in prolongation of heart QT intervals (i.e., as determined by electrocardiography in guinea pigs, minipigs or dogs). When administered daily for five or preferably ten days, such doses also do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 100%, preferably not more than 75%, and more preferably not more than 50% over matched controls in laboratory rodents (e.g., mice or rats). Such doses also preferably do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls in dogs or other non-rodent mammals.
Certain preferred compounds also do not promote substantial release of liver enzymes (e.g., ALT, LDH or AST) from hepatocytes in vivo. Preferably the above doses do not elevate serum levels of such enzymes by more than 100%, preferably not by more than 75%, and more preferably not by more than 50% over matched untreated controls in vivo in laboratory rodents. Similarly, concentrations (in culture media or other such solutions that are contacted and incubated with cells in vitro) equivalent to two-fold, preferably five-fold, and most preferably ten-fold the minimum in vivo therapeutic concentration do not cause detectable release of any of such liver enzymes from hepatocytes in vitro into culture medium above baseline levels seen in media from untreated cells.
In certain embodiments, preferred compounds exert their receptor-modulatory effects with high specificity. This means that they only bind to, activate, or inhibit the activity of certain receptors other than C5a receptors with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar. The invention also includes highly specific C5a receptor modulatory compounds that exhibit 200-fold greater affinity for the C5a receptor that for other cellular receptors. Such receptors include neurotransmitter receptors such as alpha- or beta-adrenergic receptors, muscarinic receptors (particularly ml, m2 or m3 receptors), dopamine receptors, and metabotropic glutamate receptors; as well as histamine receptors and cytokine receptors (e.g., interleukin receptors, particularly IL-8 receptors). Such receptors may also include GABAA receptors, bioactive peptide receptors (other than C5a receptors and C3a receptors, including NPY or VIP receptors), neurokinin receptors, bradykinin receptors, and hormone receptors (e.g., CRF receptors, thyrotropin releasing hormone receptors or melanin-concentrating hormone receptors). Compounds that act with high specificity generally exhibit fewer undesirable side effects.
Within certain embodiments, modulators provided herein do not bind detectably to receptors that do not mediate inflammatory responses, such as GABA receptors, MCH receptors, NPY receptors, dopamine receptors, serotonin receptors and VRl receptors, with high or even moderate affinity. In addition, or alternatively, certain preferred C5a receptor modulators exhibit an affinity for C5a receptor that is substantially higher than for receptors that do not mediate inflammatory responses (e.g., at least five times higher, at least ten times higher or at least 100 times higher). Assays for evaluating binding to receptors that do not mediate inflammatory responses include, for example, those described in US patent 6,310,212, which is incorporated herein by reference for its disclosure of a GABAA receptor binding assays in Examples 14, columns 16-17, in US patent application no. 10/152,189 which is incorporated herein by reference for its disclosure of an MCH receptor binding assay in Example 2, pages 104-105, in US patent 6,362,186, which is incorporated herein by reference for its disclosure of CRF1 and NPY receptor binding assays in Examples 19, columns 45-46, in US patent 6,355,644, which is incorporated herein by reference for its disclosure of a dopamine receptor binding assay at column 10, and in US patent 6,482,611, which is incorporated herein by reference for its disclosure of VRl receptor binding assays in Examples 4-5, column 14. It will be apparent that the C5a receptor modulators provided herein may, but need not, bind to one or more other receptors known to mediate inflammatory responses, such as C3a receptors and/or A3 receptors.
Certain preferred compounds are C5a receptor antagonists that do not possess significant (e.g., greater than 5%) agonist activity in any of the C5a receptor-mediated functional assays discussed herein. Specifically, this undesired agonist activity can be evaluated, for example, in the GTP binding assay of Example 6, by measuring small molecule mediated GTP binding in the absence of the natural agonist, C5a. Similarly, in a calcium mobilization assay (e.g., that of Example 6) a small molecule compound can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist, C5a. The preferred extent of C5a agonist activity exhibited by compounds provided herein is less than 10%, 5% or 2% of the response elicited by the natural agonist, C5a.
Additionally, preferred C5a receptor modulators do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity. Preferred C5a receptor modulators also do not exhibit cytotoxicity in vitro or in vivo, are not clastogenic (e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) and do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells). Also preferred are C5a receptor modulators that inhibit the occurrence of C5a-induced oxidative burst (OB) in inflammatory cells (e.g., neutrophil) as can be conveniently determined using an in vitro neutrophil OB assay.
COMBINATION THERAPY
Within the therapeutic methods provided herein, at least one therapeutic compound that is not a C5a antagonist (i.e., a C5a receptor-inactive therapeutic agent) is administered in combination with at least one C5a antagonist in order to provide a therapeutic effect to a patient suffering from a condition (e.g., disease, disorder or injury) associated with pathogenic inflammation. The C5a antagonist(s) and C5a receptor-inactive agent(s) may be present in the same composition during administration, or may be administered separately, either essentially simultaneously or sequentially in either order. In certain embodiments, the C5a receptor-inactive therapeutic agent(s) are packaged in combination with the C5a antagonist(s). The precise formulation of combinations described herein will vary depending on the disease to be treated, as discussed in more detail below.
COMBINATIONS FOR THE TREATMENT OF ARTHRITIS
In one aspect, the present invention provides combinations useful for the treatment of arthritis, particularly rheumatoid arthritis, comprising a C5a antagonist and a C5a receptor- inactive therapeutic agent that is an anti-arthritic agent (i.e., a C5a receptor-inactive anti- arthritic agent). C5a receptor-inactive therapeutic agents useful in such combinations include, but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and modulators of other enzymes and receptors associated with arthritis. In one embodiment, a C5 antagonist is combined with methotrexate for treatment of rheumatoid arthritis.
In one embodiment, the C5a receptor-inactive therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID). Examples of NSAIDs include, but are not limited to ibuprofen (e.g., ADVIL™, MOTRIN™), flurbiprofen (ANSAID™), naproxen or naproxen sodium (e.g., NAPROXYN, ANAPROX, ALEVE™), diclofenac (e.g., CATAFLAM™, VOLTAREN™), combinations of diclofenac sodium and misoprostol (e.g., ARTHROTEC™), sulindac (CLINORIL™), oxaprozin (DAYPRO™), diflunisal (DOLOBID™), piroxicam (FELDENE™), indomethacin (INDOCIN™), etodolac (LODBSfE™), fenoprofen calcium (NALFON™), ketoprofen (e.g., ORUDIS™, ORUVAIL™), sodium nabumetone (RELAFEN™), sulfasalazine (AZULFIDINE™), tolmetin sodium (TOLECTIN™), and hydroxychloroquine (PLAQUENIL™). In some cases, the C5a receptor-inactive therapeutic agent(s) comprise one or more NSAIDS combined with one or more anti-ulcer agents such as misoprostol (CYTOTEC™). Accordingly, the invention comprises the use of a preparation of diclofenac and misoprostol (e.g., as marketed under the brand name ARTHROTEC™) as the C5a receptor-inactive therapeutic agents.
Certain NSAIDs inhibit cyclooxygenase (COX) enzymes. In one embodiment, at least one C5a receptor-inactive therapeutic agent is a COX-2 specific inhibitor (i.e., a compound that inhibits COX-2 with an IC50 that is at least 50-fold lower than the IC50 for COX-1). Preferably, a COX-2 inhibitor such as celecoxib (CELEBREX™), valdecoxib (BEXTRA™), lumiracoxib (PREXIGE™), etoricoxib (ARCOXIA™) and/or rofecoxib (VIOXX™). In a further embodiment, at least one C5a receptor-inactive therapeutic agent is a salicylate. Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, choline and magnesium salicylates (TRILISATE™), and salsalate (DISALCID™). The C5a receptor-inactive therapeutic agent may also be a corticosteroid. For example, the corticosteroid may be cortisone (CORTONE™ acetate), dexamethasone (e.g., DECADRON™), methylprednisolone (MEDROL™) prednisolone (PRELONE™), prednisolone sodium phosphate (PEDIAPRED™), and prednisone (e.g., PREDNICEN-M™, DELTASONE™, STERAPRED™). Additional coriticosteroids are listed herein in the description of combinations for the treatment of asthma.
In further embodiments, at least one C5a receptor-inactive therapeutic agent is a gold compound such as gold sodium thiomalate (MYOCHRYSINE™) or auranofin (RID AURA™). The invention also includes embodiments in which the C5a receptor- inactive therapeutic agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate (e.g., RHEUMATREX™, TREXALL™) or a dihydroorotate dehydrogenase inhibitor, such as leflunomide (ARAVA™). In other embodiments for the treatment of joint disease, at least one C5a receptor-inactive therapeutic agent is a joint lubricant such as sodium hyaluronate (HYALGAN™ or SYNVISC™). Other embodiments of the invention are directed to combinations in which that least one C5a receptor-inactive therapeutic agent is an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine (NEORAL™, SAND MUNE™), tacrolimus (PROGRAF™), azathioprine (EVIURAN™), or mycophenolate mofetil (CellCept™).
Still other embodiments of the invention are directed to combinations in which at least one C5a receptor-inactive therapeutic agent is:
• an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab);
• a TNF antagonist, such as entanercept (ENBREL™), which is an injectible fusion protein consisting of the extracellular domain of the TNF receptor and the Fc portion of human IgGl, adalimumab (MUNTRA™), the humanized antibody CDP-571 (HUMICADE™; WO 92/11383), the anti-TNF humanized antibody fragment CDP-870 (WO 01/94585), or infliximab (REMICADE™), which is an anti-TNF alpha monoclonal antibody;
• a modulator of TNF-alpha induced inflammatory genes, such as AGIX-4207
(AtheroGenics, Inc.); • an antisense oligonucleotide specific for TNFα mRNA such as ISIS 104838 (Isis
Pharmaceuticals, Inc.);
• a natural product such as RA- 1 ;
• an IL-1 receptor antagonist, such as anakinra (KINERET™) or AMG-719
(Amgen); • IL-1 receptor, type I or type II, such as SIL-lr2 (Amgen); • an IL-1 trap, such as Regeneron's IL-1 trap;
• an IL-6 receptor antagonist, such as the humanized anti-IL-6 receptor monoclonal antibody Altizumab (WO 92/19759);
• an anti IL-12 antibody, such as the human anti-DL-12 monoclonal antibody J695 (Abbott Laboratories);
• an IL-15 antagonist such as the human anti-IL-15 monoclonal antibody HuMax
IL-15 (Genmab);
• a B-cell targeted chimeric monoclonal antibody such as Rituximab
(RITUXAN™); • a cytotoxic T lymphocyte antigen 4 immunoglobulin such as CTLA4Ig (BMS-
188667; EP 00613944);
• an inhibitor of p38 mitogen-activated protein (MAP) kinase such as AMG-548,
BIRB-796, VX-702, VX-850, VX-745, SCIO-469, SCIO-323, or GXK- 681323; • an integrin antagonist such as GSK-683699;
• a TNF alpha converting enzyme (TACE) inhibitor such as BMS-561392;
• an inhibitor of IKappaB kinase (IKK), phospholipase A2 or an LCK-selective tyrosine kinase;
• a CCR3 receptor antagonist such as DPC-168 or GXK-766994; • an ICE inhibitor such as VX-740.
COMBINATIONS FOR THE TREATMENT OF LUNG DISORDERS
Certain compositions and methods provided herein are useful for the treatment of respiratory diseases, such as respiratory distress syndrome and asthma. For asthma therapy, combinations provided herein may be used to prevent or decrease the severity of both acute early phase asthma attack and the late phase reactions that follow such an asthma attack. C5a receptor-inactive therapeutic agents useful for the treatment of asthma include anti-thrombin agents, which reduce bronchoconstriction by inhibiting the release of calcium and proliferation of smooth muscle cells, adrenergic receptor agonists, particularly Beta adrenergic receptor agonists; methylxanthines such as theophylline (e.g., AEROLATE SR™, AEROLATE JR™ THEO-DUR™, UNI-DUR™ or UNIPHYL™); corticosteroids; leukotriene modifiers such as zafirlukast (e.g., ACCOLATE™) and zileuton (e.g., ZYFLO™, or FILMTAB™); anticholinergics such as ipratropium bromide (e.g., ATROVENT™, COMBIVENT™, DUONEB™); phosphodiesterase 4 (PDE4) inhibitors such as cilomilast (ARIFLO™); and cromolyn sodium (e.g., NASALCROM™), which act by stabilizing mast cells and reducing the release of cellular mediators. Representative corticosteroids include, but are not limited to betamethasone (e.g., Celestone™), beclomethasone dipropionate (e.g., VANCERIL™, QVAR™), budesonide (e.g., PULMICORT™), cortisone (e.g., CORTONE ACETATE™), dexamethasone (e.g., DEXASONE™), fluticasone propionate, (e.g., ADVAIR™, FLOVENT™) hydrocortisone, ethylprednisolone (e.g., MEDROL™), flunisolide (AEROBID™), prednisolone (e.g., PREDALONE™, PRELONE™), prednisone (e.g., CORDROL™, DELTASONE™, STERAPRED™, STERAPRED DS™ ), and triamcinolone (AZMACORT™). Additional coriticosteroids are listed herein in the description of combinations for the treatment of arthritis. Preferred Beta adrenergic receptor agonists are Beta-2 adrenergic receptor agonists.
The Beta agonist may be a long or short acting Beta adrenergic receptor agonist. Examples of Beta adrenergic receptor agonists include, but are not limited to, albuterol (e.g PROVENTIL™, VENTELIN™), bitolterol, epinephrine (e.g., PR ATENE™ ADRENALIN CHLORIDE, BRONCAID MIST), fenoterol (e.g., FORADIL™), formoterol isoetharine, isoproterenol, metaproterenol sulfate (e.g., ALUPENT™), pirbuterol (e.g. MAXAIR), procaterol, racepinephrine, salmeterol xinafoate (e.g., ADVAIR DISKUS™ SEREVENT DISKUS™) and terbutaline (e.g., BRETHINE™).
COMBINATIONS FOR THE TREATMENT OF SKIN INJURY AND DISEASE
The present invention further provides combinations useful for the treatment of T cell- mediated inflammatory diseases such as psoriasis. The C5a receptor-inactive therapeutic agent(s) may inhibit the hyperfunctional proliferation of epidermal cells; inhibit the inflammatory response; promote immunomodulation; and/or inhibit infection by bacteria and fungi. Included in the invention are combinations in which the C5a receptor-inactive therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID), such as the non- specific nonsteroidal anti-inflammatory agents, COX-2 specific and salicylates listed above. The present invention includes combinations in which the C5a receptor-inactive therapeutic agent is a steroid (e.g., corticosteroid such as clobetasol propionate (e.g., TEMOVATE™), coal tar, a moisturizer, calendula plant extract, theophylline (which arrests the proliferation of cells during the metaphase stage of cell division; e.g., SLO-PHYLLIN™ or THEO-DUR SPRINKLE™), anthralin (a synthetic derivative of a tree bark extract; e.g., DRITHOCREME™, DRITHO-SCALP™ or MICANOL™), calcipotriene (a synthetic vitamin D-3 analog that regulates skin cell production; e.g., CALCIOPTRIOL™ or DOVONEX™), dithranol, an angiogenesis inhibitor such as ganglioside GM3 or a GM3 analog, a phospholipase A2 inhibitor such as an n-deacetyl-lysoganglioside derivative, hydroxyurea, sulfasalazine, 6-thioguanine, betamethasone valerate, mycophenolate mofetil, parathyroid hormone or an imidazole antifungal.
Further combinations comprise a C5a receptor-inactive therapeutic agent that is an immunomodulator. Such agents may be included to control the abnormal cornification of epidermal cells and the hyperfunction of leukocyte migration, and include methotrexate (a folic acid antagonist that inhibits DNA synthesis in tissues with high rates of turnover and is immunosuppressive to mononuclear cells), cyclosporine (which inhibits production of interleukin-2, the cytokine responsible for inducing T-cell proliferation), tacrolimus (FK506; e.g., PROGRAF™ or PROTOPIC™), TNF-alpha modulators such as etanercept (e.g., ENBREL™) and infliximab (e.g., REMICADE™), antileukotriene agents, and retinoid Vitamin A derivatives such as tazarotene (e.g., TAZORAC™), etretinate, isotretinoin (e.g., ACCUTANE™), bexarotene, DAB(389)IL-2 (e.g., DENILEUKIN DIFTITOX™) or acitretin (e.g., SORIATANE™).
Combinations provided herein may also be used in the treatment of other skin conditions associated with inflammation, including bullous pemphigoid and lichen planas. Within such compositions, the C5a receptor-inactive agent may be, for example, a steroid such as prednisone, an antibiotic such as tetracycline or dapsone, an immunosuppressant such as azothioprine, or methotrexate.
Still further combinations are useful for promoting healing of burns and wounds. Such compositions are generally formulated for topical administration to a wound or burn site. Any agent that facilitates healing of such conditions may be used as the C5a receptor- inactive therapeutic agent(s) including, for example, antibiotics and growth factors.
COMBINATIONS FOR THE TREATMENT OF OTHER AUTOIMMUNE DISORDERS
The present invention also provides combinations useful for treating autoimmune disorders and pathologic autoimmune responses known to have an inflammatory component including, but not limited to multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, Guillain-Barre Syndrome, lupus erythematosus and irritable bowel syndrome. A C5a receptor-antagonist may be combined with another anti- inflammatory agent to increase the effectiveness the anti-inflammatory agent, or may be combined with a C5a receptor-inactive therapeutic agent suitable for the disease of interest that is not an anti-inflammatory agent. Suitable C5a receptor-inactive therapeutic agents include, for example, steroids as discussed above.
COMBINATIONS FOR THE TREATMENT OF INFECTION
Also provided herein are combinations for use in treating sepsis and other potentially life-threatening infections, including drug-resistant bacterial infections, such as pneumococcal bacteremia, pneumococcal meningitis, nosocomial (hospital-acquired) infections (e.g., Staphylococcus aureus and Enterococcus faecium), Group A streptococci infections, multiple drug-resistant tuberculosis, and infections with other bacteria such as Acinetobacter spp., Enterobacter spp., E. coli, H. influenzae, K. pneumoniae, P. aeruginosa, S. marcescens, S. maltophilia, Bordetella pertussis, Brucella spp., Campylobacter spp., Haemophilus ducreyi, Helicobacter pylori, Legionella spp., Moraxella catarrhalis, Neisseria spp., Salmonella spp., Shigella spp., Yersinia spp., Bacillus spp., E. faecalis, S. pyogenes, and coagulase-negative Staphylococci, Corynebacterium spp., Diphtheroids, Listeria spp., and Viridans Streptococci. Suitable C5a receptor-inactive therapeutic agents for use in such combinations include, for example, antibiotic agents. Representative anti-bacterial antibiotic agents include, for example, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides (e.g., vancomycin), quinolones, tetracyclines, macrolides, and fluoroquinolones. Combinations may be administered after a patient has acquired an infection, or may be administered to a patient considered at risk for such an infection (e.g., post-surgically). COMBINATIONS FOR USE IN MEDICAL PROCEDURES
Certain combinations are provided herein are suitable for use in medical procedures in which foreign material is introduced into a patient. For example, such combinations may be used to prevent or decrease rejection of transplanted organs and tissue grafts, or in hemodialysis or cardiopulmonary bypass surgery. Certain compositions may be used in the treatment of lung inflammation associated with transplantation. C5a receptor-antagonists may be combined with another anti-inflammatory agent to increase the effectiveness the anti- inflammatory agent or combined with a C5a receptor-inactive therapeutic agent that is not an anti-inflammatory agent in order to decrease complications and improve outcome for the patient undergoing the medical procedure. Combinations may also be used to prevent activation of platelets during storage, and thereby decreasing the loss of function and viability known as "platelet storage lesion." Such combinations are typically added to platelets prior to storage.
COMBINATIONS FOR THE TREATMENT OF CARDIO- AND CEREBROVASCULAR DISEASE
Also provided herein are combinations useful for the treatment of cardio- and cerebrovascular disease and reducing the risk of cardio- and cerebrovascular events including myocardial infarction and stroke. Combinations provided herein are useful for preventing or reducing the risk of formation of thrombi and thromboemboli, for preventing or reducing the risk of thrombotic occlusions and reocclusions, for treating, preventing or reducing the risk of a first or subsequent myocardial infarction, for preventing or reducing the risk of restenosis, for treating, preventing or reducing the risk of acute cerebrovascular ischemic events such as a first or subsequent thrombotic stroke or transient ischemic attack, and for halting or slowing the progression of atherosclerotic disease. C5a receptor-inactive therapeutic agents useful in the combinations provided herein for the treatment or cardio- and cerebrovascular disease include, but are not limited to, anti-inflammatories (e.g., non-steroidal anti-inflammatory drugs (NSAIDs) such as the non-specific nonsteroidal anti-inflammatory agents, COX-2 specific and salicylates listed above), antihypertensive agents, platelet inhibitors such as aspirin, ticlopidine, and GP lib/ Ilia antagonists, antihypertensive agents, including adrenergic receptor agonists, alpha/beta adrenergic receptor antagonists, beta adrenergic receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics and periphereal vasodilators, anti-coagulants, thrombolytics, and cholesterol lowering agents such as HMG-CoA reductase inhibitors.
Within certain combinations, the C5a receptor-inactive therapeutic agent is a cholesterol lowering drug. In one embodiment the cholesterol lowering drug is a 3-hydroxy- methyl-glutaryl coenzyme A reductase inhibitor (HMG-CoA RI). Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well- known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR™; see U.S. Pat. No. 4,231,938), simvastatin (ZOCOR™; see U.S. Pat. No. 4,444,784), pravastatin (PRAVACHOL™; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOL™; see U.S. Pat. No. 5,354,772), atorvastatin (LIPITOR™.; see U.S. Pat. No. 6,273,995) and cerivastatin (also known as rivastatin; see U.S. Pat. No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (Feb. 5, 1996). The term HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters and lactone forms is included within the scope of this invention.
In further combinations, the C5a receptor-inactive therapeutic agent is a platelet aggregation inhibitor such as a salicylate as described above; a glycoprotein (GP) πb/IIIa inhibitor, such as tirofiban hydrochloride (AGGRASTAT™), abciximab (REOPRO™), or eptifibatide (INTEGRILIN™); a phosphodiesterase (PDE) inhibitor, such as dipyridimole (PERSANTINE™) or cilostazol (PLETAL™); a compound that reduces megakaryocyte hypermaturation, (e.g., anagrelide, AGRYLIN™); or ADP receptor inhibitor such as clopidogrel bisulfate (PLAVIX™) or ticlopidine hydrochloride (TICLID™).
Within other combinations, the C5a receptor-inactive therapeutic agent is an anti- hypertensive agent. In one such embodiment, the anti-hypertensive agent is an alpha adrenergic receptor antagonist such as phenoxybenzamine hydrochloride (DIBENZYLINE™), doxazosin mesylate (CARDURA™), terazosin hydrochloride (HYTRIN™), or prazosin hydrochloride (MINIPRESS™). In other embodiments, the antihypertensive agent is an adrenergic receptor stimulator.
Such antihypertensive agents may affect adrenergic receptors either directly (adrenergic receptor agonists) or through interaction with a separate receptor or enzyme that affects the activity of adrenergic receptors. Thus, adrenergic receptor stimulators that may be used in' the combinations provided herein include, but are not limited to, methyldopa (ALDOMET™), clonidine hydrochloride (CATAPRES™), and guanfacine hydrochloride (TENEX™).
In still further embodiments, the antihypertensive agent is a non-specific alpha/beta adrenergic receptor antagonist such as carvedilol (COREG™) or labetalol hydrochloride (NORMODYNE™). Within other such embodiments, the antihypertensive agent is an angiotensin converting enzyme (ACE) inhibitor. Suitable angiotensin converting enzyme (ACE) inhibitors include, but are not limited to enalaprilat (VASOTEC™ for injection), enalapril maleate (VASOTEC™), catopril, benazepril hydrochloride (LOTREL™, LOTENSIN™), fosinopril sodium (MONOPRIL™), lisinopril (PRINIVIL™ and ZESTRIL™), quinapril (ACCUPRIL™), perindopril erbumine (ACEON™), ramipril (ACEON™), moexipril hydrochloride (UNIVASC™), and trandolapril (MAVIK™).
In other embodiments, the antihypertensive agent is an angiotensin π receptor antagonist such as candesartan cilexetil (ATACAND™), irbesartan (AVAPRO™), losartan potassium (COZAAR™), valsartan (DIOVAN™), telmisartan (MICARDIS™), or eprosartan mesylate (TEVETEN™).
Within further such embodiments, the antihypertensive agent is a beta-adrenergic receptor blocker, including combinations in which the antihypertensive agent is a beta- adrenergic receptor antagonist. Beta-adrenergic receptor blockers include, but are not limited to chlorthalidone, sotalol hydrochloride (BETAPACE™ and BETAPACE AF™), timolol maleate (BLOCADREN™), nadolol (CORGARD™), propranolol hydrochloride (INDERAL™), acebutolol hydrochloride (SECTRAL™), atenolol (TENORMIN™), metoprolol succinate (TOPROL-XL™), and bisoprolol fumarate (ZEBETA™).
In other embodiments, the antihypertensive agent is a calcium channel blocker, such as felodipine (PLENDIL™), nifedipine (ADALAT™, PROCARDIA™, PROCARDIA™), nicardipine hydrochloride (CARDENE™), nimodipine (NIMOTOP™), amlodipine besylate
(NORVASC™) diltiazem hydrochloride (CARDIZEM™), verapamil hydrochloride (COVERA-HS™, ISOPTIN™, VERELAN™, VERELAN PM™), isradipine (DYNACIRC™, DYNACIRC CR™), nisoldipine (SULAR™), diltiazem hydrochloride (TIAZIC™), and bepridil hydrochloride(VASCOR™).
Also provided herein are combinations in which the C5a receptor-inactive therapeutic agent is a diuretic such as ionized potassium, chlorothiazide (DIURIL™), chlorthalidone, hydrochlorothiazide (HYDRODIURIL™, MICROZIDE™), polythiazide (RENESE™), bendroflumethiazide, atenolol, dichlorphenamide (DARANIDE™), torsemide (DEMADEX™), ethacrynic acid (EDECRIN™), furosemide, triamterene (DYRENIUM™) amioride (MIDAMOR™), hydroflumethiazide (DIUCARDIN™), indapamide, or metolazone (MYKROX™, ZAROXOLYN™).
In other aspects, the C5a receptor-inactive therapeutic agent is blood modifier, such as an anticoagulant. Anticoagulants useful in the combinations provided herein include, but are not limited to, thrombin inhibitors such as argatroban, inhibitors of thrombin and Factor X, such as dalteparin sodium injection (FRAGMIN™), heparin (e.g., TUBEX™ Heparin Sodium Injection, INNOHEP™), enoxaparin sodium a low molecular weight heparin (LOVENOX™), danaparoid sodium (ORGARAN™) inhibitors of vitamin K dependent coagulation, such as coumarin and warfarin, and hirudin.
The present invention provides, in an additional embodiment, a combination comprising a C5a antagonist and a C5a receptor-inactive therapeutic agent that is a thrombolytic. Examples of thrombolytics include, but are not limited to recombinant alteplase (ACTIVASE™), anistreplase (EMINASE™), recombinant reteplase (RETAVASE™), streptokinase (STREPTASE™), and urokinase (ABBOKINASE™).
Also provided herein are combinations in which the C5a receptor-inactive therapeutic agent is a prescribed combination, such as AGGRENOX™, a tablet comprised of dypridimole and aspirin or MINIZiDE™, a marketed combination of polythiazide (RENESE™) and prazosin hydrochloride (MINIPRESS™), MICARDIS™ HCT (telmisartan and hydrochlorothiazide), ATACAND™ HCT (candesartan cilexetil and hydrochlorothiazide), AVALIDE™ (irbesartan and hydrochlorothiazide), DIOVAN™ HCT (valsartan and hydrochlorothiazide), HYZAAR™ (losartan potassium-hydrochlorothiazide tablets), CORZIDE™ (nadolol and bendroflumethiazide), INDERIDE™ (propranolol hydrochloride and hydrochlorothiazide), TENORETIC™ (atenolol and chlorthalidone), TEVIOLIDE™ (timolol maleate and hydrochlorothiazide), ZIAC™ (bisoprolol fumarate and hydrochlorothiazide), CLORPRES™ and COMBIPRES™, both of which are marketed combinations of clonidine hydrochloride and chlorthalidone, LEXXEL™, a combination of enalapril and felodipine, ALDOCLOR™, a tablet containing methyldopa and chlorothiazide,
TAREX™, a combination of trandolapril and verapamil hydrochloride, and ALDORIL™ (methyldopa and hydrochlorothiazide).
COMBINATIONS FOR THE TREATMENT OF ISCHEMIA-REPERFUSION INJURY
Certain combinations provided herein are useful for treating or preventing reperfusion injury due to thrombosis or surgery. The invention particularly provides combinations for preventing or reducing reperfusion injury during surgeries in which blood vessels are occluded, or in which a heart bypass pump is employed. The C5a receptor-inactive agent(s) used in the combination may be one or more or an anticoagulant or thrombolyitc agent, as described above in the discussion of combinations for the treatment of cardio- and cerebrovascular disease, and/or a surgical anesthetic. COMBINATIONS FOR THE TREATMENT OF TRAUMATIC INJURY, INFECTION OR ORGAN FAILURE
The present invention includes combinations useful for the treatment of CNS trauma
(e.g., injury to the head or spinal cord). Injuries to the brain and spinal cord generally result in an upregulation of pro-inflammatory cytokines and subsequent leukocyte recruitment leading to tissue destruction beyond the original site of injury. The C5a receptor-inactive therapeutic agent(s) may further inhibit such inflammation, or may mediate pain or damage resulting form other aspects of CNS trauma. Suitable anti-inflammatory agents include those described elsewhere herein (e.g., steroids such as methylprednisone), as well as agents (e.g., antibodies) that inhibit proinflammatory cytokine responses, such as IL-1, IL-6, IL-8 and TNF. Other suitable C5a receptor-inactive therapeutic agents include, for example, diazepam (to control seizures). Further therapies that may be used in combination with the C5a receptor antagonist are surgery to control bleeding and ensure adequate blood flow to the brain, as well as therapies that promote nerve growth, reduce scar tissue barriers, repair damaged myelin and promote compensatory growth of intact nerve fibers. Combinations provided herein may also be used in the treatment of hemorrhagic shock, multiple organ system failure or sepsis.
DOSAGE INFORMATION
Therapeutically effective amounts of C5a antagonist(s) and C5a receptor-inactive therapeutic agent(s) are preferred for use in the compositions and methods of the present invention. Dosages and methods of administration of therapeutic agents that are not C5a receptor antagonists are known to those skilled in the medical and pharmaceutical arts and can be found, for example, in the manufacturer's instructions set forth in the package insert for the agent, conveniently recorded in the Physician's Desk Reference. In determining the optimal mode of administration, it will be apparent that is necessary to take into account that certain therapeutic compounds, such as NSAIDS, are suitable for oral administration while others, such as antibody-based drugs, are typically only suitable for non-oral administration. In certain particularly preferred embodiments, the combination administration of at least one C5a receptor antagonist with at least one C5a receptor-inactive therapeutic agent results in a reduction of the dosage of the C5a receptor-inactive therapeutic agent required to produce a therapeutic effect. Thus, preferably, the dosage of a C5a receptor-inactive therapeutic agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the C5a receptor- inactive therapeutic agent without combination administration of a C5a receptor antagonist. More preferably this dosage is less than %, even more preferably less than V2, and highly preferably, less than lA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the C5a receptor- inactive therapeutic agent(s) when administered without combination administration of a C5a receptor antagonist. It will be apparent that the dosage amount of C5a antagonist component of the combination needed to achieve the desired effect may similarly be affected by the dosage amount and potency of the C5a receptor-inactive therapeutic agent component of the combination.
For compounds administered orally, transdermally, intravaneously, or subcutaneously, dosage of a C5a receptor antagonist administered as part of a combination in as described herein is preferably adjusted to achieve specific levels of the C5a receptor antagonist in a body fluid that is in contact with the site of disease or injury (a target body fluid) in the patient being treated. Such target body fluids include, for example one or more of 1) in arthritis, synovial fluid, 2) in, e.g., septicemia, myocardial infarction and conditions involving a potential for reperfusion injury, blood, plasma, or preferably serum, 3) in, e.g., traumatic spinal or brain injury, cerebrospinal fluid, 4) in, e.g., retinopathy, aqueous humor, and 5) in various conditions including the foregoing, cellular interstitial fluid or lymphatic fluid. When administered as part of a combination therapy (e.g., by intravenous, intra- articular or intrathecal injection), preferred levels to be achieved in a target body fluid range from about 5 ng /mL to about 10 ug/mL, preferably from about 20 ng/mL to about 1 ug/mL, more preferably from about 30 ng/mL to about 500 ng/ml, and most preferably from about 50 ng/ml to about 100 ng/ml. Dosages and routes of administration are preferably adjusted to achieve such preferred levels.
Oral dosage amount of the C5a antagonist component of the combination preferably ranges from about 0.001 mg per kg of body weight per day (mg/kg/day) to about 50.0 mg/kg/day, more preferably 0.005-20.0 mg/kg/day and most preferably 0.005-10.0 mg/kg/day. Suitable oral tablets and capsules for human patients contain between about 0.1 mg and 5.0 g, preferably between about 0.5 mg and 2.0 g, most preferably between about 0.5 mg and 1.0 g, for example, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 150 mg, 250 mg, or 500 mg of C5a antagonist receptor antagonist. Oral administration may be in one or divided doses of two, three, or four times daily. Preferably fewer daily doses are preferred, with a single daily dose being most preferred. Preferably, for a human patient the oral dosage amount of the C5a antagonist component of the combination is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day. However, dosage amounts will vary depending on the potency, solubility and bioavailability of the specific C5a antagonist used as well as other factors noted above.
Intravenously, the most preferred doses for the C5a antagonist component of the combination will range from about 0.5 pg to about 5 mg/kg/minute during a constant rate infusion, to achieve a plasma level concentration during the period of time of administration of between 0.1 ng/ml and 1.0 mg/ml.
The combination therapy methods of the invention include administration of a single pharmaceutical dosage formulation which contains both the C5a antagonist and the C5a receptor-inactive therapeutic agent, as well as administration of each active agent in its own separate pharmaceutical dosage formulation. The C5a receptor antagonist can be administered by a number of methods, for example orally, parenterally, transdermally, intravenously, intranasally, intra-articularly, or by any other known method for pharmaceutical administration. Oral, intranasal or topical dosing is generally preferred.
Within certain embodiments, all active agents of the instant combination therapy are administered orally, and the active agents are combined in a single oral dosage formulation. For example, a C5a antagonist and the C5a receptor-inactive therapeutic agent can be administered to the patient together in one oral composition such as a tablet or capsule. Alternatively, the combination therapy may comprise administration of an oral preparation of a C5a antagonist with a separate oral preparation of a C5a receptor-inactive therapeutic agent, or with a separate intravenous, transdermal, intraocular, intranasal, or intra-articular preparation of a C5a receptor-inactive therapeutic agent.
Where separate dosage formulations are used, the combination of C5a antagonist and the C5a receptor-inactive therapeutic agent can result from administration in various temporal relationships (e.g., at essentially the same time oor concurrently, or at separately staggered times, sequentially in either order). As used herein, combination administration and combination therapy include all such regimens that result in both the C5a antagonist and the C5a receptor-inactive therapeutic agent providing therapeutic effects that overlap in time with each other. With the exception of combination treatments where one or more of the therapeutic agents are administered by direct application to an affected area (e.g., by topical administration or injection), such effect is generally achieved when target blood level concentrations of each active agent occur at substantially the same time. As used herein "combination" indicates both composition of matter and method of treatment.
The dosage regimen utilizing a C5a antagonist and a C5a receptor-inactive therapeutic agent is selected in accordance with a variety of factors including species, age, weight, sex, medical condition of the patient, and other pharmaceutical agents that are being administered to the patient during treatment in accordance with the present invention. These factors further include the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compounds (including any salts or prodrugs thereof) employed. In some cases, the therapy may be administered on a long-term chronic basis, such as a period of several months or years, for as long as deemed medically appropriate for the patient.
PHARMACEUTICAL KITS
The present invention also provides pharmaceutical kits comprising at least one C5a antagonist and at least one C5a receptor-inactive therapeutic agent together with indicia comprising instructions for using the contents of the kit to treat a patient suffering from a condition with a pathogenic inflammatory component. Such conditions include those described above, such as arthritis, asthma, psoriasis, reperfusion, traumatic brain and spinal cord injury, and cardio- and cerebrovascular disease. The active agents in a pharmaceutical kit (i.e., the C5a antagonist(s) and the C5a receptor-inactive therapeutic agent(s)), may be formulated for administration in a single pharmaceutical preparation, such as a formulation of both active agents in one tablet or capsule. Alternatively, one or more of the active agents of the pharmaceutical kit may be formulated for separate administration, for example by different routes of administration.
The packaging for the kit may be designed and manufactured in a variety of ways. For example, a pharmaceutical kit for oral administration of the active agents comprise a blister package containing rows of a C5a antagonist tablet and a tablet containing a C5a receptor- inactive therapeutic agent (e.g., COX-2 inhibitor or methotrexate), placed side by side on the same blister card, one each of the two types of tablets in its own blister bubble (or one each of the two types of tablets in a single blister bubble with no other tablets), with indicia on the card directing that one "pair" of tablets (i.e., one C5a antagonist tablet and one C5a receptor- inactive therapeutic agent ) is to be ingested per day.
KITS FOR THE TREATMENT OF ARTHRITIS
More particularly, the pharmaceutical kit is comprised of a C5a receptor-inactive therapeutic agent selected from non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase enzyme inhibitors, such as salicylates, and particularly including cyclooxygenase-2 enzyme specific inhibitors, such as rofecoxib or celecoxib; corticosteroids, such as cortisone, prednisolone and prednisone; gold compounds including injectible gold sodium thiomalate and gold compounds formulated for oral administration; methotrexate; dihydroorotate dehydrogenase inhibitors, such as leflunomide; anti-C5 monoclonal antibodies; TNF alpha antagonists, such as entanercept or infliximab; and IL-1 receptor antagonists, such as anakinra.
One example of this embodiment is a pharmaceutical kit comprised of an oral dosage formulation of a C5a antagonist and an oral dosage formulation of aspirin and instructions for using the contents of the pharmaceutical kit to treat rheumatoid arthritis. Another example of this embodiment is a pharmaceutical kit comprised of a C5a antagonist and a COX-2 inhibitor formulated for either single or separate oral administration together with instructions for using the contents of the pharmaceutical kit to treat rheumatoid arthritis.
KITS FOR THE TREATMENT OF ASTHMA
In another embodiment, the pharmaceutical kit provided is comprised of a C5a receptor antagonist and a C5a receptor-inactive therapeutic agent for the treatment of asthma. The C5a receptor-inactive therapeutic agent for the treatment of asthma may be a corticosteroid, such as fluticasone propionate or triamcinolone. The C5a receptor-inactive therapeutic agent may also be cromolyn sodium, a long- or short- acting Beta adrenergic receptor agonist, particularly a Beta-2-receptor agonist, a leukotriene modifier, and anticholinergic, or a methylxanthine, for example, theophylline. One example of this embodiment is a pharmaceutical kit comprised of an oral dosage formulation of a C5a receptor antagonist and an inhaled formulation of a Beta adrenergic receptor agonist, for example, albuterol. Other pharmaceutical kits of the invention for the treatment of asthma may also comprise inhaled formulations of both the C5a receptor antagonist and the C5a receptor-inactive therapeutic agent for the treatment of asthma, prepared as separate formulations or as a single formulation. When one agent of the kit is prepared as an inhaled formulation, an inhaler, nebulizer, or other device for inhalation may be provided in the kit.
KITS FOR THE TREATMENT OF PSORIASIS
Pharmaceutical kits for the treatment of psoriasis comprised of a C5a-antagonist and a C5a receptor-inactive therapeutic agent for the treatment of psoriasis which is preferably selected from therapeutic agents the inhibit the hyperfunctional proliferation of epidermal cells; inhibit the inflammatory response; promote immunomodulation; and/or inhibit infection by bacteria and fungi. Included in the invention are combinations in which the C5a receptor-inactive therapeutic agent of the kit is a non-steroidal anti-inflammatory drug (NSAID), a steroid, coal tar, a moisturizer, calendula plant extract, an agents that arrests the proliferation of cells during the metaphase stage of cell division; e.g., SLO-PHYLLIN™ or THEO-DUR SPRINKLE™), an angiogenesis inhibitor such as ganglioside GM3 or a GM3 analog, a phospholipase A2 inhibitor or an imidazole antifungal. A C5a receptor-inactive therapeutic agent included in a kit for the treatment of psoriasis may also be an immunomodulator, such as a folic acid antagonist, an inhibitor of interleukin-2 production, an immunosuppressant, a TNF-alpha modulators, and antileukotriene agents, or a Vitamin A derivatives.
The invention particularly includes kits for the treatment of psoriasis in which one or both or the C5a antagonist and C5a receptor-inactive therapeutic agent is formulated for topical administration.
KITS FOR THE TREATMENT OF CARDIO- AND CEREBROVASCULAR DISEASE
Pharmaceutical kits for the treatment of cardio- and cerbrovascular disease comprised of a C5a receptor-inactive therapeutic agent selected from the group that includes non- steroidal anti-inflammatory drugs (NSAIDs), cholesterol lowering drugs, particularly 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoA RI) such as lovastatin, pravastatin, or simvastatin, anti-hypertensive agents, including adrenergic receptor stimulators, including agonists, alpha/ beta adrenergic receptor antagonists, beta adrenergic receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics and periphereal vasodilators, and platelet aggregation inhibitors, particularly GP Ilb/IIIa inhibitors, PDE inhibitors, particularly PDE III inhibitors, inhibitors of megakaryocyte hypermaturation, and ADP receptor inhibitors such as clopidogrel.
An example of this embodiment is a pharmaceutical kit comprising an oral dosage formulation of a C5a antagonist and an oral dosage formulation of simvastatin (ZOCOR™) and instructions for using the contents of the pharmaceutical kit to reduce the risk of myocardial infarction and/ or stroke.
PHARMACEUTICAL PREPARATIONS
The compounds for use in the described combination therapy may be administered orally, topically, transdermally, parenterally, by inhalation or spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal and like types of injection or infusion techniques. One or more compounds of the combination may be present in association with one or more non- toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of the combination may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non- toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Compounds for use in the described combination therapy may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Compounds used in the described combination therapy may be prepared as a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectible preparation may also be sterile injectible solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectibles. Compounds of for use in the combination therapy may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, one or more adjuvants such as preservatives, buffering agents, or local anesthetics can also be present in the vehicle.
For inhalation formulations, the compounds of the present invention may be delivered via any inhalation methods known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or
HFA or propellants that are physiologically and environmentally acceptable. Other included devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
Formulation suitable for administration by inhalation includes formulations of the active ingredient in a form that can be dispensed by such inhalation devices known to those in the art. Such formulations may include carriers such as powders and aerosols. The inhalant compositions used in the present invention may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptable for intrabronchial administration. The powder compositions can be administered via an aerosol dispenser or encased in a breakable capsule which may be inserted by the patient into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation. Aerosol formulations for use in the subject method would typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Within certain embodiments, compositions provided herein are formulated for topical administration. Such formulations typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Topical formulations are useful, for example, in the treatment of psoriasis and sunburn.
Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale— The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules. The topical formulations provided herein may be prepared in a variety of physical forms. For example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions are all contemplated by the present invention. The physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifiers and viscosity adjusters present in the formulation. Particular topical formulations can often be prepared in a variety of these forms. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, behentirmonium methosulfate, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 sterate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate. Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. A gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations. Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colors for use in the formulations of the present invention include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included a topical formulation include, but are not limited to, abrasives, absorbents, anti- caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
An example of a suitable topical vehicle for formulation of a gel is: hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%); propylene glycol
(5.1%); and Polysorbate 80 (1.9%). An example of a suitable topical vehicle for formulation as a foam is: cetyl alcohol (1.1%); stearyl alcohol (0.5%; Quaternium 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.
Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing. Controlled release vehicles can also be used to administer the compounds of the present invention. The technology and products in this art are variably referred to as controlled release, sustained release, prolonged action, depot, repository, delayed action, retarded release and timed release; the words "controlled release" as used herein is intended to incorporate each of the foregoing technologies.
Numerous controlled release vehicles are known, including biodegradable or bioerodable polymers such as polylactic acid, polyglycolic acid, and regenerated collagen. Controlled release drug delivery devices include creams, lotions, tablets, capsules, gels, microspheres and liposomes. Transdermal formulations, from which active ingredients are slowly released are also well known and can be used in the present invention. Controlled release preparations can be achieved by the use of polymers to complex or absorb the active agent(s). The controlled delivery can be exercised by selecting appropriate macromolecule such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylenevinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate, and the concentration of these macromolecule as well as the methods of incorporation are selected in order to control release of active compound.
Hydrogels, wherein the active agent(s) are dissolved in an aqueous constituent to gradually release over time, can be prepared by copolymerization of hydrophilic mono- olefinic monomers such as ethylene glycol methacrylate. Matrix devices, wherein the active agent(s) are dispersed in a matrix of carrier material, can be used. The carrier can be porous, non-porous, solid, semi-solid, permeable or impermeable. Alternatively, a device comprising a central reservoir of active agent(s) surrounded by a rate controlling membrane can be used to control the release of active agent(s). Rate controlling membranes include, for example, ethylene-vinyl acetate copolymer and butylene terephthalate/polytetramethylene ether terephthalate.
The following Examples are offered by way of illustration and not by way of limitation. Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification. EXAMPLES
EXAMPLE 1. EXPRESSION OF A C5 A RECEPTOR
A human C5a receptor cDNA is obtained by PCR using 1) a forward primer adding a Kozak ribosome binding site and 2) a reverse primer that added no additional sequence, and
3) an aliquot of a Stratagene Human Fetal Brain cDNA library as template. The sequence of the resulting PCR product is as described by Gerard and Gerard, (1991) Nature 349:614-11.
