NK1 receptor antagonists

BACKGROUND OF THE INVENTION

[0001] The neurokinins are a family of mammalian neuropeptides that are involved with numerous biological activities such as pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system, and neurogenic inflammation. One such neuropeptide known as substance P is widely distributed throughout the peripheral and central nervous system of mammals, and is known to mediate a variety of biological actions via interaction with three neurokinin (NK or tachykinin) receptor types known as NK1, NK2, and NK3.

[0002] Substance P binds with higher affinity to the NK1 receptor than it does to the other receptors. Accordingly, compounds capable of antagonizing the effects of substance P at the NK1 receptor are useful for treating and controlling disorders mediated by such interactions, including disorders such as anxiety, pain, depression, schizophrenia, and emesis.

[0003] Since 1991, a number of high-affinity nonpeptide tachykinin antagonists have been reported; for a review see Sprecher A, et al (IDrugs, 1:73-91, 1998).

[0004] U.S. Pat. Nos. 5,594,022 and 5,716,979 describe nonpeptides that are relatively specific NK1 antagonists.

[0005] Since substance P mediate various biological actions, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation via an interaction with NK receptors, preferably NK1, thus compounds capable of antagonising the effects of substance P at NK1 receptors will be useful in treating or preventing a variety of: brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchitis and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.

[0006] The compounds of the invention, NK1 receptor antagonists, are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.

SUMMARY OF THE INVENTION

[0007] This invention provides NK1 receptor antagonists characterized as non-peptide acetamide derivatives. The compounds of the invention differ from those of U.S. Pat. Nos. 5,716,979 or 5,594,022 in that the compounds of Formula I below are not (N-substituted aryl-methyl) carbamates, i.e. they do not have a —O—C(O)—N— link in the backbone; certain final products being more stable than known compounds, they should show improved oral bioavailability and improved CNS penetration. The invention compounds are defined by Formula I:

[0008] and the pharmaceutically acceptable salts thereof, wherein

[0009] ▪, &Circlesolid;, and ▴ indicate all stereoisomers,

[0010] R is:

[0011] pyridyl,

[0012] thienyl,

[0013] furyl,

[0014] pyrrolyl,

[0015] pyrazolyl,

[0016] quinolyl,

[0017] isoquinolyl,

[0018] naphthyl,

[0019] indolyl,

[0020] benzofuryl,

[0021] benzothiophenyl,

[0022] benzimidazolyl, and

[0023] benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, —CF3, carboxy, sulfonamide, or nitro;

[0024] R can also be:

[0025] R1 and R2 are each independently H or C1-C4 alkyl;

[0026] m is an integer from 0 to 3;

[0027] X is NHCONH, or NR8 where R8 is H or C1-C4 alkyl;

[0028] R3 is hydrogen or C1-C4 alkyl;

[0029] n is an integer from 1 to 2;

[0030] R4 is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy or formyl;

[0031] R9 is hydrogen or C1-C4 alkyl;

[0032] R5 and R7 are each independently hydrogen or (CH2)pR10 where:

[0033] P is an integer of 1 to 3, and

[0034] R10 is H, CH3, CN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2;

[0035] q is an integer of 0 to 4;

[0036] R6 is

[0037] phenyl,

[0038] pyridyl,

[0039] thienyl,

[0040] furyl,

[0041] pyrrolyl,

[0042] pyrazolyl,

[0043] imidazolyl,

[0044] quinolyl,

[0045] isoquinolyl,

[0046] naphthyl,

[0047] indolyl,

[0048] benzofuryl,

[0049] benzothiophenyl,

[0050] benzimidazolyl, or

[0051] benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or

[0052] trisubstituted by

[0053] alkyl,

[0054] hydroxy,

[0055] alkoxy,

[0056] halogen,

[0057] CF3,

[0058] NO2,

[0059] N(CH3)2,

[0060] OCF3,

[0061] SONH2,

[0062] NH2,

[0063] CONH2,

[0064] CO2CH3, or

[0065] CO2H,

[0066] or R6 is:

[0067] straight alkyl of from 1 to 3 carbons,

[0068] branched alkyl of from 3 to 8 carbons,

[0069] cycloalkyl of from 5 to 8 carbons or

[0070] heterocycloalkyl,

[0071] each of which can be substituted with up to one or two substituents selected from

[0072] OH,

[0073] CO2H,

[0074] N(CH3)2,

[0075] NHCH3 and

[0076] CH3; and

[0077] R5 and R6, when joined by a bond, can form a ring;

[0078] R6 is also

[0079] where X1 represents the rest of the molecule.

[0080] Prodrugs of the above are also contemplated such as would occur to one skilled in the art; see Bundgaard, et al, Acta Pharm Suec, 1987; 24: 233-246. For example, a suitable moiety may be attached to a nitrogen of the linker X, to the nitrogen of the NR9 linker, or that of an indolyl radical of R4.

[0081] Preferred compounds of the invention are those of Formula I above wherein

[0082] R is

[0083] pyridyl,

[0084] thienyl,

[0085] furyl,

[0086] quinolyl

[0087] isoquinolyl

[0088] naphthyl,

[0089] indolyl,

[0090] benzofuryl,

[0091] benzothiophenyl,

[0092] benzimidazolyl,

[0093] benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or

[0094] trisubstituted by alkyl, hydroxy, alkoxy, halogen, or CF3,

[0095] m is an integer from 1 to 3;

[0096] R6 is

[0097] phenyl

[0098] pyridyl,

[0099] thienyl,

[0100] furyl,

[0101] pyrrolyl,

[0102] quinolyl,

[0103] isoquinolyl,

[0104] naphthyl,

[0105] indolyl,

[0106] benzofuryl,

[0107] benzothiophenyl,

[0108] benzimidazolyl, or

[0109] benzoxazolyl,

[0110] wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by

[0111] alkyl,

[0112] hydroxy,

[0113] alkoxy,

[0114] halogen,

[0115] CF3,

[0116] NO2

[0117] N(CH3)2,

[0118] OCF3,

[0119] SONH2,

[0120] NH2,

[0121] CONH2,

[0122] CO2CH3, or

[0123] CO2H,

[0124] cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from OH,

[0125] CO2H,

[0126] N(CH3)2,

[0127] NHCH3 and

[0128] CH3; and

[0129] R5 and R6 when joined by a bond can form a ring.