The PCR product is subcloned into the cloning vector pCR-Script AMP (STRATAGENE, La
Jolla, CA) at the Srf I site. It is then excised using the restriction enzymes EcoRI and Notl and subcloned in the appropriate orientation for expression into the baculoviral expression vector pBacPAK 9 (CLONTECH, Palo Alto, CA) that has been digested with EcoRI and
Notl.
EXAMPLE 2. BACULOVIRAL PREPARATIONS FOR C5A EXPRESSION The human C5a (hC5a) receptor baculoviral expression vector is co-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego, CA) into S/9 cells. The S 9 cell culture supernatant is harvested three days post-transfection. The recombinant virus- containing supernatant is serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Lenexa, KS) supplemented Grace's salts and with 4.1mM L-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter "insect medium") and plaque assayed for recombinant plaques. After four days, recombinant plaques are selected and harvested into 1 ml of insect medium for amplification. Each 1 ml volume of recombinant baculovirus (at passage 0) is used to infect a separate T25 flask containing 2 x 106 S 9 cells in 5 mis of insect medium. After five days of incubation at 27°C, supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum.
Two of seven recombinant baculoviral clones are then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect 1 x 10 cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eight hours post infection, passage 2 medium from each 100 ml prep is harvested and plaque assayed for titer. The cell pellets from the second round of amplification are assayed by affinity binding as described below to verify recombinant receptor expression. A third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect a liter of S 9 cells. Forty hours post-infection the supernatant medium is harvested to yield passage 3 baculoviral stock. The remaining cell pellet is assayed for affinity binding using the "Binding Assays" essentially as described by DeMartino et al. (1994) J. Biol. Chem. 269:14446-50 at page 14447, adapted as follows. Radioligand is 0.005-0.500nM [125τjC5a (human recombinant; New England Nuclear Corp., Boston, MA); the hC5a receptor-expressing baculoviral cells are used instead of 293 cells; the assay buffer contains 50 mM Hepes pH. 7.6, 1 mM CaCi2, 5 mM MgCl2, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and 100 KlU/ml aprotinin; filtration is carried out using GF/C WHATMAN filters (presoaked in 1.0% polyethyeneimine for 2 hours prior to use); and the filters are washed twice with 5 mLs cold binding buffer without BSA, bacitracin, or aprotinin.
Titer of the passage 3 baculoviral stock is determined by plaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression. A multiplicity of infection of 0.1 and a
72-hour incubation were the best infection parameters found for hC5a receptor expression in up to 1 -liter S 9 cell infection cultures.
EXAMPLE 3: BACULOVIRAL INFECTIONS Log-phase S/9 cells (INVITROGEN Corp., Carlsbad CA) are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27°C. Infections are carried out either only with virus directing the expression of the hC5a receptor or with this virus in combination with three G-protein subunit-expression virus stocks: 1) rat GDi2 G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2) bovine bl G-protein- encoding virus stock (BIOSIGNAL #V5H012), and 3) human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), all of which may be obtained from BIOSIGNAL Inc.
(Montreal, Canada).
The infections are conveniently carried out at a multiplicity of infection of
0.1:1.0:0.5:0.5. At 72 hours post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining S 9 cells are harvested via centrifugation (3000 rpm/ 10 minutes/4°C).
EXAMPLE 4. PURIFIED RECOMBINANT INSECT CELL MEMBRANES
S/9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 ug/ml leupeptin, 2 ug/ml Aprotinin, 200 uM PMSF, and 2.5 mM EDTA, pH
7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds). The homogenate is centrifuged (536 x g/ 10 minutes/4°C) to pellet the nuclei. The supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000 X g/ 30 minutes, 4°C) and the resulting pellet resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice. The final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at -80°C until needed. The protein concentration of the resulting membrane preparation (hereinafter "P2 membranes") is conveniently measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, CA). By this measure, a 1-liter culture of cells typically yields 100- 150 mg of total membrane protein.
EXAMPLE 5. RADIOLIGAND BINDING ASSAYS
Purified P2 membranes, prepared by the method given above, are resuspended by
Dounce homogenization (tight pestle) in binding buffer (50 mM Hepes pH. 7.6, 120 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, o.l% BSA, pH 7.4, 0.1 mM bacitracin, 100 KlU/ml aprotinin).
For saturation binding analysis, membranes (5-50 μg) are added to polypropylene tubes containing 0.005-0.500 nM [125I]C5a (human (recombinant), New England Nuclear
Corp., Boston, MA). Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St. Louis, MO) and accounts for less than 10 % of total binding. For evaluation of guanine nucleotide effects on receptor affinity, GTPγS is added to duplicate tubes at the final concentration of 50 μM.
For competition analysis, membranes (5-50 μg) are added to polypropylene tubes containing 0.030 nM [125I]C5a (human). Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10"10 M to 10"5 M to yield a final volume of 0.250 mL.
Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St.
Louis, MO) and accounts for less than 10% of total binding. Following a 2-hour incubation at room temperature, the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked (in 1.0% polyethyleneimine for 2 hours prior to use) GF/C WHATMAN filters and rinsed 2 times with 5 mLs cold binding buffer without BSA, bacitracin, or aprotinin. Remaining bound radioactivity is quantified by gamma counting. Ki ι and Hill coefficient ("nH") are determined by fitting the Hill equation to the measured values with the aid of SIGMAPLOT software (SPSS Inc., Chicago, IL).
EXAMPLE 6: AGONIST-INDUCED GTP BINDING Agonist-stimulated GTP-gamma 35 S binding ("GTP binding") activity can be used to identify agonist and antagonist compounds and to differentiate neutral antagonist compounds from those that possess inverse agonist activity. This activity can also be used to detect partial agonism mediated by antagonist compounds. A compound being analyzed in this assay is referred to herein as a "test compound." Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of the hC5a receptor and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of S/9 cells as described in Example 3.
Agonist-stimulated GTP binding on purified membranes (prepared as described in Example 9) is assessed using hC5a (Sigma Chemical Co., St. Louis, MO) as agonist in order to ascertain that the receptor/G-protein-alpha-beta-gamma combination(s) yield a functional response as measured by GTP binding.
P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgC12, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, lOOKIU/mL aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 30 μg protein/reaction tube. After adding increasing doses of the agonist hC5a at concentrations ranging from 10"12 M to 10"6 M, reactions are initiated by the addition of 100 pM GTP-gamma S. In competition experiments, non-radiolabeled test compounds are added to separate assays at concentrations ranging from 10"10 M to 10"5 M along with 10 nM hC5a to yield a final volume of 0.25 mL. Neutral antagonists are those test compounds that reduce the C5a-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added C5a or other agonist and in the further absence of any test compound).
In contrast, in the absence of added C5a certain preferred compounds will reduce the GTP binding activity of the receptor-containing membranes below baseline, and are thus characterized as inverse agonists. If a test compound that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the C5a agonist, it is characterized as a neutral antagonist.
An antagonist test compound that elevates GTP binding activity above baseline in the absence of added hC5a in this GTP binding assay is characterized as having partial agonist activity. Preferred antagonist compounds do not elevate GTP binding activity under such conditions more than 10%, 5% or 2% above baseline.
Following a 60-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120mM NaCl). The amount of receptor-bound (and thereby membrane-bound) GTP-gamma S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 mM GTP-gamma 35S and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments may be conveniently analyzed using SIGMAPLOT software. EXAMPLE 7. CALCIUM MOBILIZATION ASSAYS
A. Response to C5a
U937 cells are grown in differentiation media (1 mM dibutyrl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37°C then reseeded onto 96-well plates suitable for use in a FLIPR™ Plate Reader (Molecular Devices Corp., Sunnyvale CA). Cells are grown an additional 24 hours (to 70-90% confluence) before the assay. The cells are then washed once with Krebs Ringer solution. FLUO-3 calcium sensitive dye (Molecular Probes, Inc. Eugene, OR) is added to 10 μg/mL and incubated with the cells at room temperature for 1 to 2 hours. The 96 well plates are then washed to remove excess dye. Fluorescence responses, measured by excitation at 480 nM and emission at 530 nM, are monitored upon the addition of human C5a to the cells to a final concentration of 0.01-30.0 nM, using the FLIPR™ device (Molecular Devices). Differentiated U937 cells typically exhibit signals of 5,000-50,000 Arbitrary Fluorescent Light Units in response to agonist stimulation.
B. Assays for Determination of ATP Responses
Differentiated U937 cells (prepared and tested as described above under "A. Response to C5a") are stimulated by the addition of ATP (rather than C5a) to a final concentration of 0.01 to 30 μM. This stimulation typically triggers a signal of 1,000 to 12,000 arbitrary fluorescence light units. Certain preferred compounds produce less than a 10%, less than a 5%, or less than a 2% alteration of this calcium mobilization signal when this control assay is carried out in the presence of the compound, as compared to the signal when the assay is performed in the absence of the compound.
C. Assays for the Identification of Receptor Modulatory Agents: Antagonists and Agonists
The calcium mobilization assay described above may be readily adapted for identifying test compounds that have agonist or antagonist activity at the human C5a receptor.
For example, in order to identify antagonist compounds, differentiated U937 cells are washed and incubated with Fluo-3 dye as described above. One hour prior to measuring the fluorescence signal, a subset of the cells is incubated with 1 μM of at least one compound to be tested. The fluorescence response upon the subsequent addition of 0.3 nM (final concentration) human recombinant C5a is monitored using the FLIPR™ plate reader. Antagonist compounds elicit at least a 2-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone. Preferred antagonist compounds elicit at least a 5-fold, preferably at least a 10-fold, and more preferably at least a 20-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone. Agonist compounds elicit an increase in fluorescence without the addition of C5a, which increase will be at least partially blocked by a known C5a receptor antagonist.
EXAMPLE 8. ASSAY FOR C5A RECEPTOR MEDIATED CHEMOTAXIS
This assay is a standard assay of C5a receptor mediated chemotaxis. Human promonocytic U937 cells or purified human or non-human neutrophilis are treated with dibutyryl cAMP for 48 hours prior to performing the assay. Human neutrophils or those from another mammalian species are used directly after isolation. The cells are pelleted and resuspended in culture media containing 0.1% fetal bovine serum (FBS) and 10 ug/ml calcein AM (a fluorescent dye). This suspension is then incubated at 37 °C for 30 minutes such that the cells take up the fluorescent dye. The suspension is then centrifuged briefly to pellet the cells, which are then resuspended in culture media containing 0.1% FBS at a concentration of approximately 3 x 106 cells/mL. Aliquots of this cell suspension are transferred to clean test tubes, which contain vehicle (1% DMSO) or varying concentrations of a compound of interest, and incubated at room temperature for at least 30 minutes. The chemotaxis assay is performed in CHEMO TX 101-8, 96 well plates (Neuro Probe, Inc. Gaithersburg, MD). The bottom wells of the plate are filled with medium containing 0-10 nM of C5a, preferably derived from the same species of mammal as are the neutrophils or other cells (e.g., human C5a for the human U937 cells). The top wells of the plate are filled with cell suspensions (compound or vehicle-treated). The plate is then placed in a tissue culture incubator for 60 minutes. The top surface of the plate is washed with PBS to remove excess cell suspension. The number of cells that have migrated into the bottom well is then determined using a fluorescence reader. Chemotaxis index (the ratio of migrated cells to total number of cells loaded) is then calculated for each compound concentration to determine an IC50 value.
As a control to ensure that cells retain chemotactic ability in the presence of the compound of interest, the bottom wells of the plate may be filled with varying concentrations chemo-attractants that do not mediate chemotaxis via the C5a receptor (e.g., zymosan- activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4 (LTB4)), rather than C5a, under which conditions the compounds provided herein preferably do not inhibit chemotaxis.
Preferred compounds exhibit IC50 values of less than 1 μM in the above assay for C5a receptor mediated chemotaxis. EXAMPLE 9. PHARMACEUTICAL PREPARATIONS OF ORAL AND INTRAVENOUS ADMINISTRATION
A. Tablets containing a C5a antagonist and an anti-arthritic agent which is not a C5a antagonist can be prepared as illustrated below:
Ingredient Amount
C5a antagonist 5mg - 500 mg
C5a receptor-inactive therapeutic agent 1 mg -500 mg diluent, binder, distigrant, lubricant, excipients q.s. 200-400 mg.
B. Tablets containing a C5a antagonist as the only active ingredient can be prepared as illustrated below: Ingredient mg mg C5a antagonist 10 50 Microcrystalline Cellulose 70.4 352 Granular Mannitol 15.1 75.5 Croscarmellose Sodium 3.0 15.0 Colloidal Silicon Dioxide 0.5 2.5 Magnesium Stearate (Impalpable Powder) 1.0 5.0 Total (mg) 100 500
C. Tablets containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:
Ingredient mg mg
C5a antagonist 10 25
C5a receptor inactive therapeutic agent 10 25
Microcrystalline Cellulose 40 100
Modified food corn starch 1.05 4.25
Magnesium sterate 1.25 0.5
D. Intravenous formulations containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:
Ingredient Amount
C5a antagonist 0.5 - 10 mg
C5a receptor inactive therapeutic agent 0.5 - lOmg
Sodium Citrate 5 - 50 mg Citric Acid 1 - 15 mg
Sodium Chloride 1 - 8 mg
Water for Injection to 1.0 liter
E. Oral suspensions containing a C5a receptor antagonist and a C5a receptor inactive agent may be prepared as follows:
Ingredient Amount per 5 ml dose
C5a antagonist 5 -100 mg
C5a receptor inactive therapeutic agent 5 - 100 mg
Polyvinylpyrrolidone 150 mg
Poly oxyethylene sorbitan monolaurate 25 mg
10 mg to 5 mL with sorbitol solution
Benzoic Acid
(70%)
EXAMPLE 10. REPRESENTATIVE C5A ANTAGONISTS Table I provides representative C5a antagonists for use within the compositions and methods provided herein.
TABLE I - C5a receptor antagonists useful in the combination therapies described herein.
l-(l-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl methyl])aminomethylimidazole
1 -( 1 -butyl)-2-phenyl-5 -( 1 - [N- { 3 ,4-methylenedioxyphenylmethyl } -N- phenylmethyl]amino)ethylimidazole
1 -Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[ 1 -butyl])amino-methylimidazole l-(l-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-(4-fluorophenyl)-5-(N-[l,4-benzodioxan-6-yl]methyl-N-phenylmethyl) aminomethylimidazole l-(l-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole; l-(l-Butyl)-2-(2-fluorophenyl)-5-(N-[l,4-benzodioxan-6-ylmethyl]-N- phenylmethyl)amino- methylimidazole l-(l-Butyl)-2-(2-methoxyphenyl)-5-(N-[naphtha-2-ylmethyl]-N-phenylmethyl)amino- methylimidazole l-(l-Butyl)-2-(2-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole
10 l-(l-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole 11 l-(l-Butyl)-2-(2-methoxyphenyl)-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl) aminomethylimidazole 12 l-(l-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole 13 l-(l-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino- methylimidazole 14 l-(l-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino- methylimidazole 15 l-(l-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl]-N-phenylmethyl)amino methylimidazole 16 l-(l-Butyl)-2-(3-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole ' 17 l-(l-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino- methylimidazole l-(l-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)- aminomethylimidazole
19 1 -( 1 -Butyl)-2-phenyl-5 - { 1 -(N- [3 ,4-methylenedioxyphenylmethyl] -N-phenylmethyl)amino } ethylimidazole 0 l-(l-Pentyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole 1 Bis-benzo[l,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)amine 2 Benzo[l,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H- imdiazol-4-ylmethyl] -amine 23. 4-({Benzyl-[l-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl)-amino}-methyl)benzamide
24. 4-{ [Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}3-chloro- phenol
25. 4-({[l-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexymethyl-amino}-methyl)- phenol
26. 4-{[Benzyl-(3-butyl-2,5-diphenyl-5H-imidazol-4-ylmethyl)-amino]-methyl}benzamide
27. l-(l-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole
28. l-(l-Butyl)-2-phenyl-5-(N-[l-(S)-phenylethyl]-N-phenylmethyl)aminomethylimidazole
29. l-(l-Butyl)-2-phenyl-5-(N-[l-(R)-phenylethyl]-N-phenylmethyl)aminomethylimidazole
30. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dichlorophenyl]methyl)aminomethylimidazole
31. 1 -(l-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole
32. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- methoxyphenylmethyl])-aminomethylimidazole
33. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{ l- propyl}phenylmethyl])aminomethylimidazole
34. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dichlorophenylethyl])aminomethylimidazole
35. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4- nitrophenylmethyl])aminomethylimidazole
36. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{ 1-propyloxy} ' phenylmethyl])aminomethylimidazole
37. 1 -( 1 -Butyl)-2-phenyl-5 -(N- [3 ,4-methylenedioxyphenylmethyl] -N- [quinol-6-ylmethyl] )- aminomethylimidazole
38. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3- dichlorophenylmethyl])-aminomethylimidazole
39. 1 -(1 -Butyl)-2-phenyl-5-(N-[3 ,4-methylenedioxyphenylmethyl] -N-[3 ,4- dimethylphenylmethyl])-aminomethylimidazole
40. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[indan-2-yl])- aminomethylimidazole
41. 1 -( 1 -Butyl)-2-phenyl-5 -(N-[3 ,4-methylenedioxyphenylmethyl] -N- [2-phenylethyl] )amino- methylimidazole
42. l-(l-Propyl)-2-phenyl-5-(N-[l,4-benzodioxan-6-ylmethyl]-N-phenylmethyl)aminomethyl- imidazole
43. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)aminomethyl-imidazole
44. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- ethyl)aminomethylimidazole
45. 1 -( 1 -Butyl)-2-phenyl-5-(N- [3 ,4-methylenedioxyphenylmethyl] -N- [ 1 -propyl] ) aminomethylimidazole
46. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l-butyl])aminomethyl- imidazole
47. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cycloheptylmethyl)amino-methylimidazole
48. 1 -(1 -Butyl)-2-phenyl-5-(N-[3 ,4-methylenedioxyphenylmethyl] -N-isobutyl)aminomethyl- imidazole
49. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- cyclopentylethyl])amino-methylimidazole
50. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3~ cyclopentylpropyl])amino-methylimidazole
51. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l-n-octyl])aminomethyl- imidazole
52. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cyclopropylmethyl)amino-methylimidazole
53. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cyclopentylmethyl)amino-methylimidazole
54. 1 -( 1 -Butyl)-2-phenyl-5 -(N- [3 ,4-methylenedioxyphenylmethyl] -N-cyclohexylmethyl)amino- methylimidazole
55. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t- amyl])aminomethylimidazole
56. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l-{3- methyljbutyl^amino-methylimidazole
57. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l-{2,2-dimethyl}butyl]) aminomethylimidazole
58. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- methyl)aminomethylimidazole
59. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- thiophenylmethyl])amino-methylimidazole
60. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5- ylmethyl])amino-methylimidazole
61. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[{l-methylindol-5- yl }methyl])aminomethylimidazole
62. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2- chlorophenyl]-methyl)aminomethylimidazole
63. l-(l-Butyl)-2-(3-fluorophenyl)-5-(l-[N-{2-chloro-4-hydroxyphenyl}methyl-N- phenylmethyl] ) aminoethylimidazole
64. l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3- dihydrobenzo[b]furan-5-yl]methyl)aminomethylimidazole
65. l-Butyl-2-(4-fluorophenyl)-5-(l-[N-{3,4-methylenedioxyphenyl}methyl-N-phenylmethyl]- amino)ethylimidazole
66. l-(l-Butyl)-2-(2-thienyl)-5-(N-[3,4-methylenedioxyphenyl]methyl-N-phenylmethyl] aminomethylimidazole
67. l-(l-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N-phenylmethyl)amino- methylimidazole
68. l-(l-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminomethyl- imidazole
69. l-(l-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole l-(l-Butyl)-2-phenyl-5-(N-[4-methylaminophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole l-(l-Butyl)-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole)
1 -(1 -Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl] -N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenylmethyl]-N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[3,4-difluorophenylmethyl]-N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-(benzo[b]thiophen-5-ylmethyl)-N-phenylmethyl)aminomethyl- imidazole l-(l-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N- phenylmethyl)aminomethylimidazole
1 -( 1 -Butyl)-2-phenyl-4-bromo-5 -(N-phenylmethyl-N-[ 1 -butyl] )aminomethylimidazole
1 -( 1 -Butyl)-2-phenyl-5 -(N- [4-methoxyphenylmethyl] -N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[6-chloro-3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)- aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-[l-butyl])aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[3-methoxyphenylmethyl]-N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[2-chloro-4-fluorophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole l-(l-Butyl)-2-phenyl-4-bromo-5-(N-[2,3-dichlorophenylmethyl]-N-[l-butyl])aminomethyl- imidazole l-(l-Butyl)-2-phenyl-5-(N-[2,6-dichlorophenylmethyl]-N- phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N- phenylmethyl)aminomethyl-imidazole
1 -( 1 -Butyl)-2-phenyl-4-chloro-5-(N-phenylmethyl-N- [ 1 -butyl] )aminomethylimidazole
4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2-methyl- phenol
4-{ [(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amino } -methyl)-2- methyl-phenol
(3-Butyl-2,5-diphenyl--?H-imidazol-4-ylmethyl)-(2,6-difluoro-benzyl)-(4-methoxy-benzyl)- amine
Benzo[l,3]dioxol-5-ylmethyl-butyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol- 4-ylmethyl] -amine
4-( { B enzyl-[3-butyl-2-(2-methoxy-phenyl)-5 -phenyl-3H-imidazol-4-ylmethyl] -amino } - methyl)-benzenesulfonamide
Benzo[l,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H- imidazol-4-ylmethyl] -amine
93. 4-({Butyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-amino}- methyl)-3-chloro-phenol
94. 4-{[(3-Butyl-2,5-diphenyl--?H-imidazol-4-ylmethyl)-(4-methoxy-benzyl)-amino]-methyl}- benzoic acid
95. 4-( { B enzyl- [3 -butyl-2-(3 -methoxy-phenyl)-5 -phenyl-3H-imidazol-4-ylmethyl] -amino } - methyl)-3-chloro-phenol
96. Benzo[l,3]dioxol-5-ylmethyl-benzyl-[l-(3-butyl-2,5-diphenyl--?H-imidazol-4-yl)-pentyl]- amine
97. Benzo[l,3]dioxol-5-ylmethyl-benzyl-[l-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]- amine
98. 4-{[Butyl-(3-butyl-2,5-diphenyl-5H-imidazol-4-ylmethyl)-amino]-methyl}benzamide
99. B enzo [1,3] dioxol-5 -ylmethyl-benzyl- [3-butyl-5 -(4-fluoro-phenyl)-2-phenyl-3H-imidazol-4- ylmethyl] -amine
100. 3-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-phenol
101. 4-{ [Butyl-(3-butyl-5-tert-butyl-2-phenyl--?H-imidazol-4-ylmethyl)-amino]- methyl }benzamide
102. Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[l,4]dioxin-6- ylmethyl)-amine
103. (3-butyl-2,5-diphenyl--?H-imidazol-4-ylmethyl)-(2,5-difluoro-benzyl)-(4-methoxy-benzyl)- amine
104. (3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-dichloro-benzyl)-(4-methoxy-benzyl)- amine
105. 4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2,6-dimethyl- phenol
106. 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl- amino } -methyl)-2,6-dimethyl-phenol
107. [3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-JH-imidazol-4-ylmethyl]-cyclohexylmethyl- (2,3,dihydro-benzofuran-5-ylmethyl)-amine
108. 4-{[Butyl-(3-butyl-2,5-diphenyl--?H-imidazol-4-ylmethyl)-amino]-methyl}-2,6-dimethyl- phenol
109. 4-({Butyl-[l-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl)-amino}-methyl) -2,6- dimethyl-phenol
110. 4-{ [(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-dimethylamino-benzyl)-methyl}- benzoic acid
111. 4-{5-[(Bis-benzo[l,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol-l-yl}- butyric acid ethyl ester
112. 4- { 5-[(Bis-benzo[ 1 ,3] dioxol-5-ylmethyl-amino)-methyl] -2,4-diphenyl-imidazol- 1 -yl Jbutan- l-ol
113. (4- { [(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl-amino]methyl } - phenyl)-dimethyl-amine
114. l-(l-Butyl)-2-phenyl-5-(N-[4-{ l-pyrrolidinyl}phenylmethyl]-N- phenylmethyl)aminomethyl-imidazole; 115. l-(l-Butyl)-2-phenyl-5-(N-[4-diethylaminophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole;
116. l-(l-Butyl)-2-phenyl-5-(N-[pyridin-2-ylmethyl]-N-phenylmethyl)aminomethylimidazole;
117. l-(l-Butyl)-2-phenyl-5-(N-[pyridin-3-ylmethyl]-N-phenylmethyl)aminomethylimidazole;
118. l-(l-Butyl)-2-phenyl-5-(N-[pyridin-4-ylmethyl]-N-phenylmethyl)aminomethylimidazole;
119. l-(l-Butyl)-2-phenyl-5-(N-[2-fluoro-6-chlorophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole);
120. l-(l-Butyl)-2-phenyl-5-(N-[2,4-dichlorophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole);
121. l-(l-Butyl)-2-phenyl-5-(N-[4-chlorophenylmethyl]-N- phenylmethyl)aminomethylimidazole;
122. l-(l-Butyl)-2-phenyl-5-(N-[4-hydroxyphenylmethyl]-N- phenylmethyl)aminomethylimidazole;
123. l-(l-Butyl)-2-phenyl-5-(N-[4-trifluoromethoxyphenylmethyl]-N- phenylmethyl)aminomethyl-imidazole);
124. l-(l-Butyl)-2-phenyl-5-(N-[2-chloro-3,4-dimethoxyphenylmethyl]-N-phenylmethyl)amino- methylimidazole) ;
125. l-(l-Butyl)-2-phenyl-5-(N-[4-nitrophenylmethyl]-N-phenylmethyl)aminomethylimidazole;
126. l-(l-Butyl)-2-phenyl-5-(N-[4-aminophenylmethyl]-N- phenylmethyl)aminomethylimidazole;
127. l-(l-Butyl)-2,4-diphenyl-5-(N-phenylmethyl-N-[l-butyl])aminomethylimidazole;
128. l-(l-Butyl)-2-phenyl-5-(N-[2-aminopyridin-5-ylmethyl]-N-phenylmethyl)aminomethyl- imidazole
129. l-(l-Butyl)-2-phenyl-5-(N-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N-phenylmethyl)amino- methylimidazole;
130. l-(l-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-[l-butyl])aminomethyl- imidazole)
131. l-(l-Butyl)-2-phenyl-4-methyl-5-(N-phenylmethyl-N-[l-butyl])aminomethylimidazole;
132. l-(l-Butyl)-2-(4-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phenylmethyl)- aminomethylimidazole;
133. l-(l-Butyl)-2-(3-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phenylmethyl)- aminomethylimidazole;
134. 1 -(l-Butyl)-2-(3-fluorophenyl)-5-(N-[2,3-dichlorophenylmethyl]-N-phenylmethyl)amino- methylimidazole;
135. l-(l-Butyl)-2-(3-fluorophenyl)-5-(N-[4-dimethylaminophenylmethyl]-N- phenylmethyl)amino-methylimidazole;
136. l-(l-Butyl)-2-(3-fluoroρhenyl)-5-(N-[4-{l-pyrrolidinyl}phenylmethyl]-N- phenylmethyl)amino-methylimidazole;
137. 1 -(l-Butyl)-2-(3-chlorophenyl)-5-(l -[N-{ 2-chloro-4-hydroxyphenylmethyl } -N- phenylmethyl] amino)ethylimidazole;
138. l-(l-Butyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)aminomethylimidazole
139. l-(l-Butyl)-2-(4-fluoroρhenyl)-5-(l-N,N-di[3,4-methylenedioxyphenylmethyl] amino)ethylimidazole; 140. 2-{[5-({Butyl[(l-butyl-2,4-diphenylimidazol-5-yl)methyl]amino}methyl)-2- pyridyl] amino } ethan- 1 -ol;
141. 4-{[butyl(l-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl))amino]methyl}-3- chlorophenol
142. 2-phenyl-4-(N,N-di{2H-Benzo[3,4-d]-l,3-dioxolan-5-ylmethyl}amino)methyl-3- butylpyridine
143. 1 ,3-diphenyl-4-(N-{ 2H-benzo[3,4-d]- 1 ,3-dioxolan-5-ylmethyl } -N-butylamino)methyl-5- propylpyrazole
144. N-(l-fluorobenzyl)-N-indan-2-yl-2-(6, 7-dimethoxy-l -phenyl- 1,2, 3,4- tetrahydroisoquinolin-
1-yl) acetamide
145. 4'Trifluoromethyl-biphenyl-2-carboxylic acid benzo[l,3]dioxol-5-ylmethyl-benzyl-amide
146. Ν-B enzo [1,3] dioxol-5-ylmethyl-Ν-benzyl-2-pyrazol- 1 -yl-benzamide
147. l-[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]-N-(2-fluoro-5- methoxybenzyl)-N-(4-methoxybenzyl)methanamine
148. l-(2-bromophenyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(4-methoxybenzyl)methanamine
149. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(lH-indol-5-ylmethyl)methanamine
150. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(lH-indol-4-ylmethyl)-2- phenylethanamine
151. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(lH-indol-5-ylmethyl)-2- phenylethanamine
152. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-( 1 -naphthylmethyl)methanamine
153. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-naphthylmethyl)methanamine
154. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-pentyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
155. N-benzyl-l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-[(l-pentyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
156. N-benzyl- 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3 ,4-dimethoxybenzyl)methanamine
157. N-benzyl-N-[( 1 -butyl-2-phenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
158. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)methanamine
159. N-benzyl-l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-[(2-phenyl-l-propyl-lH-imidazol-5- yl)methyl]methanamine
160. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
161. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (dimethylamino)benzyl] amine
162. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (methylamino)benzyl] amine;
163. N-(4-amino-3-methylbenzyl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]amine;
164. N-benzyl- 1 -( 1 H-indol-5 -yl)-N- [(2-phenyl- 1 -propyl- 1 H-imidazol-5 -yl)methyl]methanamine ; 165. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(lH-indol-5- ylmethyl)methanamine;
166. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH- imidazol-5-yl)methyl]methanamine;
167. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- cyclopentylpropan- 1 -amine;
168. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cyclopentylmethyl)methanamine ;
169. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(2-fluoroρhenyl)-lH-imidazol-5- yljmethyl Jmethanamine;
170. N-benzyl- 1 -[ 1 -butyl-2-(2-fluorophenyl)- lH-imidazol-5-yl] -N-(2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)methanamine;
171. N-benzyl-l-[l-butyl-2-(2-fluorophenyl)-lH-imidazol-5-yl]-N-(2- naphthylmethyl)methanamine;
172. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dichlorobenzyl)methanamine;
173. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine;
174. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(thien-2- ylmethyl)methanamine;
175. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]butan-l- amine;
176. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]propan-l- amine;
177. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,4- dichlorobenzyl)methanamine;
178. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,4- dimethoxybenzyl)methanamine;
179. N-benzyl-l-(lH-indol-5-yl)-N-[(l-pentyl-2-phenyl-lH-imidazol-5-yl)methyl]methanamine;
180. N-benzyl-l-[l-(2-methoxyethyl)-2-phenyl-lH-imidazol-5-yl]-N-(l- naphthylmethyl)methanamine;
181. N-benzyl-l-[l-(2-methoxyethyl)-2-phenyl-lH-imidazol-5-yl]-N-(2- naphthylmethyl)methanamine;
182. methyl 4-( { benzyl[( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)phenyl(methyl)carbamate
183. methyl 4-( { benzyl [( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-2- methylphenylcarbamate;
184. l-(l-benzothien-5-yl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine;
185. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(3,4- dichlorophenyl)ethanamine;
186. 1 -(1 ,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- propylbenzyl)methanamine;
187. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- methylpropan- 1 -amine; 188. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- propoxybenzyι)methanamine;
189. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(2-methoxyphenyl)-lH-imidazol-5- yl]methyl Jmethanamine;
190. N-benzyl-l-[l-butyl-2-(2-methoxyphenyl)-lH-imidazol-5-yl]-N-(2- naphthylmethyl)methanamine;
191. 1 -(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-2-(2- methoxyphenyl)-lH-imidazol-5-yl]methyl}methanamine;
192. 4- [(benzyl { [ 1 -butyl-2- (2-methoxyphenyl)- 1 H-imidazol-5 -yl] methyl } amino)methyl] -N,N- dimethylaniline;
193. 1 -(1 ,3-benzodioxol-5-yl)-N-benzyl-N- { [l-butyl-2-(4-methoxyphenyl)- 1 H-imidazol-5- yl]methyl}methanamine;
194. 4-[(benzyl{ [ 1 -butyl-2-(4-methoxyphenyl)- lH-imidazol-5-yl]methyl } amino)methyl] -N,N- dimethylaniline;
195. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl}methanamine;
196. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl }methanamine;
197. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(2-methylphenyl)- 1 H-imidazol-5 -yl] methyl } methanamine ;
198. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl Jmethanamine;
199. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl}methanamine;
200. N-benzyl- 1 -[ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl] -N-(2- naphthylmethyl)methanamine;
201. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(3-methoxyphenyl)-lH-imidazol-5- yl]methyl Jmethanamine;
202. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(2-naphthyl)-lH-imidazol-5- yl]methyl Jmethanamine;
203. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)methanamine;
204. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-[(6-chloro- 1 ,3-benzodioxol-5- yl)methyl]methanamine;
205. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dichlorobenzyl)butan-l-amine;
206. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-4- yl)methyl]methanamine;
207. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-isopentyl-2-phenyl-lH-imidazol-4- yl)methyl]methanamine;
208. N-benzyl- 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3-methoxybenzyl)methanamine;
209. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chloro-4- fluorobenzyl)methanamine;
210. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,6-dichlorobenzyl)methanamine;
211. 4-({benzyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3-chlorophenol; N-benzyl- 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(4-pyrrolidin- 1 -ylbenzyl)methanamine;
N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (diethylamino)benzyl] amine;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(pyridin-2-ylmethyl)methanamine; l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(quinolin-6- ylmethyl)methanamine;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chloro-6- fluorobenzyl)methanamine;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,4-dichlorobenzyl)methanamine;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-chlorobenzyl)methanamine;
4-( { benzyl[( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)phenol ;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4- (trifluoromethoxy)benzyl]methanamine;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chloro-3,4- dimethoxybenzy l)methanamine ;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-nitrobenzyl)methanamine;
N-(4-aminobenzyl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amine; l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dichlorobenzyl)methanamine;
N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]indan-2- amine;
N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2,2- dimethylpropan- 1 -amine;
N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- methylbutan- 1 -amine;
5-({benzyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)pyridin-2-amine;
N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)methanamine;
4-({butyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3-chlorophenol
N- [( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -N- [4-(dimethylamino)benzyl] -N- isopentylamine;
4- [ (benzy 1 { [ 1 -butyl-2- (4-fluorophenyl)- 1 H-imidazol-5 -yl] methyl } amino)methyl] - 3 - chlorophenol;
4-[(benzyl{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}amino)methyl]-3- chlorophenol;
N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N-(2,3- dichlorobenzyl)methanamine;
4- [(benzyl { [ 1 -butyl-2-(3-fluorophenyl)- 1 H-imidazol-5 -yl]methyl } amino)methyl] -N,N- dimethylaniline;
N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N-(4-pyrrolidin-l- ylbenzyl)methanamine; l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(4-chlorophenyl)-lH-imidazol-5- yl]methyl}methanamine;
238. N-benzyl-l-[l-butyl-2-(4-chlorophenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)methanamine;
239. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5- yl)ethanamine;
240. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2-cyclohexyl-lH-imidazol-5- yl)methyl]methanamine;
241. N-benzyl-l-(l-butyl-2-cyclohexyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)methanamine;
242. N-benzyl-l-(l-butyl-2-cyclohexyl-lH-imidazol-5-yl)-N-(l-naphthylmethyl)methanamine;
243. N-benzyl-l-(l-butyl-2-cyclohexyl-lH-imidazol-5-yl)-N-(2-naphthylmethyl)methanamine;
244. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-cyclohexyl-lH- imidazol-5-yl)methyl]methanamine;
245. N-benzyl-l-(l-butyl-2-cyclohexyl-lH-imidazol-5-yl)-N-(2,3-dichlorobenzyl)methanamine;
246. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- cyclopentylethanamine;
247. N-( 1 ,3-benzodioxol-5-ylmethyl)-N-[( 1 -butyl-2-phenyl- lH-imidazol-5-yl)methyl] -2,2- dimethylbutan- 1 -amine;
248. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,4- dimethylbenzyl)methanamine;
249. N-(l ,3-benzodioxol-5-ylmethyl)-N-[( 1 -butyl-2-phenyl- lH-imidazol-5-yl)methyl] octan- 1 - amine;
250. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cycloheptylmethyl)methanamine ;
251. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cyclopropylmethyl)methanamine;
252. (lR)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-l-phenylethanamine;
253. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-l- phenylethanamine;
254. 2-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-l-cyclopentyl-l,2,3,4- tetrahydroisoquinoline ;
255. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-isopentyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine;
256. 4-{ [{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}(isopentyl)amino]methyl}-N,N- dimethylaniline
257. N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)methanamine;
258. N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)ethanamine;
259. 4-[(benzyl{ l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]ethyl}amino)methyl]-N,N- diethylaniline;
260. N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N-(4-pyrrolidin-l- ylbenzyl)ethanamine; 4-[(benzyl{l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]ethyl}amino)methyl]-3- chlorophenol; l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro- l-benzofuran-5-ylmethyl)methanamine;
N,N-bis(l,3-benzodioxol-5-ylmethyl)-l-[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]ethanamine;
N-( 1 ,3 -benzodioxol-5 -y lmethyl)-N-benzyl- 1 - [ 1 -butyl-2-(4-fluorophenyl)- 1 H-imidazol-5 - yljethanamine;
N-(l,3-benzodioxol-5-ylmethyl)-l-[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]-N- (cyclopentylmethyl)ethanamine; l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-thien-2-yl-lH- imidazol-5-yl)methyl]methanamine; l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2-thien-2-yl-lH-imidazol-5- yl)methyl]methanamine; l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-thien-2-yl-lH-imidazol-5-yl)methyl]-N- (cyclopentylmethyl)methanamine ; l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(l-methyl- lH-indol-5-yl)methyl]methanamine;
4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl] amino }methyl)-3-chlorophenol;
4- [(( 1 ,3-benzodioxol-5-ylmethyl) { 1 - [ 1 -butyl-2-(4-fluorophenyl)- 1 H-imidazol-5 - yl]ethyl}amino)methyl]-3-chlorophenol;
N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N-(2-chloro-4- methoxybenzyl)methanamine;
4- { [{ [ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl } (isopentyl)amino]methyl } -3- chlorophenol;
4-{[{l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]ethyl}(isopentyl)amino]methyl}-3- chlorophenol;
N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)-3-methylbutan-l-amine;
4-[(butyl{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}amino)methyl]-3- chlorophenol;
4-[(butyl{l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]ethyl}amino)methyl]-3- chlorophenol;
N-{l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]ethyl}-N-(2,3-dichlorobenzyl)butan-l- amine; l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N,N-bis(2,3-dihydro-l-benzofuran-5- ylmethyl)methanamine; l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(3-fluoro-2-methylphenyl)-lH-imidazol- 5-yl]methyl}methanamine hydrofluoride;
4-[(benzyl{(lR)-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]ethyl}amino)methyl]-3- chlorophenol;
N,N-bis(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)ethanamine;
N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N- (cyclohexylmethyl)pentan- 1 -amine;
284. 4-({(l,3-benzodioxol-5-ylmethyl)[l-(l-butyl-2-phenyl-lH-imidazol-5- yl)ethyl]amino}methyl)-3-chlorophenol;
285. 4-{[[l-(l -butyl-2-phenyl- 1 H-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino] methyl } -3- chlorophenol;
286. 4-({(l,3-benzodioxol-5-ylmethyl)[l-(l-butyl-2-phenyl-lH-imidazol-5- yl)ethyl] amino }methyl)phenol;
287. 4-{ [[l-(l-butyl-2-phenyl-lH-imidazol-5- yl)pentyl] (cyclohexylmethyl)amino]methyl Jphenol;
288. 4-{[[l-(l -butyl-2-phenyl- 1 H-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino] methyl Jbenzoic acid;
289. methyl 4-({benzyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoate;
290. methyl 4-({butyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoate;
291. methyl 4-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino] methyljbenzoate;
292. 4- { [[(1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] (cyclohexylmethyl)amino] methyl Jbenzoic acid;
293. (4-{ [[ 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino] methyl } phenyl)methanol ;
294. [4-( { benzyl[( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)phenyl] methanol ;
295. [4-({butyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenyl]methanol;
296. (4-{[[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl} phenyl)methanol;
297. methyl 3-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl) benzoate;
298. methyl 3-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino }methyl)benzoate;
299. methyl 3-{[[l-(l-butyl-2-phenyl-lH-imidazol-5- yl)pentyl] (cyclohexylmethyl)amino]methyl } benzoate;
300. 3-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)benzoic acid;
301. 3-{[[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl](cyclohexylmethyl)amino]methyl} benzoic acid;
302. [3-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenyl] methanol;
303. [3-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenyl]methanol;
304. (3- { [[ 1 -(1 -butyl-2-phenyl-lH-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino]methyl } phenyl)methanol;
305. methyl 5-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-2- hydroxybenzoate;
306. methyl 5-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino }methyl)-2- hydroxybenzoate;
307. methyl 5-{ [[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)ρentyl](cyclohexylmethyl)amino] methyl } -2-hydroxybenzoate;
308. methyl 5-({benzyl[( 1 -butyl-2-phenyl- lH-imidazol-5-yl)methyl] amino } methyl)-2- hydroxybenzoate; 309. methyl 5-({butyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzoate;
310. methyl 5-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino] methyl } -2-hydroxybenzoate;
311. 5-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-2-hydroxybenzoic acid;
312. 5- { [[ 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino]methyl } -2- hydroxybenzoic acid;
313. 5-({benzyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-hydroxybenzoic acid;
314. 5-({butyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-hydroxybenzoic acid;
315. 5-{[[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- hydroxybenzoic acid;
316. 4-( { benzylf 1 - ( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)pentyl] amino } methyl)-2- (hy droxymethy l)phenol ;
317. 4-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-2- (hydroxymethyl)phenol;
318. 4-{ [[ 1 -(1 -butyl-2-phenyl-lH-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino]methyl } -2- (hydroxymethyl)phenol;
319. methyl 5-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-2- methoxybenzoate ;
320. methyl 5-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-2- methoxybenzoate;
321. methyl 5- { [[ l-( 1 -butyl-2-phenyl- lH-imidazol-5-yl)pentyl] (cyclohexylmethyι)amino] methyl } -2-methoxybenzoate;
322. methyl 5-({benzyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzoate;
323. methyl 5-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino] methyl } -2-methoxybenzoate;
324. 5-{[[l-(l -butyl-2-phenyl- 1 H-imidazol-5-yl)pentyl] (cyclohexylmethyl)amino] methyl } -2- methoxybenzoic acid;
325. [5 -( { benzyl[ 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)pentyl] amino }methyl)-2- methoxyphenyl]methanol;
326. [5-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)ρentyl]amino}methyl)-2- methoxyphenyl]methanol;
327. (5- { [[ 1 -(1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)pentyl] (cyclohexylmethyl)amino]methyl } -2- methoxyphenyl)methanol ;
328. [5 -({ benzyl[( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-2- methoxyphenyljmethanol;
329. ■ (5-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- methoxyphenyl)methanol;
330. methyl 4-{[[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](4- hydroxybenzyl)amino]methyl}benzoate; 331. methyl 4-{ [[(l-butyl-2-phenyl-l H-imidazol-5 -yl)methyl](2-chloro-4- hydroxybenzyl)amino]methyl}benzoate;
332. methyl 4-{[[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl}benzoate;
333. methyl 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]amino}methyl)benzoate;
334. diethyl 5-({benzyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino) methyl)isophthalate;
335. diethyl 5-({butyl[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)isophthalate;
336. diethyl 5-{ [[(l-butyl-2-phenyl-l H-imidazol-5 -yl)methyl](cyclohexylmethyl)amino] methyljisophthalate;
337. 4-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](4-hydroxybenzyl)amino] methyl} benzoic acid;
338. 4- { [[( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] (2-chloro-4-hydroxybenzyl)amino] methyl Jbenzoic acid;
339. 4-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](4-methoxybenzyl)amino] methyl }benzoic acid;
340. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino} methyl)benzoic acid;
341. 4-({ [(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl] [4-(hydroxymethyl)benzyl] amino } methyl)phenol ;
342. 4-({[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl][4-(hydroxymethyl)benzyl] amino }methyl)-3-chlorophenol;
343. (4- { [ [( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] (4-methoxybenzyl)amino] methyl }phenyl)methanol;
344. [4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino} methyl)phenyl] methanol ;
345. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentan-l- amine;
346. 4-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenol;
347. 4-( { benzyl[ 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)pentyl] amino } methyl)-3-chlorophenol ;
348. 3-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenol;
349. 4-({ benzyl[ 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)pentyl] amino }methyl)phenyl acetate;
350. 3-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenyl acetate;
351. N-(l,3-benzodioxol-5-ylmethyl)-N-butyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentan-l- amine;
352. '4-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenol;
353. 4-( { butyl [ 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)pentyl] amino } methyl)-3-chlorophenol;
354. 3-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)phenol;
355. 4-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)ρhenyl acetate;
356. 3-({butyl[l-(l-butyl-2-ρhenyl-lH-imidazol-5-yl)ρentyl]amino}methyl)ρhenyl acetate;
357. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(4-methoxybenzyl)pentan- 1 -amine; 358. N-butyl- 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)-N-(4-methoxybenzyl)pentan- 1 -amine ;
359. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4-methoxybenzyl)pentan- 1 -amine;
360. N-butyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-[4-(trifluoromethoxy)benzyl]pentan- 1 - amine;
361. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3-methoxybenzyl)pentan- 1 -amine;
362. N-butyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3-methoxybenzyl)pentan- 1 -amine;
363. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3-methoxybenzyl)pentan- 1 -amine;
364. 4-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-N,N- dimethylaniline;
365. 4-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)-N,N- dimethylaniline;
366. 4-{[[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl](cyclohexylmethyl)amino]methyl}-N,N- dimethylaniline;
367. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N- (cyclohexylmethyl)pentan-l-amine;
368. 4-{[[(lR)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl](cyclohexylmethyl)amino] methyl } -3-chlorophenol;
369. (lR)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- methoxybenzyl)butan- 1 -amine.