[0130] More preferred compounds of the invention are those of Formula I above wherein

[0131] R is

[0132] pyridyl,

[0133] thienyl,

[0134] furyl,

[0135] quinolyl,

[0136] naphthyl,

[0137] benzofuryl,

[0138] benzothiophenyl,

[0139] benzimidazolyl, or

[0140] benzoxazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or —CF3,

[0141] R1 and R2 are each H;

[0142] m is an integer from 1 to 3;

[0143] X is NR8 or NHCONH, where R8 is H or methyl;

[0144] R9 is hydrogen or alkyl of 1 to 3 carbon atoms;

[0145] R6 is

[0146] phenyl,

[0147] pyridyl,

[0148] thienyl,

[0149] furyl,

[0150] pyrrolyl,

[0151] benzimidazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by

[0152] alkyl,

[0153] hydroxy,

[0154] alkoxy,

[0155] halogen,

[0156] CF3,

[0157] NO2,

[0158] N(CH3)2;

[0159] cyclohexyl or heterocycloalkyl, with up to one or two substituents selected from

[0160] OH,

[0161] CO2H,

[0162] N(CH3)2,

[0163] NHCH3 and

[0164] CH3; and

[0165] R5 and R6, when joined by a bond, can form a ring.

[0166] The most preferred compounds of the invention have Formula II:

[0167] wherein:

[0168] R is

[0169] benzofuryl,

[0170] benzoxazolyl,

[0171] 3-cyanophenyl,

[0172] 3-nitrophenyl, or

[0173] 3-trifluoromethylphenyl;

[0174] R3 is hydrogen or methyl;

[0175] X is NH or NHCONH;

[0176] R5 and R7 independently are hydrogen or CH2R10, where R10 is H, CH3 or OH;

[0177] R6 is

[0178] phenyl,

[0179] substituted phenyl,

[0180] pyridyl, or,

[0181] cyclohexyl;

[0182] and the pharmaceutically acceptable salts thereof

[0183] Most preferred compounds of the invention are:

[0184] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0185] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)]

[0186] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3 -yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R—(R*,R*)]

[0187] 2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R—(R*,R*)]

[0188] [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide

[0189] [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide

[0190] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R—(R*,S*)]

[0191] 2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0192] 3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0193] 3-(1 H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)]

[0194] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)]

[0195] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0196] 2-[(Benzoxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide

[0197] 2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)], and

[0198] 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)].

[0199] The invention additionally provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient therefor. Especially preferred formulations comprise a compound of Formula II. The invention also provides a method for antagonizing NK1 receptors in a mammal comprising administering to a mammal an NK1 binding amount of a compound of Formula I. The invention further provides a method for treating a CNS disorder including pain, anxiety, depression, obesity, or schizophrenia; an allergic or inflammatory disease; a gastrointestinal disorder; a vascular disorder; or a neuropathological disorder including emesis; comprising administering to a mammal in need of treatment an effective amount of a compound of Formula I. An especially preferred method of treatment utilizes a compound of Formula II.

DETAILED DESCRIPTION OF THE INVENTION

[0200] Throughout this application, the following abbreviations have the meanings listed below:

1Boctertiary butyloxycarbonylDCEdichloroethaneDCMdichloromethaneHBTUO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphateDIPEAN,N-diisopropylethylamineDMFN,N-dimethylformamideDCC1,3-dicyclohexylcarbodiimideEEDQ2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolineEtOAcethyl acetateEtOHethanolMeOHmethanolKOHpotassium hydroxideDIBALDiisobutylaluminium hydrideNMMN-methyl-morpholineNMRnuclear magnetic resonanceTrpTryptophan

[0201] The term “alkyl” means a straight or branched hydrocarbon having from one to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyl, and the like unless stated specifically otherwise.

[0202] The term “cycloalkyl” means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl except as otherwise stated.

[0203] The term “alkoxy” means an alkyl as described above attached through an oxygen atom.

[0204] The term “halogen” is chlorine, bromine, fluorine or iodine.

[0205] The ring formed by joining R5 and R6 is from 4 to 6 atoms total and is unsubstituted.

[0206] The compounds of Formula I are capable of forming pharmaceutically acceptable acid addition salts. All of these forms are within the scope of the present invention.

[0207] Pharmaceutically acceptable acid addition salts of the compound of Formula I include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like as well as the salts derived from nontoxic organic acids, such as the aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandalate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like. For example, see Berge S. M., et al., Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) incorporated herein by reference.

[0208] The acid addition salts of the compounds of Formula I are prepared by contacting the free base form of the compound with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably, a compound of Formula I can be converted to an acidic salt by treating an aqueous solution of the desired acid, such that the resulting pH is less than four. The solution can be passed through a C18 cartridge to absorb the compound, washed with copious amounts of water, the compound eluted with a polar organic solvent such as, for example methanol, acetonitrile, aqueous mixtures thereof, and the like, and isolated by concentrating under reduced pressure followed by lyophilisation. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for the purpose of the present invention.

[0209] Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

[0210] Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof

[0211] The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. In addition, the compounds of the present invention can be administered by inhalation, for example intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of the compound of Formula I.

[0212] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, pills, tablets, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavouring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0213] In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component.

[0214] In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0215] The powders and tablets preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0216] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.

[0217] Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0218] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents as desired.

[0219] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and other well-known suspending agents.

[0220] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents and the like.

[0221] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0222] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0223] In therapeutic use, the highly selective and competitive antagonists of the NK1 receptor and compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg/kg to about 500 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 100 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller doses, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0224] The compounds of Formula I can be prepared by any several synthetic processes well known to those skilled in the art of organic chemistry.

[0225] In a typical synthesis, a carboxylic acid of the formula

[0226] is coupled to an amine of the formula

[0227] The coupling can be achieved by routine acylation, e.g. by converting the acid to an acid halide, followed by reaction with the amine, or by utilizing a common coupling reagent such as 1,3 -dicyclohexylcarbodiimide (DCC) or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). The synthesis can be carried out on racemic reactants, to provide invention compounds in racemic form, which can then be resolved by conventional methods, if desired. Alternatively, the invention compounds can be prepared in optically active form by using enantiomeric reactants.

[0228] In a typical synthesis, an optically active acetic acid is first prepared by conventional methods. Schemes 1-5 illustrate the preparation of intermediates utilized in Examples 1-5, which illustrate the synthesis of specific compounds of Formula I in optically active form. Scheme 1 describes the synthesis of intermediates I and II, which are required for Examples 1 to 5. The N-terminal benzofuran moiety is introduced by the reductive amination of either tryptophan methyl ester or alpha-methyl-tryptophan methyl ester with benzofuran-2-carboxaldehyde and sodium triacetoxy borohydride in DCM. The methyl ester is then hydrolyzed to the corresponding carboxylic acid with lithium hydroxide.

[0229] Scheme 2 describes the synthesis of intermediate III. 3-Acetyl-l-methyl pyrrole is converted to the corresponding oxime by reaction with hydroxylamine sulfate and potassium hydroxide in water/methanol. The oxime is then reduced on palladium on carbon.