370. N,N-dibenzyl-l-[l-butyl-2-(2-fluorophenyl)-lH-imidazol-5-yl]methanamine
37 N-benzyl-l-[l-butyl-2-(2-fluorophenyl)-lH-imidazol-5-yl]-N-(3- methylbenzyl)methanamine
372. N-benzyl-l-[l-butyl-2-(2-fluorophenyl)-lH-imidazol-5-yl]-N-(4-ethylbenzyl)methanamine
373. N-benzyl-l-[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]-N-(3,4- dimethylbenzyl)methanamine
374. N-benzyl- 1 -[ 1 -butyl-2-(2-fluorophenyl)- lH-imidazol-5-yl] -N-(4- isopropylbenzyl)methanamine
375. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-phenylethanamine ,
376. N-benzyl- 1 -[ 1 -butyl-2-(4-methoxyphenyl)- 1 H-imidazol-5 -yl] -N-(4- isopropylbenzyl)methanamine
377. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]butan-l- amine
378. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- methylpropan- 1 -amine
379. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cyclobutylmethyl)methanamine
380. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]pentan-l- amine
381. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- methylbutan- 1 -amine 382. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2,2- dimethylpropan- 1 -amine
383. N-benzyl- 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)-N-(cyclopentylmethyl)methanamine
384. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cyclopentylmethyl)methanamine
385. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]hexan-l- amine
386. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-4- methylpentan-1-amine
387. N-( 1 ,3-benzodioxol-5-ylmethyl)-N-[(l -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -3 ,3- dimethylbutan- 1 -amine
388. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- ethylbutan- 1 -amine
389. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2,2-dimethylbutan-l-amine
390. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2,2- dimethylbutan- 1 -amine
391. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- cyclopentylethanamine
392. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-pheny -lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
393. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]heptan-l- amine
394. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- cyclohexylethanamine
395. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cycloheptylmethyl)methanamine
396. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- cyclopentylpropan- 1 -amine
397. N-(l ,3-benzodioxol-5-ylmethyl)-N-[( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] octan- 1 - amine
398. l-(l,3-benzodioxol-5-yl)-N-(l,l'-biphenyl-2-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol- 5-yl)methyl]methanamine
399. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- phenoxybenzyl)methanamine
400. N-benzyl-N- [( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] -2-phenylethanamine
401. N,N-dibenzyl- 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methanamine
402. N-benzyl- 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)-N-( 1 -naphthylmethyl)methanamine
403. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
404. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-methylbenzyl)-2-phenylethanamine
405. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3-methylbenzyl)methanamine
406. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-methylbenzyl)-N-(l- naphthylmethyl)methanamine 407. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- methylbenzyl)methanamine
408. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4-methylbenzyl)-2-phenylethanamine
409. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-methylbenzyl)methanamine
410. 1 -(1 -butyl-2-phenyl- 1 H-imidazol-5-yl)-N-(4-methylbenzyl)-N-( 1 - naphthylmethyl)methanamine
411. 1 -(1 ,3-benzodioxol-5-yl)-N-[( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] -N-(4- methylbenzyl)methanamine
412. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-methylbenzyl)methanamine
413. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-methylbenzyl)-N-(l- naphthylmethyl)methanamine
414. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- methylbenzyl)methanamine
415. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- fluorobenzyl)methanamine
416. N- [( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -N-(4-fluorobenzyl)-2-phenylethanamine
417. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- fluorobenzyl)methanamine
418. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2-fluorobenzyl)-2-phenylethanamine
419. N-benzyl- 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5-yl)-N-(2-fluorobenzyl)methanamine
420. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-fluorobenzyl)-N-(l- naphthylmethyl)methanamine
421. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-ρhenyl-lH-imidazol-5-yl)methyl]-N-(2- fluorobenzyl)methanamine
422. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4-ethylbenzyl)-2-phenylethanamine
423. N-benzyl- 1 -( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)-N-(4-ethylbenzyl)methanamine
424. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-ethylbenzyl)-N-(l- naphthylmethyl)methanamine
425. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- ethylbenzyl)methanamine
426. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,4-dimethylbenzyl)-2- phenylethanamine
427. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3,4-dimethylbenzyl)methanamine
428. 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3 ,4-dimethylbenzyl)-N-(l- naphthylmethyl)methanamine
429. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,4- dimethylbenzyl)methanamine
430. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3,5-dimethylbenzyl)methanamine
431. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,5- dimethylbenzyl)methanamine
432. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dimethylbenzyl)-2- phenylethanamine 433. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dimethylbenzyl)methanamine
434. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dimethylbenzyl)methanamine
435. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,5-dimethylbenzyl)-2- phenylethanamine
436. N-benzyl- 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(2,5-dimethylbenzyl)methanamine
437. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,5-dimethylbenzyl)-N-(l- naphthylmethyl)methanamine
438. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,5- dimethylbenzyl)methanamine
439. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,4-dimethylbenzyl)-2- phenylethanamine
440. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,4-dimethylbenzyl)methanamine
441. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,4-dimethylbenzyl)-N-(l- naphthylmethyl)methanamine
442. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,4- dimethylbenzyl)methanamine
443. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxybenzyl)-2-phenylethanamine
444. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-methoxybenzyl)methanamine
445. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-methoxybenzyl)-N-(l- naphthylmethyl)methanamine
446. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- methoxybenzyl)methanamine
447. N- [( 1 -butyl-2-phenyl- lH-imidazol-5 -yl)methyl] -N-(4-methoxybenzyl)-2-phenylethanamine
448. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)methanamine
449. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(l- naphthylmethyl)methanamine
450. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
451. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2-methoxybenzyl)-2-phenylethanamine
452. N-benzyl- 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(2-methoxybenzyl)methanamine
453. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-methoxybenzyl)-N-(l- naphthylmethyl)methanamine
454. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- methoxybenzyl)methanamine
455. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-4-methylbenzyl)-2- phenylethanamine
456. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-fluoro-4-methylbenzyl)methanamine
457. 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3-fluoro-4-methylbenzyl)-N-( 1 - naphthylmethyl)methanamine
458. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-4- methylbenzyl)methanamine 459. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-fluoro-2-methylbenzyl)methanamine
460. 1 -(1 ,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-2- methylbenzyl)methanamine
461. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(5-fluoro-2-methylbenzyl)-2- phenylethanamine
462. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(5-fluoro-2-methylbenzyl)methanamine
463. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(5-fluoro-2-methylbenzyl)-N-(l- naphthylmethyl)methanamine
464. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(5-fluoro-2- methylbenzyl)methanamine
465. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- chlorobenzyl)methanamine
466. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-chlorobenzyl)-N-(l- naphthylmethyl)methanamine
467. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- chlorobenzyl)methanamine
468. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2-chlorobenzyl)-2-phenylethanamine
469. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chlorobenzyl)methanamine
470. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chlorobenzyl)-N-(l- naphthylmethyl)methanamine
471. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- chlorobenzyl)methanamine
472. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3,4- difluorobenzyl)methanamine
473. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-difluorobenzyl)methanamine
474. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-difluorobenzyl)-N-(l- naphthylmethyl)methanamine
475. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- difluorobenzyl)methanamine
476. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,5-difluorobenzyl)methanamine
477. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,5-difluorobenzyl)-N-(l- naphthylmethyl)methanamine
478. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,5- difluorobenzyl)methanamine
479. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,4-difluorobenzyl)-N-(l- naphthylmethyl)methanamine
480. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,4- difluorobenzyl)methanamine
481. N- [(1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -2-phenyl-N- (4-propylbenzyl)ethanamine
482. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(4-propylbenzyl)methanamine
483. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(l-naphthylmethyl)-N-(4- propylbenzyl)methanamine 484. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- propylbenzyl)methanamine
485. N-benzyl- 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(4-isopropylbenzyl)methanamine
486. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-isopropylbenzyl)-N-(l- naphthylmethyl)methanamine
487. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- isopropylbenzyl)methanamine
488. N- [( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -N-(3-ethoxybenzyl)-2-phenylethanamine
489. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-ethoxybenzyl)methanamine
490. 1 -( 1 -butyl-2-ρhenyl- lH-imidazol-5-yl)-N-(3-ethoxybenzyl)-N-(l - naphthylmethyl)methanamine
491. 1-(1 ,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
492. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-ethoxybenzyl)-N-(l- naphthylmethyl)methanamine
493. 1 -(1 ,3-benzodioxol-5-yl)-N-[( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -N-(4- ethoxybenzyl)methanamine
494. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2-ethoxybenzyl)-2-phenylethanamine
495. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- ethoxybenzyl)methanamine
496. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- phenylethanamine
497. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(l- naphthylmethyl)methanamine
498. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH- imidazol-5-yl)methyl]methanamine
499. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4-(methylthio)benzyl]-2- phenylethanamine
500. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4-(methylthio)benzyl]methanamine
501. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4-(methylthio)benzyl]-N-(l- naphthylmethyl)methanamine
502. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (methylthio)benzyl]methanamine
503. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-4-methoxybenzyl)-2- phenylethanamine
504. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-fluoro-4- methoxybenzyl)methanamine
505. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3-fluoro-4-methoxybenzyl)-N-(l- naphthylmethyl)methanamine
506. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-4- methoxybenzyl)methanamine
507. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-chloro-3- methylbenzyl)methanamine 508. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-chloro-3-methylbenzyl)-N-(l- naphthylmethyl)methanamine
509. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4-chloro-3- methylbenzyl)methanamine
510. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-chloro-4- fluorobenzyl)methanamine
511. N-benzyl-l-(4-butylphenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]methanamine
512. 1 -(1 ,3-benzodioxol-5-yl)-N-(4-butylbenzyl)-N-[(l -butyl-2-phenyl- lH-imidazol-5- yl)methyl] methanamine
513. N-(4-tert-butylbenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- phenylethanamine
514. N-benzyl-l-(4-tert-butylphenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
515. l-(l,3-benzodioxol-5-yl)-N-(4-tert-butylbenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl] methanamine
516. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- propoxybenzyl)methanamine
517. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-isopropoxybenzyl)methanamine
518. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-isopropoxybenzyl)-N-(l- naphthylmethyl)methanamine
519. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- isopropoxybenzyl)methanamine
520. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4-(ethylthio)benzyl]-2- phenylethanamine
521. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4-(ethylthio)benzyl]methanamine
522. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4-(ethylthio)benzyl]-N-(l- naphthylmethyl)methanamine
523. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (ethylthio)benzyl]methanamine
524. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3,5,6- tetrafluorobenzyl)methanamine
525. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3,5,6- tetrafluorobenzyl)methanamine
526. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(l-naphthylmethyl)-N-(2,4,6- trifluorobenzyl)methanamine
527. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,4,6- trifluorobenzyl)methanamine
528. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(l-naphthylmethyl)-N-(2,3,6- trifluorobenzyl)methanamine
529. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3,6- trifluorobenzyl)methanamine
530. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chloro-6-fluorobenzyl)methanamine
531. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chloro-6-fluorobenzyl)-N-(l- naphthylmethyl)methanamine
532. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2-chloro-6- fluorobenzyl)methanamine
533. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(l-naphthylmethyl)-N-(2,4,6- trichlorobenzyl)methanamine
534. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,4- dimethoxyphenyl)ethanamine
535. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,6- difluorophenyl)ethanamine
536. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,6- difluorophenyl)ethanamine
537. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-[4- (methylthio)phenyl] ethanamine
538. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-[4- (methylthio)pheny 1] ethanamine
539. 2-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl] ethanamine
540. 2-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH- imidazol-5-yl)methyl] ethanamine
541. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro-5- (methylthio)benzyl]methanamine
542. N-benzyl-l-(2-bromo-5-methylphenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- y l)methy 1] methanamine
543. l-(l,3-benzodioxol-5-yl)-N-(2-bromo-5-methylbenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol- 5-yl)methyl]methanamine
544. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2-chloro-4,5-dimethoxybenzyl)-N-(l- naphthylmethyl)methanamine
545. l-(l,3-benzodioxol-5-yl)-N-(2-bromo-3-methylbenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol- 5 -yl)methy 1] methanamine
546. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro-5- (trifluoromethyl)benzyl]methanamine
547. 1 -(2-bromo-4,5 -dimethoxyphenyl)-N- [( 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -N-( 1 - naphthylmethyl)methanamine
548. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[2-(methylthio)benzyl]methanamine
549. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[2- (methylthio)benzyl]methanamine
550. N-(l,3-benzodioxol-5-ylmethyl)-2-(2-bromo-4,5-dimethoxyphenyl)-N-[(l-butyl-2-phenyl- lH-imidazol-5-yl)methyl]ethanamine
551. N-(l ,3-benzodioxol-5-ylmethyl)-2-(5-bromo-2-methoxyphenyl)-N-[(l -butyl-2-phenyl- 1H- imidazol-5 -yl)methyl] ethanamine
552. N-(l,3-benzodioxol-5-ylmethyl)-2-[4-(benzyloxy)phenyl]-N-[(l-butyl-2-phenyl-lH- imidazol-5-yl)methyl]ethanamine
553. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,3- dimethoxyphenyl)ethanamine 554. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,3- difluorophenyl)ethanamine
555. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2- phenoxyphenyl)ethanamine
556. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-iodo-4- methylbenzyl)methanamine
557. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4- iodophenyl)ethanamine
558. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-lH-imidazol-5-yl]methyl}-2- (phenyl)ethanamine
559. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(5- methylthien-2-yl)methyl]methanamine
560. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4- methylphenyl)ethanamine
561. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2- methylphenyl)ethanamine
562. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-phenylpropan-l-amine
563. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- phenylpropan- 1 -amine
564. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- phenoxyethanamine
565. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2- fluorophenyl)ethanamine
566. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-phenylbutan-l-amine
567. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- phenylbutan- 1 -amine
568. N-benzyl-N-[(l -butyl-2-phenyl- lH-imidazol-5-yl)methyl] -2-(2-methylphenyl)propan- 1 - amine
569. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2- methylphenyl)propan- 1 -amine
570. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(3- methoxyphenyl)ethanamine
571. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4- methoxyphenyl)ethanamine
572. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(2- fluorophenyl)prop-2-en- 1 -amine
573. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4- ethoxyphenyl)ethanamine
574. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2- ethoxyphenyl)ethanamine
575. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(3- methylphenoxy)ethanamine
576. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-ρhenyl-lH-imidazol-5-yl)methyl]-2-(3- methoxyphenoxy)ethanamine 577. (2Z)-N-[(1 -butyl-2-phenyl- lH-imidazol-5-yl)methyl] -3-(2,5-dimethoxyphenyl)-N-( 1 - naphthylmethyl)prop-2-en- 1 -amine
578. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- (2,5-dimethoxyphenyl)prop-2-en- 1 -amine
579. (2Z)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(3,5-dimethoxyphenyl)-N-(2- phenylethyl)prop-2-en- 1 -amine
580. (2Z)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(3,5-dimethoxyphenyl)-N-(l- naphthylmethyl)prop-2-en- 1 -amine
581. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- (3,5-dimethoxyphenyl)prop-2-en-l-amine
582. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-[3- (trifluoromethyl)phenyl]prop-2-en- 1 -amine
583. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- (2,6-dichlorophenyl)prop-2-en- 1 -amine
584. (2Z)-3-(3-bromophenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- phenylethyl)prop-2-en- 1 -amine
585. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-3-(3-bromophenyl)-N-[(l-butyl-2-phenyl-lH- imidazol-5-yl)methyl]prop-2-en-l-amine
586. (2Z)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-thien-3-ylprop-2-en-l- amine
587. (2Z)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(l-naphthylmethyl)-3-thien-3- ylprop-2-en- 1 -amine
588. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3- thien-3-ylprop-2-en- 1 -amine
589. (2Z)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(2-furyl)-N-(l- naphthylmethyl)prop-2-en-l-amine
590. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(2- furyl)prop-2-en- 1 -amine
591. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(4- isopropylphenyl)prop-2-en- 1 -amine
592. N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-phenyl-N-[(2- phenylcyclopropyl)methyl]ethanamine
593. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[(2- phenylcyclopropyl)methyl]methanamine
594. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(2- phenylcyclopropyl)methyl]methanamine
595. (2E)-N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-fluoro-3-phenylprop-2- en-1 -amine
596. (2E)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-fluoro-N-(l-naphthylmethyl)-3- phenylprop-2-en- 1 -amine
597. (2E)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- fluoro-3-phenylprop-2-en-l-amine
598. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2-chlorophenyl)ethanamine
599. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2- chlorophenyl)ethanamine
600. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-methyl-2-phenylbutan-l-amine
601. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-methyl- 2-phenylbutan- 1 -amine
602. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4-ethoxyphenyl)ethanamine
603. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-lH-imidazol-5-yl]methyl}-2-(4- ethoxyphenyl)ethanamine
604. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2-ethoxyphenyl)ethanamine
605. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-lH-imidazol-5-yl]methyl}-2-(2- ethoxyphenyl)ethanamine
606. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4-methoxyphenyl)butan-l- amine
607. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(4- methoxyphenyl)butan- 1 -amine
608. N-benzyl-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,5- dimethoxyphenyl)ethanamine
609. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,5- dimethoxyphenyl)ethanamine
610. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-[4- (trifluoromethyl)phenyl]ethanamine
611. N-(l ,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- cyclopentyl-2-phenylethanamine
612. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,4- dichlorophenyl)ethanamine
613. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2,2- diphenylethanamine
614. N-(l,3-benzodioxol-5-ylmethyl)-2-(3-bromophenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl] ethanamine
615. N-(l,3-benzodioxol-5-ylmethyl)-2-(4-bromophenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl] ethanamine
616. N-(l,3-benzodioxol-5-ylmethyl)-2-(2-bromophenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl] ethanamine
617. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- cyclohexyl-2-phenylethanamine
618. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dimethoxybenzyl)methanamine
619. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,5- dimethoxybenzyl)methanamine
620. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4-chloro-2- methoxybenzyl)methanamine
621. N-benzyl-l-(3-bromo-4-methylphenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
622. N-(3-bromo-4-methylbenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-2- phenylethanamine
623. l-(3-bromo-4-methylphenyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(l- naphthylmethyl)methanamine
624. l-(l,3-benzodioxol-5-yl)-N-(3-bromo-4-methylbenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol- 5-yl)methyl]methanamine
625. l-(l,3-benzodioxol-5-yl)-N-(3-bromo-4-fluorobenzyl)-N-[(l-butyl-2-phenyl-lH-imidazol- 5 -yl)methyl] methanamine
626. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[2-(2- phenylethyl)benzyl]methanamine
627. N-benzyl- 1 -(1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(3-iodobenzyl)methanamine
628. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-ρhenyl-lH-imidazol-5-yl)methyl]-N-(3- iodobenzyl)methanamine
629. N-benzyl-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(4-iodobenzyl)methanamine
630. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(4- iodobenzyl)methanamine
631. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2- iodobenzyl)methanamine
632. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-3-(5-bromo-2-fluorophenyl)-N-[(l-butyl-2-phenyl- lH-imidazol-5-yl)methyl]prop-2-en-l-amine
633. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-3-(4-bromo-2-fluorophenyl)-N-[(l-butyl-2-phenyl- lH-imidazol-5-yl)methyl]prop-2-en- 1 -amine
634. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(4- chloro-2-fluorophenyl)prop-2-en-l-amine
635. (2Z)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-3-(2- chloro-6-fluorophenyl)prop-2-en- 1 -amine
636. (2Z)-N-(1 ,3-benzodioxol-5-ylmethyl)-3-(5-bromo-2-ethoxyphenyl)-N-[( l-butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl]prop-2-en- 1 -amine
637. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yljmethyl }butan-l -amine
638. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-methylpropan-l-amine
639. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (cyclobutylmethyl)methanamine
640. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl Jpentan- 1 -amine
641. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yljmethyl } -3-methylbutan- 1 -amine
642. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yljmethyl } -2,2-dimethylpropan-l -amine
643. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (cyclopentylmethyl)methanamine
644. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl Jhexan- 1 -amine 645. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-4-methylpentan-l-amine
646. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-3,3-dimethylbutan-l-amine
647. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-ethylbutan- 1 -amine
648. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluoroρhenyl)-l H-imidazol-5 - yl]methyl } -2,2-dimethylbutan- 1 -amine
649. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-l H-imidazol-5 - yl]methyl}-2-cyclopentylethanamine
650. 1 -( 1 ,3-benzodioxol-5-yl)-N- { [1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N- (cyclohexylmethyl)methanamine
651. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [ l-butyl-2-(4-fluorophenyl)-l H-imidazol-5 - yl]methyl Jheptan- 1 -amine
652. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-cyclohexylethanamine
653. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N- (cycloheptylmethyl)methanamine
654. N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- 1 H-imidazol-5- yl]methyl}-3-cyclopentylpropan-l-amine
655. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl] methyl } octan- 1 -amine
656. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl] methyl } -2-ethylbutan- 1 -amine
657. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yljmethyl } -2,2-dimethylbutan- 1 -amine
658. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-cyclopentylethanamine
659. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)methanamine
660. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl] methyl } heptan- 1 - amine
661. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yljmethyl }methanamine
662. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(3- methylbenzyl)methanamine
663. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N-(4- methylbenzyl)methanamine
664. N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(cyclohexylmethyl)-N-(4- methylbenzyl)amine
665. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N-(2- fluorobenzyl)methanamine
666. N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(3,4-dimethylbenzyl)-3- methylbutan- 1 -amine 667. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (3 ,4-dimethylbenzyl)methanamine
668. N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(cyclohexylmethyl)-N-(3,4- dimethylbenzyl)amine
669. 1 -( 1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N- (2,3-dimethylbenzyl)methanamine
670. N-(2,4-dimethylphenylmethyl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- 1 H-imidazol-5-yl]methyl } - 4-methylpentan- 1 -amine
671. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)- 1 H-imidazol-5 -yl] methyl } methanamine
672. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl] methyl } -2-(cyclohexylmethyl)ethanamine
673. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[4- (methylthio)benzyl]methanamine
674. N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]-N- (cyclohexylmethyl)methanamine
675. N- { [ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl } -3-methyl-N-(4- methylbenzyl)butan- 1 -amine
676. N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(cyclohexylmethyl)-N-(4- methylbenzyl)amine
677. N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(3,4-dimethylbenzyl)-3- methylbutan- 1 -amine
678. N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(cyclohexylmethyl)-N-(4- methoxybenzyl)amine
679. N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-3-methyl-N-(4- propylbenzyl)butan- 1 -amine
680. N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(4-isopropylbenzyl)-3- methylbutan- 1 -amine
681. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(cyclohexylmethyl)-N-(4- isopropylbenzyl)amine
682. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl } -3-methylbutan- 1 -amine
683. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl}methanamine
684. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(cyclohexylmethyl)ethanamine
685. N- { [ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl } -3-methyl-N-[4- (methylthio)benzyl]butan- 1 -amine
686. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[4- (methylthio)benzyl]methanamine
687. N-(4-butylbenzyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-3- methylbutan- 1 -amine
688. N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[4-(ethylthio)benzyl]-3- methylbutan- 1 -amine 689. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (3,5-dimethoxybenzyl)methanamine
690. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N- (2,5-dimethoxybenzyl)methanamine
691. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (2,4-dimethoxybenzyl)methanamine
692. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (2,5-dichlorobenzyl)methanamine
693. 1-(1 ,3-benzodioxol-5-yl)-N-(3-bromobenzyl)-N-{ [l-butyl-2-(4-fluoroρhenyl)-lH-imidazol- 5-yl]methyl}methanamine
694. l-(l,3-benzodioxol-5-yl)-N-(4-bromobenzyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol- 5-yl]methyl}methanamine
695. l-(l,3-benzodioxol-5-yl)-N-(2-bromobenzyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol- 5-yl]methyl}methanamine
696. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[2- (2-phenylethyl)benzyl]methanamine
697. N-(2-fluorobenzyl)-3-methyl-N-{[2-phenyl-l-(2-phenylethyl)-lH-imidazol-5- yljmethyl }butan- 1 -amine
698. l-(l,3-benzodioxol-5-yl)-N-(2-fluorobenzyl)-N-{[2-phenyl-l-(2-phenylethyl)-lH-imidazol- 5-yl]methyl}methanamine
699. N-(4-ethylbenzyl)-3-methyl-N-{[2-phenyl-l-(2-phenylethyl)-lH-imidazol-5- yl]methyl}butan-l-amine
700. N-(3 ,4-dimethylbenzyl)-3-methyl-N- { [2-phenyl- 1 -(2-phenylethyl)- 1 H-imidazol-5 - yl] methyl }butan- 1 -amine
701. N-(3 ,5-dimethylbenzyl)-3-methyl-N- { [2-phenyl- 1 -(2-phenylethyl)- lH-imidazol-5- yl]methyl Jbutan- 1 -amine
702. N-(2,3-dimethylbenzyl)-3-methyl-N- { [2-phenyl- 1 -(2-phenylethyl)- lH-imidazol-5- yljmethyl } butan- 1 -amine
703. 1 -( 1 ,3-benzodioxol-5-yl)-N- { [1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl } -N- (2,4,6-trifluorobenzyl)methanamine
704. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (2,3,6-trifluorobenzyl)methanamine
705. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(3 ,4-dimethoxyphenyl)ethanamine
706. 2-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl}ethanamine
707. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(2-naphthyl)ethanamine
708. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(3-methyl- 1 -benzothien-2-yl)ethanamine
709. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (2,5-dimethoxybenzyl)methanamine
710. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (2,4-dimethoxybenzyl)methanamine 711. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-(3-chloro-4-methoxybenzyl)- 3 -methylbutan- 1 -amine
712. N-{ [ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl } -N-(cyclohexylmethyl)-N-(2,3 ,4- trimethoxybenzyl)amine
713. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(4-methylphenyl)ethanamine
714. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(3-methoxyphenyl)ethanamine
715. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(4-methoxyphenyl)ethanamine
716. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(4-chlorophenyl)ethanamine
717. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(3-methoxyphenyl)ethanamine
718. N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5- yl]methyl } -2-(4-methoxyphenyl)ethanamine
719. N-( 1 ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-2-(4-fluorophenyl)- 1 H-imidazol-5 - yl]methyl } -2-(4-iodophenyl)ethanamine
720. N-(l,3-benzodioxol-5-ylmethyl)-2-(4-bromophenyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH- imidazol-5 -yljmethyl } ethanamine
721. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-l H-imidazol-5 - yl]methyl}-2-[4-(methylthio)phenyl]ethanamine
722. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(4-iodophenyl)ethanamine
723. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-[4-(methylthio)phenyl]ethanamine
724. N-(l ,3-benzodioxol-5-ylmethyl)-2-[4-(methylthio)phenyl]-N-{ [2-phenyl- l-(2-phenylethyl)- 1 H-imidazol-5 -yl]methyl } ethanamine
725. 4- { [ { [ 1 -butyl-2-(3-fluorophenyl)- lH-imidazol-5-yl]methyl } (isopentyl)amino]methyl } -N- methylaniline
726. 4-{ [{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl } (cyclohexylmethyl)amino]methyl } -N-methylaniline
727. 3-{ [{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yljmethyl } (cyclohexylmethyl)amino]methyl } -2-methylaniline
728. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N- (2,6-difluorobenzyl)methanamine
729. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[2- (methylthio)benzyl]methanamine
730. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[2- (trifluoromethoxy)benzyl]methanamine
731. l-(l,3-benzodioxol-5-yl)-N-[2,5-bis(2,2,2-trifluoroethoxy)benzyl]-N-{[l-butyl-2-(4- fluorophenyl)-lH-imidazol-5-yl]methyl}methanamine
732. l-(l,3-benzodioxol-5-yl)-N-(2-bromo-3-methylbenzyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH- imidazol-5-yl]methyl}methanamine 733. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)- H-imidazol-5-yl]methyl}-N-[2- chloro-5-(methylthio)benzyl]methanamine
734. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)- H-imidazol-5-yl]methyl}-N-(l- naphthylmethyl)methanamine
735. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(4-fluoroρhenyl)- H-imidazol-5-yl]methyl}-N- (9H-fluoren-4-ylmethyl)methanamine
736. N-benzyl-l-[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl ■N-[2- (methylthio)benzyl]methanamine
737. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(3-fluorophenyl)- H-imidazol-5-yl]methyl } -N-[2- (methylthio)benzyl]methanamine
738. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl N-(2-chloro-3,4- dimethoxybenzyl)-3-methylbutan- 1 -amine
739. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl N-(2-chloro-4,5- dimethoxybenzyl)-N-(cyclohexylmethyl)amine
740. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)- H-imidazol-5-yl]methyl}-N-(2- naphthylmethyl)methanamine
741. N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl N-(3 -iodo-4-methylbenzyl) -3 - methylbutan- 1 -amine
742. N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl N-(3-chloro-4-methylbenzyl)-3- methylbutan- 1 -amine
743. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)- H-imidazol-5-yl]methyl}-N-(3- chloro-4-methylbenzyl)methanamine
744. N- { [ 1 -butyl-2-(4-fluorophenyl)- lH-imidazol-5-yl]methyl N-(2,3-dihydro-l-benzofuran-5- ylmethyl)-3-methylbutan-l-amine
745. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)- H-imidazol-5-yl]methyl } -N- (2,3-dihydro-l-benzofuran-5-ylmethyl)methanamine
746. N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl -N-(cyclohexylmethyl)-N-(2,3- dihydro-l-benzofuran-5-ylmethyl)amine
747. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(4-fluorophenyl)- H-imidazol-5-yl]methyl } -N-[4- (difluoromethoxy)benzyl]methanamine
748. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl 3-methyl-N-(2- naphthylmethyl)butan- 1 -amine
749. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl N-(3-iodo-4-methylbenzyl)-3- methylbutan- 1 -amine
750. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl N-(cyclohexylmethyl)-N-(3- iodo-4-methylbenzyl)amine
751. l-(l,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(3-fluorophenyl H-imidazol-5-yl]methyl } -N- (2,3-dihydro- 1 -benzofuran-5-ylmethyl)methanamine
752. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl -N-(cyclohexylmethyl)-N-(2,3- dihydro-l-benzofuran-5-ylmethyl)amine
753. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl ■N-[4-(difluoromethoxy)benzyl]- 3-methylbutan- 1 -amine
754. N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5-yl]methyl ■N-(cyclohexylmethyl)-N- [4- (difluoromethoxy)benzyl] amine 755. N-(3-iodo-4-methylbenzyl)-3-methyl-N-{[2-phenyl-l-(2-phenylethyl)-lH-imidazol-5- yl] methyl }butan- 1 -amine
756. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(2-phenoxyphenyl)ethanamine
757. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yljmethyl } -2-(2-fluorophenyl)ethanamine
758. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(2-methoxyphenyl)ethanamine
759. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(2-ethoxyphenyl)ethanamine
760. N-(l,3-benzodioxol-5-ylmethyl)-2-(2-bromophenyl)-N-{[l-butyl-2-(4-fluorophenyl)-lH- imidazol-5-yl]methyl } ethanamine
761. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-l H-imidazol-5 - yl]methyl}-2-(2,5-dimethoxyphenyl)ethanamine
762. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-l H-imidazol-5 - yl]methyl}-2-(2,3-dimethoxyphenyl)ethanamine
763. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4-fluorophenyl)-lH-imidazol-5- yl]methyl } -2-(2,4-dimethoxyphenyl)ethanamine
764. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(3,4-dimethoxyphenyl)ethanamine
765. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(4-ethoxy-3-methoxyphenyl)ethanamine
766. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(3-fluorophenyl)-lH-imidazol-5- yl]methyl}-2-(2-naphtl}yl)ethanamine
767. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-{[6- methyl-2-(4-methylphenoxy)pyridin-3-yl]methyl}methanamine
768. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(4-fluorophenyl)-lH-imidazol-5-yl]methyl}-N-[(2- phenoxypyridin-3-yl)methyl]methanamine
769. N-{ [2-(allylthio)pyridin-3-yl]methyl}-N-(l,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(4- fluorophenyl)- 1 H-imidazol-5-yl]methyl } amine
770. 2-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)benzamide
771. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2,5-difluoro-N-(4- methoxybenzyl)benzamide
772. N-(cyclohexylmethyl)-N- { [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5- yljmethyl } -2,5-difluorobenzamide
773. 5-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2- methoxy-N-(4-methoxybenzyl)benzamide
774. 5-chloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol- 5 -yl] methyl } -2-methoxybenzamide
775. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-(trifluoromethyl)benzamide
776. N-benzyl-2,5-dichloro-N- { [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5- yl]methyl}benzamide 777. 2,5-dichloro-N-{[l-'(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)benzamide
778. 2,5-dichloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH- imidazol-5-yl]methyl }benzamide
779. 2-bromo-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)benzamide
780. N- { [ 1 -(2,3-dihydro- 1 H-indan-2-yl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -N-(4- methoxybenzyl)-2-(2-phenylethyl)benzamide
781. N- { [ 1 -(2,3-dihydro- 1 H-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -2-iodo-N-(4- methoxybenzyl)benzamide
782. 3-chloro-N-{ [l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl }-2,6- dimethoxy-N-(4-methoxybenzyl)benzamide
783. 2-bromo-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-5- methoxy-N-(4-methoxybenzyl)benzamide
784. 3-bromo-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2,6- dimethoxy-N-(4-methoxybenzyl)benzamide
785. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2-fluoro-6-iodo-N- (4-methoxybenzyl)benzamide
786. 2-bromo-N-{ [l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl }-N-(4- methoxybenzyl)-5-methylbenzamide
787. 2-bromo-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol- 5-yl]methyl}-5-methylbenzamide
788. 2-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-5-(methylthio)benzamide
789. 2-chloro-N-{ [l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl }-N-(4- methoxybenzyl)-5 - (trifluoromethyl)benzamide
790. 2-chloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol- 5 -yl] methyl } -5 -(trifluoromethyl)benzamide
791. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-( 1 H-pyrrol- 1 -yl)benzamide
792. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)methanamine
793. N-benzyl-N-[(4-bromo- 1 -butyl-2-phenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
794. N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dichlorobenzyl)butan-l- amine
795. N-benzyl-N- [( 1 -butyl-4-chloro-2-phenyl- 1 H-imidazol-5 -yl)methyl]butan- 1 -amine
796. N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
797. N-benzyl-N-[(l-butyl-4-methyl-2-phenyl-lH-imidazol-5-yl)methyl]butan-l-amine
798. 1 -(1 ,3-benzodioxol-5-yl)-N-benzyl-N-[(5-butyl- 1 -phenyl- 1 H-imidazol-4- yl)methyl]methanamine
799. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](isopentyl)amino]methyl}-3- chlorophenol
800. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3-chlorophenol
801. 4-( { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-3-chlorophenol 802. 4-({butyl[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3- chlorophenol
803. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
804. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-tert-butyl-2- phenyl-lH-imidazol-5-yl)methyl]methanamine
805. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5- yl)methyl]amino}methyl)-3-chlorophenol
806. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5- yl)methyl] amino }methyl)-2-chlorophenol
807. 4-[(butyl { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
808. 2-{ [5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino }methyl)pyridin-2- yl] amino} ethanol
809. 4-[(butyl { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- lH-imidazol-5- yljmethyl } amino)methyl]phenol
810. 4- [(benzyl { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- 1 H-imidazol-5 - yl]methyl } amino)methyl]phenol
811. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol- 5-yl]methyl}butan-l-amine
812. N-benzyl-N-{ [l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}butan-l- amine
813. 4- [(butyl { [ 1 -butyl-4- (4-fluorophenyl)-2-phenyl- 1 H-imidazol-5-yl] methyl } amino)methyl] -3 - chlorophenol
814. { 4-[(benzyl{ [l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]-
3-chlorophenol
815. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}butan-l-amine
816. 1 -( 1 ,3-benzodioxol-5-yl)-N-benzyl-N- { [ 1 -butyl-4-(4-fluorophenyl)-2-phenyl- lH-imidazol- 5-yl]methyl }methanamine
817. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(6-chloropyridin-3- yl)methyl]butan- 1 -amine
818. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(6-chloropyridin-3- y l)methyl] methanamine
819. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(6-pyrrolidin-l-ylpyridin-3- yl)methyl]butan-l-amine
820. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(6-pyrrolidin-l-ylpyridin-3- yl)methyl]methanamine
821. 4-[(benzyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
822. 2-{[5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)pyridin-2- yl] amino} ethanol
823. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzene-l,3-diol
824. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenol 825. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenol
826. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)methanamine
827. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)butan- 1 -amine
828. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)methanamine
829. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)butan- 1 -amine
830. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
831. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan- 1 -amine
832. N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]ethanamine
833. 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)pyridin-2-amine
834. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(l,3-thiazol-2-ylmethyl)butan-l- amine
835. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(l,3-thiazol-2- ylmethyl)methanamine
836. N-benzyl-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
837. ethyl N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]glycinate
838. 2-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenol
839. 3-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenol
840. 2-({ butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino }methyl)phenol
841. 3-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenol
842. 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N-(2- methoxyethyl)pyridin-2-amine
843. 5 -({ butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-N-methylpyridin- 2-amine
844. 5 -( { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-N-ethylpyridin-2- amine
845. methyl 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoate
846. methyl 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino }methyl)benzoate
847. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)-N-(quinolin-3 -ylmethyl)methanamine
848. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(quinolin-3-ylmethyl)butan- 1 -amine
849. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(quinolin-3- ylmethyl)methanamine
850. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-methoxybenzyl)butan-l-amine
851. 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N-(2- methoxyethyl)pyridin-2-amine
852. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoic acid 853. 4-( { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)benzoic acid
854. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino] methyl } benzoic acid
855. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(quinolin-2-ylmethyl)butan-l-amine
856. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(quinolin-2- ylmethyl)methanamine
857. 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N-ethylpyridin- 2-amine
858. l-(4-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
859. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N,N- dimethylaniline
860. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N,N- dimethylaniline
861. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(cyclohexylmethyl)-N-[4- (dimethylamino)benzyl] amine
862. N-(lH-benzimidazol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
863. N-benzyl- 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-[4-( 1 ,3-thiazol-5- yl)benzyl]methanamine
864. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(l,3-thiazol-5-yl)benzyl]butan-l- amine
865. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4-(l,3-thiazol-5- yl)benzyl]methanamine
866. 4-( { benzyl [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yι)methyι] amino } methyl)-N- methylbenzamide
867. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N- methylbenzamide
868. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N,N- dimethylbenzamide
869. 4-{[[(l -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] (cyclohexylmethyl)amino]methyl } - N,N-dimethylbenzamide
870. [4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)phenyl]methanol
871. [4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenyl]methanol
872. (4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl }phenyl)methanol
873. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-methoxybenzyl)methanamine
874. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-methoxybenzyl)butan-l-amine
875. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2- methoxybenzyl)methanamine
876. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-methoxybenzyl)methanamine
877. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxybenzyl)butan-l-amine l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3- methoxybenzyl)methanamine
4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl }phenyl acetate methyl 4-({butyl[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzoate
[4-({butyl[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5- yl)methyl] amino }methyl)phenyl]methanol
[4-( { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)phenoxy] acetic acid
(4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl }phenoxy)acetic acid
2-[4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- y l)methyl] amino } methy l)phenoxy] ethanol
2-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)phenoxy] ethanol
2-(4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl }phenoxy)ethanol
4-({butyl[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-N- methylbenzamide
4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-nitrophenol
4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-nitrophenol
4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- nitrophenol
5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-nitrophenol
5 -( { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-2-nitrophenol
5 - { [ [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] (cyclohexylmethyl)amino] methyl } -2- nitrophenol
N,N-dibutyl-4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)aniline
N,N-dibutyl-4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}aniline
N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-{4-[3- (dimethylamino)propoxy]benzyl } butan- 1 -amine
3-(4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}phenoxy)-N,N-dimethylpropan-l-amine
4-({butyl[(l-butyl-4-tert-butyl-2-phenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzamide methyl 2-( { benzyl [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino }methyl)benzoate methyl 2-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoate methyl 2-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl Jbenzoate
[2-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]amino}methyl)phenyl]methanol
903. [2-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenyl]methanol
904. (2-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}phenyl)methanol
905. 4-( { benzyl [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)phenyl glycinate
906. N- [4-(aminomethyl)benzyl] -N- [( 1 -butyl-4-tert-butyl-2-phenyl- 1 H-imidazol-5- yl)methyl]butan- 1 -amine
907. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzenesulf onamide
908. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzenesulf onamide
909. N-{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)butan- 1 -amine
910. N-{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
911. methyl 6-{benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino }hexanoate
912. methyl 6-{butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}hexanoate
913. 6- { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } hexanoic acid
914. 6-{benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}hexan-l-ol
915. 6- (butyl[( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] amino }hexan- 1 -ol
916. methyl 3-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino }methyl)benzoate
917. methyl 3-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoate
918. methyl 3-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}benzoate
919. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
920. methyl 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzoate
921. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzoic acid
922. N-( 1 ,3-benzodioxol-5-ylmethyl)-N-benzyl- 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5- yl)ethanamine
923. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)pentan- 1 -amine
924. N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenyl]-N- (methylsulfonyl)methanesulfonamide
925. N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]amino}methyl)phenyl]methanesulfonamide
926. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzamide
927. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzamide
928. 3-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoic acid 3-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}benzoic acid
[3-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)phenyl]methanol
[3-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)phenyl]methanol methyl 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzoate methyl 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzoate methyl 5-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl } -2-hydroxybenzoate
5 -( { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-2- hydroxybenzoic acid
5-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- hydroxybenzoic acid
4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- (hydroxymethyl)phenol
4-( { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-2- (hydroxymethyl)phenol
4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- (hydroxymethyl)phenol
N-[4-( { butyl[( l-butyl-2,4-diphenyl- lH-imidazol-5- yl)methyl]amino}methyl)benzoyl]methanesulfonamide
N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
N-({ l-butyl-4-[4-(2-chloroethoxy)phenyl]-2-phenyl-lH-imidazol-5-yl}methyl)-N-[4- (difluoromethoxy)benzyl]butan-l-amine
3-({butyl[(l-butyl-4-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenyl-lH-imidazol-5- y l)methyl] amino } methy l)phenol
4-({butyl[(l-butyl-4-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenyl-lH-imidazol-5- yl)methyl]amino}methyl)-3-chlorophenol
N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-{4-[2-(dimethylamino)ethoxy]phenyl}-2- phenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine methyl 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzoate methyl 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzoate methyl 5-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl } -2-methoxybenzoate
[5 -( { benzyl [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-2- methoxyphenyl]methanol
[5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxyphenyl]methanol
(5-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- methoxyphenyl)methanol
952. N-[4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]amino}methyl)benzoyl]methanesulfonamide
953. 4-({benzyl[(l -butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino }methyl)benzamide
954. N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzoyl]- 1,1,1 -trifluoromethanesulf onamide
955. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-{4- [(methylthio)methoxy]benzyl } butan- 1 -amine
956. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-{4- [(methylthio)methoxy]benzyl}methanamine
957. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzenesulfonamide
958. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl}benzenesulfonamide
959. N-acetyl-4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzenesulf onamide
960. 4-(5-{ [(1 ,3-benzodioxol-5-ylmethyl)(butyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol- 4-yl)benzonitrile
961. N-[4-(5-{ [(1 ,3-benzodioxol-5-ylmethyl)(butyl)amino]methyl}-l-butyl-2-phenyl-lH- imidazol-4-yl)benzyl]methanesulfonamide
962. N'-[4-(5- { [(1 ,3-benzodioxol-5-ylmethyl)(butyl)amino]methyl } - 1 -butyl-2-phenyl- 1H- imidazol-4-yl)benzyl]-N,N-dimethylsulfamide
963. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-{4-[(dimethylamino)methyl]phenyl}-2- phenyl-lH-imidazol-5-yl)methyl]butan-l-amine
964. methyl 4-(5-{ [(1 ,3-benzodioxol-5-ylmethyl)(butyl)amino]methyl}-l-butyl-2-phenyl-lH- imidazol-4-yl)benzylcarbamate
965. 4- [(butyl { [ 1 -butyl-4-(4-cy anophenyl)-2-phenyl- 1 H-imidazol-5 - yl]methyl } amino)methyl]phenyl acetate
966. 4-[(butyl{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
967. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol- 5-yl]methyl}butan-l-amine
968. 4-[(butyl{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
969. N-{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)butan- 1 -amine
970. 4-[(benzyl{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]-3-chlorophenol
971. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4- hydroxybenzyl)amino]methyl}benzenesulfonamide
972. N-acetyl-4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzenesulf onamide
973. N-acetyl-4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzenesulf onamide N-[4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzoyl]methanesulfonamide
N- [4-( { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)phenyl] -N - ethylurea
N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzyl]methanesulfonamide
N-(4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-hydroxybenzyl)methanesulfonamide
4-( { ( 1 ,3-benzodioxol-5 -ylmethyl) [ 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 - yl)ethyl]amino}methyl)benzoic acid
4-({[4-(aminosulfonyl)benzyl][(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzoic acid
N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzyl]methanesulfonamide
N-(4- { [[(1 -butyl-2,4-diphenyl- lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-methoxybenzyl)methanesulfonamide l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH- imidazol-5-yl]methyl}methanamine
4-[(benzyl{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-4- methylbenzenesulfonamide
4-({[4-(aminosulfonyl)benzyl][(l-butyl-2,4-diphenyl-lH-imidazol-5- y l)methyl] amino } methyl)benzamide methyl 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4- hydroxybenzyl)amino]methyl}benzoate methyl 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](2-chloro-4- hydroxybenzyl)amino]methyl}benzoate methyl 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl}benzoate diethyl 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)isophthalate diethyl 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)isophthalate
4- { [[(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] (4- hydroxybenzyl)amino]methyl Jbenzoic acid
4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](2-chloro-4- hydroxybenzyl)amino]methyl}benzoic acid
4- { [[(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] (4- methoxybenzyl)amino]methyl Jbenzoic acid
5 -( { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)isophthalic acid
N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzyl]methanesulfonamide
4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (hydroxymethyl)benzyl] amino } methyl)phenol
997. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (hydroxymethyl)benzyl]amino}methyl)-3-chlorophenol
998. (4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl}phenyl)methanol
999. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4- dihydroxymethylbenzyl)methanamine
1000. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-cyclohexylmethyl-N-(2,4- dihydroxymethylbenzyl)methanamine
1001. 4-({(l,3-benzodioxol-5-ylmethyl)[(2,4-diphenyl-l-propyl-lH-imidazol-5- yl)methyl] amino } methyl)benzenesulf onamide
1002. methyl 4-[((l,3-benzodioxol-5-ylmethyl){ [l-(4-ethoxy-4-oxobutyl)-2,4-diphenyl-lH- imidazol-5-yl]methyl } amino)methyl]benzoate
1003. methyl 4-[((2-chloro-4-hydroxybenzyl){ [l-(4-ethoxy-4-oxobutyl)-2,4-diphenyl-lH- imidazol-5-yl]methyl } amino)methyl]benzoate
1004. methyl 4-{ [{ [l-(4-ethoxy-4-oxobutyl)-2,4-diphenyl-lH-imidazol-5-yl]methyl}(4- methoxybenzyl)amino]methyl}benzoate
1005. methyl 4-[([4-(dimethylamino)benzyl]{[l-(4-ethoxy-4-oxobutyl)-2,4-diphenyl-lH- imidazol-5-yl]methyl } amino)methyl]benzoate
1006. ethyl 4-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-2,4-diphenyl-lH-imidazol-l- yl)butanoate
1007. ethyl 4-(5-{ [(1 ,3-benzodioxol-5-ylmethyl)(2-chloro-4-hydroxybenzyl)amino]methyl}-2,4- diphenyl-lH-imidazol-1 -y l)butano ate
1008. ethyl 4-(5-{[(l,3-benzodioxol-5-ylmethyl)(4-methoxybenzyl)amino]methyl}-2,4-diphenyl- 1 H-imidazol- 1 -yl)butanoate
1009. ethyl 4-[5-({ (1 ,3-benzodioxol-5-ylmethyl)[4-(dimethylamino)benzyl]amino }methyl)-2,4- diphenyl-lH-imidazol-l-yl]butanoate
1010. methyl 4-({ [(l-butyl-2,4-diphenyl-l H-imidazol-5 -yl)methyl] [4- (trifluoromethoxy)benzyl]amino}methyl)benzoate
1011. methyl 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3- methoxybenzyl)amino]methyl}benzoate
1012. methyl 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] [4- (dimethylamino)benzyl]amino}methyl)benzoate
1013. 4-[5-({(l,3-benzodioxol-5-ylmethyl)[4-(hydroxymethyl)benzyl]amino}methyl)-2,4- diphenyl- lH-imidazol- 1 -yljbutan- 1 -ol
1014. 4-[5-({[4-(dimethylamino)benzyl][4-(hydroxymethyl)benzyl]amino}methyl)-2,4-diphenyl- 1 H-imidazol- 1 -yl]butan- 1 -ol
1015. 4-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-2,4-diphenyl-lH-imidazol-l- yl)butan-l-ol
1016. 4-[((l,3-benzodioxol-5-ylmethyl){[l-(4-hydroxybutyl)-2,4-diphenyl-lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
1017. 4-(5-{[(l,3-benzodioxol-5-ylmethyl)(4-methoxybenzyl)amino]methyl}-2,4-diphenyl-lH- imidazol- 1 -yl)butan- 1 -ol
1018. 4-[5-({(l,3-benzodioxol-5-ylmethyl)[4-(dimethylamino)benzyl]amino}methyl)-2,4- diphenyl- 1 H-imidazol- 1 -yl] butan- 1 -ol
1019. [4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (trifluoromethoxy)benzyl]amino}methyl)phenyl]methanol
1020. (4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3- methoxybenzyl)amino]methyl}phenyl)methanol
1021. [4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (dimethylamino)benzyl] amino } methyl)phenyl] methanol
1022. 4-(5-{[[4-(hydroxymethyl)benzyl](4-methoxybenzyl)amino]methyl}-2,4-diphenyl-lH- imidazol- 1 -yl)butan- 1 -ol
1023. 4-(5- { [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl } -2,4-diphenyl- 1 H-imidazol- 1 - yl)butanoic acid
1024. 4-(5-{ [(1 ,3-benzodioxol-5-ylmethyl)(2-chloro-4-hydroxybenzyl)amino]methyl}-2,4- diphenyl- 1 H-imidazol- 1 -yl)butanoic acid
1025. 4-[(benzyl{[l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
1026. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-{[l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH- imidazol-5-yl]methyl Jmethanamine
1027. 4-[(benzyl{[l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
1028. 4-[(butyl{[l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
1029. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH-imidazol- 5-yl]methyl }butan- 1 -amine
1030. 4-[(butyl{[l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl] methyl } amino)methyl]phenol
1031. 4-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl] methyl } amino)methyl]benzoic acid
1032. 4-[(butyl{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzamide
1033. 4-[(butyl{[l-butyl-2-(2-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
1034. 4-[(butyl{[l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
1035. 4-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
1036. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] [4- (trifluoromethoxy)benzyl] amino } methyl)benzoic acid
1037. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3- methoxybenzyl)amino]methyl Jbenzoic acid
1038. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] [4- (dimethylamino)benzyl]aminoJmethyl)benzoic acid
1039. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
1040. l-[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis(4- methoxybenzyl)methanamine
1041. methyl 3-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-5- methoxybenzoate
1042. methyl 3-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (methoxycarbonyl)benzy 1] amino J methyl)-5 -methoxybenzoate
1043. 4-( { butyl[ 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)ethyl] amino J methyl)benzamide
1044. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methylJ- 2,6-dimethylphenol
1045. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- methylphenol
1046. 4-({butyl[l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]amino}methyl)-2,6- dimethylphenol
1047. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenol
1048. [3-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]aminoJmethyl)-5- methoxyphenyl]methanol
1049. [3-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (hydroxymethyl)benzyl]aminoJmethyl)-5-methoxyphenyl]methanol
1050. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-nitrophenol
1051. N-benzyl-N- [(1 -butyl-2,4-diphenyl- lH-imidazol-5 -yl)methyl]butan- 1 -amine
1052. N,N-dibenzyl-l-(l-butyl-2,4-diphenyl-l H-imidazol-5 -yl)methanamine
1053. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)-N-(4-methoxybenzyl)methanamine
1054. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)methanamine
1055. N-(2-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1056. N-benzyl-l-(2-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
1057. l-(2-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
1058. l-(2-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
1059. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-fluorobenzyl)butan-l-amine
1060. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-fluorobenzyl)methanamine
1061. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-fluorobenzyl)-N-(4- methoxybenzyl)methanamine
1062. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2- fluorobenzyl)methanamine
1063. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-chlorobenzyl)butan-l-amine
1064. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chlorobenzyl)methanamine
1065. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chlorobenzyl)-N-(4- methoxybenzyl)methanamine
1066. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chlorobenzyl)-N- (cyclohexylmethyl)methanamine 1067. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-methylbenzyl)butan-l-amine
1068. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-methylbenzyl)methanamine
1069. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(2- methylbenzyl)methanamine
1070. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2- methylbenzyl)methanamine
1071. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(2-methoxybenzyl)butan- 1 -amine
1072. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)-N-(2-methoxybenzyl)methanamine
1073. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-methoxybenzyl)-N-(4- methoxybenzyl)methanamine
1074. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2- methoxybenzyl)methanamine
1075. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-(trifluoromethyl)benzyl]butan-l- amine
1076. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2- (trifluoromethyl)benzyl]methanamine
1077. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-[2- (trifluoromethyl)benzyl]methanamine
1078. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[2- (trifluoromethyl)benzyl]methanamine
1079. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-ethoxybenzyl)butan-l-amine
1080. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-ethoxybenzyl)methanamine
1081. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-ethoxybenzyl)-N-(4- methoxybenzyl)methanamine
1082. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2- ethoxybenzyl)methanamine
1083. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,4-dichlorobenzyl)butan-l-amine
1084. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4-dichlorobenzyl)methanamine
1085. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,4- dichlorobenzyl)methanamine
1086. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,4-dimethoxybenzyl)butan-l- amine
1087. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4- dimethoxybenzyl)methanamine
1088. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4-dimethoxybenzyl)-N-(4- methoxybenzyl)methanamine
1089. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,4- dimethoxybenzyl)methanamine
1090. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,5-dimethoxybenzyl)butan-l- amine
1091. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,5- dimethoxybenzyl)methanamine 1092. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,5-dimethoxybenzyl)-N-(4- methoxybenzyl)methanamine
1093. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,5- dimethoxybenzyl)methanamine
1094. N-(4-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1095. N-benzyl-l-(4-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] methanamine
1096. l-(4-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
1097. l-(4-bromophenyl)-N-[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
1098. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-fluorobenzyl)butan-l-amine
1099. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)-N-(4-fluorobenzyl)methanamine
1100. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- fluorobenzyl)methanamine
1101. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-chlorobenzyl)butan-l-amine
1102. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-chlorobenzyl)methanamine
1103. 1 -( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(4-chlorobenzyl)-N-(4- methoxybenzyl)methanamine
1104. 1 -( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(4-chlorobenzyl)-N- (cyclohexylmethyl)methanamine
1105. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(4-methylbenzyl)butan- 1 -amine
1106. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)-N-(4-methylbenzyl)methanamine
1107. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(4- methylbenzyl)methanamine
1108. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- methylbenzyl)methanamine
1109. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(4-ethylbenzyl)butan- 1 -amine
1110. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethylbenzyl)methanamine
1111. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethylbenzyl)-N-(4- methoxybenzyl)methanamine
1112. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- ethylbenzyl)methanamine
1113. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-methoxybenzyl)butan-l-amine
1114. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N,N-bis(4-methoxybenzyl)methanamine
1115. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- methoxybenzyl)methanamine
1116. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-ethoxybenzyl)butan-l-amine
1117. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethoxybenzyl)methanamine
1118. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethoxybenzyl)-N-(4- methoxybenzyl)methanamine 1119. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- ethoxybenzyl)methanamine
1120. N-(4-butoxybenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1121. N-benzyl-l-(4-butoxyphenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] methanamine
1122. l-(4-butoxyphenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
1123. l-(4-butoxyphenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
1124. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(trifluoromethyl)benzyl]butan-l- amine
1125. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (trifluoromethyl)benzyl]methanamine
1126. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-[4- (trifluoromethyl)benzyl]methanamine
1127. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (trifluoromethyl)benzyl]methanamine
1128. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-isopropylbenzyl)butan-l-amine
1129. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-isopropylbenzyl)methanamine
1130. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-isopropylbenzyl)-N-(4- methoxybenzyl)methanamine
1131. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- isopropylbenzyl)methanamine
1132. N-(l,l'-biphenyl-4-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1133. N-benzyl-l-(l,l'-biphenyl-4-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
1134. N-(l,l'-biphenyl-4-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)amine
1135. N-(l,l'-biphenyl-4-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)amine
1136. N-(l ,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan- 1 -amine
1137. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
1138. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
1139. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
1140. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)butan- 1 -amine
1141. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)methanamine 1142. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N- (4-methoxybenzyl)methanamine
1143. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)methanamine
1144. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-phenoxybenzyl)butan-l-amine
1145. 1 -(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- phenoxybenzyl)methanamine
1146. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,4,6-trimethoxybenzyl)butan-l- amine
1147. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4,6- trimethoxybenzyl)methanamine
1148. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(2,4,6- trimethoxybenzyl)methanamine
1149. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,4,6- trimethoxybenzyl)methanamine
1150. N-[3-(benzyloxy)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)amine
1151. N- [4-(benzyloxy)benzyl] -N-[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl]butan- 1 -amine
1152. N-[4-(benzyloxy)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)amine
1153. N-[4-(benzyloxy)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)amine
1154. N-[3-(benzyloxy)-4-methoxybenzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1155. N-benzyl-l-[3-(benzyloxy)-4-methoxyphenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- y l)methyl] methanamine
1156. l-[3-(benzyloxy)-4-methoxyphenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]- N-(cyclohexylmethyl)methanamine
1157. 1 -[4-(benzyloxy)-3-methoxyphenyl]-N-[(l -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] - N-(cyclohexylmethyl)methanamine
1158. N- [( 1 -butyl-2,4-diphenyl- lH-imidazol-5 -yl)methyl] -N-(3 ,4-diethoxybenzyl)butan- 1 -amine
1159. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)-N-(3 ,4-diethoxybenzyl)methanamine
1160. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-diethoxybenzyl)-N-(4- methoxybenzyl)methanamine
1161. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,4- diethoxybenzyl)methanamine
1162. N-[( 1 -butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dimethoxybenzyl)butan- 1 - amine
1163. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3- dimethoxybenzyl)methanamine
1164. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(2,3-dimethoxybenzyl)-N-(4- methoxybenzyl)methanamine
1165. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- dimethoxybenzyl)methanamine
1166. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4-dimethoxybenzyl)butan-l- amine
1167. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4- dimethoxybenzyl)methanamine
1168. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-dimethoxybenzyl)-N-(4- methoxybenzyl)methanamine
1169. l-(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,4- dimethoxybenzyl)methanamine
1170. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(2- nitrobenzyl)methanamine
1171. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxy-2-nitrobenzyl)butan-l- amine
1172. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3-methoxy-2- nitrobenzyl)methanamine
1173. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-chloro-6-nitrobenzyl)butan-l- amine
1174. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-6-nitrobenzyl)-N-(4- methoxybenzyl)methanamine
1175. 1 -( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(2-chloro-6-nitrobenzyl)-N- (cyclohexylmethyl)methanamine
1176. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(5-chloro-2-nitrobenzyl)-N-(4- methoxybenzyl)methanamine
1177. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,4-dimethylbenzyl)butan-l-amine
1178. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4-dimethylbenzyl)methanamine
1179. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4-dimethylbenzyl)-N-(4- methoxybenzyl)methanamine
1180. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,4- dimethylbenzyl)methanamine
1181. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,5-difluorobenzyl)butan-l-amine
1182. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,5-difluorobenzyl)methanamine
1183. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,5-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
1184. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,5- difluorobenzyl)methanamine
1185. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dichlorobenzyl)butan-l-amine
1186. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dichlorobenzyl)-N-(4- methoxybenzyl)methanamine
1187. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- dichlorobenzyl)methanamine
1188. N-[3,5-bis(trifluoromethyl)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1189. l-[3,5-bis(trifluoromethyl)phenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (4-methoxybenzyl)methanamine
1190. l-[3,5-bis(trifluoromethyl)ρhenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
1191. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4-difluorobenzyl)butan-l-amine
1192. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-difluorobenzyl)methanamine
1193. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
1194. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,4- difluorobenzyl)methanamine
1195. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4-dichlorobenzyl)butan-l-amine
1196. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-dichlorobenzyl)-N-(4- methoxybenzyl)methanamine
1197. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,4- dichlorobenzyl)methanamine
1198. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,6-dichlorobenzyl)butan-l-amine
1199. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,6-dichlorobenzyl)methanamine
1200. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,6-dichlorobenzyl)-N-(4- methoxybenzyl)methanamine
1201. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,6- dichlorobenzyl)methanamine
1202. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-chloro-6-fluorobenzyl)butan-l- amine
1203. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-6- fluorobenzyl)methanamine
1204. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-6-fluorobenzyl)-N-(4- methoxybenzyl)methanamine
1205. l-(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)-N-(2-chloro-6-fluorobenzyl)-N- (cyclohexylmethyl)methanamine
1206. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-difluorobenzyl)butan-l-amine
1207. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-difluorobenzyl)methanamine
1208. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
1209. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- difluorobenzyl)methanamine
1210. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(2,6-difluorobenzyl)butan- 1 -amine
1211. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,6-difluorobenzyl)methanamine
1212. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,6-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
1213. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,6- difluorobenzyl)methanamine
1214. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,4-difluorobenzyl)butan-l-amine
1215. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4-difluorobenzyl)methanamine 1216. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,4-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
1217. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,4- difluorobenzyl)methanamine
1218. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-(trifluoromethoxy)benzyl]butan- 1 -amine
1219. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (trifluoromethoxy)benzyl]methanamine
1220. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-[3- (trifluoromethoxy)benzyl]methanamine
1221. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethoxy)benzyl]methanamine
1222. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]butan- 1 -amine
1223. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]methanamine
1224. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(4- methoxybenzyl)methanamine
1225. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]methanamine
1226. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(trifluoromethoxy)benzyl]butan- 1 -amine
1227. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (trifluoromethoxy)benzyl]methanamine
1228. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-[4- (trifluoromethoxy)benzyl]methanamine
1229. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (trifluoromethoxy)benzyl]methanamine
1230. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,5-difluorobenzyl)butan-l-amine
1231. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,5-difluorobenzyl)methanamine
1232. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,5-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
1233. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3 ,5- difluorobenzyl)methanamine
1234. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-chloro-4-fluorobenzyl)butan-l- amine
1235. N-benzyl- 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(3-chloro-4- fluorobenzyl)methanamine
1236. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-chloro-4-fluorobenzyl)-N-(4- methoxybenzyl)methanamine
1237. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-chloro-4-fluorobenzyl)-N- (cyclohexylmethyl)methanamine
1238. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-fluoro-3- (trifluoromethyl)benzyl]butan- 1 -amine 1239. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-fluoro-3- (trifluoromethyl)benzyl]methanamine
1240. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-fluoro-3-(trifluoromethyl)benzyl]-N-(4- methoxybenzyl)methanamine
1241. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4-fluoro-3- (trifluoromethyl)benzyl]methanamine
1242. N-(3-bromo-4-fluorobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1243. N-benzyl-l-(3-bromo-4-fluorophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
1244. l-(3-bromo-4-fluorophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)methanamine
1245. l-(3-bromo-4-fluorophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
1246. N-(3-bromo-4-methoxybenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1247. N-benzyl-l-(3-bromo-4-methoxyphenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] methanamine
1248. N-(3-bromo-4-methoxybenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxybenzyl)amine
1249. N-(3-bromo-4-methoxybenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)amine
1250. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-propoxybenzyl)butan-l-amine
1251. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-propoxybenzyl)methanamine
1252. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(4- propoxybenzyl)methanamine
1253. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- propoxybenzyl)methanamine
1254. N-(4-tert-butylbenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1255. N-benzyl-N-(4-tert-butylbenzyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methanamine
1256. N-(4-tert-butylbenzyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4- methoxybenzyl)methanamine
1257. N-(4-tert-butylbenzyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N- (cyclohexylmethyl)methanamine
1258. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-4-methoxybenzyl)butan-l- amine
1259. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-fluoro-4- methoxybenzyl)methanamine
1260. l-(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)-N-(3-fluoiO-4-methoxybenzyl)-N-(4- methoxybenzyl)methanamine
1261. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3-fluoro-4- methoxybenzyl)methanamine
1262. N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]ethanamine 1263. N-benzyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]propan-l-amine
1264. N-(2-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]ethanamine
1265. N-(2-bromobenzyl)-N-[(l -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]ρropan- 1 -amine
1266. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-fluorobenzyl)ethanamine
1267. N-[(l -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]-N-(2-fluorobenzyl)ρropan- 1 -amine
1268. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(2-chlorobenzyl)ethanamine
1269. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyι] -N-(2-chlorobenzyl)ρropan- 1 -amine
1270. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-methylbenzyl)ethanamine
1271. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(2-methylbenzyl)ρropan- 1 -amine
1272. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-methoxybenzyl)propan-l-amine
1273. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2- (trifluoromethyl)benzyl]ethanamine
1274. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-(trifluoromethyl)benzyl]propan- 1 -amine
1275. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-ethoxybenzyl)ethanamine
1276. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-ethoxybenzyl)propan-l-amine
1277. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(2,4-dichlorobenzyl)propan- 1 -amine
1278. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,4-dimethoxybenzyl)propan-l- amine
1279. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,5-dimethoxybenzyl)ethanamine
1280. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,5-dimethoxybenzyl)propan-l- amine
1281. N-(3-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]ethanamine
1282. N-(3-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]propan-l-amine
1283. N-(3-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1284. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-fluorobenzyl)ethanamine
1285. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(3 -fluorobenzyl)propan- 1 -amine
1286. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-fluorobenzyl)butan-l-amine
1287. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methylbenzyl)ethanamine
1288. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methylbenzyl)propan-l-amine
1289. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methylbenzyl)butan-l-amine
1290. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3- (trifluoromethyl)benzyl]ethanamine
1291. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-(trifluoromethyl)benzyl]propan- 1 -amine
1292. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-(trifluoromethyl)benzyl]butan-l- amine
1293. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxybenzyl)ethanamine
1294. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxybenzyl)propan-l-amine 1295. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxybenzyl)butan-l-amine
1296. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-chlorobenzyl)ethanamine
1297. N- [( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]-N-(3 -chlorobenzyl)propan- 1 -amine
1298. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-chlorobenzyl)butan-l-amine
1299. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(3-phenoxybenzyl)ethanamine
1300. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-phenoxybenzyl)propan-l-amine
1301. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-phenoxybenzyl)butan-l-amine
1302. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2,2-difluoro-l,3-benzodioxol-5- yl)methyl] ethanamine
1303. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2,2-difluoro-l,3-benzodioxol-5- yl)methyl]propan- 1 -amine
1304. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2,2-difluoro-l,3-benzodioxol-5- yl)methyl]butan- 1 -amine
1305. l-(4-bromophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- methylmethanamine
1306. N-(4-bromobenzyl)-N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] ethanamine
1307. N-(4-bromobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]propan-l-amine
1308. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-fluorobenzyl)ethanamine
1309. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-fluorobenzyl)propan-l-amine
1310. N-[(l -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(4-chlorobenzyl)ethanamine
1311. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-chlorobenzyl)propan-l-amine
1312. N-[(l -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(4-methylbenzyl)ethanamine
1313. N-[(l -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]-N-(4-methylbenzyl)propan- 1 -amine
1314. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethylbenzyl)-N-methylmethanamine
1315. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-ethylbenzyl)ethanamine
1316. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-ethylbenzyl)propan-l-amine
1317. N-[(l -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(4-methoxybenzyl)ethanamine
1318. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)mefhyl] -N-(4-methoxybenzyl)propan- 1 -amine
1319. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(4-ethoxybenzyl)ethanamine
1320. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-ethoxybenzyl)propan-l-amine
1321. l-(4-butoxyphenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- methylmethanamine
1322. N-(4-butoxybenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]ethanamine
1323. N-(4-butoxybenzyl)-N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl]propan- 1 -amine
1324. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(trifluoromethyl)benzyl]propan- 1 -amine
1325. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-isopropylbenzyl)-N-methylmethanamine
1326. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-isopropylbenzyl)ethanamine
1327. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-isopropylbenzyl)propan-l-amine 1328. N-(l,l'-biphenyl-4-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]propan-l- amine
1329. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- methylmethanamine
1330. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] ethanamine
1331. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]propan- 1 -amine
1332. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)ethanamine
1333. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)propan- 1 -amine
1334. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-phenoxybenzyl)ethanamine
1335. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-phenoxybenzyl)propan-l-amine
1336. N- [4-(benzyloxy)benzyl] -N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] ethanamine
1337. N-[4-(benzyloxy)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]propan-l- amine
1338. N-[3-(benzyloxy)-4-methoxybenzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]propan-l-amine
1339. N-[4-(benzyloxy)-3-methoxybenzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1340. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(3 ,4-diethoxybenzyl)propan- 1 -amine
1341. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dimethoxybenzyl)propan-l- amine
1342. N-benzyl-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1343. N-benzyl-N-[(l -pentyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1344. N-(2-bromobenzyι)-N- [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5 -yl)methyl]butan- 1 -amine
1345. N-(2-bromobenzyl)-N- [( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl]butan- 1 -amine
1346. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(2-fluorobenzyl)butan-l-amine
1347. N-(2-fluorobenzyl)-N- [( 1 -pentyl-2,4-diphenyl- lH-imidazol-5 -yl)methyl]butan- 1 -amine
1348. N-(2-chlorobenzyl)-N-[( 1 -ethyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1349. N-(2-chlorobenzyl)-N- [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5 -yl)methyl]butan- 1 -amine
1350. N-(2-chlorobenzyl)-N-[(l -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl]butan- 1 -amine
1351. N-(2-methylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1352. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(2-methoxybenzyl)butan-l-amine
1353. N-(2-methoxybenzyl)-N-[( 1 -pentyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1354. N-[(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5-yl)methyl]-N-[2-(trifluoromethyl)benzyl]butan- 1 -amine
1355. N- [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5 -yl)methyl] -N-(2-ethoxybenzyl)butan- 1 -amine
1356. N-(2-ethoxybenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1357. N-(2,4-dimethoxybenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l- amine
1358. N-(2,4-dimethoxybenzyl)-N-[( 1 -pentyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]butan- 1 - amine
1359. N-(2,5-dimethoxybenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l- amine
1360. N-(2,5-dimethoxybenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1361. N-[(2,4-diphenyl- 1 -propyl- lH-imidazol-5-yl)methyl] -N-(3-fluorobenzyl)butan- 1 -amine
1362. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(3-methylbenzyl)butan-l-amine
1363. N-(3-methylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1364. N- [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5-yl)methyl] -N-(3 -methoxybenzyl)butan- 1 -amine
1365. N-(3-methoxybenzyl)-N-[( 1 -pentyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1366. N-(3-chlorobenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1367. N-(4-bromobenzyl)-N-[(2,4-diphenyl- 1 -propyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1368. N-(4-bromobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1369. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(4-fluorobenzyl)butan-l-amine
1370. N-(4-fluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1371. N-(4-chlorobenzyl)-N-[(2,4-diphenyl- 1 -propyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1372. N-(4-chlorobenzyl)-N-[(l -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl]butan- 1 -amine
1373. N-[(l -ethyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] -N-(4-methylbenzyl)butan- 1 -amine
1374. N-[(2,4-diphenyl- 1-propyl- lH-imidazol-5-yl)methyl] -N-(4-methylbenzyl)butan- 1 -amine
1375. N-(4-methylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l -amine
1376. N-(4-ethylbenzyl)-N-[(l-methyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1377. N-(4-ethylbenzyl)-N-[(l -ethyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]butan- 1 -amine
1378. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(4-ethylbenzyl)butan-l-amine
1379. N-(4-ethylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1380. N-[(2,4-diphenyl-l -propyl- lH-imidazol-5-yl)methyl] -N-(4-methoxybenzyl)butan- 1 -amine
1381. N-(4-methoxybenzyl)-N- [( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl]butan- 1 -amine
1382. N-(4-ethoxybenzyl)-N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1383. N-[(2,4-diphenyl- 1-propyl- lH-imidazol-5-yl)methyl] -N-(4-ethoxybenzyl)butan- 1 -amine
1384. N-(4-ethoxybenzyl)-N-[( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl]butan- 1 -amine
1385. N-(4-butoxybenzyl)-N-[(2,4-diphenyl- 1-propyl- 1 H-imidazol-5-yl)methyl]butan- 1 -amine
1386. N-(4-butoxybenzyl)-N-[(l-ρentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1387. N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(trifluoromethyl)benzyl]butan-l- amine
1388. N- [( 1 -ethyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(4-isopropylbenzyl)butan- 1 -amine
1389. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(4-isopropylbenzyl)butan-l-amine
1390. N-(4-isopropylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine 1391. N-(l ,3-benzodioxol-5-ylmethyl)-N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan- 1 -amine
1392. N-(l,3-benzodioxol-5-ylmethyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1393. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1394. N-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)-N-[( 1 -ethyl-2,4-diphenyl- 1 H-imidazol-5- yl)methyl]butan- 1 -amine
1395. N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1396. N-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)-N-[( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5- yl)methyl]butan-l-amine
1397. N-[( 1 -pentyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]-N-(4-phenoxybenzyl)butan- 1 -amine
1398. N-[4-(benzyloxy)benzyl]-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1399. N-[3-(benzyloxy)-4-methoxybenzyl]-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan-l-amine
1400. N-(3 ,4-dimethoxybenzyl)-N- [( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl]butan- 1 - amine
1401. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-[(6-nitro-l ,3-benzodioxol-5- yl)methyl]butan-l-amine
1402. N-[(6-nitro-l,3-benzodioxol-5-yl)methyl]-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan-l-amine
1403. N-(2,4-dimethylbenzyl)-N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1404. N-(2,4-dimethylbenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l- amine
1405. N-(2,4-dimethylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1406. N-(2,5-difluorobenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1407. N-(2,5-difluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1408. N-(2,6-dichlorobenzyl)-N- [( 1 -ethyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl]butan- 1 -amine
1409. N-(2,6-dichlorobenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1410. N-(2,6-dichlorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1411. N-(2-chloro-6-fluorobenzyl)-N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1412. N-(2-chloro-6-fluorobenzyl)-N- [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5-yl)methyl]butan- 1 - amine
1413. N-(2-chloro-6-fluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1414. N-(2,3-difluorobenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1415. N-(2,3-difluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1416. N-(2,6-difluorobenzyl)-N- [( 1 -methyl-2,4-diphenyl- lH-imidazol-5 -yl)methyl]butan- 1 -amine
1417. N-(2,6-difluorobenzyl)-N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine 1418. N-(2,6-difluorobenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1419. N-(2,6-difluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1420. N-(2,4-difluorobenzyl)-N-[(l-methyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1421. N-(2,4-difluorobenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]butan-l-amine
1422. N-(2,4-difluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
1423. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(2-fluoro-5-methoxybenzyl)butan- 1 -amine
1424. N-(2-fluoro-5-methoxybenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan- 1 -amine
1425. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(2,3,4-trimethoxybenzyl)butan-l- amine
1426. N- [( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(2,3 ,4-trimethoxybenzyl)butan- 1 - amine
1427. N-(l,3-benzodioxol-4-ylmethyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1428. N- [( 1 -ethyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(4-methoxy-3 -methylbenzyl)butan- 1 -amine
1429. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(4-methoxy-3-methylbenzyl)butan- 1 -amine
1430. N-(4-methoxy-3-methylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan- 1 -amine
1431. N-(2,4-dimethoxy-3-methylbenzyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1432. N-(2,4-dimethoxy-3-methylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1433. N-[(2,4-diphenyl- 1 -propyl- lH-imidazol-5-yl)methyl] -N-(2,3 ,6-trifluorobenzyl)butan- 1 - amine
1434. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro-6- (trifluoromethyl)benzyl]butan- 1 -amine
1435. N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-methoxy-2,5- dimethylbenzyl)butan- 1 -amine
1436. N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(4-methoxy-2,5- dimethylbenzyl)butan- 1 -amine
1437. N-(4-methoxy-2,5-dimethylbenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1438. N-(2-chloro-3 ,4-dimethoxybenzyl)-N- [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5 - yl)methyl]butan- 1 -amine
1439. N-(2-chloro-3,4-dimethoxybenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1440. N-(2-chloro-4-fluorobenzyl)-N-[(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5-yl)methyl]butan- 1 - amine
1441. N-(2-chloro-4-fluorobenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine 1442. N-(2,6-dimethoxybenzyl)-N-[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
1443. 2-({butyl[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-6- methoxyphenol
1444. 2-({butyl[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]amino}methyl)-6-ethoxyphenol
1445. 2-({butyl[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-6-ethoxyphenol
1446. 2-( { butyl[( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-5 - methoxyphenol
1447. 4-bromo-2-( { butyl [(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5-yl)methyl] amino }methyl)-6- methoxyphenol
1448. 4-bromo-2-( { butyl[( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-6- methoxyphenol
1449. 2-({butyl[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]aminoJmethyl)-6-methylphenol
1450. 2-({butyl[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-6-methylphenol
1451. 2-( { butyl[( 1 -ethyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino J methyl)-4-methylphenol
1452. 2-({butyl[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]aminoJmethyl)-4-methylphenol
1453. 4-( { butyl[(2,4-diphenyl- 1 -propyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-2-ethoxyphenol
1454. 4-( { butyl[( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-2-ethoxyphenol
1455. 4-({butyl[(l-methyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]aminoJmethyl)-2,6- dimethylphenol
1456. 4-({butyl[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenol
1457. 4-({butyl[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenol
1458. 4-({butyl[(l-pentyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenol
1459. 4-( { butyl[( 1 -methyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methyl)-2-methylphenol
1460. 4-({butyl[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-methylphenol
1461. 4-({butyl[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]amino }methyl)-2-methylphenol
1462. 4-( { butyl[( 1 -pentyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-2-methylphenol
1463. N-(2-bromobenzyl)-N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol-5 - yljmethyl Jbutan- 1 -amine
1464. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methylJ-N-(2- fluorobenzyl)butan- 1 -amine
1465. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methylJ-N-(2- fluorobenzyl)butan- 1 -amine
1466. N-{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl }-N-(2- chlorobenzyl)butan- 1 -amine
1467. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,4- dichlorobenzyl)butan- 1 -amine
1468. N-{[l-butyl-4-(4-chloroρhenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3- methylbenzyl)butan- 1 -amine 1469. N- { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(3- methylbenzyl)butan- 1 -amine
1470. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N- [3- (trifluoromethyl)benzyl]butan- 1 -amine
1471. N- { [1 -butyl-4-(4-fluorophenyl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -N-(3- methoxybenzyl)butan- 1 -amine
1472. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3- methoxybenzyl)butan- 1 -amine
1473. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methylJ-N-(3- methoxybenzyl)butan- 1 -amine
1474. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methylJ-N-(3- chlorobenzyl)butan- 1 -amine
1475. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(3- phenoxybenzyl)butan-l-amine
1476. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(4- chlorobenzyl)butan- 1 -amine
1477. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methylbenzyl)butan- 1 -amine
1478. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methylbenzyl)butan- 1 -amine
1479. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- ethylbenzyl)butan- 1 -amine
1480. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl]-N-(4- ethylbenzyl)butan- 1 -amine
1481. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)butan- 1 -amine
1482. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)butan-l-amine
1483. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- ethoxybenzyl)butan- 1 -amine
1484. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- ethoxybenzyl)butan- 1 -amine
1485. N-(4-butoxybenzyl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}butan-l-amine
1486. N-(4-butoxybenzyl)-N- { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- 1 H-imidazol-5- yl]methyl}butan-l-amine
1487. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-ρhenyl- lH-imidazol-5 -yl]methyl } -N- [4- (trifluoromethyl)benzyl]butan- 1 -amine
1488. N-{[l-butyl-4-(4-chlorophenyl)-2-ρhenyl-lH-imidazol-5-yl]methyl}-N-(4- isopropylbenzyl)butan-l-amine
1489. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- isopropylbenzyl)butan- 1 -amine
1490. N-(l,l'-biphenyl-4-ylmethyl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl }butan- 1 -amine 1491. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5- yljmethyl } butan- 1 -amine
1492. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl }butan-l-amine
1493. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol- 5 -yl] methyl } butan- 1 -amine
1494. N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol- 5 -y 1] methyl } butan- 1 -amine
1495. N- { [ 1 -butyl-4-(4-fluorophenyl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -N-(2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)butan- 1 -amine
1496. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan- 1 -amine
1497. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan- 1 -amine
1498. N-{ [l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)butan- 1 -amine
1499. N-[4-(benzyloxy)benzyl]-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yljmethyl }butan- 1 -amine