[0230] Scheme 3 shows the synthesis of intermediate IV. This compound was prepared from (R)-2-phenylglycinol, which was first N-terminal protected as the carbobenzoxy (CBZ) analogue. The alcohol was then treated with triethylamine and methane sulfonylchloride, followed by dimethylamine to introduce the tertiary amine. Removal of the CBZ protection with hydrogen over Pearlman's catalyst gave the required intermediate.

[0231] Scheme 4 describes the synthesis of Examples 1 to 4. Each was prepared by activation of the acid, intermediate I, with HBTU in the presence of DIPEA and then reacting with the required amine in DMF.

[0232] The synthesis of Example 5 is outlined in scheme 5. Intermediate I was activated with HBTU in DMF and then coupled with methoxybenzylamine. The methyl ether was then reduced with boron tribromide in DCM.

EXAMPLE 1

2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-methyl-1-phenyl-ethyl)-propionamide, (R)

[0233] Step 1

[0234] Alpha methyl tryptophan methyl ester (26.8 g, 0.115 mol) and benzofuran-2-carboxaldehyde (17.57 g, 0.115 mol) were dissolved in DCM (400 mL) under an atmosphere of nitrogen and sodium triacetoxyborohydride (34.12 g, 0.161 mol) was added portionwise over 20 min at 0° C. The mixture was stirred at room temperature for 2 h and then quenched by the addition of sat. NaHCO3 (500 mL). The organic layer was collected and the aqueous layer was extracted three times with EtOAc. The organics were combined, dried (MgSO4), filtered, and evaporated to dryness. The residue was crystallized from ether/heptane to give the product (34.13 g, 82%); IR (film): 3410, 2948, 1724, 1455, 1253, 1104, 742cm−1; NMR (CDCl3)δ1.48 (3H, s); 3.18 (1H, d, J=14 Hz); 3.21 (1H, d, J=14 Hz); 3.53 (3H, s); 3.85 (1H, d, J=Hz); 3.92 (1H, d, J=14 Hz); 6.55 (1H, s); 7.04-7.59 (9H, m); 8.07 (1H, s); MS; ES+ 363, ES− 361.

[0235] Step 2. Intermediate I

[0236] The methyl ester from step one (24.94 g, 68.8 mmol) was dissolved in dioxan (800 mL) and aq. LiOH (8.66 g, 206 mmol in 400 mL) was added. The reaction mixture was stirred overnight at room temperature and then heated to 60° C. for 5 h. The mixture was reduced in vacuo to a volume of approximately 200 ml. Water (1200 mL) was added and the reaction was stirred vigorously while it was neutralized with 1N HCl. Ether (1200 mL) was added and the mixture was stirred for two h, the precipitate was filtered off, washed with water, ether and dried to give a white solid; (24.5 g, 100%); NMR (Dmso-d6) 1.28 (3H, s); 3.05 (1H, d, J=14 Hz); 3.07 (1H, d, J=14 Hz); 3.33 (2H, br s); 3.87 (2H, s); 6.72 (1H, s); 6.97-7.07 (3H, m); 7.14 (1H, d, J=2 Hz); 7.18-7.33 (3H, m); 7.50-7.58 (3H, m); 10.89 (1H, s); MS; ES+ 349, ES− 347.

[0237] Step 3

[0238] Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol), DIPEA (0.35 mL, 2 mmol) and cumylamine (0.20 g, 1.48 mmol) were stirred in DMF (25 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10% Na2CO3, and brine. Drying and purification by column chromatography using 20% EtOAc/Heptane gave a white solid (0.285 g, 61%). mp=57-62° C.; NMR (CDCl3): δ1.40 (3H, s); 1.70 (6H, s); 1.92 (1H, b s); 3.17 and 3.22 (2H, 2×d, J=14.4,14.6); 3.82 and 3.89 (2H, 2×d, J=14.6, 14.1); 6.46 (1H, s); 7.02-7.68 (15H, m); 8.10 (1H, s); IR (film): 3317, 2987, 1661, 1506, 1455 cm−1; [α]D23=26.1° (c=1, MeOH); MS(ES+) 466 (M+1); Analysis calculated for C30H31N3O2. 0.25H2O: C, 76.65; H, 6.75; N, 8.94%. Found: C, 76.73; H, 6.54; N, 8.80%.

EXAMPLE 2

2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(1-methyl- 1H-pyrrol-3-yl)-ethyl]-propionamide, [R—(R*,R*)] and [R—(R*,S*)]

[0239]

[0240] Step 1

[0241] 3-Acetyl-1-methyl pyrrole (2.00 g, 16.2 mmol) was dissolved in MeOH (60 mL) and treated with potassium hydroxide (4.10 g, 73 mmol) in water (10 mL) and hydroxylamine sulfate (4.00 g, 24.3 mmol) in water (10 mL) and stirred for 18 h. The methanol was removed in vacuo and the residue was diluted with water and extracted with EtOAc. Drying (MgSO4) and evaporation gave an off-white solid (1.82 g, 81%). (E:Z=9:1); NMR (CDCl3): δ2.17 (3H, s); 3.65 (3H, s); 3.69 (3H, s); 6.39 (1H, m); 6.46 (1H, m); 6.56 (1H, m); 6.58 (1H, m); 6.85 (1H, m); 7.59 (1H, m); 8.10 (1H, bs); IR(film): 3240, 2916, 1644, 1554, 1422, 1257, 892cm−1;

[0242] Step 2 Intermediate III

[0243] The oxime from step one (0.25 g, 1.8 mmol) was dissolved in methanol and 10% Palladium on carbon (50 mg) was added. The mixture was shaken under an atmosphere of hydrogen at 35 psi and at 30° C. for 5 h. Filtering through Kieselguhr and evaporation gave a colorless oil (220 mg) which was a mixture of starting material and product ˜1:1. The crude, intermediate III was used in step 3.

[0244] Step 3

[0245] Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol), DIPEA (0.35 mL, 2 mmol) and the amine (Intermediate III) (220 mg, 1.8 mmol) were stirred in DMF (13 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10%Na2CO3, and brine. Drying and purification by column chromatography using 20% EtOAc/Heptane followed by reverse phase chromatography using 50-100% MeOH/H2O gave a white solid (0.205 g, 45%); mp=53-57° C.; NMR (CDCL3): δ1.35 and 1.43 (3H, 2×d, J=6.6 and 6.6 Hz); 1.45 (obs H2O) and 1.5 (3H, 2×s); 1.89 (1H, bs); 3.21 and 3.22 (2H, 2×s,); 3.49 and 3.54 (3H, 2×s); 3.72-3.86 (2H, 2×AB, J=14.4,14.4); 5.05 (1H, m); 6.00 (1H, m); 6.34-7.72 (13H, m); IR (film): 3278, 2969, 1648, 1507, 1455 cm−1; MS(ES+): 455(M+H) Analysis calculated for C28H30N4O4; C, 73.98; H, 6.65; N,12.32%. Found: C, 73.69; H, 6.44; N, 12.12%.

EXAMPLE 3

2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl) -propionamide, [R—(R*,S*)]

[0246]

[0247] Intermediate I (0.174 g, 0.5 mmol), HBTU (0.190 g, 0.5 mmol), DIPEA (0.348 mL, 2 mmol) and the amine (prepared as described in U.S. Pat. No. 5,594,022) (252 mg, 0.6 mmol) were stirred in DMF (25 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10%Na2CO3, and brine. Drying and purification by column chromatography using 3%MeOH/DCM gave a white solid (0.14 g, 62%). mp=66-69° C.; NMR (CDCl3): δ1.44(3H,d, J=7.2 Hz); 1.50 (3H, s); 1.96 (1H, bs) 3.12 (1H, d, J=14.4 Hz) and 3.23 (1H, d, J=14.4 Hz); 3.80 (1H, d, J=14.2 Hz) and 3.92(1H, d, J=14.2 Hz); 5.02 (1H, m); 6.48 (1H, s); 6.89-8.00 (12H, m); 8.03 (1H, s); 8.46(2H, m); IR (film) 3326, 2978, 1660, 1602, 1505, 1455 cm−1; MS(ES+) 453 (M+1); [α]D23=−29.0° (c=0.39, MeOH); Analysis calculated for C28H28N4O2. 0.2H2O: C, 73.73; H, 6.28; N, 12.28% Found: C, 73.76; H, 6.2; N, 12.08%.

EXAMPLE 4

2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-dimethylamino-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, (R,R)

[0248]

[0249] Step 1

[0250] To a solution of (R)-2-phenyl glycinol (2.11 g, 15 mmol) and benzyl chloroformate (2.35 mL, 16.5 mmol) in THF (30 mL) at 0° C. was added triethylamine (2.30 mL, 16.5 mmol) in THF (5 mL). After stirring for 18 h at room temperature, the mixture was filtered and evaporated to a white solid which was purified by column chromatography on silica using 50% EtOAc/heptane, giving a white solid (4.00 g, 98%); NMR (CDCl3): δ3.88 (2H, m); 4.85 (1H, m); 5.10 (2H, m); 5.48 (1H, m); 7.23-7.40 (10H, m); IR (film): 3324, 2950, 1687, 1540, 1259 cm−1;

[0251] Step 2

[0252] To a solution of the alcohol from step one (1.00 g, 3.68 mmol) and triethylamine (1.16 mL, 8 mmol) in THF (20mL) was added a solution of methane sulphonylchloride (0.31 mL, 4.0 mmol) in THF (3 mL). The mixture was stirred for 1 h. 2M dimethylamine in THF solution. (1 7 mL, 34 mmol) was added and the sealed mixture was stirred for 12 days. Evaporation of the solvent and purification by column chromatography using 2% MeOH/DCM gave a yellow oil (0.399 g, 36%); NMR (CDCl3): δ2.23 (6H, s); 2.35-2.58 (2H, m); 4.64 (1H, bs); 5.06 (2H, m); 5.77 (1H, bs); 7.20-7.40 (10 H, m); IR (film): 3330, 2945, 1716, 1538, 1246, 1050 cm−1.

[0253] Step 3 Intermediate IV

[0254] The protected amine from step one (0.226 g, 0.75 mmol) was dissolved in methanol (30 mL) and Pearlman's catalyst (30 mg) was added. The mixture was shaken for 2 h at 50 psi and then filtered through kieselguhr. Evaporation gave a yellow syrup (0.127 g, 100%); NMR (CDCl3): δ2.22-2.51 (8H, m); 4.07 (1H, m); 7.22-7.39 (5H, m).

[0255] Step 4

[0256] Intermediate I (0.174 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol), DIPEA (0.174 mL, 1.0 mmol) and the amine (Intermediate IV) (0.12 mg, 0.73 mmol) were stirred in DMF (15 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10% Na2CO3, and brine. Drying and purification by column chromatography using 1% MeOH/DCM and reverse phase chromatography using 40-100% MeOH/H2O gave a white solid (0.10 g, 40%). mp=130-134° C.; NMR (CDCl3) δ1.44 (3H, s); 2.16 (6H, s); 2.41 (1H, dd, J=5.6, 12.4 Hz) and 2.59 (1H, dd, H=10.0, 12.4); 3.17 (2H, s); 3.86 (1H, d, 14.4 Hz) and 3.92 (1H, d, J=14.6 Hz); 4.95 (1H, m); 6.55 (1H, s); 6.90 (1H, s); 7.09-7.67 (13H, m); 8.01 (1H, s); 8.18, d, J=6.6 Hz); IR (film) 3317, 2934, 1658, 1496, 1455 cm−1; MS(ES+) 482 (M+1); [α]D23=31.9 (c=0.72, MeOH); Analysis calculated for C31H34N4O2: C, 75.28; H, 6.93; N, 11.33% Found: C, 75.24; H, 6.92; N, 11.15%.

EXAMPLE 5

2-[(Benzofuran-2-ylmethyl)-amino]-N-(3-hydroxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, R

[0257]

[0258] Step 1

[0259] Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol), DIPEA (0.35 mL, 2 mmol) and 3-methoxybenzylamine (0.206 g, 1.5 mmol) were stirred in DMF (17 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10%Na2CO3, and brine. Drying and purification by column chromatography using 40% EtOAc/Heptane gave a white solid (0.190 g; 41%). mp=42-47° C.; NMR (CDCl3): δ1.50 (3H, s); 1.90 (1H, bs); 3.20 (1H, d, J=14.4 Hz) and 3.28 (1H, d, J=14.4 Hz); 3.72-3.82 (4H, m); 3.88 (1H, d, J=14.0 Hz); 4.37 (2H, d, J=6.0 Hz); 6.37 (1H, s); 6.75-7.70 (14H, m); 8.12 (1H, s); IR (film): 3322, 2920, 1654, 1602, 1455, 1256 cm−1; MS(ES+) 468 (M+1); [α]D23.5=−31.3° (c=1.01, MeOH); Analysis calculated for C29H29N3O3: C, 74.50; H, 6.25; N, 8.99%; Found: C, 74.20; H, 6.24; N, 8.78%