1500. N-[3-(benzyloxy)-4-methoxybenzyl]-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH- imidazol-5-yl]methyl } butan- 1 -amine
1501. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3,4- diethoxybenzyl)butan- 1 -amine
1502. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3- dimethoxybenzyl)butan- 1 -amine
1503. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3- dimethoxybenzyl)butan- 1 -amine
1504. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3,4- dimethoxybenzyl)butan- 1 -amine
1505. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2- nitrobenzyl)butan-l-amine
1506. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3- nitrobenzyl)butan- 1 -amine
1507. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3-methoxy-2- nitrobenzyl)butan- 1 -amine
1508. N- { [ l-butyl-4-(4-methoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl }-N-(3-methoxy-2- nitrobenzyl)butan- 1 -amine
1509. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2-chloro-6- nitrobenzyl)butan- 1 -amine
1510. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2-fluoro-5- nitrobenzyl)butan- 1 -amine
1511. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,5- difluorobenzyl)butan- 1 -amine
1512. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3- dichlorobenzyl)butan- 1 -amine 1513. N- [3 ,5-bis(trifluoromethyl)benzyl] -N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol- 5-yl]methyl }butan- 1 -amine
1514. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,6- dichlorobenzyl)butan- 1 -amine
1515. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(2-chloro-6- fluorobenzyl)butan- 1 -amine
1516. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,6- difluorobenzyl)butan- 1 -amine
1517. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,6- difluorobenzyl)butan- 1 -amine
1518. N- { [ 1 -butyl-4- (4-chlorophenyl)-2-phenyl- 1 H-imidazol-5 -yl]methyl } -N-(2,4- difluorobenzyl)butan- 1 -amine
1519. 2- [(butyl { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol-5 -yl]methyl } amino)methyl] - 4-chlorophenol
1520. 4-bromo-2-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-6-methoxyphenol
1521. 2-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]-6- methylphenol
1522. 2-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]- 6-methylphenol
1523. 2-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]- 4-methylphenol
1524. 4-tert-butyl-2-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1525. 4-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]-2- ethoxyphenol
1526. 4-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2~phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2-ethoxyphenol
1527. 4-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]- 2,6-dimethylphenol
1528. 4-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]- 2,6-dimethylphenol
1529. 4-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2,6-dimethylphenol
1530. 4-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]-2,6-dimethylphenol
1531. 4-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]-2- methylphenol
1532. 4-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]- 2-methylphenol
1533. 4-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2-methylphenol
1534. 4-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2-methylphenol 1535. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-ρhenyl- lH-imidazol-5-yl]methyl } -N-[(9-ethyl-9H- carbazol-3-yl)methyl]butan- 1 -amine
1536. 3-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1537. 3-[(butyl{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1538. 3-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1539. 3-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1540. 5-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}amino)methyl]-2- methoxyphenol
1541. 5-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]-2-methoxyphenol
1542. 4-[(butyl{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1543. 4-[(butyl{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl- lH-imidazol-5- yl]methyl } amino)methyl]phenol
1544. 4-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenol
1545. 4-[(butyl { [ 1 -butyl-4-(4-fluorophenyl)-2-phenyl- 1 H-imidazol-5-yl]methyl } amino)methyl] -2- methoxyphenol
1546. 4-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]-2-methoxyphenol
1547. 4-[(butyl { [ 1 -butyl-4-(4-fluorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } amino)methyl] -3- chlorophenol
1548. 4- [(butyl { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol-5 -yl] methyl } amino)methyl] - 3-chlorophenol
1549. 4-[(butyl{[l-butyl-4-(2-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-3-chlorophenol
1550. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3,4- trimethoxybenzyl)butan- 1 -amine
1551. N-(l,3-benzodioxol-4-ylmethyl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl }butan- 1 -amine
1552. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4-methoxy-3- methylbenzyl)butan- 1 -amine
1553. N- { [1 -butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl } -N-(4-methoxy-3- methylbenzyl)butan- 1 -amine
1554. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,4-dimethoxy-3- methylbenzyl)butan- 1 -amine
1555. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,4-dimethoxy-3- methylbenzyl)butan- 1 -amine
1556. N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,4-dimethoxy- 3-methylbenzyl)butan- 1 -amine 1557. N- { [1 -butyl-4-(2-methoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(2,4-dimethoxy- 3 -methylbenzyl)butan- 1 -amine
1558. N-{ [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -N-(2,3 ,4- trifluorobenzyl)butan- 1 -amine
1559. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl-l H-imidazol-5-yl]methyl } -N- [2-fluoro-6- (trifluoromethyl)benzyl]butan- 1 -amine
1560. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol-5-yl] methyl } -N-(2-chloro-3 ,4- dimethoxybenzyl)butan- 1 -amine
1561. N-{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2-chloro-4- fluorobenzyl)butan- 1 -amine
1562. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
1563. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
1564. N-{ [ 1 -butyl-4-(2-methoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
1565. N-{ [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-[4- (trifluoromethoxy)benzyl]butan- 1 -amine
1566. N-{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4-fluoro-3- (trifluoromethyl)benzyl]butan-l-amine
1567. N-(3-bromo-4-fluorobenzyl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } butan- 1 -amine
1568. N-(3-bromo-4-methoxybenzyl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- y 1] methyl } butan- 1 - amine
1569. N-(3-bromo-4-methoxybenzyl)-N-{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl }butan-l-amine
1570. N-{ [l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- propoxybenzyl)butan-l-amine
1571. N-{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- propoxybenzyl)butan- 1 -amine
1572. N-{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- propoxybenzyl)butan- 1 -amine
1573. N-(4-tert-butylbenzyl)-N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5- yl]methyl }butan-l -amine
1574. N-(4-tert-butylbenzyl)-N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- y 1] methyl } butan- 1 - amine
1575. N-{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(3-fluoro-4- methoxybenzyl)butan- 1 -amine
1576. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-methyl-l,3-diphenyl-lH- pyrazol-4-yl)methyl] methanamine
1577. l-(l,3-benzodioxol-5-yl)-N-(cyclopentylmethyl)-N-[(5-methyl-l,3-diphenyl-lH-pyrazol-4- yl)methyl]methanamine
1578. 4-({(l,3-benzodioxol-5-ylmethyl)[(l,3-diphenyl-5-propyl-lH-pyrazol-4- yl)methyl]amino}methyl)-3-chlorophenol 1579. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l,3-diphenyl-5-propyl-lH-pyrazol-4- yl)methyl]methanamine
1580. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l,3-diphenyl-5-propyl-lH- pyrazol-4-yl)methyl]methanamine
1581. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l,3-diphenyl-5-propyl-lH-pyrazol-4-yl)methyl]butan- 1 -amine
1582. 4-({benzyl[(l,3-diphenyl-5-propyl-lH-pyrazol-4-yl)methyl]amino}methyl)-3-chlorophenol
1583. 4-({butyl[(l,3-diphenyl-5-propyl-lH-pyrazol-4-yl)methyl]amino}methyl)-3-chlorophenol
1584. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1585. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1586. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1587. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-l,l'-biphenyl-2-carboxamide
1588. N-(2,3-dihydro-lH-indan-2-yl)-3-methyl-N-(4-methylbenzyl)-2-(2- methylphenyl)butanamide
1589. 2-cyclopentyl-N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methylbenzyl)-2-phenylacetamide
1590. N-(4-chlorobenzyl)-N-(2,3-dihydro-lH-indan-2-yl)- 1 , 1 '-biphenyl-2-carboxamide
1591. N-benzyl-N-(l,2,3,4-tetrahydronaphthalen-2-yl)-l,l'-biphenyl-2-carboxamide
1592. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-phenylethyl)-l,l'-biphenyl-2-carboxamide
1593. N-(2,3-dihydro- lH-indan-2-yl)-N-(3-phenylpropyl)- 1 , 1 -biphenyl-2-carboxamide
1594. N-(2,3-dihydro-lH-indan-2-yl)-8-iodo-N-(2-methylbenzyl)-l-naphthamide
1595. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methylbenzyl)-9H-fluorene-4-carboxamide
1596. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methylbenzyl)-9H-fluorene-4-carboxamide
1597. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-9H-fluorene-4-carboxamide
1598. 8-bromo-N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methylbenzyl)-l-naphthamide
1599. 8-bromo-N-[(6-chloro-l-cyclopentyl-lH-benzimidazol-2-yl)methyl]-N-cyclopentyl- 1 - naphthamide
1600. N-(2-cyclohexylethyl)-N-(2,3-dihydro-lH-indan-2-yl)-2-(methylthio)benzamide
1601. N-(2-cyclohexylethyl)-N-(2,3-dihydro-lH-indan-2-yl)-2,6-dimethoxybenzamide
1602. 3,5-dichloro-N-(2-cyclohexylethyl)-2,6-dimethoxy-N-(3-phenylpropyl)benzamide
1603. N-(2-cyclohexylethyl)-N-(2,3-dihydro-lH-indan-2-yl)-2-fluoro-6-iodobenzamide
1604. N-(2-cyclohexylethyl)-8-iodo-N-(2-phenylpropyl)-l-naphthamide
1605. N-(2-cyclopentylethyl)-N-(2-phenylethyl)-9H-fluorene-4-carboxamide
1606. N-(2-cyclohexylethyl)-N-(2-phenylpropyl)-9H-fluorene-4-carboxamide
1607. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methylbenzyl)-2-phenoxybenzamide
1608. 2-butoxy-N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methylbenzyl)benzamide
1609. 2-butoxy-N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methylbenzyl)benzamide
1610. N-benzyl-2-butoxy-N-(l,2,3,4-tetrahydronaphthalen-2-yl)benzamide
1611. N-(2,3-dihydro-lH-indan-2-yl)-2,3-dimethoxy-N-(2-methylbenzyl)benzamide
1612. N-(2,3-dihydro-lH-indan-2-yl)-2,3-dimethoxy-N-(4-methylbenzyl)benzamide 1613. N-(4-chlorobenzyl)-N-(2,3-dihydro-lH-indan-2-yl)-2,3-dimethoxybenzamide
1614. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-(trifluoromethoxy)benzamide
1615. l-(2-cyclohexylethyl)-2-(3,5-dimethoxybenzoyl)-l,2,3,4-tetrahydroisoquinoline
1616. 1 -(2-cyclohexylethyl)-2-(2,3-dimethoxybenzoyl)- 1 ,2,3 ,4-tetrahydroisoquinoline
1617. 1 -(2-cyclohexylethyl)-2- [2-(trifluoromethyl)benzoyl] -1,2,3 ,4-tetrahydroisoquinoline
1618. 2-[l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2-methylbenzyl)-N-(2- phenylethyl)acetamide
1619. N-(2-chlorobenzyl)-2-[l-(2-methoxyphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2- phenylethyl)acetamide
1620. N-(2-chlorobenzyl)-2-[l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2- phenylethyl)acetamide
1621. N-(2-chlorobenzyl)-N-(2-phenylethyl)-2-[l-[2-(trifluoromethyl)phenyl]-3,4- dihydroisoquinolin-2(lH)-yι]acetamide
1622. l-(2-chlorophenyl)-2-[2-oxo-2-(2-phenylazepan-l-yl)ethyl]-l,2,3,4-tetrahydroisoquinoline
1623. 2- [2-oxo-2-(2-phenylazepan- 1 -yl)ethyl] - 1 - [2-(trifluoromethyl)phenyl] - 1 ,2,3 ,4- tetrahydroisoquinoline
1624. N-{[l-(3-fluorobenzyl)-lH-benzimidazol-2-yl]methyl}-N-pentyl-2-(lH-pyrrol-l- yl)benzamide
1625. N-(4-fluorobenzyl)-l ,2,5-trimethyl-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]- lH-pyrrole-3-carboxamide
1626. N-benzyl-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-(lH-pyrrol-l- yl)benzamide
1627. N-(2-fluorobenzyl)-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-(lH-pyrrol-l- yl)benzamide
1628. N-(4-fluorobenzyl)-N-[(3-propyl-3H-imidazo[4,5-b]ρyridin-2-yl)methyl]-2-(lH-pyrrol-l- yl)benzamide
1629. N-(4-methoxybenzyl)-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-(lH-pyrrol-l- yl)benzamide
1630. N-(3-cyclohexyl- 1 -phenylpropyl)-N-methyl-2- ( 1 H-pyrrol- 1 -yl)benzamide
1631. l-(2-cyclohexylethyl)-2-[2-(lH-pyrrol-l-yl)benzoyl]-l,2,3,4-tetrahydroisoquinoline
1632. N-benzyl-N-pentyl-2-(l H-pyrrol- l-yl)benzamide
1633. N,N-dibenzyl-2-(lH-pyrrol-l-yl)benzamide
1634. 5-tert-butyl-N-{[l-(2,6-dimethoxybenzyl)-lH-benzimidazol-2-yl]methyl}-2-methyl-N- pentyl-3-furamide
1635. N-butyl-N- { [ 1 -(2,6-dimethoxybenzyl)- lH-benzimidazol-2-yl]methyl } -4- (methylthio)benzamide
1636. N-{[l-(2,6-dimethoxybenzyl)-lH-benzimidazol-2-yl]methyl}-4-(methylthio)-N- pentylbenzamide
1637. N-{[l-(2,6-dimethoxybenzyl)-lH-benzimidazol-2-yl]methyl}-3-fluoro-4-methoxy-N- pentylbenzamide
1638. N-butyl-4-chloro-N- { [1 -(2,6-dimethoxybenzyl)- 1 H-benzimidazol-2-yl]methyl } -3- methylbenzamide 1639. N-{[l-(2,6-dimethoxybenzyl)-lH-benzimidazol-2-yl]methyl}-N-pentyl-4- propoxybenzamide
1640. N- { [ 1 -(2,6-dimethoxybenzyl)- lH-benzimidazol-2-yl]methyl }-4-isopropoxy-N- pentylbenzamide
1641. N-{[l-(2,6-dimethoxybenzyl)-lH-benzimidazol-2-yl]methyl}-3,4-dimethoxy-N- pentylbenzamide
1642. N- { [ 1 -(2,6-dimethoxybenzyl)- lH-benzimidazol-2-yl] methyl } -N-isopentyl-3 ,4- dimethoxybenzamide
1643. N-butyl-N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-9H-fluorene-4- carboxamide
1644. N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-N-isobutyl-9H-fluorene-4- carboxamide
1645. N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-N-pentyl-9H-fluorene-4- carboxamide
1646. 2-chloro-N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-3,4-dimethoxy-N- pentylbenzamide
1647. 8-bromo-N-butyl-N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]ρyridin-2-yl]methyl}-l- naphthamide
1648. 8-bromo-N- { [3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl } -N-isobutyl- 1 - naphthamide
1649. 8-bromo-N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-N-pentyl-l- naphthamide
1650. N-butyl-N- { [3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl } -2-( lH-pyrrol- 1 - yl)benzamide
1651. N-{ [3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl } -N-isobutyl-2-( 1 H-pyrrol- 1 - yl)benzamide
1652. N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-N-pentyl-2-(lH-pyrrol-l- yl)benzamide
1653. N-{[3-(2-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-N-isopentyl-2-(lH-pyrrol- l-yl)benzamide
1654. N-butyl-N-{[3-(3-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-9H-fluorene-4- carboxamide
1655. N-butyl-N-{[3-(3-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-2-(lH-pyrrol-l- yl)benzamide
1656. N-{[3-(3-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-N-isobutyl-2-(lH-pyrrol-l- yl)benzamide
1657. N- { [3-(3-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl } -N-pentyl-2-( lH-pyrrol- 1 - yl)benzamide
1658. N- { [3-(3-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl } -N-isopentyl-2-( 1 H-pyrrol- l-yl)benzamide
1659. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-(3-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
1660. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-(4-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide 1661. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-(4-fluorophenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
1662. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-(4-methoxyphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
1663. 2-[l-(3-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-indan-2-yl)-N- (2-fluorobenzyl)acetamide
1664. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-[l-(3-methylphenyl)-3,4-dihydroisoquinolin- 2(lH)-yl]acetamide
1665. N-benzyl-N-(2,3-dihydro- lH-indan-2-yl)-2-[ 1 -(4-methylphenyl)-3 ,4-dihydroisoquinolin- 2(lH)-yl]acetamide
1666. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-[l-(4-methoxyphenyl)-3,4-dihydroisoquinolin- 2(lH)-yl]acetamide
1667. N-[(5-bromo-2-phenyl-l,3-thiazol-4-yl)methyl]-N-isopentyl-2-(lH-pyrrol-l-yl)benzamide
1668. N-butyl-N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-2-(lH-pyrrol-l-yl)benzamide
1669. N- [(5-chloro-2-phenyl- 1 , 3-thiazol-4-yl)methyl] -N-isobutyl-2-( 1 H-pyrrol- 1 -yl)benzamide
1670. N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-N-isopentyl-2-(lH-pyrrol-l-yl)benzamide
1671. N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-N-cyclopentyl-2-(lH-pyrrol-l- yl)benzamide
1672. 8-bromo-N-[(2-phenylquinolin-4-yl)methyl]-N-propyl-l-naphthamide
1673. N-(2-chlorobenzyl)-N-(2-phenylethyl)-9H-fluorene-4-carboxamide
1674. 2-(2-iodophenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide
1675. 2-(2-phenoxyphenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide
1676. 2-(2-methoxyphenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide
1677. 2-(2-bromophenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide
1678. N-benzyl-N- [2-(2-chlorophenyl)ethyl] -9H-fluorene-4-c arboxamide
1679. N-benzyl-N-(3-phenylbutyl)-9H-fluorene-4-carboxamide
1680. N-benzyl-N-[2-(4-chlorophenyl)ethyl]-9H-fluorene-4-carboxamide
1681. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2-carboxamide
1682. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-9H-fluorene-4-carboxamide
1683. N-benzyl-N-[2-(4-fluorophenyl)ethyl]-9H-fluorene-4-carboxamide
1684. N-benzyl-N-[2-(4-methoxyphenyl)ethyl]-9H-fluorene-4-carboxamide
1685. N-benzyl-N-[2-(4-methoxyphenyl)- 1 -methylethyl]-9H-fluorene-4-carboxamide
1686. 2-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)benzamide
1687. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2,5-difluoro-N-(4- methoxybenzyl)benzamide
1688. N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5- yl]methyl}-2,5-difluorobenzamide
1689. 5-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2- methoxy-N-(4-methoxybenzyl)benzamide
1690. 5-chloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol- 5-yl]methyl } -2-methoxybenzamide
1691. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-(trifluoromethyl)benzamide
1692. N-benzyl-2,5-dichloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5- yl]methyl Jbenzamide
1693. 2,5-dichloro-N-{ [ 1 -(2,3-dihydro- 1 H-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(4- methoxybenzyl)benzamide
1694. 2,5-dichloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH- imidazol-5-yl]methyl Jbenzamide
1695. 2-bromo-N- { [1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(4- methoxybenzyl)benzamide
1696. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-(2-phenylethyl)benzamide
1697. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2-iodo-N-(4- methoxybenzyl)benzamide
1698. 3-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2,6- dimethoxy-N-(4-methoxybenzyl)benzamide
1699. 2-bromo-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-5- methoxy-N-(4-methoxybenzyl)benzamide
1700. 3-bromo-N-{ [l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl }-2,6- dimethoxy-N-(4-methoxybenzyl)benzamide
1701. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2-fluoro-6-iodo-N- (4-methoxybenzyl)benzamide
1702. 2-bromo-N- { [ 1 -(2,3-dihydro- 1 H-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(4- methoxybenzyl)-5-methylbenzamide
1703. 2-bromo-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol- 5-yl]methyl}-5-methylbenzamide
1704. 2-chloro-N-{ [l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl }-N-(4- methoxybenzyl)-5-(methylthio)benzamide
1705. 2-chloro-N-{ [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(4- methoxybenzyl)-5-(trifluoromethyl)benzamide
1706. 2-chloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol- 5-yl]methyl } -5-(trifluoromethyl)benzamide
1707. N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-( 1 H-pyrrol- 1 -yl)benzamide
1708. l-(cyclopentylmethyl)-2-[(2-phenylpiperidin-l-yl)carbonyl]-l,2,3,4-tetrahydroisoquinoline
1709. l-(cyclopentylmethyl)-2-[(2-phenylazepan-l-yl)carbonyl]-l,2,3,4-tetrahydroisoquinoline
1710. l-hexyl-2-[(2-phenylpiperidin-l-yl)carbonyl]-l,2,3,4-tetrahydroisoquinoline
1711. l-hexyl-2-[(2-phenylazepan-l-yl)carbonyl]-l,2,3,4-tetrahydroisoquinoline
1712. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-5'-isopropyl-2'-methoxy-l,l'-biphenyl-2- carboxamide
1713. N-benzyl-N-(l -naphthylmethyl)- 1 , 1 -biphenyl-2-carboxamide
1714. N-(l-benzothien-5-ylmethyl)-N-benzyl-l,l'-biphenyl-2-carboxamide 1715. N-benzyl-2'-fluoro-N-(l-naphthylmethyl)-l, -biphenyl-2-carboxamide
1716. N-(4-chlorobenzyl)-N-(2,3-dihydro-lH-indan-2-yl)-2'-fluoro-l,l'-biphenyl-2-carboxamide
1717. N-benzyl-N-( 1 -naphthylmethyl)-2-thien-3-ylbenzamide
1718. N-(4-chlorobenzyl)-N-(2,3-dihydro- 1 H-indan-2-yl)-2-thien-3-ylbenzamide
1719. N-benzyl-2-(5-chlorothien-2-yl)-N-(2,3-dihydro-lH-indan-2-yl)benzamide
1720. N-(4-chlorobenzyl)-2-(5-chlorothien-2-yl)-N-(2,3-dihydro-lH-indan-2-yl)benzamide
1721. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-(5-methylthien-2-yl)benzamide
1722. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methoxybenzyl)-l,l'-biphenyl-2-carboxamide
1723. N-(2,3-dihydro- lH-indan-2-yl)-N-(3-methoxybenzyl)- 1 , 1 '-biphenyl-2-carboxamide
1724. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methoxybenzyl)-l, -biphenyl-2-carboxamide
1725. N-(2,3-dihydro- lH-indan-2-yl)-N-(3-hydroxybenzyl 1 , 1 '-biphenyl-2-carboxamide
1726. ethyl (3-{ [(1,1 '-biphenyl-2-ylcarbonyl)(2,3-dihydro-lH-indan-2- yl)amino]methyl }phenoxy)acetate
1727. N-(3-methoxybenzyl)-N-(2-phenylethyl)-l,l'-biphenyl-2-carboxamide
1728. N-(2,3-dihydro- lH-indan-2-yl)-N-(2-hydroxybenzyl)- 1 , 1 '-biphenyl-2-carboxamide
1729. ethyl (2-{[(l,l'-biphenyl-2-ylcarbonyl)(2,3-dihydro-lH-indan-2- yl)amino]methyl }phenoxy)acetate
1730. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-hydroxybenzyl)-l,l'-biphenyl-2-carboxamide
1731. ethyl (4-{[(l,l'-biphenyl-2-ylcarbonyl)(2,3-dihydro-lH-indan-2- yl)amino]methyl }phenoxy)acetate
1732. N-(4-methoxybenzyl)-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-l,l'-biphenyl- 2-carboxamide
1733. N-(4-fluorobenzyl)-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-l ,1 -biphenyl-2- carboxamide
1734. N-(2,4-difluorobenzyl)-N-[(3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-(lH-pyrrol- l-yl)benzamide
1735. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-[4-(trifluoromethyl)phenyl]nicotinamide
1736. N-benzyl-N-[(l-butyl-lH-benzimidazol-2-yl)methyl]-l-naphthamide
1737. N~2~-(l,3-benzodioxol-5-ylmethyl)-N~l~,N~2~-dibenzyl-N~l~-butylglycinamide
1738. N~ 1 ~,N~2~-dibenzyl-N~ 1 ~-butyl-N~2~-(2-naphthylmethyl)glycinamide
1739. l-(l,3-benzodioxol-5-yl)-N-[(3-butyl-2-phenylquinolin-4-yl)methyl]methanamine
1740. 1 -(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N-[(3-butyl-2-phenylquinolin-4- yl)methyl]methanamine
1741. 1-(1 ,3-benzodioxol-5-yl)-N-benzyl-N-[(3-butyl-2-phenylquinolin-4-yl)methyl]methanamine
1742. 1 -(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N-[(3-butyl-2-phenylpyridin-4- yl)methyl] methanamine
1743. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(3-butyl-2-phenylpyridin-4-yl)methyl]methanamine
1744. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-l,l'-biphenyl-2-carboxamide
1745. N-(l ,3-benzodioxol-5-ylmethyl)-N-(cyclopentylmethyl)- 1 , 1 -biphenyl-2-carboxamide
1746. N,N-bis(l,3-benzodioxol-5-ylmethyl)-l,l'-biphenyl-2-carboxamide 1747. N-benzyl-N-[4-(dimethylamino)benzyl]-l,l -biphenyl-2-carboxamide
1748. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-4-(trifluoromethyl)-l,l'-biphenyl-2- carboxamide
1749. N-benzyl-N-(l-naphthylmethyl)-4'-(trifluoromethyl)-l, -biphenyl-2-carboxamide
1750. N-(l,3-benzodioxol-5-ylmethyl)-N-(cyclopentylmethyl)-4'-(trifluoromethyl)-l, -biphenyl- 2-carboxamide
1751. N-benzyl-N-[4-(dimethylamino)benzyl]-4'-(trifluoromethyl)-l, -biphenyl-2-carboxamide
1752. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-4'-(trifluoromethyl)-l ,1 -biphenyl-2-carboxamide
1753. N-benzyl-2-methoxy-N-( 1 -naphthylmethyl)- 1 , 1 -biphenyl-3-carboxamide
1754. N-(l,3-benzodioxol-5-ylmethyl)-N-(cyclopentylmethyl)-2-methoxy-l,l'-biphenyl-3- carboxamide
1755. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-methoxy-l,l'-biphenyl-3-carboxamide
1756. 4-({(l,3-benzodioxol-5-ylmethyl)[(3-butyl-2-phenylpyridin-4-yl)methyl]amino}methyl)-3- chlorophenol
1757. N-(l,3-benzodioxol-4-ylmethyl)-N-benzyl-l-butyl-2-phenyl-4,5,6,7-tetrahydro-lH- benzimidazol-7-amine
1758. 4-{[benzyl(l-butyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7-yl)amino]methyl}-3- chlorophenol
1759. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-3-butyl-2-phenyl-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4-amine
1760. N-(l,3-benzodioxol-5-ylmethyl)-N,3-dibutyl-2-phenyl-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4-amine
1761. 4-{[benzyl(3-butyl-2-phenyl-3,4,5,6-tetrahydrocyclopenta[d]imidazol-4-yl)amino]methyl}- 3-chlorophenol
1762. 4-{[butyl(3-butyl-2-phenyl-3,4,5,6-tetrahydrocyclopenta[d]imidazol-4-yl)amino]methyl}-3- chlorophenol
1763. 4-({butyl[(3-butyl-2-phenylpyridin-4-yl)methyl]amino}methyl)-3-chlorophenol
1764. 4-({benzyl[(3-butyl-2-phenylpyridin-4-yl)methyl]amino}methyl)-3-chlorophenol
1765. 4-{[benzyl(3-butyl-2-phenyl-3,4,5,6-tetrahydrocyclopenta[d]imidazol-4- yl)amino]methyl Jphenol
1766. 4-{[butyl(3-butyl-2-phenyl-3,4,5,6-tetrahydrocyclopenta[d]imidazol-4- yl)amino]methyl Jphenol
1767. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-l-butyl-5,5-dimethyl-2-phenyl-4,5,6,7- tetrahydro- 1 H-benzimidazol-7-amine
1768. 4-{[butyl(l-butyl-5,5-dimethyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7- yl)amino]methyl}-3-chlorophenol
1769. 3-{[butyl(l-butyl-5,5-dimethyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7- yl)amino]methyl}phenol
1770. 4-{[butyl(l-butyl-5,5-dimethyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7- yl)amino] methyl Jphenol
1771. 4-{ [benzyl(l-butyl-5,5-dimethyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7- yl)amino]methyl}-3-chlorophenol 1772. N-(l,3-benzodioxol-5-ylmethyl)-N-benzyl-2-(lH-imidazol-l-yl)benzamide 1773. methyl 4- { [butyl(l -butyl-5 ,5-dimethyl-2-phenyl-4,5 ,6,7-tetrahydro- lH-benzimidazol-7- yl)amino]methyl Jbenzoate
1774. 4-{[butyl(l-butyl-5,5-dimethyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7- yl)amino]methyl Jbenzoic acid
1775. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
1776. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-(2-fluorophenyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
1777. 2-[l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-indan-2-yl)-N- (2-fluorobenzyl)acetamide
1778. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-[l-[2-(trifluoromethyl)phenyl]-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
1779. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-2-(l-phenyl-3,4-dihydroisoquinolin- 2(lH)-yl)acetamide
1780. 2-[l-(4-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-indan-2-yl)-N- (2-fluorobenzyl)acetamide
1781. N,N-dibenzyl-4'-fluoro- 1 , 1 -biphenyl-2-carboxamide 1782. 3 '-(acetylamino)-N,N-dibenzyl- 1 , 1 -biphenyl-2-carboxamide 1783. N,N-dibenzyl-4 '-(trifluoromethoxy)-l, -biphenyl-2-carboxamide 1784. N,N-dibenzyl-2 '-(methylthio)- 1 , 1 '-biphenyl-2-carboxamide 1785. N,N-dibenzyl-4 '-(ethylthio)- 1 , 1 '-biphenyl-2-carboxamide 1786. N,N-dibenzyl-3 '-fluoro- 1 , 1 -biphenyl-2-carboxamide 1787. N,N-dibenzyl-3 ',4 '-dimethyl- 1 , 1 '-biphenyl-2-carboxamide 1788. N,N-dibenzyl-2^ thien-3-ylbenzamide 1789. N,N-dibenzyl-4 '-(trifluoromethyl)- 1 , 1 -biphenyl-2-carboxamide 1790. N,N-dibenzyl-2 '-methoxy- 1 ,1 -biphenyl-2-carboxamide 1791. N,N-dibenzyl-4: '-methoxy- 1 , 1 '-biphenyl-2-carboxamide 1792. N,N-dibenzyl-2 ',4'-dimethoxy- 1 , 1 '-biphenyl-2-carboxamide 1793. N,N-dibenzyl-3 ',4'-dimethoxy-l , 1 -biphenyl-2-carboxamide 1794. N,N-dibenzyl-l , 1 '-biphenyl-2-carboxamide 1795. N,N-dibenzyl-2 '-chloro- 1 , 1 '-biphenyl-2-carboxamide 1796. N,N-dibenzyl-3 '-chloro- 1 , 1 -biphenyl-2-carboxamide 1797. N,N-dibenzyl-4 '-chloro- 1 ,1 -biphenyl-2-carboxamide 1798. N,N-dibenzyl-2 ',3'-dichloro-l,l'-biphenyl-2-carboxamide 1799. N,N-dibenzyl-2 ',4'-dichloro- 1 , 1 -biphenyl-2-carboxamide 1800. N,N-dibenzyl-2 '-methyl- 1 , 1 '-biphenyl-2-carboxamide 1801. N,N-dibenzyl-3 '-methyl- 1 , 1 -biphenyl-2-carboxamide 1802. N,N-dibenzyl-4 -methyl- 1 , 1 -biphenyl-2-carboxamide 1803. N,N-dibenzyl-3 ',5 '-dichloro- 1 , 1 -biphenyl-2-carboxamide 1804. N-benzyl-N-[2-(4-methoxyphenyl)-l-methylethyl]-4'-methyl-l,l'-biphenyl-2-carboxamide
1805. N-benzyl-N-(2,3-dihydro- lH-indan-2-yl)-4'-methyl- 1 , 1 -biphenyl-2-carboxamide
1806. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-(4-methylthien-2-yl)benzamide
1807. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2-carboxamide
1808. N-benzyl-N-(2,3-dihydro-lH-indan-l-yl)-2'-fluoro-l, -biphenyl-2-carboxamide
1809. N-benzyl-N-(2,3 -dihydro- 1 H-indan-2-yl)-3 '-methoxy- 1 , 1 -biphenyl-2-carboxamide
1810. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-thien-2-ylbenzamide
1811. N-(l ,3-benzodioxol-5-ylmethyl)-N-(2,3-dihydro-lH-indan-2-yl)-3'-methoxy-l , 1 '-biphenyl- 2-carboxamide
1812. N-(l ,3-benzodioxol-5-ylmethyl)-N-(2,3-dihydro- lH-indan-2-yl)-9H-fluorene-4- carboxamide
1813. N-benzyl-N-(2,3-dihydro- lH-indan-2-yl)-4-methoxy- 1 , 1 '-biphenyl-2-carboxamide
1814. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-3-methoxy-l , 1 '-biphenyl-2-carboxamide
1815. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-4-hydroxy-l,l'-biphenyl-2-carboxamide
1816. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-3-hydroxy-l,l'-biphenyl-2-carboxamide
1817. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-5-methoxy-2-(5-methylthien-2-yl)benzamide
1818. N-benzyl-N-(5-methoxy-2,3-dihydro- lH-indan-2-yl)- 1 , 1 -biphenyl-2-carboxamide
1819. N-benzyl-N-(5-methyl-2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2-carboxamide
1820. N-(2,3-dihydro- lH-indan-2-yl)-N-(2-methylbenzyl)- 1 , 1 -biphenyl-2-carboxamide
1821. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1822. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1823. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-fluorobenzyl)-l,l'-biphenyl-2-carboxamide
1824. N-(2,3-dihydro- lH-indan-2-yl)-N-(3-fluorobenzyl)- 1 , 1 -biphenyl-2-carboxamide
1825. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-l,l'-biphenyl-2-carboxamide
1826. N-(l,3-benzodioxol-5-ylmethyl)-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2- carboxamide
1827. N-(3,4-difluorobenzyl)-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2-carboxamide
1828. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-methoxybenzyl)-2-thien-3-ylbenzamide
1829. N-(2,3-dihydro-lH-indan-2-yl)-2'-fluoro-N-(2-methoxybenzyl)-l,l'-biphenyl-2- carboxamide
1830. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methoxybenzyl)-2-thien-3-ylbenzamide
1831. N-(2,3-dihydro-lH-indan-2-yl)-N-(3,5-dimethoxybenzyl)-2-thien-3-ylbenzamide
1832. N-(2,3-dihydro-lH-indan-2-yl)-2-thien-3-yl-N-(3-thien-3-ylbenzyl)benzamide
1833. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-naphthylmethyl)-2-thien-3-ylbenzamide
1834. N,N-dibenzyl-2'-fluoro- 1 , 1 '-biphenyl-2-carboxamide
1835. N-(2,3-dihydro- lH-indan-2-yl)-4'-methyl-N-(4-methylbenzyl)- 1 , 1 -biphenyl-2-carboxamide
1836. N-(2,3-dihydro-lH-indan-2-yl)-3'-methoxy-N-(4-methylbenzyl)-l,l'-biphenyl-2- carboxamide
1837. N-(2,3-dihydro- lH-indan-2-yl)-2'-fluoro-N-(4-methylbenzyl)- 1 , 1 '-biphenyl-2-carboxamide 1838. N-(2,3-dihydro- lH-indan-2-yl)-N-(4-fluorobenzyl)-4 -methyl- 1,1 -biphenyl-2-carboxamide
1839. N-(2,3-dihydro- lH-indan-2-yl)-N-(4-fluorobenzyl)-3 -methoxy- l,l'-biphenyl-2- carboxamide
1840. N-(2,3-dihydro-lH-indan-2-yl)-2'-fluoro-N-(4-fluorobenzyl)-l,l -biphenyl-2-carboxamide
1841. N-(2,3-dihydro- lH-indan-2-yl)-N-(2-fluorobenzyl)-4'-methyl- 1 , 1 '-biphenyl-2-carboxamide
1842. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-fluorobenzyl)-4'-methyl-l,l'-biphenyl-2-carboxamide
1843. N-(2,3-dihydro-lH-indan-2-yl)-2'-fluoro-N-(3-fluorobenzyl)-l,l'-biphenyl-2-carboxamide
1844. N-(2,3-dihydro- lH-indan-2-yl)-4'-methyl-N-(3-methylbenzyl)- 1 , 1 -biphenyl-2-carboxamide
1845. N-(2,3-dihydro-lH-indan-2-yl)-3 '-methoxy-N-(3-methylbenzyl)- 1 , 1 '-biphenyl-2- carboxamide
1846. N-(2,3-dihydro-lH-indan-2-yl)-2'-fluoro-N-(3-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1847. N-(2,3-dihydro-lH-indan-2-yl)-4'-methyl-N-(2-methylbenzyl)-l,l'-biphenyl-2-carboxamide
1848. N-(2,3-dihydro-lH-indan-2-yl)-3-methoxy-N-(3-methoxybenzyl)-l,l'-biphenyl-2- carboxamide
1849. N-(2,3-dihydro-lH-indan-2-yl)-5-methoxy-N-(3-methoxybenzyl)-2-(5-methylthien-2- yl)benzamide
1850. N-(2,3-dihydro-lH-indan-2-yl)-4-methoxy-N-(3-methoxybenzyl)-l,l'-biphenyl-2- carboxamide
1851. N-(2,3-dihydro-lH-indan-2-yl)-5-methoxy-N-(3-methoxybenzyl)-2-thien-3-ylbenzamide
1852. N-(2,3-dihydro-lH-indan-2-yl)-4-methoxy-N-(2-methylbenzyl)-l,l'-biphenyl-2- carboxamide
1853. N-(2,3-dihydro-lH-indan-2-yl)-4-methoxy-N-(3-methylbenzyl)-l,l'-biphenyl-2- carboxamide
1854. N-(2,3-dihydro-lH-indan-2-yl)-4-methoxy-N-(4-methylbenzyl)-l,l'-biphenyl-2- carboxamide
1855. N-(2,3-dihydro- lH-indan-2-yl)-N-(2-fluorobenzyl)-4-methoxy- 1 , 1 '-biphenyl-2- carboxamide
1856. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-fluorobenzyl)-4-methoxy-l,l'-biphenyl-2- carboxamide
1857. N-(2,3-dihydro- lH-indan-2-yl)-N-(4-fluorobenzyl)-4-methoxy- 1 , 1 '-biphenyl-2- carboxamide
1858. N-(3,4-difluorobenzyl)-N-(2,3-dihydro-lH-indan-2-yl)-4-methoxy-l,l'-biphenyl-2- carboxamide
1859. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-3-fluoro-l,l'-biphenyl-2-carboxamide
1860. N-benzyl-N-(2,3-dihydro- lH-indan-2-yl)-3-methyl- 1 , 1 -biphenyl-2-carboxamide
1861. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-fluoro-6-(5-methylthien-2-yl)benzamide
1862. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-methyl-6-(5-methylthien-2-yl)benzamide
1863. N-benzyl-N-(2,3-dihydro- lH-indan-2-yl)-4-methyl- 1 , 1 -biphenyl-2-carboxamide
1864. N-benzyl-4-chloro-N-(2,3-dihydro- lH-indan-2-yl)- 1 , 1 -biphenyl-2-carboxamide
1865. N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-5-methyl-2-thien-3-ylbenzamide
1866. N-benzyl-5-chloro-N-(2,3-dihydro-lH-indan-2-yl)-2-thien-3-ylbenzamide 867. N-(2,3-dihydro-lH-indan-2-yl)-3-methyl-N-(2-methylbenzyl)-l,l'-biphenyl-2-carboxamide
868. N-(2,3-dihydro-lH-indan-2-yl)-3-methyl-N-(3-methylbenzyl)-l,l'-biphenyl-2-carboxamide
869. N-(2,3-dihydro-lH-indan-2-yl)-3-methyl-N-(4-methylbenzyl)-l,l'-biphenyl-2-carboxamide
870. N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-3-methyl-l,l'-biphenyl-2-carboxamide
871. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-fluorobenzyl)-3-methyl-l,l'-biphenyl-2-carboxamide
872. N-(2,3-dihydro-lH-indan-2-yl)-N-(4-fluorobenzyl)-3-methyl-l,l'-biphenyl-2-carboxamide
873. N-(3 ,4-difluorobenzyl)-N-(2,3-dihydro- 1 H-indan-2-yl)-3 -methyl- 1 , 1 '-biphenyl-2- carboxamide
874. N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methoxybenzyl)-3-methyl-l,l'-biphenyl-2- carboxamide
875. N-(2,3-dihydro- lH-indan-2-yl)-N-(4-methoxybenzyl)-3-methyl- 1 , 1 '-biphenyl-2- carboxamide
876. N-(l,3-benzodioxol-5-ylmethyl)-N-(2,3-dihydro-lH-indan-2-yl)-3-methyl-l,l'-biphenyl-2- carboxamide
877. N-(2,3-dihydro-lH-indan-2-yl)-3-methyl-N-(2-phenylethyl)-l,l'-biphenyl-2-carboxamide
878. 4-chloro-N-(2,3-dihydro- lH-indan-2-yl)-N-(2-methylbenzyl)- 1 , 1 '-biphenyl-2-carboxamide
879. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methylbenzyl)-l,l'-biphenyl-2-carboxamide
880. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methylbenzyl)-l , 1 -biphenyl-2-carboxamide
881. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(2-fluorobenzyl)-l, -biphenyl-2-carboxamide
882. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(3-fluorobenzyl)-l,l'-biphenyl-2-carboxamide
883. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(4-fluorobenzyl)-l,l'-biphenyl-2-carboxamide
884. 4-chloro-N-(3,4-difluorobenzyl)-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2- carboxamide
885. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(4-methoxybenzyl)-l,l'-biphenyl-2- carboxamide
886. N-(l,3-benzodioxol-5-ylmethyl)-4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2- carboxamide
887. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(3-methoxybenzyl)-l,l'-biphenyl-2- carboxamide
888. 4-chloro-N-(2,3-dihydro-lH-indan-2-yl)-N-(2-phenylethyl)-l,l'-biphenyl-2-carboxamide
889. N-benzyl-4-chloro-N-(4-hydroxy-3 ,5-dimethylbenzyl)- 1 , 1 '-biphenyl-2-carboxamide
890. N-benzyl-N- {(IS ,2S)-2-[4- (2-methoxyphenyl)piperazin- 1 -yl] cyclohexyl J - 1 , 1 -biphenyl-2- carboxamide
891. N-benzyl-4-chloro-N-(2,3-dihydro- 1 -benzofuran-6-ylmethyl)- 1 , 1 -biphenyl-2-carboxamide
892. 4-chloro-N-(3-methoxybenzyl)-N-(2-phenylethyl)- 1 , 1 -biphenyl-2-carboxamide
893. N-benzyl-4-chloro-N-( 1 -naphthylmethyl)- 1 , 1 '-biphenyl-2-carboxamide
894. N-benzyl-N-(4-hydroxy-3,5-dimethylbenzyl)-2-(5-methylthien-2-yl)benzamide
895. N-benzyl-N-[4-(difluoromethoxy)benzyl]-2-(5-methylthien-2-yl)benzamide
896. N-benzyl-N-(2-chloro-4-hydroχybenzyl)-2-(5-methylthien-2-yl)benzamide
897. N-benzyl-N-(4-hydroxy-3 ,5-dimethylbenzyl)- 1 , 1 '-biphenyl-2-carboxamide 1898. N-benzyl-N-[4-(difluoromethoxy)benzyl]-l,l'-biphenyl-2-carboxamide
1899. N-benzyl-2-(5-methylthien-2-yl)-N-[3-(trifluoromethyl)benzyl]benzamide
1900. 1 -( 1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-4-(methylthio)-2- phenyl-lH-imidazol-5-yl]methylJmethanamine
1901. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(methylsulfonyl)- 2-phenyl-lH-imidazol-5-yl]methylJmethanamine
1902. 1 -( 1 ,3-benzodioxol-5-yl)-N-{ [ 1 -butyl-4-(methylsulf onyl)-2-phenyl- 1 H-imidazol-5- yl]methylJ-N-[4-(difluoromethoxy)benzyl]methanamine
1903. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl }-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1904. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methylJ-N-(3-ethoxybenzyl)methanamine
1905. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-ethoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl J-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1906. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[4-(methylthio)phenyl]-2-phenyl-lH-imidazol-5- yl}methyl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1907. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[4-(ethylthio)phenyl]-2-phenyl-lH-imidazol-5- yl}methyl)-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1908. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methylJ-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1909. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-ethoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1910. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[3-(methylthio)phenyl]-2-phenyl-lH-imidazol-5- yl }methyl)-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1911. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-methylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-[3-( 1 , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1912. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-4-(4-methylphenyl)-2-phenyl-lH-imidazol-5- yl] methyl } -N- [3 -( 1 , 1 ,2,2-tetrafluoroethoxy)benzyl] methanamine
1913. 1 -( 1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(3,4-dimethylphenyl)-2-phenyl- 1 H-imidazol-5- yl]methyl }-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1914. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,5-dimethylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1915. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-4-(3~fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl }-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1916. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(4-fluorophenyl)-2-phenyl- 1 H-imidazol-5- yl]methyl }-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1917. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,4-difluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1918. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,5-difluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1919. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(4-ethoxyphenyl)-2-phenyl- lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
1920. 1 -(1 ,3-benzodioxol-5-yl)-N-({ 1 -butyl-4-[4-(methylthio)phenyl]-2-phenyl- 1 H-imidazol-5 - yl}methyl)-N-(3-ethoxybenzyl)methanamine 1921. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[4-(ethylthio)phenyl]-2-phenyl-lH-imidazol-5- yl}methyl)-N-(3-ethoxybenzyl)methanamine
1922. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-methoxyphenyl)-2-ρhenyl-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
1923. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-ethoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
1924. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[3-(methylthio)phenyl]-2-phenyl-lH-imidazol-5- yl}methyl)-N-(3-ethoxybenzyl)methanamine
1925. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-methylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1926. 1 -( 1 ,3-benzodioxol-5-yl)-N-{ [ 1 -butyl-4-(4-methylphenyl)-2-phenyl- lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1927. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,4-dimethylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1928. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,5-dimethylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1929. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
1930. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
1931. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,4-difluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1932. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,5-difluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1933. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[3-(trifluoromethyl)phenyl]-lH-imidazol- 5-yl}methyl)-N-(3-ethoxybenzyl)methanamine
1934. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[4-(trifluoromethyl)phenyl]-lH-imidazol- 5 -yl } methyl)-N-(3 -ethoxybenzyl)methanamine
1935. l-(l,3-benzodioxol-5-yl)-N-({ l-butyl-2-phenyl-4-[3-(trifluoromethoxy)phenyl]-lH- imidazol-5-yl}methyl)-N-(3-ethoxybenzyl)methanamine
1936. 1 -( 1 ,3-benzodioxol-5-yl)-N-( { 1 -butyl-2-phenyl-4-[4-(trifluoromethoxy)phenyl]- 1H- imidazol-5-yl}methyl)-N-(3-ethoxybenzyl)methanamine
1937. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[(lE)-pent-l-enyl]-2-phenyl-lH-imidazol-5- yl}methyl)-N-(3-ethoxybenzyl)methanamine
1938. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[3-(trifluoromethyl)phenyl]-lH-imidazol- 5-yl}methyl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1939. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[4-(trifluoromethyl)phenyl]-lH-imidazol- 5-yl}methyl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1940. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[3-(trifluoromethoxy)phenyl]-lH- imidazol-5-yl}methyl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1941. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[4-(trifluoromethoxy)phenyl]-lH- imidazol-5-yl}methyl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1942. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-4-[(lE)-pent-l-enyl]-2-phenyl-lH-imidazol-5- yl}methyl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine 1943. 1 -(1 ,3-benzodioxol-5-yl)-N- { [1 -butyl-4-(4-chlorophenyl)-2-phenyl- lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1944. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-chlorophenyl)-2-phenyl-lH-imidazol-5- yljmethyl } -N-(3-ethoxybenzyl)methanamine
1945. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-isopropylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
1946. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(2,4-difluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
1947. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
1948. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1949. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-isopropylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1950. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(2,4-difluorophenyl)-2-phenyl-lH-imidazol-5- yljmefhyl } -N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1951. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3- isopropylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
1952. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3,4- dimethylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
1953. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(2,4- difluorophenyl)-2-phenyl- 1 H-imidazol-5 -yl]methyl Jmethanamine
1954. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3,5- difluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
1955. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({ l-butyl-2-phenyl-4-[(E)-2- phenylethenyl] - 1 H-imidazol-5-yl } methyl)methanamine
1956. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[(E)-2-phenylethenyl]-lH-imidazol-5- yl}methyl)-N-(3-ethoxybenzyl)methanamine
1957. l-(l,3-benzodioxol-5-yl)-N-({l-butyl-2-phenyl-4-[(E)-2-phenylethenyl]-lH-imidazol-5- yl}methyl)-N-[3-(l , 1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
1958. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
1959. 4-({ (1 ,3-benzodioxol-5-ylmethyl)[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzamide
1960. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzenesulfonamide
1961. methyl 4-({(l, 3-benzodioxol-5-ylmethyl)[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzoate
1962. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- methoxybenzyl)methanamine
1963. 6-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } (cyclohexylmethyl)amino]methyl } -3 ,4-dihydroquinolin-2(l H)-one
1964. 6-[(butyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}amino)methyl]- 3 ,4-dihydroquinolin-2( 1 H)-one 1965. 6-[((l ,3-benzodioxol-5-ylmethyl){ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl] -3 ,4-dihydroquinolin-2( 1 H)-one
1966. 6-( { benzyl[( 1 -butyl-2,4-diphenyl- lH-imidazol-5 -yl)methyl] amino } methyl)-3 ,4- dihydroquinolin-2( 1 H)-one
1967. 6-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3,4- dihydroquinolin-2( 1 H)-one
1968. 6-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)-3 ,4-dihydroquinolin-2( 1 H)-one
1969. 6-{[[(l -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] (cyclohexylmethyl)amino]methyl } - 3 ,4-dihydroquinolin-2( 1 H)-one
1970. 6-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]amino}methyl)-3,4-dihydroquinolin-2(lH)-one
1971. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N,N-bis(2,3-dihydro-l ,4-benzodioxin-6- ylmethyl)methanamine
1972. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N,N-bis(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)methanamine
1973. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N,N-bis(2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)methanamine
1974. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)methanamine
1975. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dihydro- 1 -benzofuran-5-ylmethyl)methanamine
1976. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N,N-bis(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amine
1977. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } -N-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)methanamine
1978. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yljmethyl } -N-(2,3-dihydro- 1 -benzofuran-5-ylmethyl)methanamine
1979. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-phenyl-2-(lH- pyrazol- 1 -yl)- lH-imidazol-5-yl]methyl } methanamine
1980. 4-[(butyl{[l-butyl-4-(5-methylthien-2-yl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzamide
1981. N- { [ 1 -butyl-4-(5-methylthien-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(3- ethoxybenzyl)butan- 1 -amine
1982. N-{[l-butyl-4-(5-methylthien-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]butan- 1 -amine
1983. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-4-(5-methylthien-2-yl)-2-phenyl-lH- imidazol-5-yl]methyl Jbutan- 1 -amine
1984. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-butyl-5-phenyl-4H-l,2,4- triazol-3 -yl)methyl] methanamine
1985. l-(l,3-benzodioxol-5-yl)-N-[(4-butyl-5-phenyl-4H-l,2,4-triazol-3-yl)methyl]-N- (cyclohexylmethyl)methanamine
1986. N-(l ,3-benzodioxol-5-ylmethyl)-N-[(4-butyl-5-phenyl-4H-l ,2,4-triazol-3-yl)methyl]butan- 1 -amine 1987. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-2- morpholin-4-ylethanamine
1988. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzoxazol-2-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
1989. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (tetrahydro-2H-pyran-4-ylmethyl)methanamine
1990. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-2- piperidin- 1 -ylethanamine
1991. N~ 1 ~-(l ,3-benzodioxol-5-ylmethyl)-N~ 1 —[(1 -butyl-2,4-diphenyl- 1 H-imidazol-5- yl)methyl]-N~2~,N~2~-diethylethane-l,2-diamine
1992. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-2- thiomorpholin-4-ylethanamine
1993. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2S)- tetrahydrofuran-2-ylmethyl]methanamine
1994. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-methylchroman-4-amine
1995. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-pyrimidin-2-yl- 1 H-imidazol-5 -yl)methyl] methanamine
1996. N,N-bis(l,3-benzodioxol-5-ylmethyl)-2-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)acetamide
1997. N,N-bis(l,3-benzodioxol-5-ylmethyl)-2-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethanamine
1998. l'-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-butyl-l-methyl-3-phenyl- lH-pyrazol-5-yl)methyl]methanamine
1999. N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-butyl-l-methyl-3-phenyl-lH-pyrazol-5- yl)methyl]butan-l-amine
2000. l-(l,3-benzodioxol-5-yl)-N-[(4-butyl-l-methyl-3-phenyl-lH-pyrazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2001. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(4-butyl-l-methyl-3-phenyl-lH-pyrazol-5- yl)methyl]methanamine
2002. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-butyl-l-methyl-5-phenyl- lH-pyrazol-3-yl)methyl]methanamine
2003. N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-butyl-l-methyl-5-phenyl-lH-pyrazol-3- yl)methyl]butan-l-amine
2004. N,N-bis(l,3-benzodioxol-5-ylmethyl)-3-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)propanamide
2005. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(l,4- dioxaspiro[4.5]dec-8-ylmethyl)methanamine
2006. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)cyclohexanone
2007. N,N-bis(l,3-benzodioxol-5-ylmethyl)-3-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)propan-l- amine
2008. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)- 1 -methylcyclohexanol
2009. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2- methyl-l,3-benzoxazol-5-yl)methyl]methanamine 2010. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- methylethanamine
2011. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)cyclohexanol
2012. N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-butyl-l,3-diphenyl-lH-pyrazol-4-yl)methyl]butan-l- amine
2013. l-(l,3-benzodioxol-5-yl)-N-[(5-butyl-l,3-diρhenyl-lH-pyrazol-4-yl)methyl]-N-(lH- imidazol-2-ylmethyl)methanamine
2014. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-butyl-l,3-diphenyl-lH- pyrazol-4-yl)methyl]methanamine
2015. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2- methyl- 1 ,3-benzothiazol-5-yl)methyl]methanamine
2016. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(l-ethyl-3,5-dimethyl-lH-pyrazol- 4-yl)methyl]butan- 1 -amine
2017. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(3,5-dimethyl-lH-pyrazol-4- yl)methyl]butan- 1 -amine
2018. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-4-thien-3-yl-lH-imidazol-5-yl)methyl]-N- [3-(l ,1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
2019. methyl 2-amino-4- [(butyl { [l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzoate
2020. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)methanamine
2021. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dihydro-l-benzofuran-5-ylmethyl)methanamine
2022. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-4-thien-3-yl-lH-imidazol-5-yl)methyl]-N- (3-ethoxybenzyl)methanamine
2023. 1 -(1 ,3-benzodioxol-5-yl)-N-( 1 ,3-benzodioxol-5-ylmethyl)-N- { [1 -butyl-2-(4-fluorophenyl)- 4-phenyl-lH-imidazol-5-yl]methyl}methanamine
2024. 1 -( 1 -butyl-2-phenyl- lH-imidazol-5-yl)-N-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)-N- (2,3-dihydro- 1 -benzofuran-5-ylmethyl)methanamine
2025. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
2026. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(2,3-dihydro-l-benzofuran-5-ylmethyl)methanamine
2027. 1 -[ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5-yl]-N-(2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2028. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(4-methylphenyl)- 4-phenyl-lH-imidazol-5-yl]methyl}methanamine
2029. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(2-methylphenyl)- 4-phenyl-lH-imidazol-5-yl]methyl}methanamine
2030. 1 -( 1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-2-(3-fiuorophenyl)- 4-phenyl-lH-imidazol-5-yl]methyl}methanamine