[0260] Step 2

[0261] 1.0M Boron tribromide in dichloromethane (0.62 mL; 0.62 mmol) was added dropwise to a solution of the methoxy compound from step one (0.146 g; 0.31 mmol) in dichloromethane at −70° C. under N2, warmed slowly to room temperature and stirred for 18 h. The mixture was poured onto 10 g crushed ice/2M HCl (15 mL) and stirred for 10 min. Neutralizing with Na2CO3, extraction with EtOAc and purification by column chromatography using 40% EtOAc/heptane gave a white solid (0.115 g; 82%). mp=60-69° C.; NMR (CDCl3): δ1.53 (3H, s); 1.96 (1H, bs); 3.14 (1H, d, J=14.4 Hz) and 3.37 (1H, d, J=14.4 Hz); 3.81 (1H, d, J=14.0 Hz) and 3.93 (1H, d, J=14.0 Hz); 4.14-4.50 (2H, m); 5.23 (1H, bs); 6.32-7.82 (15H, m); 8.14 (1H, s); IR (film): 3333, 2907, 1645, 1599, 1520, 1455, 1254 cm−1; MS(ES+): 454 (M+1); [α]D23.5=−25.9° (c=0.73, MeOH); Analysis calculated for C28H27N3O3. 0.5 H2O: C, 72.71; H, 6.10; N, 9.08% Found: C, 72.83, 72.86; H, 6.03, 5.96; N, 8.81, 8.83%.

[0262] Scheme 6 describes the synthesis of intermediate V, which is required for Examples 6to 17.

[0263] Boc-tryptophan was coupled to alpha-methylbenzylamine using HBTU activation. The Boc group was removed using formic acid in DCM to give Intermediate V.

[0264] Examples 6, 8 and 10 to 21 were prepared by a reductive amination of the relative aldehydes and Intermediate V with sodium triacetoxyborohydride as shown in scheme 7.

[0265] Scheme 8 outlines the synthesis of Example 7. 2-Benzofuranacetic acid was reacted with ethyl chloroformate in THF and then reduced with lithium borohydride. The alcohol was then converted to the corresponding mesylate and reacted with Intermediate V to give Example7.

[0266] Scheme 9 describes the synthesis of Example 9. 2-Hydroxymethyl benzimidazole was reacted with bis(4-nitrophenyl)carbonate in DMF to form the cyclic carbamate. This compound was then reacted with intermediate V to give Example 9.

[0267] The synthesis of Intermediate VI is shown in scheme 10; the intermediate was used to prepare Example 10. Benzo[b]thiophene-2-carboxylic acid was activated with ethyl chloroformate and then coupled with N,O-dimethylhydroxylamine. The Weinreb amide was then reduced to the corresponding aldehyde with DIBAL.

[0268] The synthesis of Example 22 is described in scheme 11. 2-benzofurancarboxaldehyde was reacted with hydroxylamine in aqueous potassium hydroxide/EtOH. The oxime was then reduced with lithium aluminum hydride to give the amine. The corresponding isocyanate, prepared by reacting the amine with triphosgene in DCM/pyridine, was reacted with 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide to give Example 22.

[0269] Scheme 12 shows the synthesis of the key intermediate VII that was used in the synthesis of Examples 192 to 308. This N-carboxyanhydride was prepared by reacting intermediate I with phosgene in toluene.

2ExampleR1R26H2-Benzofuran-CH28H2-(4,5-Dimethylfuran)-CH210H2-Benzothiophene-CH211H3-quinoline-CH212H2-(5-Cl-thiophene)-CH213H(3-SCF3—Ph)—CH214H(3-CN—Ph)—CH215H(3-NO2—Ph)—CH216H(3-OCF3—Ph)—CH217H(3-OH—Ph)—CH218CH32-Benzofuran-CH219CH33-Benzofuran-CH220CH32-pyrrole-CH221CH33-pyrazole-CH2

[0270]

EXAMPLE 6

2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0271]

[0272] Step 1. Intermediate V

[0273] To a stirred solution of Boc-(R)-Trp-OH (6.08 g, 0.02mol) in DMF (50 mL) was added HBTU (7.59, 0.02 mol) and DIPEA (3.57 mL, 0.02 mol). After 5 min DIPEA (3.57 mL, 0.02 mol) and (S)-(−)-α-methylbenzylamine in DMF (10 mL) was added. After a further 60 min, the solvent was removed under reduced pressure. The residue was taken up in EtOAc (250 mL) and washed with brine (50 mL), 1N HCl (100 mL), saturated NaHCO3 (3×100 mL), brine (50 mL), dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and formic acid (30 mL). The reaction was stirred over night at room temperature before refluxing for 4 h. The solvent was removed under reduced pressure and the product was crystallized from ether. Stirring in EtOAc (100 mL) for 4 h and filtration gave pure product (4.17 g, 68%). The filtrate was purified by chromatography using EtOAc and then EtOAc/MeOH/NH3(aq) (95:5:0.5) as eluent. Crystallization from ether gave white crystalline solid (0.98 g , 16%); mp 142-144° C.; [αD19=−83.9° (c=1, MeOH); IR (film): 3338, 3295, 3059, 2975, 2928, 1649, 1518, 1494, 1455, 1342, 1104, 894, 740 cm−1; NMR (CDCl3): δ1.44 (3H, d, J=7.1 Hz); 1.51 (2H, s); 2.95 (1H, d.d, J=14.4 and 8.5 Hz); 3.36 (1H, d,d, J=14.4 and 4.4 Hz); 3.74 (1H, d.d, J=8.5 and 4.4 Hz); 5.05-5.15 (1H, m); 6.95 (1H, d, J=2.2 Hz); 7.10-7.38 (8H, m); 7.48-7.52 (1H, m); 7.66-7.69 (1H, m); 7.98 (1H, s); MS m/e (APCI+): 309.1 (20%), 308.1 (100%, M++H); Analysis calculated for C19H21N3O: C, 74.24; H, 6.89; N, 13.66%. Found: C, 74.07; H, 6.87; N, 13.70%.

[0274] Step 2

[0275] To a stirred solution of 2-benzofurancarboxaldehyde (0.73 g, 5 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (1.54 g, 5 mmol) followed by sodium triacetoxyborohydride (1.48 g, 7 mmol). After stirring for 3 h the reaction was cautiously quenched with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography using 30% EtOAc in heptane as eluent to give pure product as a glass (2.0 g, 91%); [αD]20=+34.0° (c=0.5, MeOH); IR (film): 3316, 3059, 2973, 2925, 1653, 1517, 1455, 1341, 1254, 1104, 1010, 909, 741 cm−1; NMR (CDCl3): δ1.38 (3H, d, J=7.1 Hz); 1.93 (1H, s); 2.92 (1H, d.d, J=14.6 and 9.3 Hz); 3.29-3.35 (1H, m); 3.58 (1H, d.d, J=9.3 and 4.2 Hz); 3.75 (1H, d, J=14.9 Hz); 3.82 (1H, d, J=14.9 Hz); 5.07-5.15 (1H, m); 6.36 (1H, s); 6.87 (1H, d, J=2.2 Hz); 7.04-7.08 (1H, m); 7.15-7.35 (10H, m); 7.43-7.45 (1H, m); 7.58-7.64 (2H, m); 7.92 (1H, s); MS m/e (APCI+): 439.9 (5%), 438.9 (34%), 437.9 (100%, M++H), 307.0 (9%); Analysis calculated for C28H27N3O2: C, 76.86; H, 6.22; N, 9.60%. Found: C, 77.11; H, 6.31; N, 9.67%.

EXAMPLE 7

2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0276]

[0277] Step 1

[0278] A solution of N-methylmorpholine (NMM, 5.31 g, 52.5 mmol) in THF (30 mL) was added dropwise over 15 min to a stirred solution of 2-benzofuranacetic acid (8.80 g, 50 mmol) and ethyl chloroformate (5.70 g, 52.5 mmol) in THF (150 mL, anhydrous) at 0° C. The reaction mixture was stirred for 1 h at room temperature before filtering off the precipitate of NMM.HCl. The filtrate was cooled to 0° C. and a solution of lithium borohydride (30 mL, 60 mmol, 2M in THF) was added dropwise over 30 min. The reaction was allowed to reach room temperature and stirred over night before being cautiously quenched with 1N HCl (100 mL)—vigorous effervescence. The THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc (200 mL). The organic phase was washed with 1N HCl, H2O, saturated NaHCO3 (×2), brine, and dried (MgSO4). Removal of solvent under reduced pressure gave intermediate VI (7.74 g, 93%). Used in the next step without further purification. IR (film): 3347, 2957, 2887, 1603, 1587, 1455, 1422, 1317, 1252, 1167, 1105, 1049, 945, 926, 881, 854, 807, 751 cm−1; NMR (CDCl3): δ1.64 (1H, t, J=6.0 Hz); 3.05 (2H, t, J=6.2 Hz); 4.00 (2H, q, J=6.1 Hz); 6.51 (1H, d, J=1.0 Hz); 7.17-7.25 (2H, m); 7.41-7.44 (1H, m); 7.49-7.52 (1H, m).

[0279] Step 2

[0280] To an ice-cold solution of alcohol VI (1.62 g, 10 mmol) and NEt3 (1.01 g, 10 mmol) in ether (50 mL, anhydrous) was added a solution of methanesulphonyl chloride (1.20 g, 10.5 mmol) dropwise over 5 min. The ice bath was removed and the reaction was stirred at room temperature for 30 min before filtering off the NEt3.HCl. The ether was removed under reduced pressure. To a portion of the mesylate (240 mg, 1 mmol) dissolved in toluene (50 mL, anhydrous) was added amine V. The reaction was refluxed for 48 h, a further equivalent of NEt3 was added, and reflux was continued for a further 48 h. The reaction mixture was cooled and washed with 1N NaOH, the organic layer was dried (MgSO4), and solvent removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 20% EtOAc in heptane as eluent and then on reverse phase silica using 70% MeOH in H2O as elan. Product crystallized on drying in vacuum oven to give pure product (82 mg, 18%); mp 105-107° C.; [α]D22=−1.2° (c=0.25, MeOH); IR (film): 3305, 3058, 2924, 2851, 1651, 1515, 1455, 1356, 1342, 1252, 1166, 1105,742 cm−1;NMR (CDCl3): δ1.37 (3H, d, J=7.1 Hz); 1.57 (1H, s); 2.72-2.97 (5H, m); 3.28-3.34 (1H, m); 3.44-3.48 (1H, m); 5.07-5.15 (1H, m); 6.06 (1H, s); 6.75 (1H, d, J=2.2 Hz); 7.06-7.33 (11H, m); 7.40-7.44 (1H, m); 7.51 (1H, d, J=8.5 Hz); 7.62-7.65 (2H, m); MS m/e (ES+): 453.1 (33%), 452.2 (100%, M++H); Analysis calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.31%. Found: C, 77.06; H, 6.48; N, 9.30%.

EXAMPLE 8

2-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0281]

[0282] To a stirred solution of the 4,5-dimethyl-2-furaldehyde (124 mg, 1 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (307 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 25% EtOAc in heptane as eluent to give pure product as a glass (196 mg, 47%); [α]D21=+18.6° (c=0.5, MeOH); IR (film): 3312, 3059, 2971, 2922, 1651, 1516, 1455, 1342, 1220, 1106, 741 cm−1; NMR (CDCl3): δ1.44 (3H, d, J=6.8 Hz); 1.60-1.90 (1H, br.s); 1.83 and 2.06 (each 3H, s); 2.89 (1H, d,d, J=14.6 and 9.3 Hz); 3.26-3.32 (1H, m); 3.49 (1H, d, J=14.4 Hz); 3.50-3.54 (1H, m); 3.58(1H, d, J=14.4 Hz); 5.08-5.16 (1H, m); 5.76 (1H, s); 6.89 (1H, d, J=2.2 Hz); 7.01-7.11 (1H, m); 7.17-7.36 (7H, m); 7.62-7.65 (2H, m); 7.95 (1H, s); MS m/e (ES+): 417.3 (31%), 416.3 (100%, M++H), 308.3 (34%); Analysis calculated for C26H29N3O2.0.2H2O: C, 74.51; H, 7.07; N, 10.03%. Found: C, 74.43; H, 6.82; N, 10.03%.

EXAMPLE 9

2-[(1H-Benzoimidazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0283]

[0284] Step 1

[0285] A solution of 2-hydroxymethyl benzimidazole (1.19 g, 8 mmol) and bis(4-nitrophenyl)carbonate (2.43 g, 8 mmol) in DMF (20 mL, anhydrous) was stirred for 12 h at room temperature. The DMF was removed under reduced pressure and the residue stirred in ether (50 mL) for 2 h. Filtration and washing with ether (50 mL) gave crystalline intermediate VII (1.04 g, 74%); IR (film): 1819, 1623, 1592, 1568, 1486, 1445, 1411, 1369, 1359, 1147, 1106, 1076, 1009, 997, 941, 862, 847, 765, 750, 741 cm−1; NMR (CDCl3): δ5.49 (2H, s); 7.42-7.50 (2H, m); 7.79-7.84 (1H, m); 7.88-7.93 (1H, m).