2031. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-fluoro-2-phenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine 2032. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-fluoro-2-phenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
2033. l-(l,3-benzodioxol-5-yl)-N-benzyl-N-[(l-butyl-4-fluoro-2-phenyl-lH-imidazol-5- yl)methyl]methanamine
2034. N-[(l-butyl-4-fluoro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(cyclohexylmethyl)-N-(lH- indol-5-ylmethyl)amine
2035. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
2036. N-{[l-butyl-4-phenyl-2-(lH-pyrazol-l-yl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine
2037. 4-(2-{(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } ethyl)phenol
2038. methyl 2-amino-4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5-yl]methyl}amino)methyl]benzoate
2039. 7-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]quinazolin-4-ol
2040. methyl 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]amino}methyl)-2-nitrobenzoate
2041. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-fluorophenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2042. 7-({ (1 ,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)quinazolin-4-ol
2043. 7-({ (1 ,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)quinazolin-4-amine
2044. 7-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)-N,N-diethylquinazolin-4-amine
2045. 7-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino }methyl)-N-ethylquinazolin-4-amine
2046. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(4- ethoxyquinazolin-7-yl)methyl]methanamine
2047. 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)-N-(cyclohexylmethyl)-N-methylmethanamine
2048. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(cyclohexylmethyl)butan-l-amine
2049. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-l-cyclohexyl-N-methylethanamine
2050. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)butan- 1 -amine
2051. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
2052. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-ethoxybenzyl)butan-l- amine
2053. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-methoxybenzyl)butan-l- amine
2054. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-4- (phenylsulfonyl)-lH-imidazol-5-yl]methyl}methanamine 2055. 1 -(1 ,3-benzodioxol-5-yl)-N-[(l -butyl-4-fluoro-2-phenyl- 1 H-imidazol-5-yl)methyl] -N-(3- ethoxybenzyl)methanamine
2056. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-fluoro-2-phenyl- lH-imidazol-5-yl)methyl]methanamine
2057. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- methylmethanamine
2058. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] ethanamine
2059. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]propan-l-amine
2060. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-3- ethoxypropan- 1 -amine
2061. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N- (2,3-dihydro-l-benzofuran-5-ylmethyl)methanamine
2062. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N- (3-ethoxybenzyl)methanamine
2063. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N- methylmethanamine
2064. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl] ethanamine
2065. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl]propan- 1 -amine
2066. N-( 1 ,3-benzodioxol-5-ylmethyl)-N-[( 1 -butyl-4-chloro-2-phenyl- 1 H-imidazol-5 -yl)methyl] - 3 -ethoxypropan- 1 -amine
2067. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(2,3-dihydro-l-benzofuran-5-ylmethyl)amine
2068. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)amine
2069. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-phenyl-2-(lH-pyrazol-l-yl)-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
2070. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(2,6- dimethylphenyl)-4-phenyl- 1 H-imidazol-5-yl] methyl } methanamine
2071. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l-benzofuran-5- ylmethyl)butan- 1 -amine
2072. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[3- (difluoromethoxy)benzyl]butan- 1 -amine
2073. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-butyl-l-phenyl-lH- pyrazol-4-yl)methyl]methanamine
2074. N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-butyl-l-phenyl-lH-pyrazol-4-yl)methyl]butan-l- amine
2075. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(l,l- dioxidotetrahydro-2H-thiopyran-4-yl)methyl]methanamine
2076. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanesulfonamide 2077. N-[l-(l,3-benzodioxol-5-yl)ethyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan-l-amine
2078. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[l-(3-ethoxyphenyl)ethyl]butan-l- amine
2079. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-{ l-[4- (difluoromethoxy)phenyl] ethyl Jbutan- 1 -amine
2080. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[l-(2,3-dihydro-l,4-benzodioxin-6- yl)ethyl]butan- 1 -amine
2081. 4-( 1 - { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } ethyl)benzoic acid
2082. N-{ [3-(benzyloxy)isoxazol-5-yl]methyl}-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
2083. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(2- methyl- 1 ,3-benzothiazol-5-yl)methyl]methanamine
2084. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(2-methyl-l,3-benzothiazol-5- yl)methyl]butan- 1 -amine
2085. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-butyl-3-chloro-6- phenylpyridazin-4-yl)methyl]methanamine
2086. N-(l,3-benzodioxol-5-ylmethyl)-N-[(5-butyl-3-chloro-6-phenylpyridazin-4- yl)methyl]butan- 1 -amine
2087. 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)isoxazol-3-ol
2088. N-[l-(l,3-benzodioxol-5-yl)ethyl]-N-[(l-butyl-4-chloro-2-ρhenyl-lH-imidazol-5- yl)methyl]propan- 1 -amine
2089. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[l-(2,3-dihydro-l,4- benzodioxin-6-yl)ethyl]propan-l-amine
2090. l-(l,3-benzodioxol-5-yl)-N-[(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2091. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzamide
2092. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2093. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dichlorophenol
2094. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-chlorophenol
2095. 4-({(l,3-benzodioxol-5-ylmethyl)[l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl] amino } methyl)-2,6-dimethylphenol
2096. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(3 ,4-dichlorobenzyl)butan- 1 -amine
2097. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N- (cyclohexylmethyl)pentan- 1 -amine
2098. (lR)-N,N-bis(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)pentan- 1 -amine
2099. (1R)- 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3-dihydro- 1 - benzofuran-6-ylmethyl)pentan- 1 -amine
2100. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3- dihydro- 1 -benzofuran-6-ylmethyl)pentan- 1 -amine
2101. 4-{[[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)pentyl] (cyclohexylmethyl)amino]methyl } -2,6-dimethylphenol
2102. 4-({(l,3-benzodioxol-5-ylmethyl)[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)pentyl]amino}methyl)-2,6-dimethylphenol
2103. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N- (cyclohexylmethyl)ethanamine
2104. (lR)-N,N-bis(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethanamine
2105. (1 S)-N,N-bis( 1 ,3-benzodioxol-5-ylmethyl)- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5- yl)ethanamine
2106. (lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3-dihydro-l- benzofuran-6-ylmethyl)ethanamine
2107. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3- dihydro- 1 -benzofuran-6-ylmethyl)ethanamine
2108. (lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3-dihydro-l- benzofuran-6-ylmethyl)ethanamine
2109. 4-{[[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl](cyclohexylmethyl)amino]methyl}-2,6-dimethylphenol
2110. 4-{ [[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl] (cyclohexylmethyl)amino]methyl } -2,6-dimethylphenol
2111. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-fluoro-4-methoxybenzyl)butan-l- amine
2112. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-fluoro-4- methoxybenzyl)methanamine
2113. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-methoxy-3-methylbenzyl)butan- 1 -amine
2114. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxy-3- methylbenzyl)methanamine
2115. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-chloro-4-fluorobenzyl)butan-l- amine
2116. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-chloro-4- fluorobenzyl)methanamine
2117. methyl 4-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)ethyl]amino }methyl)benzoate
2118. methyl 4-({benzyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)ethyl]amino }methyl)benzoate
2119. methyl 4-({butyl[l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentyl]amino}methyl)benzoate
2120. 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxyphenol
2121. 4-( { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-2-methoxyphenol
2122. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- _ methoxyphenol
2123. 4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)benzene-l,2-diol
2124. 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)-N,N-bis(4-methoxybenzyl)methanamine 2125. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N,N-bis(3,4-dihydroxybenzyl)methanamine
2126. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro-5- (trifluoromethyl)benzyl]butan-l-amine
2127. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-methoxy-3,5- dimethylbenzyl)butan- 1 -amine
2128. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,5-dichloro-4- methoxybenzyl)butan-l-amine
2129. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-chloro-4-methoxybenzyl)butan-l- amine
2130. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxy-3,5- dimethylbenzyl)methanamine
2131. 4-({butyl[(l -buty 1-2-phenyl- 1 H-imidazol-5 -yl)methyl] amino } methy l)benzamide
2132. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,5-dichloro-4- methoxybenzyl)methanamine
2133. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-chloro-4- methoxybenzyl)methanamine
2134. 4-{[[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l-benzofuran-5- ylmethyl)amino]methyl}benzenesulfonamide
2135. N-(l,3-benzodioxol-5-ylmethyl)-N-[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl]butan-l-amine
2136. N-[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)butan- 1 -amine
2137. 4-({butyl[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]amino}methyl)benzoic acid
2138. N-(l,3-benzodioxol-5-ylmethyl)-N-[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl]butan- 1 -amine
2139. N-[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)butan- 1 -amine
2140. 4-({butyl[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]amino }methyl)benzoic acid
2141. methyl 4-({butyl[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl] amino }methyl)benzoate
2142. methyl 4-({butyl[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl] amino } methyl)benzoate
2143. 4-({butyl[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]amino}methyl)benzamide
2144. 4-({butyl[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)ethyl]amino}methyl)benzamide
2145. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dichlorophenol
2146. 5 -( { butyl [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)-2-methoxyphenol
2147. 4-( { benzyl [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino } methy l)-2-methylphenol
2148. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-methylphenol
2149. 4-( { butyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] amino ) methyl)-2-chlorophenol
2150. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-fluoro-3- (trifluoromethyl)benzyl]methanamine 2151. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro-3- (trifluoromethyl)benzyl]butan- 1 -amine
2152. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[2-fluoro-3- (trifluoromethyl)benzyl]methanamine
2153. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro- 3-(trifluoromethyl)benzyl]methanamine
2154. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-fluoro-4- (trifluoromethyl)benzyl]methanamine
2155. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro-4- (trifluoromethyl)benzyl]butan- 1 -amine
2156. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[2-fluoro-4- (trifluoromethyl)benzyl]methanamine
2157. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro- 4-(trifluoromethyl)benzyl]methanamine
2158. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-fluoro-5- (trifluoromethyl)benzyl]methanamine
2159. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[2-fluoro-5- (trifluoromethyl)benzyl]methanamine
2160. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-fluoro- 5-(trifluoromethyl)benzyl]methanamine
2161. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]methanamine
2162. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]butan- 1 -amine
2163. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2164. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2165. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-fluoro-4- (trifluoromethyl)benzyl]methanamine
2166. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-fluoro-4- (trifluoromethyl)benzyl]butan- 1 -amine
2167. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3-fluoro-4- (trifluoromethyl)benzyl]methanamine
2168. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-fluoro- 4-(trifluoromethyl)benzyl]methanamine
2169. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]methanamine
2170. N-[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl]-N-[3-(trifluoromethyl)benzyl]butan-l- amine
2171. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2172. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3- (trifluoromethyl)benzyl]methanamine 2173. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (methylthio)benzyl]methanamine
2174. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(methylthio)benzyl]butan-l- amine
2175. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(2,2-dimethyl-3,4-dihydro-2H- chromen-6-yl)methyl]methanamine
2176. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2,2-dimethyl-3,4-dihydro-2H- chromen-6-yl)methyl]butan- 1 -amine
2177. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-isopropylbenzyl)methanamine
2178. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-isopropylbenzyl)butan-l-amine
2179. 2-{[l-(2,3-dihydro-lH-inden-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-l-(2- methylphenyl)- 1 ,2,3,4-tetrahydroisoquinoline
2180. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-fluoro- 3-(trifluoromethyl)benzyl]methanamine
2181. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-fluoro-5- (trifluoromethyl)benzyl]butan- 1 -amine
2182. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3-fluoro-5- (trifluoromethyl)benzyl]methanamine
2183. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-fluoro- 5-(trifluoromethyl)benzyl]methanamine
2184. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-chloro-3- (trifluoromethyl)benzyl]methanamine
2185. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-chloro-3- (trifluoromethyl)benzyl]butan- 1 -amine
2186. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-chloro-3-(trifluoromethyl)benzyl]-N- (cyclohexylmethyl)methanamine
2187. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-chloro- 3-(trifluoromethyl)benzyl]methanamine
2188. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro-3- (trifluoromethyl)benzyl]butan-l-amine
2189. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-chloro-3-(trifluoromethyl)benzyl]-N- (cyclohexylmethyl)methanamine
2190. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro- 3-(trifluoromethyl)benzyl]methanamine
2191. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-chloro-5- (trifluoromethyl)benzyl]methanamine
2192. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro-5- (trifluoromethyl)benzyl]butan- 1 -amine
2193. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-chloro-5-(trifluoromethyl)benzyl]-N- (cyclohexylmethyl)methanamine
2194. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro- 5-(trifluoromethyl)benzyl]methanamine
2195. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2,3-difluoro-4- (trifluoromethyl)benzyl]methanamine 2196. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2,3-difluoro-4- (trifluoromethyl)benzyl]butan- 1 -amine
2197. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[2,3-difluoro-4- (trifluoromethyl)benzyl]methanamine
2198. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2,3- difluoro-4-(trifluoromethyl)benzyl]methanamine
2199. N-benzyl-l-[2,4-bis(trifluoromethyl)ρhenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
2200. N-[2,4-bis(trifluoromethyl)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
2201. l-[2,4-bis(trifluoromethyl)phenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
2202. N-benzyl-l-[2,5-bis(trifluoromethyl)phenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
2203. l-(l,3-benzodioxol-5-yl)-N-[2,5-bis(trifluoromethyl)benzyl]-N-[(l-butyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2204. N-[3,5-bis(trifluoromethyl)benzyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
2205. l-[3,5-bis(trifluoromethyl)phenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
2206. l-(l,3-benzodioxol-5-yl)-N-[3,5-bis(trifluoromethyl)benzyl]-N-[(l-butyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2207. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-methylphenyl acetate
2208. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-methylphenyl acetate
2209. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenyl acetate
2210. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenyl acetate
2211. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-fluoro-4-(trifluoromethyl)benzyl]-N-(4- methoxybenzyl)methanamine
2212. N,N-dibenzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methanamine
2213. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenyl methanesulfonate
2214. N-butyl-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l-amine
2215. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2,6- dimethylphenyl methanesulfonate
2216. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (trifluoromethyl)benzyl]amino}methyl)-2,6-dimethylphenol
2217. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[4- (trifluoromethyl)benzyl]methanamine
2218. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine 2219. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(trifluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
2220. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
2221. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[4- (trifluoromethoxy)benzyl]methanamine
2222. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] [3- (trifluoromethyl)benzyl] amino } methy l)-3-chlorophenol
2223. l-(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[2-fluoro-4- (trifluoromethyl)benzyl]methanamine
2224. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4- dimethoxybenzyl)methanamine
2225. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4-dimethoxybenzyl)butan-l- amine
2226. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,4- dimethoxybenzyl)methanamine
2227. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4- dimethoxybenzyl)methanamine
2228. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- lH-imidazol-5 -yl)-N-(3 ,5 - dimethoxybenzyl)methanamine
2229. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,5-dimethoxybenzyl)butan-l- amine
2230. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,5- dimethoxybenzyl)methanamine
2231. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl]-N-(3,5- dimethoxybenzyl)methanamine
2232. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-diethoxybenzyl)methanamine
2233. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4-diethoxybenzyl)butan-l-amine
2234. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,4- diethoxybenzyl)methanamine
2235. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,4- diethoxybenzyl)methanamine
2236. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(3,4- dimethoxybenzyl)methanamine
2237. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,5-dimethoxybenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2238. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(3,5- dimethoxybenzyl)methanamine
2239. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,4-diethoxybenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2240. 4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][3- (trifluoromethyl)benzyl] amino }methyl)benzenesulfonamide
2241. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl] amino }methyl)benzenesulf onamide 2242. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (trifluoromethoxy)benzyl] amino } methyl)benzenesulf onamide
2243. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]pentan-l-amine
2244. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]ethanamine
2245. (lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]ethanamine
2246. (lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]pentan-l-amine
2247. (lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4- (difluoromethoxy)benzyl]ethanamine
2248. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-chloro-4- (difluoromethoxy)benzyl]butan-l-amine
2249. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-chloro-4- (difluoromethoxy)benzyl]methanamine
2250. 4-({[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl][2-chloro-4- (difluoromethoxy)benzyl] amino }methyl)benzenesulfonamide
2251. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)-3- methylbenzyl]butan- 1 -amine
2252. N-benzyl-3-butyl-N-[4-(difluoromethoxy)benzyl]-2-phenyl-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4-amine
2253. N-benzyl-3-butyl-2-phenyl-N-[3-(trifluoromethyl)benzyl]-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4-amine
2254. N,3-dibutyl-N-[4-(difluoromethoxy)benzyl]-2-phenyl-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4-amine
2255. N,3-dibutyl-2-phenyl-N-[3-(trifluoromethyl)benzyl]-3,4,5,6- tetrahydrocyclopenta[d]imidazol-4-amine
2256. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)-3- methylbenzyl]methanamine
2257. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)-3,5- dimethylbenzyl]methanamine
2258. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)-3,5- dimethylbenzyl]butan- 1 -amine
2259. N,l-dibutyl-5,5-dimethyl-2-phenyl-N-[3-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydro-lH- benzimidazol-7-amine
2260. l-butyl-N-[4-(difluoromethoxy)benzyl]-5,5-dimethyl-2-phenyl-N-[3- (trifluoromethyl)benzyl]-4,5,6,7-tetrahydro-lH-benzimidazol-7-amine
2261. bis(l,3-benzodioxol-5-ylmethyl)(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methylamine oxide
2262. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)-3- fluorobenzyl]butan- 1 -amine
2263. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)-3- fluorobenzyfjmethanamine 2264. 4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4-(difluoromethoxy)-3- fluorobenzyl] amino } methyl)benzenesulf onamide
2265. 4-({ [(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] [4-(difluoromethoxy)-3 ,5-dimethyl benzyl]amino}methyl)benzenesulfonamide
2266. (lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]pentan- 1 -amine
2267. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]pentan- 1 -amine
2268. (lR)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl] ethanamine
2269. (lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]ethanamine
2270. (lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl]pentan-l-amine
2271. (1S)-1 -(1 -butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (trifluoromethyl)benzyl] ethanamine
2272. (lS)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl] ethanamine
2273. (lS)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (trifluoromethyl)benzyl]pentan- 1 -amine
2274. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethoxybenzyl)methanamine
2275. N-[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] -N-(4-ethoxybenzyl)butan- 1 -amine
2276. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4- ethoxybenzyl)methanamine
2277. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- ethoxybenzyl)methanamine
2278. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-ethoxybenzyl)methanamine
2279. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N-(3-ethoxybenzyl)butan- 1 -amine
2280. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3- ethoxybenzyl)methanamine
2281. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2282. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]methanamine
2283. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]butan- 1 -amine
2284. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]methanamine
2285. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3- (1,1 ,2,2-tetrafluoroethoxy)benzyl]methanamine
2286. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3- (difluoromethoxy)benzyl]methanamine
2287. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3-(difluoromethoxy)benzyl]butan- 1 -amine
2288. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[3- (difluoromethoxy)benzyl]methanamine
2289. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[3- (difluoromethoxy)benzyl]methanamine
2290. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
2291. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2292. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2- (difluoromethoxy)benzyl]methanamine
2293. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2-(difluoromethoxy)benzyl]butan- 1 -amine
2294. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[2- (difluoromethoxy)benzyl]methanamine
2295. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[2- (difluoromethoxy)benzyl]methanamine
2296. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-(difluoromethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
2297. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-(difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2298. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4-(difluoromethoxy)- 3 ,5-dimethylbenzyl]methanamine
2299. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)-3,5-dimethylbenzyl]methanamine
2300. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)-3,5-dimethylbenzyl]-N- [3-(trifluoromethyl)benzyl]methanamine
2301. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3,5-dimethylbenzyl]methanamine
2302. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[4-(difluoromethoxy)- 3-fluorobenzyl]methanamine
2303. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)-3-fluorobenzyl]methanamine
2304. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)-3-fluorobenzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
2305. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3-fluorobenzyl]methanamine
2306. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)-3-methylbenzyl]-N-[3- (trifluoromethyl)benzyl] methanamine
2307. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)-3-methylbenzyl]methanamine
2308. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4- methoxy-3,5-dimethylbenzyl)methanamine
2309. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-ethoxybenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2310. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(4- ethoxybenzyl)methanamine
2311. l-(l-butyl-2,4-diphenyl-lH-imidazol-5)-yl)-N-(3-ethoxybenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2312. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
2313. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]-N-[3- (trifluoromethyl)benzyl]methanamine
2314. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]methanamine
2315. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxy-3-methylbenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2316. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(4-methoxy- 3 -methylbenzyl)methanamine
2317. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l-benzofuran-5-ylmethyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2318. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(2,3-dihydro- l-benzofuran-5-ylmethyl)methanamine
2319. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxy-3,5-dimethylbenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2320. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(4-methoxy- 3 ,5-dimethylbenzyl)methanamine
2321. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-4- (trifluoromethyl)-lH-imidazol-5-yl]methyl}methanamine
2322. l-butyl-N-[4-(difluoromethoxy)benzyl]-N-[4-(difluoromethoxy)-3-fluorobenzyl]-5,5- dimethyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7-amine
2323. N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]ethanamine
2324. methyl 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzoate
2325. methyl 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl](cyclohexylmethyl)amino]methyl}-2-methoxybenzoate
2326. methyl 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)-2-methoxybenzoate
2327. methyl 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](isopentyl)amino]methyl}-2- methoxybenzoate
2328. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzamide
2329. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzamide
2330. 4-({ (1 ,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yι)methyl] amino }methyl)-2-methoxybenzamide
2331. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[4- (ethylthio)phenyl]-2-phenyl-lH-imidazol-5-yl}methyl)methanamine
2332. 5-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} [4- (difluoromethoxy)benzyl] amino } methyl)- 1 ,3-benzoxazol-2(3H)-one
2333. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[2- (methylthio)phenyl] -2-phenyl- 1 H-imidazol-5 -yl } methy l)methanamine
2334. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[(E)-2-(4- fluorophenyl)ethenyl] -2-phenyl- lH-imidazol-5 -yl } methyl)methanamine
2335. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[3- (methylthio)phenyl] -2-phenyl- lH-imidazol-5 -yl } methyl)methanamine
2336. l-(l,3-benzodioxol-5-yl)-N-{[4-(l,3-benzodioxol-5-yl)-l-butyl-2-phenyl-lH-imidazol-5- yl]methyl}-N-(l,3-benzodioxol-5-ylmethyl)methanamine
2337. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4- (dimethoxymethyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2338. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(difluoromethyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2339. N,N-bis(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[(methylamino)methyl]-2-phenyl-lH- imidazol-5-yl }methyl)amine
2340. (5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)methanol
2341. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3- methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2342. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-2-phenyl-4-[4- (trifluoromethoxy)phenyl]- 1 H-imidazol-5 -yl } methyl)methanamine
2343. 1-(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-4-(3,4- difluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2344. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } -N-(3-ethoxybenzyl)methanamine
2345. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
2346. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3-nitrophenyl)-2- phenyl-lH-imidazol-5-yl]methyl}methanamine
2347. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,6-difluorobenzyl)-N-(4- methoxybenzyl)methanamine
2348. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzoic acid
2349. 4- { [[(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] (cyclohexylmethyl)amino]methyl } -2- methoxybenzoic acid
2350. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- hydroxybenzamide
2351. 4-( { benzyl[( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)methyl] amino }methyl)-2- hydroxybenzamide
2352. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](isopentyl)amino]methyl}-2- methoxybenzamide
2353. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- methoxybenzoic acid
2354. 4- { [[( 1 -butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] (isopentyl)amino]methyl } -2- hydroxybenzamide
2355. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- hydroxybenzoic acid
2356. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-6-fluorobenzyl)-N-(4- methoxybenzyl)methanamine
2357. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-methylphenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2358. l-[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH-imidazol-5-yl]-N,N-bis(3- ethoxybenzyl)methanamine
2359. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N,N-bis(3- ethoxybenzyl)methanamine
2360. 4-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)benzonitrile
2361. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({ l-butyl-2-phenyl-4-[4- (trifluoromethyl)phenyl] - 1 H-imidazol-5 -yl } methy l)methanamine
2362. 7-[(butyl{[l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]quinazolin-4-amine
2363. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2364. methyl 4-[(butyl{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}amino)methyl]-2-methoxybenzoate
2365. 4-[(butyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}amino)methyl]- 2-methoxybenzoic acid
2366. 4-[(butyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}amino)methyl]- 2-methoxybenzamide
2367. 4-[(butyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}amino)methyl]- 2-hydroxybenzamide
2368. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(lH-indol- 5 -ylmethyl)methanamine
2369. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)-N-( 1 H-indol-5 -ylmethyl)methanamine
2370. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(lH-indol-5-ylmethyl)butan-l-amine
2371. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2372. 5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazole-4- carboxylic acid
2373. methyl 5- { [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl } - 1 -butyl-2-phenyl- 1H- imidazole-4-carboxylate
2374. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N,N-bis(3-ethoxybenzyl)methanamine
2375. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2376. 2-(5- { [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl } - 1 -butyl-2-phenyl- lH-imidazol-4- yl)propan-2-ol
2377. l-(l,3-benzodioxol-5-yl)-N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2378. l-[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis(3- ethoxybenzyl)methanamine
2379. l-[l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis(3- ethoxybenzyl)methanamine
2380. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-ethoxy-2-phenyl- lH-imidazol-5-yl)methyl]methanamine
2381. 1 -[ l-butyl-2-(3-methoxyphenyl)-4-phenyl-lH-imidazol-5-yl]-N,N-bis(3- ethoxybenzyl)methanamine
2382. N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N,N-bis(3-ethoxybenzyl)amine
2383. N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N,N-bis[4- (difluoromethoxy)benzyl] amine
2384. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N,N-bis(3-ethoxybenzyl)amine
2385. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N,N-bis[4- (difluoromethoxy)benzyl] amine
2386. l-[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)methanamine
2387. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2388. l-[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
2389. l-[l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)methanamine
2390. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2391. l-[l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
2392. N-{ [l-butyl-4-(3-ethoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl }-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2393. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-ethoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2394. N-{[l-butyl-4-(3-ethoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis(3- ethoxybenzyl)amine
2395. N-{[l-butyl-4-(3-ethoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis[4- (difluoromethoxy)benzyl] amine
2396. l-(l-butyl-2-phenyl-4-thien-3-yl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
2397. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-4-thien-3-yl-lH-imidazol-5-yl)methyl]-N- [4-(difluoromethoxy)benzyl]methanamine
2398. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4-hydroxy-3,5- dimethylbenzyl)amino]methyl}benzenesulfonamide 2399. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4-hydroxy-3-methylbenzyl)amino] methyl Jbenzenesulf onamide
2400. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] [4-(difluoromethoxy)-3-methylbenzyl] amino } methyl)benzenesulf onamide
2401. N-benzyl-l-[3,4-bis(difluoromethoxy)phenyl]-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] methanamine
2402. N- [( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5-yl)methyl] -N- [4-(difluoromethoxy)benzyl]propan- 1 -amine
2403. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]pentan- 1 -amine
2404. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]cyclopentanamine
2405. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]propan- 2-amine
2406. N-[(l -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] -N-[4-(difluoromethoxy)benzyl] -2,2- dimethylpropan-1-amine
2407. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]-3- methylbutan- 1 -amine
2408. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]cyclohexanamine
2409. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]ethanamine
2410. N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]pentan- 1 -amine
2411. N-benzyl-l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]methanamine
2412. N, 1 -dibutyl-N- [4-(difluoromethoxy)benzyl] -2-phenyl-4,5 ,6 ,7-tetrahydro- 1 H-benzimidazol- 7-amine
2413. N,l-dibutyl-N-(4-methoxy-3,5-dimethylbenzyl)-2-phenyl-4,5,6,7-tetrahydro-lH- benzimidazol-7-amine
2414. 4-{[butyl(l-butyl-2-phenyl-4,5,6,7-tetrahydro-lH-benzimidazol-7-yl)amino]methyl}-2,6- dimethylphenol
2415. N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]butan- 1 -amine
2416. 4-[(butyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulf onamide
2417. 1 - [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- 1 H-imidazol-5 -yl] -N- [4-(difluoromethoxy)benzyl] - N-(4-methoxy-3,5-dimethylbenzyl)methanamine
2418. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)-3,5-dimethylbenzyl]methanamine
2419. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2420. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-[4-(difluoromethoxy)-3-fluorobenzyl]methanamine 2421. N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-(4-methoxy-3,5- dimethylbenzyl)butan- 1 -amine
2422. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} [4- (difluoromethoxy)benzyl] amino } methyl)benzenesulf onamide
2423. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
2424. 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- (difluoromethoxy)phenol
2425. 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- (difluoromethoxy)phenol
2426. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4-methoxy-3,5- dimethylbenzyl)amino]methyl}benzenesulfonamide
2427. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](2-chloro-4-hydroxybenzyl)amino] methyl Jbenzenesulf onamide
2428. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3-fluoro-4-methoxybenzyl)amino] methyl }benzenesulfonamide
2429. 4-({[4-(aminosulfonyl)benzyl][(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)phenyl acetate
2430. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4- methoxybenzyl)amino]methyl } phenyl acetate
2431. 2-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)phenol
2432. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-methylphenyl 3 -methylbutanoate
2433. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-methylphenyl 3 -methylbutanoate
2434. 2-(5- { [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl } - 1 -butyl-4-phenyl- lH-imidazol-2- yl)phenol
2435. 4-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)phenol
2436. N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl }butan-l -amine
2437. N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)-3-fluorobenzyl]butan-l-amine
2438. N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)-3,5-dimethylbenzyl]butan-l-amine
2439. 4-[(benzyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
2440. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-(4-methoxy-3,5- dimethylbenzyl)methanamine
2441. l-(l-butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(4-methoxy-3,5- dimethylbenzyl)methanamine
2442. 4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-fluorophenol
2443. 4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2-fluorophenol 2444. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3-fluoro-4-hydroxybenzyl)amino] methyl Jbenzenesulf onamide
2445. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](4-methoxybenzyl)amino]methyl}-2- fluorophenol
2446. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohex-3-en-l-ylmethyl)-N- (cyclohexylmethyl)methanamine
2447. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] (cyclohexylmethyl)amino]methyl Jcyclohexane- 1 ,2-diol
2448. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(hexahydro-l,3- benzodioxol-5-ylmethyl)methanamine
2449. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohex-3-en-l-ylmethyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2450. 4-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl] amino }methyl)cyclohexane- 1 ,2-diol
2451. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(hexahydro- l,3-benzodioxol-5-ylmethyl)methanamine
2452. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(2,2-difluoro-l,3-benzodioxol-5-yl)methyl]- N-[4-(difluoromethoxy)benzyl]methanamine
2453. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-[(2,2-difluoro-l,3- benzodioxol-5-yl)methyl]methanamine
2454. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2,2-difluoro-l,3-benzodioxol-5- yl)methyl] -3-methylbutan- 1 -amine
2455. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]hexan- 1 -amine
2456. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(2,2-difluoro-l,3-benzodioxol-5- yl)methyl]butan- 1 -amine
2457. N- [( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] -N- [4-(difluoromethoxy)benzyl] heptan- 1 -amine
2458. N- [( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] -N- [4-(difluoromethoxy)benzyl] octan- 1 -amine
2459. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]-3,3- dimethylbutan- 1 -amine
2460. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-2-cyclohex-l-en-l-yl-N-[4- (difluoromethoxy)benzyl]ethanamine
2461. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](cyclohexylmethyl)amino]methyl}-2- fluorophenol
2462. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(2,2-difluoro-l,3-benzodioxol-5- yl)methyl] methanamine
2463. 4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][(2,2-difluoro-l,3-benzodioxol-5- yl)methyl] amino } methyl)benzenesulf onamide
2464. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(2,2-difluoro-l,3-benzodioxol-5-yl)methyl]- N-(4-methoxybenzyl)methanamine
2465. 4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][3-(l, 1,2,2- tetrafluoroethoxy)benzyl] amino }methyl)benzenesulf onamide 2466. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3- ethoxybenzyl)amino]methyl}benzenesulfonamide
2467. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-methoxybenzyl)-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]methanamine
2468. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-ethoxybenzyl)-N-(4- methoxybenzyl)methanamine
2469. N-benzyl-l-[l-butyl-2-ρhenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4- (difluoromethoxy)-3-fluorobenzyl]methanamine
2470. N-benzyl-l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(4-methoxy-3,5- dimethylbenzyl)methanamine
2471. N,N-dibenzyl- 1 - [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- 1 H-imidazol-5 -yl]methanamine
2472. 1 -(1 ,3-benzodioxol-5-yl)-N-benzyl-N- { [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol- 5-yl]methyl Jmethanamine
2473. N-benzyl-l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[3-(l,l,2,2- tetrafluoroethoxy)benzyl]methanamine
2474. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}(4-hydroxy-3,5- dimethylbenzyl)amino]methyl}benzenesulfonamide
2475. 4- [(benzyl { [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- 1 H-imidazol-5-yl] methyl } amino)methyl] - 2-fluorophenol
2476. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N- [3-( 1 , 1 ,2,2-tetrafluoroethoxy)benzyl] methanamine
2477. 1 - [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5 -yl] -N-[4-(difluoromethoxy)benzyl] - N-(3-fluoro-4-methoxybenzyl)methanamine
2478. 4-({{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl]amino}methyl)-2-fluorophenol
2479. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} [4-(difluoromethoxy)- 3 -fluorobenzyl] amino } methyl)benzenesulfonamide
2480. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}(2-chloro-4- hydroxybenzyl)amino] methyl Jbenzenesulfonamide
2481. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
2482. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl]methanamine
2483. N-benzyl-l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(3-fluoro-4- methoxybenzyl)methanamine
2484. 4-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-4-phenyl-lH-imidazol-2- yl)phenol
2485. 4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][3- (difluoromethoxy)benzyl]amino}methyl)benzenesulfonamide
2486. 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](3- methoxybenzyl)amino]methyl}benzenesulfonamide
2487. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]-N-(4- methoxybenzyl)methanamine
2488. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-methoxybenzyl)-N-(4- methoxybenzyl)methanamine
2489. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[(2,2-difluoro-l,3- benzodioxol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]methanamine
2490. 4-({{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[(2,2-difluoro-l,3- benzodioxol-5 -yl)methyl] amino } methy l)benzenesulf onamide
2491. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-bromo-l-butyl-2-phenyl- lH-imidazol-5-yl)methyl]methanamine
2492. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(2- methoxyphenyl)-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}methanamine
2493. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)methanamine
2494. N-benzyl-l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(3- ethoxybenzyl)methanamine
2495. 4-({(l,3-benzodioxol-5-ylmethyl)[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazoi-5- yl)ethyl] amino }methyl)benzenesulfonamide
2496. 4-({(l,3-benzodioxol-5-ylmethyl)[(lS)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl] amino } methyl)benzenesulf onamide
2497. 4-{ [[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)ethyl] (cyclohexylmethyl)amino]methyl jbenzenesulfonamide
2498. 4-({(l,3-benzodioxol-5-ylmethyl)[(lS)-l-(l-butyl-2,4-diρhenyl-lH-imidazol-5- yl)pentyl] amino }methyl)benzenesulfonamide
2499. N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[(2,2-difluoro- l,3-benzodioxol-5-yl)methyl]pentan-l-amine
2500. N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4- (difluoromethoxy)benzyl]pentan- 1 -amine
2501. N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(3- ethoxybenzyl)pentan- 1 -amine
2502. N,N-bis(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2-phenyl-lH-imidazol-5-yl)pentan-l- amine
2503. 4-({(l,3-benzodioxol-5-ylmethyl)[(lR)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)pentyl] amino } methyl)benzenesulf onamide
2504. methyl 4-[(butyl{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzoate
2505. 4-[(butyl { [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5- yl] methyl } amino)methyl]benzoic acid
2506. 4-[(butyl{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzamide
2507. 4-({{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[3-(l, 1,2,2- tetrafluoroethoxy)benzyl] amino }methyl)benzenesulfonamide
2508. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4- (diphenylphosphoryl)-2-phenyl- 1 H-imidazol-5 -yljmethyl } methanamine
2509. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(2- methoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl jmethanamine
2510. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)- 1H- imidazol-5-yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2511. 4-{ [ { [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5-yl]methyl } (3- ethoxybenzyl)amino] methyl Jbenzenesulfonamide
2512. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-(2-methoxyρhenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl}amino)methyl]benzenesulfonamide
2513. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl } amino)methyl]-2,6-dimethylphenol
2514. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl } -N-(3-ethoxybenzyl)methanamine
2515. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl)-N-[4-(difluoromethoxy)-3-fluorobenzyl]methanamine
2516. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl}-N-[3-(difluoromethoxy)benzyl]methanamine
2517. N-benzyl- 1 -( 1 -butyl-2,4-diphenyl- 1 H-imidazol-5 -yl)-N-(2,3 -difluorobenzyl)methanamine
2518. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-difluorobenzyl)butan-l-amine
2519. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(2,3- difluorobenzyl)methanamine
2520. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3- difluorobenzyl)methanamine
2521. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-difluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2522. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-difluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2523. N-benzyl- 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(3,5 -difluorobenzyl)methanamine
2524. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,5-difluorobenzyl)butan-l-amine
2525. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(3,5- difluorobenzyl)methanamine
2526. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3,5- difluorobenzyl)methanamine
2527. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,5-difluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2528. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3,5-difluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2529. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-chloro-4-fluorobenzyl)-N- (cyclohexylmethyl)methanamine
2530. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(3-chloro- 4-fluorobenzyl)methanamine
2531. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(3-chloro-4-fluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2532. N-benzyl- 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(4-chloro-3- fluorobenzyl)methanamine
2533. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-chloro-3-fluorobenzyl)butan-l- amine 2534. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-(4-chloro-3-fluorobenzyl)-N- (cyclohexylmethyl)methanamine
2535. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(4-chloro- 3 -fluorobenzyl)methanamine
2536. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(4-chloro-3-fluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2537. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-chloro-4-fluorobenzyl)butan-l- amine
2538. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-4-fluorobenzyl)-N- (cyclohexylmethyl)methanamine
2539. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2-chloro- 4-fluorobenzyl)methanamine
2540. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-4-fluorobenzyl)-N-[3- (trifluoromethyl)benzyl]methanamine
2541. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2-chloro-4-fluorobenzyl)-N-[4- (difluoromethoxy)benzyl]methanamine
2542. N-benzyl-l-(3-bromo-4-fluorophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
2543. N-(3-bromo-4-fluorobenzyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan-l- amine
2544. l-(3-bromo-4-fluorophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N- (cyclohexylmethyl)methanamine
2545. l-(l,3-benzodioxol-5-yl)-N-(3-bromo-4-fluorobenzyl)-N-[(l-butyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2546. l-(3-bromo-4-fluorophenyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]methanamine
2547. 3-(5- { [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl} - 1 -butyl-2-phenyl- lH-imidazol-4- yl)phenol
2548. 3-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-4-phenyl-lH-imidazol-2- yl)phenol
2549. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl } amino)methyl]-3-chlorophenol
2550. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-4-thien-3- yl-lH-imidazol-5-yl)methyl]methanamine
2551. methyl 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } (isopentyl)amino]methyl Jbenzoate
2552. methyl 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } (isobutyl)amino]methyl Jbenzoate
2553. methyl 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl J (cyclohexylmethyl)amino]methyl Jbenzoate
2554. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } (isopentyl)amino]methyl Jbenzoic acid
2555. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } (isobutyl)amino]methyl Jbenzoic acid 2556. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}(cyclohexylmethyl) amino]methyl Jbenzoic acid
2557. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methylJ (cyclohexylmethyl) amino]methyl Jbenzamide
2558. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methylJ(isobutyl)amino]methyl}benzamide
2559. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}(isopentyl)amino]methylJbenzamide
2560. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4- (pentafluoroethyl)-2-phenyl-lH-imidazol-5-yl]methylJmethanamine
2561. 1 -( 1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(pentafluoroethyl)-2-phenyl- 1 H-imidazol-5 - yl]methyl}-N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
2562. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(pentafluoroethyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2563. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(pentafluoroethyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
2564. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(pentafluoroethyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[3-(difluoromethoxy)benzyl]methanamine
2565. methyl 4-({ {[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methylJ[3- (difluoromethoxy)benzyl] amino } methyl)benzoate
2566. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(3- ethoxybenzyl)methanamine
2567. l-[4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]aminoJmethyl)phenyl]ethanone
2568. l-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- y l)methyl] amino } methyl)phenyl] ethanone
2569. l-[4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)phenyl] ethanone
2570. l-[4-({[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl]aminoJmethyl)phenyl]ethanone
2571. N-[4-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)phenyl] acetamide
2572. N-[4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]amino}methyl)phenyl]acetamide
2573. N-[4-({ (1 ,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino Jmethyl)phenyl] acetamide
2574. N-[4-({ [(l-butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl] [4- (difluoromethoxy)benzyl] amino } methyι)phenyι] acetamide
2575. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(6-methylpyridin-2- yl)methyl]methanamine
2576. N-[(l-butyl-2,4-diρhenyl-lH-imidazol-5-yl)methyl]-N-[(6-methylpyridin-2- yl)methyl]butan-l-amine
2577. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(6- methylpyridin-2-yl)methyl]methanamine 2578. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[(6- methylpyridin-2-yl)methyl]methanamine
2579. N- [(4-bromo- 1 -butyl-2-phenyl- 1 H-imidazol-5 -yl)methyl] -N-[4-(difluoromethoxy)benzyl] - N-(3-ethoxybenzyl)amine
2580. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[4- (methylthio)phenyl] -2-phenyl- 1 H-imidazol-5 -yl } methyl)methanamine
2581. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[4- (methylsulf onyl)phenyl] -2-phenyl- 1 H-imidazol-5 -yl } methy l)methanamine
2582. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4-(difluoromethoxy)benzyl]- N-[4-(methylthio)benzyl]methanamine
2583. 4-({{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[4- (methylthio)benzyl] amino J methyl)benzenesulf onamide
2584. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH- imidazol-5-yl]methyl}-N-[4-(methylthio)benzyl]methanamine
2585. l-[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-[4- (difluoromethoxy)benzyl]-N-[4-(methylthio)benzyl]methanamine
2586. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[3-(difluoromethoxy)benzyl]-N-[4- (methylthio)benzyl]methanamine
2587. 1-(1 ,3-benzodioxol-5-yl)-N-{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}-N-[4-(methylsulfonyl)benzyl]methanamine
2588. methyl 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methylJ [4- (difluoromethoxy)benzyl]amino}methyl)benzoate
2589. methyl 4-[((l ,3-benzodioxol-5-ylmethyl){ [l-butyl-2-phenyl-4-(trifluoromethyl)- 1H- imidazol-5-yl]methyl } amino)methyl]benzoate
2590. 4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
2591. 4-({{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[4- (difluoromethoxy)benzyl] amino }methyl)benzoic acid
2592. 4-({ { [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5-yl]methyl } [4-(difluoromethoxy) benzyl] amino } methyl)benzamide
2593. 4-[((l ,3-benzodioxol-5-ylmethyl){ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl J amino)methyl]benzamide
2594. methyl 4-({ {[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[3-(l, 1,2,2- tetrafluoroethoxy)benzyl] amino }methyl)benzoate
2595. methyl 4-{[{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]methyl}benzoate
2596. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} [3- (difluoromethoxy)benzyl] amino } methyl)benzoic acid
2597. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} [3-(l,l,2,2- tetrafluoroethoxy)benzyl] amino }methyl)benzoic acid
2598. 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} (3- ethoxybenzyl)amino]methyl Jbenzoic acid
2599. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methylJ [3- (trifluoromethyl)benzyl] amino } methyl)benzoic acid 2600. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methylJ [3- (difluoromethoxy)benzyl] amino Jmethyl)benzamide
2601. 4-{[{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino] methyl } benzamide
2602. 4-({{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}[3-(l, 1,2,2- tetrafluoroethoxy)benzyl] amino J methy l)benzamide
2603. 4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl J [3- (trifluoromethyl)benzyl] amino } methyl)benzamide
2604. 5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazole-4- carbonitrile
2605. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-4-pyrazin- 2-yl-lH-imidazol-5-yl)methyl]methanamine
2606. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-4-(l,3- thiazol-2-yl)- 1 H-imidazol-5-yl] methyl } methanamine
2607. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-phenyl-4- (phenylethynyl)-lH-imidazol-5-yl]methyl}methanamine
2608. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-4-[(lE)-pent-l- enyl]-2-phenyl-lH-imidazol-5-yl}methyl)methanamine
2609. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-4-vinyl- lH-imidazol-5-yl)methyl]methanamine
2610. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-4-pyridin- 2-yl-lH-imidazol-5-yl)methyl]methanamine
2611. l-[4-({ { [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl} [4- (difluoromethoxy)benzyl]amino}methyl)phenyl]ethanone
2612. l-{4-[((l,3-benzodioxol-5-ylmethyl){[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]phenyl } ethanone
2613. 4-[((4-acetylbenzyl){[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
2614. N,N-bis(l,3-benzodioxol-5-ylmethyl)-l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH- imidazol-5-yl]ethanamine
2615. 1 -(1 ,3-benzodioxol-5-yl)-N-( 1 ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-4-( 1 -naphthyl)-2- phenyl-lH-imidazol-5-yl]methyl}methanamine
2616. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-4-pyridin- 3-yl-lH-imidazol-5-yl)methyl]methanamine
2617. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3-ethoxyphenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2618. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(5-methylthien-2- yl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2619. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-2-phenyl-4-[2- (trifluoromethyl)phenyl] - lH-imidazol-5 -yl } methy l)methanamine
2620. 5-({(l,3-benzodioxol-5-ylmethyl)[4-(difluoromethoxy)benzyl]amino}methyl)-l-butyl-2- phenyl-lH-imidazole-4-carbonitrile
2621. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-4-cyano-2-phenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzenesulf onamide 2622. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-4-cyano-2-phenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzamide
2623. 5-{[(l,3-benzodioxol-5-ylmethyl)(3-ethoxybenzyl)amino]methyl}-l-butyl-2-phenyl-lH- imidazole-4-carbonitrile
2624. 5-( { (1 ,3-benzodioxol-5-ylmethyl)[3-( 1 , 1 ,2,2-tetrafluoroethoxy)benzyl] amino } methyl)- 1 - butyl-2-phenyl-lH-imidazole-4-carbonitrile
2625. 5-({(l,3-benzodioxol-5-ylmethyl)[3-(difluoromethoxy)benzyl]amino}methyl)-l-butyl-2- phenyl-lH-imidazole-4-carbonitrile
2626. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-methyl-2-phenyl- lH-imidazol-5-yl)methyl]methanamine
2627. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-4-ethyl-2-phenyl- lH-imidazol-5-yl)methyl]methanamine
2628. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4-(difluoromethoxy)benzyl]- N-(3-ethoxybenzyl)amine
2629. 5-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- (methylamino)benzenethiol
2630. 5-({benzyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-2- (methylamino)benzenethiol
2631. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-ethoxyphenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2632. ethyl (2E)-3-(5-{ [bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH- imidazol-4-yl)prop-2-enoate
2633. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-phenyl-4-thien-2- yl-lH-imidazol-5-yl)methyl]methanamine
2634. l-[5-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)thien-2-yl] ethanone
2635. 6-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3-methyl-l,3- benzothiazol-2(3H)-one
2636. l-(l-butyl-2-phenyl-4-thien-3-yl-lH-imidazol-5-yl)-N,N-bis(3-ethoxybenzyl)methanamine
2637. l-(l-butyl-2-phenyl-4-thien-3-yl-lH-imidazol-5-yl)-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
2638. 2-(aminocarbonyl)-5-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]phenyl acetate
2639. 4-[(butyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2-hydroxybenzamide
2640. 2-(aminocarbonyl)-5-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } (isopentyl)amino]methyl Jphenyl acetate
2641. 4-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yfjmethyl } (isopentyl)amino]methyl } -2-hydroxybenzamide
2642. 2-(aminocarbonyl)-5-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } (cyclohexylmethyl)amino]methyl Jphenyl acetate
2643. 4-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}(cyclohexylmethyl)amino]methyl}-2-hydroxybenzamide
2644. 2-(aminocarbonyl)-5-[((l ,3-benzodioχol-5-ylmethyl){ [l-butyl-4-(4-methoxyphenyl)-2- phenyl- lH-imidazol-5-yl]methyl } amino)methyl]phenyl acetate
2645. 4-[((l ,3-benzodioxol-5-ylmethyl){ [l-butyl~4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } amino)methyl] -2-hydroxybenzamide
2646. ethyl 5-{ [bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazole- 4-carboxylate
2647. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[4- (difluoromethoxy)benzyl]mfethanamine
2648. 1-(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-4-(methoxymethyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2649. N-{ [l-butyl-4-(4-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl } -N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2650. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-methylphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-[4-(difluoromethoxy)benzyl]methanamine
2651. N- { [ 1 -butyl-4-(4-methylphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N,N-bis(3- ethoxybenzyl)amine
2652. N- { [ 1 -butyl-4-(4-methylphenyl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -N,N-bis [4- (difluoromethoxy)benzyl] amine
2653. N-{[l-butyl-4-(3-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2654. 1 -(1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(3-methylphenyl)-2-phenyl- lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2655. N- { [ 1 -butyl-4-(3-methylphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N,N-bis(3- ethoxybenzyl)amine
2656. N-{[l-butyl-4-(3-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis[4- (difluoromethoxy)benzyl] amine
2657. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2658. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2659. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis(3- ethoxybenzyl)amine
2660. N-{[l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis[4- (difluoromethoxy)benzyl] amine
2661. 5 - { [bis( 1 , 3-benzodioxol-5 -ylmethyl)amino]methyl } - 1 -butyl-N,N-dimethyl-2-phenyl- 1 H- imidazole-4-carboxamide
2662. isopropyl 5-{ [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH- imidazole-4-carboxylate
2663. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(ethoxymethyl)-2- phenyl-lH-imidazol-5-yl]methyl}methanamine
2664. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3,5- dimethylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2665. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({l-butyl-2-phenyl-4-[3- (trifluoromethyl)phenyl] - 1 H-imidazol-5 -yl } methy l)methanamine
2666. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-({ l-butyl-2-phenyl-4-[3- (trifluoromethoxy)phenyl]-lH-imidazol-5-yl}methyl)methanamine
2667. 7-[(butyl{ [l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2,3-dihydroquinazolin-4(lH)-one
2668. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(l- methyl-lH-indol-5-yl)methyl]methanamine
2669. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(cyclohexylmethyl)-N-(lH- indol-5-ylmethyl)methanamine
2670. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-[(l- methyl-2,3-dihydro-lH-indol-5-yl)methyl]methanamine
2671. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[(l-methyl-lH-indol-5- yl)methyl]methanamine
2672. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[(l-methyl- 2,3-dihydro-lH-indol-5-yl)methyl]methanamine
2673. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}-N-(lH-indol-5-ylmethyl)methanamine
2674. N-{ [l-butyl-2-ρhenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-(lH-indol-5- ylmethyl)butan- 1 -amine
2675. N-{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}-N-[(l-methyl-lH- indol-5 -yl)methyl]butan- 1 -amine
2676. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(cyclohexylmethyl)-N-[(l- methyl-lH-indol-5-yl)methyl]methanamine
2677. 1 -(1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-[(l -methyl- lH-indol-5-yl)methyl]methanamine
2678. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5- yl]methyl}-N-[(l-methyl-lH-indol-5-yl)methyl]methanamine
2679. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[4-(difluoromethoxy)benzyl]-N-(lH-indol-5- ylmethyl)methanamine
2680. l-(l,3-benzodioxol-5-yl)-N-(2,l,3-benzoxadiazol-5-ylmethyl)-N-{ [l-butyl-2-phenyl-4- (trifluoromethyl)- 1 H-imidazol-5 -yl]methyl } methanamine
2681. l-(l,3-benzodioxol-5-yl)-N-(2,l,3-benzoxadiazol-5-ylmethyl)-N-{ [l-butyl-4-(3- methoxyphenyl)-2-phenyl- 1 H-imidazol-5 -yl]methyl } methanamine
2682. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2683. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[3-(l, 1,2,2- tetrafluoroethoxy)benzyl]methanamine
2684. l-(l,3-benzodioxol-5-yl)-N-[(l-butyl-4-ethoxy-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2685. l-(l,3-benzodioxol-5-yl)-N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2686. l-(l,3-benzodioxol-5-yl)-N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-[3- (l,l,2,2-tetrafluoroethoxy)benzyl]methanamine
2687. l-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)ethanol
2688. N-{ [l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2689. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl } -N-[4-(difluoromethoxy)benzyl]methanamine
2690. N-{[l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis(3- ethoxybenzyl)amine
2691. N-{[l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis[4- (difluoromethoxy)benzyl] amine
2692. N-{[l-butyl-4-(4-ethoxyρhenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2693. 1 -( 1 ,3-benzodioxol-5-yl)-N- { [ 1 -butyl-4-(4-ethoxyphenyl)-2-phenyl- lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2694. N-{[l-butyl-4-(4-ethoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis(3- ethoxybenzyl)amine
2695. N- { [ 1 -butyl-4-(4-ethoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N,N-bis[4- (difluoromethoxy)benzyl] amine
2696. 1 -[ 1 -butyl-4-(3 ,4-difluorophenyl)-2-phenyl- lH-imidazol-5-yl] -N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)methanamine
2697. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3,4-difluorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2698. l-[l-butyl-4-(3,4-difluorophenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis(3- ethoxybenzyl)methanamine
2699. l-[l-butyl-4-(3,4-difluorophenyl)-2-phenyl-lH-imidazol-5-yl]-N,N-bis[4- (difluoromethoxy)benzyl]methanamine
2700. N- { [1 -butyl-4-(3-chlorophenyl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2701. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(3-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2702. N- { [ 1 -butyl-4-(3-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl } -N,N-bis(3- ethoxybenzyl)amine
2703. N- { [ 1 -butyl-4-(3-chlorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N,N-bis[4- (difluoromethoxy)benzyl] amine
2704. N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-[4- (difluoromethoxy)benzyl]-N-(3-ethoxybenzyl)amine
2705. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5- yl]methyl}-N-[4-(difluoromethoxy)benzyl]methanamine
2706. N-{[l-butyl-4-(4-chloroρhenyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N,N-bis(3- ethoxybenzyl)amine
2707. N- { [ 1 -butyl-4-(4-chlorophenyl)-2-phenyl- 1 H-imidazol-5 -yl]methyl } -N,N-bis [4- (difluoromethoxy)benzyl] amine
2708. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3-chlorophenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2709. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(4-chlorophenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2710. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3-fluorophenyl)- 2-phenyl- lH-imidazol-5-yl]methyl Jmethanamine
2711. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-4-(3-methylphenyl)- 2-phenyl-lH-imidazol-5-yl]methyl}methanamine
2712. l-(5-{[bis(l,3-benzodioxol-5-ylmethyl)amino]methyl}-l-butyl-2-phenyl-lH-imidazol-4- yl)ethanone
2713. 5- { [bis(l ,3-benzodioxol-5-ylmethyl)amino]methyl } - 1 -butyl-2-phenyl- 1 H-imidazole-4- carbaldehyde
2714. 1 -(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-2-phenyl-4- (phenylthio)-lH-imidazol-5-yl]methyl}methanamine
2715. ethyl 5-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)indoline- 1 -carboxylate
2716. ethyl 5-({ [(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl] [4- (difluoromethoxy)benzyl] amino }methyl)indoline- 1 -carboxylate
2717. N-benzyl-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-[2-chloro-3- (trifluoromethyl)benzyl]methanamine
2718. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[8-methoxy-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2719. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-methyl-l-(2-methylρhenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2720. N-(2,3-dihydro- lH-inden-2-yl)-2-[l -ethyl- 1 -(2-methylphenyl)-3 ,4-dihydroisoquinolin- 2(1 H)-yl] -N-(2-fluorobenzyl) acetamide
2721. 2-[l-(2,4-difluorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2-yl)- N-(2-fluorobenzyl)acetamide
2722. N-(2-fluorobenzyl)-N-{3-[l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3- oxopropyl}indan-2-amine
2723. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]propanamide
2724. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N- (pyridin-2-ylmethyl)acetamide
2725. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N- (pyridin-3-ylmethyl)acetamide
2726. 2-[l-(2-bromophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2-yl)-N- (2-fluorobenzyl)acetamide
2727. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N- (l,3-thiazol-2-ylmethyl)acetamide
2728. N-(2,3-dihydro- lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[ 1 -(2-methoxyphenyl)-3 ,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2729. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2,3-dimethylphenyl)-3,4-dihydroisoquinolin-2(lH)- yl]-N-(2-fluorobenzyl)acetamide
2730. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR)-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
2731. N-(2,3-dihydro- lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(4R)-4-methyl- 1 -(2-methylphenyl)- 3,4-dihydroisoquinolin-2(lH)-yl]acetamide
2732. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2-ethylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N- (2-fluorobenzyl)acetamide
2733. N-(2-Fluoro-benzyl)-N-indan-2-yl-2- (4-methyl- 1 -o-tolyl-3 ,4-dihydro- 1 H- isoquinolin-2-yl)-acetamide
2734. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR,4S)-4-methyl-l-(2- methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]acetamide
2735. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lS,4S)-4-methyl-l-(2- methylphenyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl] acetamide
2736. 2- { [ 1 -(2,3-dihydro- lH-inden-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } - 1 -(2- methylphenyl)- 1 ,2,3,4-tetrahydroisoquinoline
2737. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR)-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl]propanamide
2738. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(3,4-dimethylphenyl)-3,4-dihydroisoquinolin-2(lH)- yl]-N-(2-fluorobenzyl)acetamide
2739. 2-[l-(2,3-dichlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2- yl)-N-(2-fluorobenzyl)acetamide
2740. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-[4-fluoro-2- (trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-2(lH)-yl]acetamide
2741. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-[5-fluoro-2- (trifluoromethyl)phenyl] -3 ,4-dihydroisoquinolin-2( 1 H)-yl] acetamide
2742. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lS)-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]propanamide
2743. 2-[(lS)-l-(2-bromophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2- yl)-N-(2-fluorobenzyl)acetamide
2744. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lS)-l-[2-(trifluoromethyl)phenyl]- 3,4-dihydroisoquinolin-2(lH)-yl]acetamide
2745. 2-[l-(l,l'-biphenyl-2-yl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2-yl)- N-(2-fluorobenzyl)acetamide
2746. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-(l-naphthyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
2747. 2-[l-(2-chloro-3-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)acetamide
2748. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-(3-fluoro-2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2749. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2,5-dimethylphenyl)-3,4-dihydroisoquinolin-2(lH)- yl]-N-(2-fluorobenzyl)acetamide
2750. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-[3-(trifluoromethyl)phenyl]-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2751. 2-[l-(5-chloro-2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)acetamide
2752. 2-[l-(2-chloro-5-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)acetamide
2753. 2-[l-(2,3-dihydro-l-benzofuran-7-yl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)acetamide 2754. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR,4R)-l-(2-fluorophenyl)-4- methyl-3,4-dihydroisoquinolin-2(lH)-yl]acetamide
2755. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(3S)-3-methyl-l-(2-methylphenyl)- 3,4-dihydroisoquinolin-2(lH)-yl]acetamide
2756. N-(2,3-dihydro-lH-inden-2-yl)-2-[l-(2,6-dimethylphenyl)-3,4-dihydroisoquinolin-2(lH)- yl]-N-(2-fluorobenzyl)acetamide
2757. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-(5-fluoro-2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2758. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR)-l-(2-fluorophenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2759. 2-[(lR,4R)-l-(2-chlorophenyl)-4-methyl-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro- lH-inden-2-yl)-N-(2-fluorobenzyl)acetamide
2760. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR)-l-(2-fluorophenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl]propanamide
2761. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-(3-fluoro-4-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2762. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-(l-quinolin-8-yl-3,4- dihydroisoquinolin-2( 1 H)-yl)acetamide
2763. (2S)-N-(2,3-dihydro- lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[( 1R)- 1 -( 1 -naphthyl)-3 ,4- dihydroisoquinolin-2( 1 H)-yl]propanamide
2764. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)propanamide
2765. 2-[l-(3-chloro-2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)acetamide
2766. N-(2,3-dihydro- lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[ 1 -(2-fluoro-5-methylphenyl)-3 ,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2767. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-2-[(lR)-l-(2,3-dimethylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] -N-(2-fluorobenzyl)propanamide
2768. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-2-[(lS)-l-(2,3-dimethylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] -N-(2-fluorobenzyl)propanamide
2769. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR)-l-[2- (trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-2(lH)-yl]propanamide
2770. (2S)-2-[(lR)-l-(2-bromophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)propanamide
2771. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-2-[(lR)-l-(2,6-dimethylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] -N-(2-fluorobenzyl)propanamide
2772. N-(2,3-dihydro- lH-inden-2-yl)-2-[6,7-dimethyl- 1 -(2-methylphenyl)-3 ,4- dihydroisoquinolin-2( 1 H)-yl] -N-(2-fluorobenzyl)acetamide
2773. N-(2,3-dihydro-lH-inden-2-yl)-2-[7,8-dimethyl-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]-N-(2-fluorobenzyl)acetamide
2774. 2-[l-(2,3-difluorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2-yl)- N-(2-fluorobenzyl)acetamide
2775. (2S)-2-[(lR)-l-(2,3-dihydro-l-benzofuran-7-yl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3- dihydro- 1 H-inden-2-yl)-N-(2-fluorobenzyl)propanamide 2776. methyl 4-(2-{2-[2,3-dihydro-lH-inden-2-yl(2-fluorobenzyl)amino]-2-oxoethyl}-l,2,3,4- tetrahydroisoquinolin- 1 -yl)benzoate
2777. (2S)-N-benzyl-2-[(lR)-l-(2-bromophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2-chloro- 4-hydroxybenzyl)propanamide
2778. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[8-methyl-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2779. N-(2,3-dihydro- lH-inden-2-yl)-N-(3-methoxybenzyl)-2-[ 1 -(2-methylphenyl)-3 ,4- dihydroisoquinolin-2(lH)-yl]acetamide
2780. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-(l-mesityl-3,4-dihydroisoquinolin- 2(1 H)-yl)acetamide
2781. 2-[l-(2,6-difluoroρhenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2-yl)- N-(2-fluorobenzyl)acetamide
2782. N-(2-fluorobenzyl)-2-[l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N- phenylacetamide
2783. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-(2-methyl-l-naphthyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
2784. (2S)-2-[(lR)-l-(2-chloro-5-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3- dihydro- 1 H-inden-2-yl)-N-(2-fluorobenzyl)propanamide
2785. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-2-[(lS)-l-(2,5-dimethylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] -N-(2-fluorobenzyl)propanamide
2786. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[(lR)-l-(2-fluoro-5- methylphenyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl]propanamide
2787. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N,N-bis(2- fluorobenzyl)propanamide
2788. 4-[(2,3-dihydro-lH-inden-2-yl{[l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)- yl] acetyl } amino)methyl]benzoic acid
2789. (2S)-2-[(lR)-l-(2,6-difluorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)propanamide
2790. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-hydroxybenzyl)propanamide
2791. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2-fluorobenzyl)-N- (2-phenylethyl)propanamide
2792. N-(2,3-dihydro-lH-inden-2-yl)-N-(3-hydroxybenzyl)-2-[l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
2793. 2-[l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2-fluorobenzyl)-N-(5-methoxy- 2,3-dihydro-lH-inden-2-yl)acetamide
2794. N-(2-fluorobenzyl)-N-(5-methoxy-2,3-dihydro-lH-inden-2-yl)-2-[l-[2- (trifluoromethyl)phenyl] -3 ,4-dihydroisoquinolin-2( 1 H)-yl] acetamide
2795. 2-[l-(2,6-dichlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden-2- yl)-N-(2-fluorobenzyl)acetamide
2796. 2-[l-(2-chloro-6-fluorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH-inden- 2-yl)-N-(2-fluorobenzyl)acetamide
2797. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-( 1 H-imidazol-4-ylmethyl)propanamide 2798. 3-{[{(2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]propanoyl}(2,3- dihydro-lH-inden-2-yl)amino]methyl}benzoic acid
2799. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[l-[2-fluoro-6- (trifluoromethyl)phenyl] -3 ,4-dihydroisoquinolin-2( 1 H)-yl] acetamide
2800. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluorobenzyl)-2-[8-fluoro-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2801. N-(2,3-dihydro-lH-inden-2-yl)-N-(2-fluoro-5-hydroxybenzyl)-2-[l-(2-methylphenyl)-3,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2802. (2S)-2-[(lR)-l-(2,6-dichlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)propanamide
2803. (2S)-2-[(lR)-l-(2-chloro-6-fluorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3- dihydro- 1 H-inden-2-yl)-N-(2-fluorobenzyl)propanamide
2804. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-[2-(2- fluorophenyl)ethyl]-N-(4-hydroxybenzyl)propanamide
2805. 3-{[{(2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]propanoyl}(2,3- dihydro-lH-inden-2-yl)amino]methyl}-N,N-dimethylbenzamide
2806. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(4-hydroxy-3,5-dimethylbenzyl)propanamide
2807. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-[2-(2- fluorophenyl)ethyl]-N-(2-phenylethyl)propanamide
2808. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2-fluorobenzyl)-N- [2-(2-fluorophenyl)ethyl]propanamide
2809. (2S)-2-[(lR)-l-(2,6-dichlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(4-hydroxy-3,5-dimethylbenzyl)propanamide
2810. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(3-cyanobenzyl)-N- (2,3-dihydro-lH-inden-2-yl)propanamide
2811. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(3-nitrobenzyl)propanamide
2812. N-(2,3-dihydro-lH-inden-2-yl)-N-(3-hydroxybenzyl)-2-[(lS)-l-(2-methylphenyl)-3,4- dihydroisoquinolin-2(lH)-yl]acetamide
2813. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(3-hydroxybenzyl)propanamide
2814. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluoro-3-hydroxybenzyl)propanamide
2815. 2-[8-chloro-l-(2-methylphenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro-lH- inden-2-yl)-N-(2-fluorobenzyl)acetamide
2816. 2-[8-chloro-l-(2-chloro-6-fluorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-(2,3-dihydro- lH-inden-2-yl)-N-(2-fluorobenzyl)acetamide
2817. (2S)-N-(2-fluorobenzyl)-N-[2-(4-hydroxyphenyl)ethyl]-2-[(lR)-l-(l-naphthyl)-3,4- dihydroisoquinolin-2(lH)-yl]propanamide
2818. (2S)-N-(2-fluorobenzyl)-N-[2-(lH-indol-3-yl)ethyl]-2-[(lR)-l-(l-naphthyl)-3,4- dihydroisoquinolin-2( 1 H)-yl]propanamide
2819. (2S)-2-[(lR)-l-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(lH)-yl]-N-[3-(difluoromethoxy)- 2-fluorobenzyl]-N-(2,3-dihydro-lH-inden-2-yl)propanamide 2820. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-[(2-methoxypyridin-3-yl)methyl]-2-[(lR)-l-(l- naphthyl)-3,4-dihydroisoquinolin-2(lH)-yl]propanamide
2821. (2S)-N-(2-fluorobenzyl)-N-[(2-methoxypyridin-3-yl)methyl] -2-[( 1R)- 1 -(1 -naphthyl)-3,4- dihydroisoquinolin-2(lH)-yl]propanamide
2822. N-(2,3-dihydro- 1 H-inden-2-yl)-N-(2-fluorobenzyl)-2-[ 1 -(4-hydroxyphenyl)-3 ,4- dihydroisoquinolin-2( 1 H)-yl] acetamide
2823. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-[(6-methoxypyridin-2-yl)methyl]-2-[(lR)-l-(l- naphthyl)-3,4-dihydroisoquinolin-2(lH)-yl]propanamide
2824. (2S)-N-(2-fluorobenzyl)-N-[(6-methoxypyridin-2-yl)methyl]-2-[(lR)-l-(l-naphthyl)-3,4- dihydroisoquinolin-2( 1 H)-yl]propanamide
2825. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-[(3-fluoropyridin-2-yl)methyl]-2-[(lR)-l-(l- naphthyl)-3,4-dihydroisoquinolin-2(lH)-yl]propanamide
2826. (2S)-N-(2,3-dihydro-lH-inden-2-yl)-N-[(5-methoxypyridin-3-yl)methyl]-2-[(lR)-l-(l- naphthyl)-3,4-dihydroisoquinolin-2(lH)-yl]propanamide
2827. 7-({butyl[( 1 -butyl-4-chloro-2-phenyl- 1 H-imidazol-5 -yl)methyl] amino }methyl)quinazolin- 4-ol
2828. methyl 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl } (neopentyl)amino]methyl } -2-methoxybenzoate
2829. 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl } (neopentyl)amino]methyl } -2-methoxybenzoic acid
2830. 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl}(neopentyl)amino]methyl}-2-methoxybenzamide
2831. 4- { [ { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- 1 H-imidazol-5- yl]methyl}(neopentyl)amino]methyl}-2-hydroxybenzamide
2832. 4-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } (neopentyl)amino]methyl } -2-hydroxybenzamide
2833. 4-[(benzyl{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl}amino)methyl]-2-hydroxybenzamide
2834. 5- { [bis(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl } - 1 -butyl-2-phenyl- 1H- imidazole-4-carbonitrile
2835. N-[(l-butyl-4-fluoro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)amine
2836. N-[(l-butyl-4-fluoro-2-phenyl-lH-imidazol-5-yl)methyl]-N,N-bis(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amine
2837. 4-({butyl[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5- yl)methyl] amino }methyl)benzenesulfonamide
2838. 4-( { butyl[( 1 -butyl-4-chloro-2-phenyl- 1 H-imidazol-5 -yl)methyl] amino } methyl)benzamide
2839. methyl 2-amino-4-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methyl)benzoate
2840. 7-({butyl[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]amino}methyl)quinazolin-4-ol
2841. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-4- isopropylaniline
2842. l-[l-butyl-2-(2-methoxyphenyl)-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine 2843. 4-({(l,3-benzodioxol-5-ylmethyl)[(l-butyl-2,4-diphenyl-lH-imidazol-5- yl)methyl] amino } methy l)-N,N-dimethylcyclohexanamine
2844. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N- (tetrahydro-2H-pyran-4-ylmethyl)methanamine
2845. N- { [ 1 -butyl-2-(2-methylphenyl)-4-(trifluoromethyl)~ 1 H-imidazol-5-yl]methyl } -N-(2,3- dihydro-l,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine
2846. N-[l-(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)ethyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)amine
2847. 1 -(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N- { [ 1 -butyl-4-chloro-2-(2- methoxyphenyl)-lH-imidazol-5-yl]methyl}methanamine
2848. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)- 1 -(3-ethoxyphenyl)ethanamine
2849. methyl 4-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}cyclohexanecarboxylate
2850. 4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl}cyclohexanecarboxylic acid
2851. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-l-(2,3-dihydro-l,4-benzodioxin- 6-yl)-N-(3-ethoxybenzyl)ethanamine
2852. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(cyclopropylmethyl)-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)amine
2853. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-[(6-methoxypyridin-3-yl)methyl]amine
2854. l-[l-butyl-4-chloro-2-(2-methoxyphenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2855. 5-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl}pyridin-2-ol
2856. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-propoxybenzyl)amine
2857. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-isopropoxybenzyl)amine
2858. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(lH-indazol-6-ylmethyl)amine
2859. methyl 4-({ [(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl][(2-methyl-l,3- benzothiazol-5-yl)methyl]amino}methyl)benzoate
2860. 4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl }benzoic acid
2861. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N- [(3 ,5-dimethyl- 1 H-pyrazol-4-yl)methyl] amine
2862. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N- [(6-methoxypyridin-2-yl)methyl] amine
2863. 4-({[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl][(2-methyl-l,3-benzothiazol-5- y l)methyl] amino } methyl)benzoic acid
2864. 3-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]propan- 1 -ol 2865. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(lH-indazol-5-ylmethyl)amine
2866. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-3-morpholin-4-ylpropan-l-amine
2867. 4- { 1 -[[( 1 -butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin- 6-ylmethyl)amino] ethyl Jbenzoic acid
2868. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-[(5-methoxypyridin-3-yl)methyl]amine
2869. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-3-(3-methyl-lH-pyrazol-l-yl)propan-l-amine
2870. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-2-cyclopropyl-N-(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)ethanamine
2871. N-[(4-chloro-2-phenyl-l-propyl-lH-imidazol-5-yl)methyl]-l-(2,3-dihydro-l,4-benzodioxin- 6-yl)-N-(3-ethoxybenzyl)ethanamine
2872. l-butyl-5-{[(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl}-2- (2-methoxyphenyl)- 1 H-imidazole-4-carbonitrile
2873. N- { [4-chloro- 1 -methyl-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl } - 1 -(2,3-dihydro-l ,4- benzodioxin-6-yl)-N-(3-ethoxybenzyl)ethanamine
2874. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-methyl-2,4-diphenyl-lH-imidazol-5- y l)methyl] butan- 1 -amine
2875. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-methyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2876. N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-ethyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]butan- 1 -amine
2877. 1-(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N-[(l-ethyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2878. N-(l,3-benzodioxol-5-ylmethyl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5- yl)methyl]butan- 1 -amine
2879. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(2,4-diphenyl-l-propyl-lH- imidazol-5-yl)methyl]methanamine
2880. l-butyl-5-{[(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl}-2- phenyl- 1 H-imidazole-4-carbonitrile
2881. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(l-butyl-2-cyclohex-l-en-l- yl-4-phenyl-lH-imidazol-5-yl)methyl]methanamine
2882. l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2883. 1-(1 ,3-benzodioxol-5-yl)-N-(l ,3-benzodioxol-5-ylmethyl)-N-{ [l-butyl-4-chloro-2-(2- methylphenyl)- 1 H-imidazol-5-yl] methyl } methanamine
2884. l-(4-chloro-2-phenyl-l-propyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
2885. 1 -(4-chloro-2-phenyl- 1 -propyl- lH-imidazol-5-yl)-N,N-bis(2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)methanamine
2886. l-(l,3-benzodioxol-5-yl)-N-[(4-chloro-2-phenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine 2887. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-[(4-chloro-2-phenyl-l-propyl- lH-imidazol-5-yl)methyl]methanamine
2888. l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-[(l-methyl-2,4-diphenyl-lH- imidazol-5-yl)methyl]methanamine
2889. 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-N-(2,3-dihydro-l ,4-benzodioxin-6-ylmethyl)-N-[(l- methyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]methan amine
2890. l-(l,3-benzodioxol-5-yl)-N-(3-ethoxybenzyl)-N-[(l-methyl-2,4-diphenyl-lH-imidazol-5- yl)methyl]methanamine
2891. l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]- N-(3-ethoxybenzyl)methanamine
2892. l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N-[(2,4- diphenyl-l-propyl-lH-imidazol-5-yl)methyl]methanamine
2893. l-(l,3-benzodioxol-5-yl)-N-[(2,4-diphenyl-l-propyl-lH-imidazol-5-yl)methyl]-N-(3- ethoxybenzyl)methanamine
2894. l-(l,3-benzodioxol-5-yl)-N-{[l-butyl-4-fluoro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl}-N-(3-ethoxybenzyl)methanamine
2895. l-[l-butyl-4-fluoro-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2896. l-(l,3-benzodioxol-5-yl)-N-(l,3-benzodioxol-5-ylmethyl)-N-{[l-butyl-2-(2-chlorophenyl)- 4-phenyl-lH-imidazol-5-yl]methyl}methanamine
2897. N-{[l-butyl-2-(2-chlorophenyl)-4-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine
2898. 5-{ [(1 ,3-benzodioxol-5-ylmethyl)(3-ethoxybenzyl)amino]methyl}-l-butyl-2-(2- methylphenyl)- 1 H-imidazole-4-carbonitrile
2899. l-butyl-5-{ [(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl}-2- (2-methylphenyl)- 1 H-imidazole-4-carbonitrile
2900. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(2-fluoro-5-methoxybenzyl)amine
2901. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l ,4-benzodioxin- 6-ylmethyl)-N-(4-fluoro-3-methoxybenzyl)amine
2902. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,6-difluorobenzyl)-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)amine
2903. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-fluorobenzyl)amine
2904. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(3-chlorobenzyl)-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)amine
2905. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-methylbenzyl)amine
2906. l-(3-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]methyl}phenyl)ethanone
2907. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-methoxybenzyl)amine
2908. 3-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid 2909. 3-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzamide
2910. 3-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methylJbenzonitrile
2911. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-2-methoxyethanamine
2912. N-[( 1 -butyl-2,4-diphenyl- lH-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)-3-methoxypropan- 1 -amine
2913. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-2-ethoxyethanamine
2914. 4-[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]butan- 1 -ol
2915. N-[(l -butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1 ,4-benzodioxin- 6-ylmethyl)-2-methoxyethanamine
2916. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-3 -methoxypropan- 1 -amine
2917. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-2-ethoxyethanamine
2918. 4-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]butan- 1 -ol
2919. l-[l-butyl-2-(2-methyl-l,3-thiazol-4-yl)-4-phenyl-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2920. l-[4-chloro-l-methyl-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2921. l-[4-chloro-l-methyl-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(3-ethoxybenzyl)-N-(lH- indol-5-ylmethyl)methanamine
2922. l-[l-butyl-4-chloro-2-(4-fluorophenyl)-lH-imidazol-5-yl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
2923. l-(4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]methyl}phenyl)ethanone
2924. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(4-methylbenzyl)amine
2925. N-[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)amine
2926. N-[(l-butyl-4-methyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)amine
2927. l-[l-butyl-4-fluoro-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(3-ethoxybenzyl)-N-(lH- indol-5-ylmethyl)methanamine
2928. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(lH-indol-5-ylmethyl)amine
2929. l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-[(4-methyl-2-phenyl-l-propyl- lH-imidazol-5-yl)methyl]methanamine
2930. 6-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyI)amino]methyl } - 1 ,2-benzisoxazol-3-amine 2931. 2-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]-l-(3-methoxyphenyl)ethanone
2932. 2-[Butyl-(3-butyl-5-chloro-2-phenyl-3H-imidazol-4-ylmethyl)-amino]-N-(2,3-dihydro- benzo [ 1 ,4] dioxin-6-ylmethyl)-acetamide
2933. 2-[[( 1 -butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]-l-(3-methoxyphenyl)ethanol
2934. N-[2-(benzyloxy)ethyl]-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]butan-l- amine
2935. N-[2-(benzyloxy)ethyl]-N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)amine
2936. methyl 3-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2937. 5-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl } -N-(2-methoxyethyl)pyridin-2-amine
2938. N-[( 1 -butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1 ,4-benzodioxin- 6-ylmethyl)-N-[(6-morpholin-4-ylpyridin-3-yl)methyl]amine
2939. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(6-chloropyridin-3- yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)amine
2940. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-2-(2,3-dihydro-l,4-benzodioxin- 6-yl)-N-(3-ethoxybenzyl)propan-2-amine
2941. 4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methylJ-3-chlorobenzoic acid
2942. 4-({[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl][l-(2,3-dihydro-l,4-benzodioxin- 6-yl)ethyl] amino J methy l)benzoic acid
2943. 4-({butyl[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]amino}methyl)-3- chlorobenzoic acid
2944. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-methyl-l,2,3,4- tetrahydronaphthalen- 1 -a ine
2945. 4-({[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl][4- (difluoromethoxy)benzyl] amino }methyl)benzoic acid
2946. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(lH-pyrazol-4-ylmethyl)amine
2947. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N- [( 1 -ethyl- 1 H-pyrazol-4-yl)methyl] amine
2948. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(lH-pyrazol-5-ylmethyl)amine
2949. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro- 1 ,4-benzodioxin- 6-ylmethyl)-N- [( 1 ,4-dimethyl- 1 H-pyrazol-3-yl)methyl] amine
2950. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(pyridin-4-ylmethyl)amine
2951. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-[4-(lH-tetraazol-5-yl)benzyl]amine
2952. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N- [( 1 -oxidopyridin-4-yl)methyl] amine 2953. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-[(5-chloro-l,3-dimethyl-lH- pyrazol-4-yl)methyl] -N-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amine
2954. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-{[5-chloro-l-methyl-3- (trifluoromethyl)- 1 H-pyrazol-4-yl]methyl } -N-(2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amine
2955. 4- { [[(1 -butyl-4-chloro-2-phenyl- 1 H-imidazol-5-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]methyl J -3-fluorobenzoic acid
2956. 5-{3-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]propylJisoxazol-3-ol
2957. 5-{5-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]pentylJisoxazol-3-ol
2958. 4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl}-2-fluorobenzoic acid
2959. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-[(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-6-yl)methyl]amine
2960. 6-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jnicotinic acid
2961. methyl 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2962. 4- { [{ [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid
2963. methyl 4-{ [[(4-chloro-2-phenyl-l-propyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
2964. methyl 4-{ [{ [l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]methyl}(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2965. methyl 4-{ [[(l-butyl-4-cyano-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2966. methyl 4-{ [[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]methyl}benzoate
2967. methyl 4-{ [[(l-butyl-4-methyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2968. methyl 4-({(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)[(4-methyl-2-phenyl-l-propyl-lH- imidazol-5-yl)methyl]aminoJmethyl)benzoate
2969. 4-{ [[(4-chloro-2-phenyl-l-proρyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4-benzodioxin- 6-ylmethyl)amino]methyl Jbenzoic acid
2970. 4- { [{ [ 1 -butyl-2-phenyl-4-(trifluoromethyl)- lH-imidazol-5-yl]methyl J (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl) amino] methyl } benzoic acid
2971. 4-{[[(l-butyl-4-cyano-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
2972. 4-{[[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
2973. 4-{[[(l-butyl-4-methyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
2974. 4-({(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)[(4-methyl-2-phenyl-l-propyl-lH-imidazol- 5 -yl)methyl] amino } methyl)benzoic acid
2975. methyl 4-{ [{ [l-butyl-4-cyano-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate
2976. methyl 4-{ [{ [l-butyl-4-fluoro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]methyl Jbenzoate
2977. 4-{ [{ [l-butyl-4-cyano-2-(2-methylρhenyl)-lH-imidazol-5-yl]methylJ(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
2978. 4-{ [{ [l-butyl-4-fluoro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(3- ethoxybenzyl)amino]methyl}benzoic acid
2979. 4- { [ { [ 1 -butyl-4-fluoro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
2980. methyl 4-{ [{ [l-butyl-4-fluoro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl J(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2981. N-{ [ 1 -butyl-4-chloro-2-(2-methylphenyl)- 1 H-imidazol-5-yl]methyl J -N-( 1 H-indol-5- ylmethyl)-3-methylbutan- 1 -amine
2982. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methylJ-N-(lH-indol-5- ylmethyl)butan- 1 -amine
2983. methyl 4-{ [[(l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoate
2984. 4- { [[(1 -butyl-2-phenyl- 1 H-imidazol-5-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
2985. methyl 4-{ [[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
2986. 4-{[[(4-bromo-l-butyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
2987. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-3-methylbutan-l-amine
2988. methyl 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methylJ(isopentyl)amino]methyl}benzoate
2989. 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl] methyl J (isopentyl)amino] methyl Jbenzoic acid
2990. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-3 -methylbutan- 1 -amine
2991. methyl 2-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
2992. methyl 6-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]hexanoate
2993. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)prop-2-yn- 1 -amine
2994. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)prop-2-en- 1 -amine
2995. ethyl 2-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methylJcyclopropanecarboxylate
2996. 2-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
2997. 6-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]hexanoic acid
2998. ethyl 4-{ 3-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]propyl}benzoate
2999. ethyl 4-(3-{butyl[(4-chloro-2-phenyl-l-propyl-lH-imidazol-5- yl)methyl] amino }propyl)benzoate
3000. ethyl 4-[3-(butyl{ [l-butyl-4-chloro-2-(2-methylphenyl)-l H-imidazol-5 - yl]methyl } amino)propyl]benzoate
3001. 4-{3-[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]propyl Jbenzoic acid
3002. 4-[3-(butyl{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl J amino)propyl]benzoic acid
3003. methyl (4-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methylJphenyl)acetate
3004. methyl 2-(4-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)propanoate
3005. methyl 2-(4- { [[(1 -butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl] (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)-2-methylpropanoate
3006. methyl (3-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methylJphenyl)acetate
3007. (4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl }phenyl)acetic acid
3008. 2-(4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]methyl }phenyl)propanoic acid
3009. 2-(4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]methyl Jphenyl)-2-methylpropanoic acid
3010. (3-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jphenyl)acetic acid
3011. N-{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan-l-amine
3012. 4-[(butyl{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzenesulfonamide
3013. 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yljmethyl } (isopentyl)amino]methyl Jbenzenesulfonamide
3014. 4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl}benzenesulfonamide
3015. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- 1 H-imidazol-5-yl]methyl } -N- [(3-chloro- 1 H- indol-5 -yl)methyl] -3-methylbutan- 1 -amine
3016. 5-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methylJ(isopentyl)amino]methyl}-lH-indole-3-carbonitrile
3017. 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzenesulfonamide
3018. N-{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(quinoxalin-6- ylmethyl)butan- 1 -amine
3019. 5-(5-{butyl[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]aminoJpentyl)isoxazol-3- ol
3020. methyl [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino](phenyl)acetate
3021. N-[(l-butyl-2-phenyl-4-vinyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine
3022. methyl 4-{ [[(l-butyl-2-phenyl-4-vinyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
3023. N-[(l-butyl-4-phenyl-2-vinyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine
3024. N-[(l-butyl-4-ethyl-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine
3025. methyl 4-{ [[(l-butyl-4-ethyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzoate
3026. (lS)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N- methylpentan- 1 -amine
3027. N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)-N-(quinoxalin-6-ylmethyl)amine
3028. 4-{ [[(l-butyl-2-phenyl-4-vinyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
3029. N-{ l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]ethyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan- 1 -amine
3030. N- { 1 -[ l-butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl] ethyl J -N-(2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)-3-methylbutan-l-amine
3031. N-{l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]ethyl}-N-(lH-indol-5- ylmethyl)butan- 1 -amine