[0286] Step 2

[0287] The product from step 1 (174 mg, 1 mmol) and intermediate V (307 mg, 1 mmol) were dissolved in DMF (10 mL, anhydrous) and stirred at 60° C. for 10 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on reverse phase silica using 60% MeOH in H2O as eluent. The solvent was removed under reduced pressure and the residue was crystallized from EtOAc to give pure product (396 mg, 91%); mp 148-152.5° C.; [α]D21=+24.2° (c=0.5, MeOH); IR (film): 3300, 3058, 2923, 1651, 1520, 1455, 1340, 1271, 1235, 1218, 1109, 1013, 909, 739 cm−1; NMR (CDCl3): δ1.31 (3H, d, J=7.1 Hz); 2.00-2.50 (1H, br.s); 3.04 (1H, d.d, J=14.4 and 8.8 Hz); 3.29 (1H, d.d, J=14.4 and 5.2 Hz); 3.50 (1H, d.d, J=8.8 and 5.2 Hz); 3.94 (1H, d, J=15.9 Hz); 4.04 (1H, d, J=15.9 Hz); 5.03-5.10 (1H, m); 6.85 (1H, d, J=7.8 Hz); 6.99 (1H, d, J=2.2 Hz); 7.10-7.30 (10H, m); 7.20-7.70 (1H, br.s); 7.42 (1H, d, J=8.1 Hz); 7.66 (1H, d, J=7.8 Hz); 8.06 (1H, s); 8.80-9.20 (1H, br.s); MS m/e (ES+): 439.3 (28%), 438.3 (100%, M++H); Analysis calculated for C27H27N5O: C, 74.12; H, 6.22; N, 16.01%. Found: C, 74.04; H, 6.19; N, 15.95%.

EXAMPLE 10

2-[(Benzo[b]thiophen-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide

[0288]

[0289] Step 1

[0290] A solution of NMM (2.309 mL, 21 mmol) in THF (10 mL) was added dropwise to a stirred ice cooled solution of benzo[b]thiophene-2-carboxylic acid (3.56 g, 20 mmol) and ethyl chloroformate (2.008 mL, 21 mmol) in THF (150 mL) over 15 mins. The reaction mixture was stirred at room temperature for 1 h before adding N,O-dimethylhydroxylamine hydrochloride (2.146 g, 22 mmol) and NMM (2.419 mL, 22 mmol). The reaction was stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with 2N HCl (3×100 mL), 2N NaOH (100 mL), H2O, brine, dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 30% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (3.24 g, 73%).

[0291] To a stirred solution of the Weinreb amide (2.06 g, 9.3 mmol) in THF (100 mL, anhydrous) under nitrogen at 0° C. was added diisobutylaluminum hydride (11 mL, 11 mmol, 1M in CH2Cl2) dropwise. After 20 min the reaction mixture was poured onto ice cold 2N HCl and extracted with ether. The organic phase was washed with brine, dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 5% EtOAc in heptane as eluent to give solid benzo[b]thiophene-2-carboxaldehyde (Intermediate VI) (665 mg, 44%). IR (film): 1669, 1592, 1516, 1431, 1255, 1224, 1135, 840, 747, 725 cm−1; NMR (CDCl3): δ7.42-7.54 (2H, m); 7.91 (1H, d, J=8.1 Hz); 7.95(1H, d, J=7.8 Hz); 8.04 (1H, s); 10.12 (1H, s).

[0292] Step 2

[0293] To a stirred solution of the benzo[b]thiophene-2-carboxaldehyde (Intermediate VI) (162 mg, 1 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (307 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (2×20 mL).

[0294] The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 20% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (305 mg, 67%); mp 102-108° C.; [α]D21=+51.4° (c=0.5, MeOH); IR (film): 3311, 3059, 2925, 1651, 1515, 1456, 743 cm−1; NMR (CDCl3): δ1.40 (3H, d, J=7.1 Hz); 1.97 (1H, s); 2.99 (1H, d.d, J=14.7 and 8.8 Hz); 3.35 (1H, d.d, J=14.4 and 4.2 Hz); 3.59 (1H, d.d, J=8.5 and 4.4 Hz); 3.94 (2H, m); 5.07-5.16 (1H, m); 6.91-6.93 (2H, m); 7.06-7.11 (1H, m); 7.17-7.37 (9H, m); 7.50 (1H, d, J=8.5 Hz); 7.60 (1H, d.d, J=7.0 and 1.6 Hz); 7.65 (1H, d, J=8.1 Hz); 7.72-7.76 (1H, m); 7.95 (1H, s); MS m/e (ES+): 476.1 (60%, M++Na), 454.1 (100%, M++H), 402.2 (25%); (ES−): 453.2 (25%), 452.1 (100%, M−−H); Analysis calculated for C28H27N3OS: C, 74.14; H, 6.00; N, 9.26; S, 7.07%. Found: C, 74.27; H, 6.16; N, 9.31; S, 7.11%.

EXAMPLE 11

3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-[(quinolin-3-ylmethyl)-amino]-propionamide, [R—(R*,S*)]

[0295]

[0296] Method as for Example 10, step 2. The residue was purified by chromatography on normal phase silica using 2% MeOH in CH2Cl2 as eluent. Crystallization from EtOAc/heptane gave pure product (340 mg, 76%); mp 161-163° C.; [α]D22=+40° (c=0.5, MeOH); IR (film): 3280, 3055, 2972, 2926, 1655, 1515, 1497, 1456, 1342, 1127, 742 cm−; NMR (CDCl3): δ1.40 (3H, d, J=7.1 Hz); 1.90 (1H, s); 2.96 (1H, d.d, J=14.7 and 9.0 Hz); 3.36 (1H, d.d, J=14.5 and 4.5 Hz); 3.53-3.56 (1H, m); 3.78 (1H, d, J=13.7 Hz); 3.92 (1H, d, J=13.7 Hz); 5.08-5.16 (1H, m); 6.90 (1H, d, J=2.2 Hz); 7.03-7.08 (1H, m); 7.15-7.20 (1H, m); 7.23-7.37 (6H, m); 7.43 (1H,d J=8.3 Hz); 7.49-7.51 (1H, m); 7.59-7.72 (4H, m); 8.02 (1H, s); 8.04 (1H, d, J=8.3 Hz); 8.66 (1H, d, J=2.2 Hz); MS m/e (ES+): 471.1 (31%, M++Na), 449.1 (100%, M++H); Analysis calculated for C29H28N4O: C, 77.65; H, 6.29; N, 12.49%. Found: C, 78.02; H, 6.30; N, 12.48%.