3032. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methylJ-3-methyl-N-[(2- methyl- lH-indol-5-yl)methyl]butan- 1 -amine
3033. l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-methylpentan-l-amine
3034. 4-{[[(l-butyl-4-ethyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
3035. N-{ [4-chloro- 1 -(ethoxymethyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine
3036. l-(4-chloro-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine
3037. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl J -N-methyl- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -amine
3038. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(l,2,3,4- tetrahydroquinolin-6-ylmethyl)methanamine
3039. l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(cyclohexylmethyl)-N- (l,2,3,4-tetrahydroquinolin-6-ylmethyl)methanamine
3040. N-{ [4-bromo-l-butyl-2-(2,6-diethylphenyl)-lH-imidazol-5-yl]methyl}-N-methyl-l ,2,3,4- tetrahydronaphthalen- 1 -amine 3041. methyl 4-{ [{ [l-butyl-4-(4-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methylJ (2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3042. methyl 4-{[{[l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3043. 4- { [ { [ 1 -butyl-4-(4-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
3044. 4-{[{[l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid
3045. N- { [ l-butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } -N-(3- methoxybenzyl)butan-l-amine
3046. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)butan-l-amine
3047. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(lH-indol-5- ylmethyl)-3 ,3-dimethylbutan- 1 -amine
3048. 6-[(butyl { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- 1 H-imidazol-5 -yl]methyl } amino)methyl] - 3 ,4-dihydroquinolin-2( 1 H)-one
3049. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(l,2,3,4- tetrahydroquinolin-6-ylmethyl)butan- 1 -amine
3050. N- { [1 -butyl-4-chloro-2-(2,6-diethylphenyl)- lH-imidazol-5-yl]methyl J -N-methyl- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -amine
3051. (lS)-N-{[l-butyl-4-chloro-2-(2,6-diethylphenyl)-lH-imidazol-5-yl]methyl}-N-methyl- 1,2,3,4-tetrahydronaphthalen-l-amine
3052. 6-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methylJ(isopentyl)amino]methyl}-3,4-dihydroquinolin-2(lH)-one
3053. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } -N-(2,3-dihydro- 1 - benzofuran-5-ylmethyl)-3-methylbutan- 1 -amine
3054. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)-l H-imidazol-5-yl]methyl } -N-(4-methoxybenzyl 3 -methylbutan- 1 -amine
3055. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methylJ-N-(3-methoxybenzyl)- 3-methylbutan-l-amine
3056. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(4-ethoxybenzyl)-3- methylbutan- 1 -amine
3057. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methylJ-N-(3-ethoxybenzyl)-3- methylbutan- 1 -amine
3058. ethyl N-{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)-beta-alaninate
3059. 4-[{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]-2-methylbutan-2-ol
3060. ethyl N-{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl J-N-(lH-indol-5- ylmethyl)-beta-alaninate
3061. 4-[{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(lH-indol-5- ylmethyl)amino]-2-methylbutan-2-ol
3062. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-[(3-chloro-lH- indol-5-yl)methyl]-3,3-dimethylbutan-l-amine 3063. N-{ [ 1 -butyl-2-(2,6-diethylphenyl)-4-(4-methylρhenyl)- lH-imidazol-5-yl]methyl } -N- methyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine
3064. N- { [ 1 -butyl-2-(2,6-diethylphenyl)- lH-imidazol-5-yl]methyl J -N-methyl- 1 ,2,3,4- tetrahydronaphthalen- 1 -amine
3065. N-{ [ 1 -butyl-2-(2,6-diethylphenyl)-4-methyl- 1 H-imidazol-5-yl]methyl J -N-methyl- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -amine
3066. methyl 4-{ [{ [l-butyl-4-(4-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methylJ (2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3067. methyl 4-{ [{ [l-butyl-4-(3-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3068. methyl 4-{ [{ [l-butyl-4-(3-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3069. methyl 4-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl J(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3070. methyl 4-{ [{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3071. 4-{{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}[(3-chloro-lH-indol-5- yl)methyl] amino J -2-methylbutan-2-ol
3072. N- { [1 -butyl-4-chloro-2-(2-methylphenyl)- 1 H-imidazol-5-yl]methyl } -N-(l H-indol-5- ylmethyl)-2,2-dimethylpropan-l-amine
3073. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } -N-[(3-chloro- 1H- indol-5-yl)methyl]-2,2-dimethylpropan-l-amine
3074. N-{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)-2,2-dimethylpropan-l-amine
3075. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(2-fluoro-4- methoxybenzyl)-3-methylbutan- 1 -amine
3076. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } -N-(2-chloro-4- methoxybenzyl)-3-methylbutan- 1 -amine
3077. N-{[4-bromo-2-(2,6-diethylphenyl)-l-(l,3-dioxolan-2-ylmethyl)-lH-imidazol-5- yl]methyl}-N-methyl-l,2,3,4-tetrahydronaphthalen-l-amine
3078. N-{[4-bromo-2-(2,6-diethylphenyl)-l-(ethoxymethyl)-lH-imidazol-5-yl]methyl}-N-methyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine
3079. 4-{[{[l-butyl-4-(4-fluoroρhenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid
3080. 4-{ [{ [l-butyl-4-(3-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
3081. 4- { [ { [ 1 -butyl-4-(3-methoxyphenyl)-2-phenyl- lH-imidazol-5-yl]methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
3082. 4-{ [{ [l-butyl-4-(4-chlorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl J (2,3-dihydro- 1,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
3083. 4-{[{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid
3084. N-{[4-bromo-2-(2,6-diethylphenyl)-l-(2-morpholin-4-ylethyl)-lH-imidazol-5-yl]methylJ- N-methyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine 3085. N- { [4-bromo-2-(2,6-diethylphenyl)- lH-imidazol-5-yl]methyl J-N-methyl- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -amine
3086. l-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]-N-methyl-N-[(8- methylimidazo[ 1 ,2-a]pyridin-2-yl)methyl]methanamine
3087. N- { [4-chloro-l -(2-morpholin-4-ylethyl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine
3088. 1 -[4-chloro-2-phenyl- 1 -(2-piperidin- 1 -ylethyl)- 1 H-imidazol-5-yl] -N-(2, 3 -dihydro- 1 ,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
3089. methyl 4-[(butyl{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzoate
3090. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methylJ(isobutyl)amino]methyl}benzoate
3091. methyl 4- { [ { [ 1 -butyl-2-(2-methylphenyl)-4-(4-methylphenyl)- 1 H-imidazol-5-yl]methyl } (2- ethylbutyl)amino]methyl}benzoate
3092. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yljmethyl } (isopentyl)amino]methyl Jbenzoate
3093. methyl 4- { [ { [ 1 -butyl-2-(2-methylphenyl)-4-(4-methylphenyl)- 1 H-imidazol-5- yl]methylJ(cyclohexylmethyl)amino]methyl}benzoate
3094. methyl 4-[(benzyl{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzoate
3095. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methylJ(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate
3096. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-phenyl-lH-imidazol-5- yljmethyl J (isopentyl)amino]methyl Jbenzoate
3097. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate
3098. methyl 4-[(benzyl{ [l-butyl-2-(2-methylphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyι]benzoate
3099. 4-[(butyl{[l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
3100. 4-{[{[l-butyl-2-(2-methylρhenyl)-4-(4-methylρhenyl)-lH-imidazol-5- yljmethyl J (isobutyl)amino]methyl Jbenzoic acid
3101. 4-{ [ { [ 1 -butyl-2-(2-methylphenyl)-4-(4-methylphenyl)~ 1 H-imidazol-5-yl]methyl } (2- ethylbutyl)amino]methyl Jbenzoic acid
3102. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } (isopentyl)amino]methyl Jbenzoic acid
3103. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yljmethyl } (cyclohexylmethyl)amino]methyl Jbenzoic acid
3104. 4-[(benzyl{[l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
3105. N-{[4-chloro-2-(2,6-dimethylphenyl)-l-methyl-lH-imidazol-5-yl]methyl}-N-methyl- 1,2,3,4-tetrahydronaphthalen-l-amine
3106. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5-yl]methyl}(2,3- dihydro-1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid 3107. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-phenyl-lH-imidazol-5- yl]methyl J (isopentyl)amino]methyl Jbenzoic acid
3108. 4- { [ { [ 1 -butyl-2-(2-methylphenyl)-4-phenyl- lH-imidazol-5-yl]methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl}benzoic acid
3109. 4-[(benzyl{[l-butyl-2-(2-methylphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
3110. 4-[(butyl{[l-butyl-2-(2-methylphenyl)-4-phenyl-lH-imidazol-5- yl]methyl } amino)methyl]benzoic acid
3111. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } (propyl)amino]methyl Jbenzoate
3112. methyl 4-{[{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } (neopentyl)amino]methyl Jbenzoate
3113. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methylJ(3,3-dimethylbutyl)amino]methyl}benzoate
3114. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } (pentyl)amino]methyl Jbenzoate
3115. methyl 4-{[{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl J (hexyl)amino]methyl } benzoate
3116. methyl 4- { [{ [ 1 -butyl-2-(2-methylphenyl)-4-(4-methylρhenyl)- lH-imidazol-5-yl]methyl } (3- methylbut-2-enyl)amino]methyl}benzoate
3117. methyl 4-[((bicyclo[2.2. l]hept-5-en-2-ylmethyl){ [l-butyl-2-(2-methylphenyl)-4-(4- methylphenyl)-lH-imidazol-5-yl]methyl}amino)methyl]benzoate
3118. methyl 4-{ [ { [ 1 -butyl-2-(2-methylphenyl)-4-(4-methylphenyl)- 1 H-imidazol-5- yl]methyl J (tetrahydrofuran-3-ylmethyl)amino]methyl Jbenzoate
3119. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yljmethyl } (thien-3-ylmethyl)amino]methyl Jbenzoate
3120. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl J (propyl)amino]methyl Jbenzoic acid
3121. 4-{[{[l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl}(neopentyl)amino]methyl Jbenzoic acid
3122. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5-yl]methyl}(3,3- dimethylbutyl)amino]methyl Jbenzoic acid
3123. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl J (pentyl)amino]methyl Jbenzoic acid
3124. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methyl } (hexyl)amino]methyl}benzoic acid
3125. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5-yl]methyl}(3- methylbut-2-enyl)amino]methyl}benzoic acid
3126. 4-[((bicyclo[2.2.1]hept-5-en-2-ylmethyl){[l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)- lH-imidazol-5-yl]methyl } amino)methyl]benzoic acid
3127. 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5-yl]methyl}(thien-3- ylmethyl)amino]methyl Jbenzoic acid
3128. methyl 4-{ [{ [l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)-lH-imidazol-5- yl]methylJ(lH-indol-5-ylmethyl)amino]methyl}benzoate 3129. 4- { [ { [ l-butyl-2-(2-methylphenyl)-4-(4-methylphenyl)- 1 H-imidazol-5-yl]methyl J (lH-indol- 5-ylmethyl)amino]methyl}benzoic acid
3130. N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- 1 H-imidazol-5-yl]methyl J -N-(l H-indazol-5- ylmethyl)-3-methylbutan- 1 -amine
3131. 4- { [ { [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- 1 H-imidazol-5 - yl]methyl } (ethyl)amino]methyl } -2-hydroxybenzamide
3132. (1 S)-N-{ [ 1 -butyl-4-chloro-2-(2,6-dimethylphenyl)- lH-imidazol-5-yl]methyl } -N-methyl- 1,2,3,4-tetrahydronaphthalen-l-amine
3133. N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methylJ-N-(lH-indazol-5- ylmethyl)-2,2-dimethylpropan- 1 -amine
3134. l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(lH-indazol-5-ylmethyl)-N- (3 -methoxybenzyl)methanamine
3135. l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]-N-(lH-indazol-5-ylmethyl)-N- (4-methoxybenzyl)methanamine
3136. 4-{ [{ [l-butyl-4-chloro-2-(2-methylρhenyl)-lH-imidazol-5-yl]methyl}(4- methoxybenzyl)amino]methyl}-2-hydroxybenzamide
3137. 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}(3- methoxybenzyl)amino]methyl } -2-hydroxybenzamide
3138. 4-{[{[l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5-yl]methylJ(2- methoxyethyl)amino]methyl } -2-hydroxybenzamide
3139. 4-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-pyridin-3-yl-lH-imidazol-5- yl]methyl J (cyclohexylmethyl)amino]methyl } -2-hydroxybenzamide
3140. 7-{ [{ [l-butyl-4-(4-methoxyphenyl)-2-phenyl-lH-imidazol-5- yl]methyl } (neopentyl)amino]methyl } -2H- 1 ,3-benzoxazine-2,4(3H)-dione
3141. l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(lH-indazol-5- ylmethyl)methanamine
3142. N-[(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)methyl]-N-(lH-indazol-5-ylmethyl)-2,2- dimethylpropan- 1 -amine
3143. 1 - [ 1 -butyl-4-(4-methoxyphenyl)-2-phenyl- 1 H-imidazol-5-yl] -N-(cyclohexylmethyl)-N-( 1 H- indazol-5-ylmethyl)methanamine
3144. methyl 4-[((cyclohexylmethyl){ [l-[2-(dimethylamino)ethyl]-4-(4-methoxyphenyl)-2- phenyl-lH-imidazol-5-yl]methyl}amino)methyl]-2-methoxybenzoate
3145. N-{[4-chloro-2-(2,6-diethylphenyl)-l-(2-methoxyethyl)-lH-imidazol-5-yl]methyl}-N- propylpropan- 1 -amine
3146. 4-[((cyclohexylmethyl){ [l-[2-(dimethylamino)ethyl]-4-(4-methoxyphenyl)-2-phenyl-lH- imidazol-5-yl]methyl}amino)methyl]-2-hydroxybenzamide
3147. l-butyl-5-{[(lH-indazol-5-ylmethyl)(neopentyl)amino]methyl}-2-(2-methylphenyl)-lH- imidazole-4-carbonitrile
3148. l-butyl-5-{[(cyclohexylmethyl)(lH-indazol-5-ylmethyl)amino]methyl}-2-(2- methylphenyl)-lH-imidazole-4-carbonitrile
3149. N-{[4-chloro-2-(2,6-diethylphenyl)-l-(2-methoxyethyl)-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2,2-dimethylpropan- 1 -amine
3150. 4-{ [{ [l-butyl-4-cyano-2-(2-methylphenyl)-lH-imidazol-5- yl]methylJ(cyclohexylmethyl)amino]methylJ-2-hydroxybenzamide 3151. N-{[4-chloro-2-(2,6-diethylphenyl)-l-(2-methoxyethyl)-lH-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)-2,2-dimethylpropan- 1 -amine
3152. N-{[4-chloro-2-(2,6-diethylphenyl)-l-(2-methoxyethyl)-lH-imidazol-5-yl]methyl}-N- (cyclohexylmethyl)-2,2-dimethylpropan-l-amine
3153. N- { [4-chloro-2-(2,6-diethylphenyl)- 1 -(2-methoxyethyl)- 1 H-imidazol-5-yl]methyl } -N- (cyclohexylmethyl)-2-methylpropan-2-amine
3154. l-(5-butyl-3-morpholin-4-yl-6-phenylpyridazin-4-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
3155. N- 1 -(5-butyl-4- { [(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)(3- ethoxybenzyl)amino]methyl}-6-phenylpyridazin-3-yl)-N-2-,N-2-dimethylethane-l,2- diamine
3156. N-[(5-butyl-6-phenylpyrimidin-4-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)- N-(3-ethoxybenzyl)amine
3157. l-(5-butyl-6-phenyl-3-pyrrolidin-l-ylpyridazin-4-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-methylmethanamine
3158. l-(5-butyl-6-phenyl-3-piperidin-l-ylpyridazin-4-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-methylmethanamine
3159. 5-butyl-4-{[(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)(methyl)amino]methyl}-6-phenyl- N,N-dipropylpyridazin-3-amine
3160. 1 -[3-chloro-5-methyl-6-(2-methylphenyl)pyridazin-4-yl]-N-(2,3-dihydro- 1 ,4-benzodioxin- 6-ylmethyl)-N-(3-ethoxybenzyl)methanamine
3161. 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-{ [5-methyl-6-(2- methylphenyl)-3-pyrrolidin-l-ylpyridazin-4-yl]methyl}methanamine
3162. l-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-(3-ethoxybenzyl)-N-{[5-methyl-6-(2- methylphenyl)-3-piperidin- 1 -ylpyridazin-4-yl]methyl Jmethanamine
3163. l-(5-butyl-6-phenyl-3-pyrrolidin-l-ylpyridazin-4-yl)-N-(2,3-dihydro-l ,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
3164. l-(5-butyl-6-phenyl-3-piperidin-l-ylpyridazin-4-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
3165. 1 -(5-butyl-3-isopropoxy-6-phenylpyridazin-4-yl)-N-(2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
3166. l-(5-butyl-3-isobutoxy-6-phenylpyridazin-4-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
3167. 4-[(5-butyl-4-{[(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methylJ- 6-phenylpyridazin-3-yl)oxy]-2-methylbutan-2-ol
3168. N-[(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)butan- 1 -amine
3169. N-[(5-butyl-6-phenyl-3-piperidin-l-ylpyridazin-4-yl)methyl]-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan-l-amine
3170. N-[(5-butyl-3-isobutoxy-6-phenylpyridazin-4-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)butan- 1 -amine
3171. N,5-dibutyl-4- { [butyl(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl J -6- phenylpyridazin-3-amine
3172. N-{[5-butyl-3-(4-methylpiperazin-l-yl)-6-phenylpyridazin-4-yl]methylJ-N-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)butan- 1 -amine
3173. N-{[5-butyl-3-(2-methoxyethoxy)-6-phenylpyridazin-4-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan-l-amine
3174. l-(5-butyl-2-methoxy-6-phenylpyrimidin-4-yl)-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)methanamine
3175. N-{[5-butyl-3-(3,5-dimethylpiperidin-l-yl)-6-phenylpyridazin-4-yl]methylJ-N-(2,3- dihydro- 1 ,4-benzodioxin-6-ylmethyl)butan- 1 -amine
3176. 5-butyl-4- { [butyl(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)amino]methyl } -N-methyl-6- phenyl-N-propylpyridazin-3-amine
3177. 4- { [[(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
3178. 4-{[[(5-butyl-3-isopropoxy-6-phenylpyridazin-4-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
3179. 4-{[[(5-butyl-3-isobutoxy-6-phenylpyridazin-4-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
3180. 5-butyl-4- { [(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)(3-ethoxybenzyl)amino]methyl } -6- phenylpyrimidin-2-ol
3181. 4- { [[(5-butyl-2-methoxy-6-phenylpyrimidin-4-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
3182. 4-({ [(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl] [4- (difluoromethoxy)benzyl] amino }methyl)benzoic acid
3183. 4- { [[(5-butyl-2-isopropoxy-6-phenylpyrimidin-4-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin- 6-ylmethyl)amino]methyl Jbenzoic acid
3184. 4-{[[(5-butyl-2-isobutoxy-6-phenylpyrimidin-4-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid
3185. 4- { [[(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]methyl } -3-fluorobenzoic acid
3186. 4- { [[(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)amino]methyl}-3-chlorobenzoic acid
3187. 4-{[[(5-butyl-2-methyl-6-phenylpyrimidin-4-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl}benzoic acid
3188. N-[(5-butyl-3-chloro-6-phenylpyridazin-4-yl)methyl]-N-(2-fluoro-4-methoxybenzyl)-2,2- dimethylpropan- 1 -amine
3189. N-[(5-butyl-3-ethoxy-6-phenylpyridazin-4-yl)methyl]-N-(2-fluoro-4-methoxybenzyl)-2,2- dimethylpropan- 1 -amine
3190. N-benzyl-N-(2-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3191. N-(2-methoxybenzyl)-N-(2-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3192. N-(2,2-diphenylethyl)-N-(2-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3193. N-(2,4-difluorobenzyl)-N-(2-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3194. N-(2,4-difluorobenzyl)-N-(2,2-diphenylethyl)-2-(lH-pyrrol-l-yl)benzamide
3195. N-(2,6-dichlorobenzyl)-N-(2-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3196. N-benzyl-N-(l,l'-biρhenyl-2-ylmethyl)-2-(lH-pyrrol-l-yl)benzamide 3197. N-(l,l'-biphenyl-2-ylmethyl)-N-(2-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3198. N-(l,l'-biphenyl-2-ylmethyl)-N-(2-phenylbutyl)-2-(lH-pyrrol-l-yl)benzamide
3199. N-(l,l'-biphenyl-2-ylmethyl)-N-(2,2-diphenylethyl)-2-(lH-pyrrol-l-yl)benzamide
3200. N-(l,l'-biphenyl-2-ylmethyl)-N-(cyclohexylmethyl)-2-(lH-pyrrol-l-yl)benzamide
3201. N-(2,4-dimethoxybenzyl)-N-(4-fluorobenzyl)-2-(lH-pyrrol-l-yl)benzamide
3202. N-(2-methoxybenzyl)-N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3203. N-(3-methoxybenzyl)-N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3204. N-(4-methoxybenzyl)-N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3205. N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide
3206. N-(2,4-dimethoxybenzyl)-N-(4-methylbenzyl)-2-( lH-pyrrol- 1 -yl)benzamide
3207. N-(3,5-dimethoxybenzyl)-N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3208. N-(4-chlorobenzyl)-N-(2-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3209. N-(4-chlorobenzyl)-N-(3-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3210. N-(4-chlorobenzyl)-N-(4-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3211. N-(l ,3-benzodioxol-5-ylmethyl)-N-(4-chlorobenzyl)-2-(lH-pyrrol-l-yl)benzamide
3212. N-(4-chlorobenzyl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide
3213. N-(4-chlorobenzyl)-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3214. N-(2-methoxybenzyl)-2-( 1 H-pyrrol- 1 -yl)-N- [4-(trifluoromethyl) benzyljbenzamide
3215. N-(4-methoxybenzyl)-2-( lH-pyrrol- 1 -yl)-N-[4-(trifluoromethyl) benzyl]benzamide
3216. N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethyl) benzyl]benzamide
3217. N-(3,5-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethyl) benzyl]benzamide
3218. N-(2-methoxybenzyl)-2-(lH-pyrrol-l-yl)-N-[2,4-(difluoro) benzyl]benzamide
3219. N-(2,4-difluorobenzyl)-N-(4-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3220. N-(2,4-difluorobenzyl)-N-(2,4-dimethoxybenzyl)-2-( 1 H-pyrrol- 1 -yl)benzamide
3221. N-(2,4-dichlorobenzyl)-N-(2-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3222. N-(2,4-dichlorobenzyl)-N-(3-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3223. N-(2,4-dichlorobenzyl)-N-(4-methoxybenzyl)-2-( lH-pyrrol- 1 -yl)benzamide
3224. N-(l,3-benzodioxol-5-ylmethyl)-N-(2,4-dichlorobenzyl)-2-(lH-pyrrol-l-yl)benzamide
3225. N-(2,4-dichlorobenzyl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide
3226. N-(2,4-dichlorobenzyl)-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3227. N-(2,4-dichlorobenzyl)-N-(3,5-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3228. N-(2-chloro-4-fluorobenzyl)-N-(3-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3229. N-(2-chloro-4-fluorobenzyl)-N-(4-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3230. N-(l,3-benzodioxol-5-ylmethyl)-N-(2-chloro-4-fluorobenzyl)-2-(lH-pyrrol-l-yl)benzamide
3231. N-(2-chloro-4-fluorobenzyl)-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3232. N-(2-chloro-4-fluorobenzyl)-N-(3,5-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3233. N-(2,3-difluorobenzyl)-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide 3234. N-(3-chloro-2-fluorobenzyl)-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3235. N-(3-chloro-2-fluorobenzyl)-N-(3,5-dimethoxybenzyl)-2-( 1 H-pyrrol- 1 -yl)benzamide
3236. N-[(5-chlorothien-2-yl)methyl]-N-(4-methoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3237. N-[(5-chlorothien-2-yl)methyl]-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3238. N-[(5-chlorothien-2-yl)methyl]-N-(3,5-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3239. N-(2,5-difluorobenzyl)-N-(2,4-dimethoxybenzyl)-2-(lH-pyrrol-l-yl)benzamide
3240. N-(2,4-difluorobenzyl)-N-[2-(2-fluorophenyl)ethyl]-2-(lH-pyrrol-l-yl)benzamide
3241. N-(indan-2-yl)-N-(3-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3242. N-(indan-2-yl)-N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3243. N-(indan-l-yl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethyl)benzyl]benzamide
3244. N-(2,3-dihydro-lH-inden-l-yl)-N-(4-methylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3245. N-Indan-2-yl-N-(4-methyl-benzyl)-2-pyrrol-l-yl-benzamide
3246. N-(4-chlorobenzyl)-N-(2,3-dihydro- lH-inden- 1 -yl)-2-( lH-pyrrol- 1 -yl)benzamide
3247. N-(4-chlorobenzyl)-N-(indan-2-yl)-2-(lH-pyrrol-l-yl)benzamide
3248. N-(indan-2-yl)-2-(lH-pyrrol-l-yl)-N-[4-(trifluoromethyl)benzyl]benzamide
3249. N-(2,3-dihydro-lH-inden-l-yl)-N-(3,5-dimethylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3250. N-(indan-2-yl)-N-(3,5-dimethylbenzyl)-2-(lH-pyrrol-l-yl)benzamide
3251. N-(indan-2-yl)-N-(l-naphthylmethyl)-2-(lH-pyrrol-l-yl)benzamide
3252. N-(2,3-dihydro- lH-inden- 1 -yl)-N-(2-naphthylmethyl)-2-( lH-pyrrol- 1 -yl)benzamide
3253. N-(indan-2-yl)-N-(2-naphthylmethyl)-2-(lH-pyrrol-l-yl)benzamide

Claims

What is claimed is:
1. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is a compound of the formula:
Figure imgf000201_0001
or a pharmaceutically acceptable salts thereof, wherein
- . N ^?)x
G
Ε J is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms. R and Rt independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, -CHO, -CONH2, Cι-C6haloalkyl, or
Ci-Cβ haloalkoxy; ii) Cι-C6alkyl, Cι-C6alkenyl, Cι-C6alkynyl, Cι-C6 alkoxy, C3-C7cycloalkyl, (C3-C cycloalkyl)Cι-C4alkyl, mono- or di-Cι-C6alkylamino, mono- or di- - C6alkylaminoCι-C6alkyl, mono- or di-Cι-C6alkylcarboxamide, Cι-C6alkoxycarbonyl, -NHSOnCι-C6alkyl, -SOnN(Cι-C6alkyl) (Cι-C6alkyl), or phenyl-SOn-, each of which is optionally substituted, wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylCi- carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heteroaryl - carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from Cι-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-
C7cycloalkyl(Cι-C4alkyl), benzyl and Ci-Cδhaloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, Cι-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, Cι-C7alkoxy, Cι-C7alkylamino, C3-C7cycloalkyl(Cι-C4alkyl), benzyl, Cι-C6haloalkyl, and Cι-C6haloalkoxy; R3 is hydrogen, Cι-C6alkyl, C2-C6alkenyl, hydroxyCι-C6alkyl, CrC6haloalkyl, C3- C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, or phenyl(Cι-C4alkyl); or when x is 0, Ri and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R is i) hydrogen; ii) Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C cycloalkyl, C3-C7cycloalkenyl, (C3-
C7cycloalkyl)Cι-C4alkyl, (C3-C7cycloalkenyl)Cι-C4alkyl, or hexahydro-1,3- benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylCι-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylC1-C4alkyl, wherein the aryl portion is fused to a 5- to 7- membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(Co-C4alkyl); vi) optionally substituted heteroarylC1-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(Co-C alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and Cι-C6alkyl; z is 1, 2, or 3; Ari is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(Cι-C4alkyl), C3-
C cycloalkenyl, C3-C7cycloalkenyl(Cι-C4alkyl), or hexahydro-l,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.
2. A composition according to claim 1, wherein x is 0, A and G are carbon, and E is nitrogen.
3. A composition according to claim 2, wherein:
Ar-. is phenyl, substituted with from 0 to 3 substituents independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy; and
Ri is phenyl substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, -CONH2, -OC(=O)CH3, -COOH, methylthio, ethylthio, and -SO2CH3.
4. A composition according to claim 3, wherein z is 1, R2 is C3-C5alkyl and R3 is hydrogen or methyl.
5. A composition according to claim 4, wherein i is: i) l,3-benzodioxol-5-ylmethyl or 2,3-dihydro- l,4-benzodioxin-6-ylmethyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, methyl and methoxy; or ii) benzyl substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, -CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, -OCF2CHF2, -CONH2, -C(=O)OCH3, -OC(=O)CH3, -COOH, methylthio, ethylthio, -SO2NH2, and -SO2CH3.
6. A composition according to claim 5, wherein R5 is hydrogen or methyl;
R6 is hydrogen; and
Ar2 is: i) benzo[l,3]dioxole or 2,3-dihydro-benzo[l,4]dioxine, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, methyl and methoxy; or ii) phenyl substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, -CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, -OCF2CHF2, -CONH2, -C(=O)OCH3, -OC(=O)CH3, -COOH, methylthio, ethylthio, -SO2NH2, and -SO2CH3
7. A composition according to claim 1, wherein the C5a antagonist exhibits C5a antagonist activity with an IC50 of less than 100 nM in a standard assay for C5a antagonist activity.
8. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is an NSAID.
9. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a cyclo-oxygenase enzyme inhibitor.
10. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is an inhibitor of the cyclo-oxygenase 2 enzyme.
11. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a gold compound or a salicylate.
12. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is a steroid.
13. A composition according to claim 12, wherein C5a receptor-inactive therapeutic agent is a corticosteroid.
14. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is methotrexate or leflunomide.
15. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is a TNF antagonist.
16. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a cholesterol lowering agent.
17. A composition according to claim 16, wherein the cholesterol lowering agent is an HMG-CoA reductase inhibitor.
18. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a platelet aggregation inhibitor.
19. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is an anti-hypertensive agent.
20. A composition according to claim 19, wherein the antihypertensive agent is an adrenergic receptor stimulator.
21. A composition according to claim 19, wherein the antihypertensive agent is an alpha/beta adrenergic receptor antagonist, beta adrenergic receptor antagonist, ACE inhibitor, angiotensin II receptor antagonist, calcium channel blocker, diuretic, or periphereal vasodilator.
22. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is selected from: l-(l-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole; l-(l-Butyl)-2-(2-methoxyphenyl)-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl) aminomethylimidazole; l-(l-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole ; l-(l-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino- methylimidazole; l-(l-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino- methylimidazole; l-(l-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl]-N-phenylmethyl)amino methylimidazole; l-(l-Butyl)-2-(3-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole ; l-(l-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino- methylimidazole; l-(l-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)- aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-{ l-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)amino} ethylimidazole; l-(l-Pentyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole ; Bis-benzo[l,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)amine; Benzo[l,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-JH-imdiazol-
4-ylmethyl] -amine ; 4-({Benzyl-[l-(3-butyl-2,5-diphenyl-5H-imidazol-4-yl)-ethyl)-amino}-methyl)benzamide; 4-{[Benzyl-(3-butyl-2,5-diphenyl-5H-imidazol-4-ylmethyl)-amino]-methyl}3-chloro-phenol; 4-({[l-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexymethyl-amino}-methyl)- phenol; 4-{[Benzyl-(3-butyl-2,5-diphenyl--?H-imidazol-4-ylmethyl)-amino]-methyl}benzamide; l-(l-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[l-(S)-phenylethyl]-N-phenylmethyl)aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[l-(R)-phenylethyl]-N-phenylmethyl)aminomethylimidazole l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dichlorophenyl]methyl)aminomethylimidazole; 1 -( 1 -Butyl)-2-phenyl-5 -(N,N-di[3 ,4-methylenedioxyphenylmethyl] ) aminomethylimidazole ; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- methoxyphenylmethyl])-aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{ l- propyl}phenylmethyl])aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dichlorophenylethyl])aminomethylimidazole; 1 -( 1 -Butyl)-2-phenyl-5 -(N- [3 ,4-methylenedioxyphenyl]methyl-N- [4- nitrophenylmethyl])aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{l-propyloxyJ phenylmethyl] )aminomethylimidazole ; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[quinol-6-ylmethyl])- aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3- dichlorophenylmethyl])-aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dimethylphenylmethyl])-aminomethylimidazole; 1 -( 1 -Butyl)-2-phenyl-5 -(N- [3 ,4-methylenedioxyphenyl]methyl-N- [indan-2-yl] )- aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-phenylethyl])amino- methylimidazole; l-(l-Propyl)-2-phenyl-5-(N-[l,4-benzodioxan-6-ylmethyl]-N-phenylmethyl)aminomethyl- imidazole; (1 -Butyl)-2-phenyl-5 -(N- [3 ,4-methylenedioxyphenylmethyl] -N- phenylmethyl)aminomethyl-imidazole; ■( 1 -Butyl)-2-phenyl-5-(N- [3 ,4-methylenedioxyphenylmethyl] -N- ethyl)aminomethylimidazole; (1 -Butyl)-2-phenyl-5-(N-[3 ,4-methylenedioxyphenylmethyl]-N-[ 1 -propyl])aminomethyl- imidazole; (1 -Butyl)-2-phenyl-5-(N-[3 ,4-methylenedioxyphenylmethyl] -N-[ 1 -butyl])aminomethyl- imidazole; (l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cycloheptylmethyl)amino- methylimidazole ; (l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-isobutyl)aminomethyl- imidazole; (l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- cyclopentylethyl])amino-methylimidazole; (l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3- cyclopentylpropyl])amino-methylimidazole; (1 -Butyl)-2-phenyl-5-(N- [3 ,4-methylenedioxyphenylmethyl] -N- [ 1 -n-octyl] )aminomethyl- imidazole; -(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopropylmethyl)amino- methylimidazole; ■(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopentylmethyl)amino- methylimidazole; ■(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclohexylmethyl)amino- methylimidazole; -(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t- amyl])aminomethylimidazole; -(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l-{3- methylJbutyl)]amino-methylimidazole; -(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l-{2,2-dimethylJbutyl]) aminomethylimidazole; •(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- methyl)aminomethylimidazole; -(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- thiophenylmethyl])amino-methylimidazole;
-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5-ylmethyl])amino- methylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[{l-methylindol-5- yl}methyl])aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2- chlorophenyl] -methyl)aminomethylimidazole ; l-(l-Butyl)-2-(3-fluoroρhenyl)-5-(l-[N-{2-chloro-4-hydroxyphenyl}methyl-N- phenylmethyl] ) aminoethylimidazole ; l-(l-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3-dihydrobenzo[b]furan-
5-yl]methyl)aminomethylimidazole; l-Butyl-2-(4-fluorophenyl)-5-(l-[N-{3,4-methylenedioxyphenyl}methyl-N-phenylmethyl]- amino)ethylimidazole; l-(l-Butyl)-2-(2-thienyl)-5-(N-[3,4-methylenedioxyphenyl]methyl-N-phenylmethyl] aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N-phenylmethyl)amino- methylimidazole ; l-(l-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminomethyl- imidazole; l-(l-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole; l-(l-Butyl)-2-phenyl-5-(N-[4-methylaminophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole; l-(l-Butyl)-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl]-N-phenylmethyl)aminomethyl- imidazole); l-(l-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N- phenylmethyl)aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenylmethyl]-N- phenylmethyl)aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-[3,4-difluorophenylmethyl]-N- phenylmethyl)aminomethylimidazole; l-(l-Butyl)-2-phenyl-5-(N-(benzo[b]thiophen-5-ylmethyl)-N-phenylmethyl)aminomethyl- imidazole; and l-(l-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole.
23. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is selected from: N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-[l-(3-methylphenyl)-3,4-dihydroisoquinolin- 2(lH)-yl] acetamide;
N-benzyl-N-(2,3 -dihydro- 1 H-indan-2-yl)-2- [ 1 -(4-methylphenyl)-3 ,4-dihydroisoquinolin- 2( 1 H)-yl] acetamide;
N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-2-[l-(4-methoxyphenyl)-3,4-dihydroisoquinolin- 2( 1 H)-yl] acetamide;
N- [(5 -bromo-2-phenyl- 1 , 3-thiazol-4-yl)methyl] -N-isopentyl-2-( 1 H-pyrrol- 1 -yl)benzamide ;
N-butyl-N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-2-(lH-pyrrol-l-yl)benzamide;
N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-N-isobutyl-2-(lH-pyrrol-l-yl)benzamide;
N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-N-isopentyl-2-(lH-pyrrol-l-yl)benzamide;
N-[(5-chloro-2-phenyl-l,3-thiazol-4-yl)methyl]-N-cyclopentyl-2-(lH-pyrrol-l-yl)benzamide;
8-bromo-N-[(2-phenylquinolin-4-yl)methyl]-N-propyl-l-naphthamide;
N-(2-chlorobenzyl)-N-(2-phenylethyl)-9H-fluorene-4-carboxamide;
2-(2-iodophenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide;
2-(2-phenoxyphenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide;
2-(2-methoxyphenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide;
2-(2-bromophenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide;
N-benzyl-N-[2-(2-chlorophenyl)ethyl]-9H-fluorene-4-carboxamide;
N-benzyl-N-(3-phenylbutyl)-9H-fluorene-4-carboxamide;
N-benzyl-N-[2-(4-chlorophenyl)ethyl]-9H-fluorene-4-carboxamide;
N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-l,l'-biphenyl-2-carboxamide;
N-benzyl-N-(2,3-dihydro-lH-indan-2-yl)-9H-fluorene-4-carboxamide;
N-benzyl-N-[2-(4-fluorophenyl)ethyl]-9H-fluorene-4-carboxamide;
N-benzyl-N-[2-(4-methoxyphenyl)ethyl]-9H-fluorene-4-carboxamide;
N-benzyl-N-[2-(4-methoxyphenyl)-l-methylethyl]-9H-fluorene-4-carboxamide;
2-chloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methylJ-N-(4- methoxybenzyl)benzamide;
N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-2,5-difluoro-N-(4- methoxybenzyl)benzamide; N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5- yl]methyl } -2,5-difluorobenzamide;
5-chloro-N-{ [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -2- methoxy-N-(4-methoxybenzyl)benzamide;
5-chloro-N-(cyclohexylmethyl)-N- { [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- 1 H-imidazol-5- yl]methyl } -2-methoxybenzamide;
N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-(trifluoromethyl)benzamide;
N-benzyl-2,5-dichloro-N- { [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5- yl]methyl}benzamide;
2,5-dichloro-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)benzamide;
2,5-dichloro-N-(cyclohexylmethyl)-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH- imidazol-5-yl]methyl Jbenzamide;
2-bromo-N-{ [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl } -N-(4- methoxybenzyl)benzamide;
N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(4- methoxybenzyl)-2-(2-phenylethyl)benzamide;
N-{ [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- 1 H-imidazol-5-yl]methyl } -2-iodo-N-(4- methoxybenzyl)benzamide;
3-chloro-N- { [ 1 -(2,3-dihydro- lH-indan-2-yl)-2-phenyl- lH-imidazol-5-yl]methyl }-2,6- dimethoxy-N-(4-methoxybenzyl)benzamide; and
2-bromo-N-{[l-(2,3-dihydro-lH-indan-2-yl)-2-phenyl-lH-imidazol-5-yl]methyl}-5- methoxy-N-(4-methoxybenzyl)benzamide.
24. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is selected from: Ethyl 4-(3- { butyl [(4-chloro-2-phenyl- 1 -propyl-1 H-imidazol-5- yl)methyl] amino }propyl)benzoate; Ethyl 4-[3-(butyl{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl J amino)propyl]benzoate; 4-{3-[[(l-Butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin- 6-ylmethyl)amino]propyl Jbenzoic acid; 4-[3-(Butyl{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl J amino)propyl]benzoic acid; methyl (4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetate; methyl 2-(4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}phenyl)propanoate; methyl 2-(4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methylJphenyl)-2-methylpropanoate; methyl (3-{ [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l ,4- benzodioxin-6-ylmethyl)amino]methylJphenyl)acetate; (4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jphenyl)acetic acid; 2-(4-{ [[( 1 -butyl-4-chloro-2-phenyl- lH-imidazol-5-yl)methyl] (2,3-dihydro- 1 ,4-benzodioxin-
6-ylmethyl)amino]methyl}phenyl)propanoic acid; 2-(4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-
6-ylmethyl)amino]methyl }phenyl)-2-methylpropanoic acid; (3-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl }phenyl)acetic acid; N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan- 1 -amine ; 4-[(butyl{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl J amino)methyl]benzenesulfonamide; 4-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl]methyl } (isopentyl)amino]methyl Jbenzenesulfonamide; 4-{[[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzenesulfonamide; N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl } -N-[(3-chloro- 1 H-indol-
5 -y l)methy 1] -3 -methylbutan- 1 -amine ; 5-{ [{ [l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5- yl] methyl } (isopentyl)amino]methyl } - 1 H-indole-3-carbonitrile ; 4-{[{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methylJ(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl}benzenesulfonamide; N- { [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl J -N-(quinoxalin-6- ylmethyl)butan- 1 -amine ;
5-(5-{butyl[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]amino}pentyl)isoxazol-3- ol; methyl [[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-
6-ylmethyl)amino](phenyl)acetate; N-[(l-butyl-2-phenyl-4-vinyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine; methyl 4-{ [[(l-butyl-2-phenyl-4- vinyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl) amino] methyl } benzoate ; N-[(l-butyl-4-phenyl-2-vinyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine; N- [( 1 -butyl-4-ethyl-2-phenyl- 1 H-imidazol-5-yl)methyl] -N-(2, 3 -dihydro- 1 ,4-benzodioxin-6- ylmethyl)-N-(3-ethoxybenzyl)amine; methyl 4-{ [[(l-butyl-4-ethyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoate; (lS)-N-(l,3-benzodioxol-5-ylmethyl)-l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N- methylpentan- 1 -amine; N-[(l-butyl-4-chloro-2-phenyl-lH-imidazol-5-yl)methyl]-N-(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)-N-(quinoxalin-6-ylmethyl)amine; 4-{[[(l-butyl-2-phenyl-4-vinyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid; N-{l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]ethyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)butan-l-amine; N-{l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]ethylJ-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-3-methylbutan-l-amine; N-{l-[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]ethyl}-N-(lH-indol-5- ylmethyl)butan- 1 -amine ; N-{ [ 1 -butyl-4-chloro-2-(2-methylphenyl)- lH-imidazol-5-yl]methyl J -3-methyl-N-[(2-methyl-
1 H-indol-5 -yl)methyl]butan- 1 -amine; l-(l-butyl-2-phenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-methylpentan-l-amine; 4-{[[(l-butyl-4-ethyl-2-phenyl-lH-imidazol-5-yl)methyl](2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]methyl Jbenzoic acid; N-{[4-chloro-l-(ethoxymethyl)-2-phenyl-lH-imidazol-5-yl]methyl}-N-(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine; l-(4-chloro-2-phenyl-lH-imidazol-5-yl)-N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-N-(3- ethoxybenzyl)methanamine ;
N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-methyl-l,2,3,4- tetrahydronaphthalen- 1 -amine ; l-(l-butyl-2,4-diphenyl-lH-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(l,2,3,4- tetrahydroquinolin-6-ylmethyl)methanamine; l-[l-butyl-2-phenyl-4-(trifluoromethyl)-lH-imidazol-5-yl]-N-(cyclohexylmethyl)-N-(l,2,3,4- tetrahydroquinolin-6-ylmethyl)methanamine; N-{[4-bromo-l-butyl-2-(2,6-diethylphenyl)-lH-imidazol-5-yl]methylJ-N-methyl-l,2,3,4- tetrahydronaphthalen- 1 -amine ; methyl 4-{ [{ [l-butyl-4-(4-methylphenyl)-2-phenyl-lH-imidazol-5-yl]methyl}(2,3-dihydro-
1 ,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate; methyl 4-{ [{ [l-butyl-4-(3-fluorophenyl)-2-phenyl-lH-imidazol-5-yl]methyl J(2,3-dihydro- l,4-benzodioxin-6-ylmethyl)amino]methyl Jbenzoate; 4- { [ { [ 1 -butyl-4-(4-methylphenyl)-2-phenyl- 1 H-imidazol-5-yl] methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid; 4- { [ { [ 1 -butyl-4-(3-fluorophenyl)-2-phenyl- lH-imidazol-5-yl]methyl } (2,3-dihydro- 1 ,4- benzodioxin-6-ylmethyl)amino]methyl Jbenzoic acid; N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(3- methoxybenzyl)butan-l-amine; N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(3- ethoxybenzyl)butan-l-amine; N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(lH-indol-5- ylmethyl)-3,3-dimethylbutan-l-amine; 6-[(butyl{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}amino)methyl]-
3,4-dihydroquinolin-2(lH)-one; and N-{[l-butyl-4-chloro-2-(2-methylphenyl)-lH-imidazol-5-yl]methyl}-N-(l,2,3,4- tetrahydroquinolin-6-ylmethyl)butan- 1 -amine.
25. A pharmaceutical composition comprising a therapeutically effective amount of a C5a antagonist, a therapeutically effective amount of a C5a receptor-inactive therapeutic agent and a physiologically acceptable carrier, wherein the C5a antagonist is a compound of the formula:
Figure imgf000213_0001
or a pharmaceutically acceptable salts thereof, wherein
Figure imgf000214_0001
is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms.
R and Ri independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, -CHO, -CONH2, Cι-C6haloalkyl, or
Cι-C6 haloalkoxy; ii) Cι-C6alkyl, Ci-Cόalkenyl, Cι-C6alkynyl, Cι-C6 alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, mono- or di-Cι-C6alkylamino, mono- or di-Ci- C6alkylaminoCι-C6alkyl, mono- or di-Ci-Cβalkylcarboxamide, Ci-Cδalkoxycarbonyl, -NHSOnCι-C6alkyl, -SOnN(Cι-C6alkyl) (Cι-C6alkyl), or phenyl-SOn-, each of which is optionally substituted, wherein n is 0, 1, or 2; or iii) naphthyl, phenyl, phenylCi- carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heteroarylCι-C carbhydryl, each of which is optionally substituted;
If E is nitrogen, R2 is chosen from Cι-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3- C7cycloalkyl(C!-C4alkyl), benzyl and Ci-Cβhaloalkyl;
If E is carbon, R2 is chosen from halogen, hydroxy, Cι-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, Cι-C7alkoxy, Cι-C7alkylamino, C3-C7cycloalkyl(Cι-C alkyl), benzyl, Cι-C6haloalkyl, and Cι-C6haloalkoxy;
R3 is hydrogen, Cι-C6alkyl, C2-C6alkenyl, hydroxyCι-C6alkyl, Cι-C6haloalkyl, C3~ C7cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, or phenyl(Cι-C alkyl); or when x is 0, Ri and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl;
R4 is i) hydrogen; ii) Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-
C7cycloalkyl)Cι-C4alkyl, (C3-C7cycloalkenyl)Cι-C4alkyl, or hexahydro-1,3- benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylCι-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylCι-C4alkyl, wherein the aryl portion is fused to a 5- to 7- membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(Co-C4alkyl); vi) optionally substituted heteroarylCι-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(Co-C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and Cι-C6alkyl; z is 1, 2, or 3; Ari is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(Cι-C4alkyl), C3-
C7cycloalkenyl, C3-C7cycloalkenyl(Cι-C4alkyl), or hexahydro-l,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.
26. A pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is an injectible solution, a tablet, a capsule, or a pill.
27. A pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is an inhalable preparation.
28. A pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is a topical preparation.
29. A package comprising a pharmaceutical composition according to claim 25 and instructions for using the pharmaceutical composition to treat a patient suffering from a condition with a pathogenic inflammatory component.
30. A package according to claim 29, wherein the condition is an autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burn, traumatic CNS or spinal cord injury, rheumatoid arthritis, psoriasis, asthma, or cardio or cerebrovascular disease.
31. A package comprising a pharmaceutical composition according to claim 25 and instructions for using the pharmaceutical composition to reduce the risk of myocardial infarction or stroke in a patient at risk for myocardial infarction or stroke.
32. A method for treating a condition with a pathogenic inflammatory component in a patient, comprising administering to a patient a therapeutically effective amount of a C5a receptor antagonist and a therapeutically effective amount of a C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is a compound of the formula:
Figure imgf000216_0001
or a pharmaceutically acceptable salts thereof, wherein
Figure imgf000216_0002
is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms.
R and Ri independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, -CHO, -CONH2, Cι-C6haloalkyl, or
Cι-C6 haloalkoxy; ii) Cι-C6alkyl, Cι-C6alkenyl, Cι-C6alkynyl, Cι-C6 alkoxy, C3-C7cycloalkyl,
(C3-C7cycloalkyl)Cι-C alkyl, mono- or di-Cι-C6alkylamino, mono- or di-C
C6alkylaminoCι-C6alkyl, mono- or di-Ci-Cδalkylcarboxamide, Cι-C6alkoxycarbonyl, -NHSOnCι-C6alkyl, -SOnN(Cι-C6alkyl) (Cι-C6alkyl), or phenyl-SOn-, each of which is optionally substituted, wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylCi-Qcarbhydryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heteroarylCi- carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from Cι-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-
C7cycloalkyl(Cι-C4alkyl), benzyl and Cι-C6haloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, Cι-C7alkyl, C2-C7alkenyl, C2-C7alkynyl,
Cι-C7alkoxy, Cι-C7alkylamino, C3-C cycloalkyl(Cι-C4alkyl), benzyl, Cι-C6haloalkyl, and Cι-C6haloalkoxy; R3 is hydrogen, Ci-Cβalkyl, C2-C6alkenyl, hydroxyCι-C6alkyl, Cι-C6haloalkyl, C3-
C7cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, or phenyl(Cι-C4alkyl); or when x is 0, Ri and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R4 is i) hydrogen; ii) Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-
C7cycloalkyl)Cι-C4alkyl, (C3-C7cycloalkenyl)Cι-C4alkyl, or hexahydro-1,3- benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylCι-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylCι-C4alkyl, wherein the aryl portion is fused to a 5- to 7- membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(Co-C4alkyl); vi) optionally substituted heteroarylCι-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic (Co-C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and Cι-C6alkyl; z is 1, 2, or 3; Ari is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(Cι-C4alkyl), C3- C7cycloalkenyl, C3-C7cycloalkenyl(Cι-C4alkyl), or hexahydro-l,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.
33. A method according to claim 32, wherein the disorder is an autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burn, traumatic CNS or spinal cord injury, rheumatoid arthritis, asthma, psoriasis, or cardio- or cerebrovascular disease.
34. A method according to claim 32, wherein the patient is a human.
35. A process for preparing a pharmaceutical composition, which comprises combining a therapeutically effective amount of a C5a antagonist, a therapeutically effective amount of a therapeutic agent that is not a C5a antagonist, and a pharmaceutically acceptable carrier, wherein the C5a antagonist is a compound of the formula:
Figure imgf000218_0001
or a pharmaceutically acceptable salts thereof, wherein
Figure imgf000218_0002
is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl rin system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms. R and Ri independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, -CHO, -CONH2, Cι-C6haloalkyl, or
Cι-C6 haloalkoxy; ii) Ci-Cβalkyl, C!-C6alkenyl, Cι-C6alkynyl, Cι-C6 alkoxy, C -C7cycloalkyl,
(C3-C7cycloalkyl)Cι-C4alkyl, mono- or di-Ci-Cβalkylamino, mono- or di-Ci-
C6alkylaminoCι-C6alkyl, mono- or di-Cι-C6alkylcarboxamide, Cι-C6alkoxycarbonyl,
-NHSOnCι-C6alkyl, -SOnN(Cι-C6alkyl) (Ci- alkyl), or phenyl-SOn-, each of which is optionally substituted, wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylCι-C4carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heteroarylCι-C4carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from Cι-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-
C7cycloalkyl(Cι-C alkyl), benzyl and Cι-C6haloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, Cι-C alkyl, C2-C7alkenyl, C2-C alkynyl,
Cι-C7alkoxy, Cι-C7alkylamino, C3-C7cycloalkyl(Cι-C4alkyl), benzyl, Cι-C6haloalkyl, and Cι-C6haloalkoxy; R3 is hydrogen, Cι-C6alkyl, C2-C6alkenyl, hydroxyCι-C6alkyl, Ci-Cδhaloalkyl, C3-
C7cycloalkyl, (C3-C7cycloalkyl)Cι-C4alkyl, or phenyl(Cι-C4alkyl); or when x is 0, Ri and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R-ι is i) hydrogen; ii) Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-
C7cycloalkyl)Cι-C4alkyl, (C3-C7cycloalkenyl)Cι-C4alkyl, or hexahydro-1,3- benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylCι-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylCι-C4alkyl, wherein the aryl portion is fused to a 5- to 7- membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(Co- alkyl); vi) optionally substituted heteroarylCι-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(Co-C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon;
R5 and R6 are independently chosen from hydrogen and Cι-C6alkyl; z is 1, 2, or 3;
Ari is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(Cι-C alkyl), C3-
C7cycloalkenyl, C3-C7cycloalkenyl(Cι-C4alkyl), or hexahydro-l,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.
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US20040014782A1 (en) 2004-01-22
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