EXAMPLE 12

2-[(5-Chloro-thiophen-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0297]

[0298] Method as for Example 10, step 2. The residue was dissolved in aqueous acetonitrile and acidified using formic acid before being purified by chromatography on reverse phase silica using 40% CH3CN in H2O (0.1% formic acid in mobile phases) as eluent. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (245 mg, 56%); [α]D22=+26.2° (c=0.5, MeOH); IR (film): 3307, 3059, 2973, 2925, 1652, 1515, 1455, 1342, 1230, 1105, 1061, 1000, 796, 742 cm−1; NMR (CDCl3): δ1.43 (3H, d, J=6.8 Hz); 1.85 (1H, s); 2.96 (1H, d.d, J=14.7 and 8.5 Hz); 3.31 (1H, d.d, J=14.5 and 4.5 Hz); 3.49-3.53 (1H, m); 3.71-3.79 (2H, m); 5.07-5.15 (1H, m); 6.50 (1H, d, J=3.7 Hz); 6.65 (1H, d, J=3.9 Hz); 6.91 (1H, d, J=2.4 Hz); 7.09-7.14 (1H, m); 7.18-7.39 (8H, m); 7.63 (1H, d, J=7.6 Hz); 7.98 (1H, s); MS m/e (ES+): 437.9 (100%, M++H); Analysis calculated for C24H24N3OSCl: C, 65.81; H, 5.52; N, 9.59; Cl, 8.09; S, 7.32%. Found: C, 65.54; H, 5.45; N, 9.40; Cl, 7.85; S, 7.42%.

EXAMPLE 13

3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethylsulfanyl-benzylamino)-propionamide, [R—(R*,S*)]

[0299]

[0300] To a stirred solution of 3-(trifluoromethylthio)benzaldehyde (72 mg, 0.55 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (154 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (148 mg, 0.7 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 30% EtOAc in heptane as eluent. The solvent was removed under reduced pressure to give pure product as a glass (193 mg, 77%); IR (film): 3306, 3058, 2972, 2923, 1651, 1516, 1456, 1342, 1114, 743 cm−1; NMR (CDCl3): δ1.41 (3H, d, J=6.8 Hz); 1.60-1.90 (1H, br.s); 2.96 (1H, d.d, J=14.5 and 8.9 Hz); 3.32 (1H, d.d, J=14.4 and 4.4 Hz); 3.48 (1H, d.d, J=8.9 and 4.5 Hz); 3.62 (1H, d, J=13.9 Hz); 3.76 (1H, d, J=13.7 Hz); 5.08-5.16 (1H, m); 6.91 (1H, d, J=2.2 Hz); 7.07-7.48 (13H, m); 7.60 (1H, d, J=7.8 Hz); 7.97 (1H, s); MS m/e (ES+): 499.4 (32%), 498.4 (100%, M++H); Analysis calculated for C27H26N3OSF3.0.25H2O: C, 64.59; H, 5.32; N, 8.37; S, 6.39%. Found: C, 64.69; H, 5.34; N, 8.30; S, 6.27%.

EXAMPLE 14

2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0301]

[0302] Method as for Example 13. Chromatography on normal phase silica using 45% EtOAc in heptane as the eluent and subsequent removal of the solvent under reduced pressure gave pure product as a glass (130 mg, 62%); IR (film): 3312, 3059, 2973, 2924, 2229, 1652, 1516, 1456, 1342, 1231, 1101, 743 cm−1; NMR (CDCl3): δ1.42 (3H, d, J=6.8 Hz); 1.87 (1H, s); 2.91 (1H, d.d, J=14.5 and 9.2 Hz); 3.32 (1H, d.d, J=14.5 and 4.0 Hz); 3.41 (1H, d.d, J=9.0 and 4.4 Hz); 3.58 (1H, d, J=14.2 Hz); 3.76 (1H, d, J=14.2 Hz); 5.08-5.17 (1H, m); 6.94 (1H, d, J=2.2 Hz); 7.07-7.12 (1H, m); 7.19-7.45 (12H, m); 7.58 (1H, d, J=8.1 Hz); 8.05 (1H, s); MS m/e (ES+): 424.4 (30%), 423.4 (100%, M++H); (ES−): 422.3 (30%, M−), 421.3 (100%, M−−H); Analysis calculated for C27H26N4O: C, 76.75; H, 6.20; N, 13.26%. Found: C, 76.58; H, 6.14; N, 13.24%.

EXAMPLE 15

3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0303]

[0304] To a stirred solution of 3-nitrobenzaldehyde (332 g, 2.2 mmol) in 1,2-dichloroethane (60 mL) was added intermediate V (614 mg, 2 mmol) followed by sodium triacetoxyborohydride (594 mg, 2.8 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 45% EtOAc in heptane as eluent. The solvent was removed under reduced pressure to give pure product as a glass (648 mg, 73%); IR (film): 3317, 2925, 1652, 1526, 1456, 1349, 733 cm−1;NMR (CDCl3): δ1.43 (3H, d, J=6.8 Hz); 1.85-1.95 (1H, br.s); 2.90 (1H, d.d, J=14.5 and 9.1 Hz); 3.33 (1H, d.d, J=14.4 and 4.4 Hz); 3.43 (1H, d.d, J=9.0 and 4.5 Hz); 3.65 (1H, d, J=14.2 Hz); 3.83 (1H, d, J=14.2 Hz); 5.09-5.17 (1H, m); 6.94 (1H, d, J=2.4 Hz); 7.06 (1H, t, J=7.5 Hz); 7.18 (1H, t, J=7.5 Hz); 7.22-7.40 (10H, m); 7.87 (1H, m); 7.97-8.10 (2H, m); MS m/e (ES+): 444.4 (30%), 443.4 (100%, M++H); Analysis calculated for C26H26N4O3: C, 70.57; H, 5.92; N, 12.66%. Found: C, 70.55; H, 5.88; N, 12.67%.

EXAMPLE 16

3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)]

[0305]

[0306] Method as for Example 13. Chromatography on normal phase silica using 35% EtOAc in heptane as the eluent and subsequent removal of the solvent under reduced pressure gave pure product as a glass (130 mg, 54%); IR (film): 3307, 3060, 2974, 2925, 1652, 1589, 1516, 1495, 1456, 1260, 1217, 1164, 1012, 743 cm−1; NMR (CDCl3): δ1.40 (3H, d, J=6.8 Hz); 1.60-2.00 (1H, br.s); 2.97 (1H, d.d, J=14.7 and 8.8 Hz); 3.29-3.35 (1H, m); 3.48 (1H, d.d, J=8.8 and 4.6 Hz); 3.62 (1H, d, J=13.9 Hz); 3.74 (1H, d, J=13.9 Hz); 5.07-5.15 (1H, m); 6.91 (1H, d, J=2.2 Hz); 6.96-7.39 (13H, m); 7.63 (1H, d, J=7.8 Hz); 7.97 (1H, m); MS m/e (ES+): 483.4 (30%), 482.4 (100%, M++H); Analysis calculated for C27H26N3O2F3: C, 67.35; H, 5.44; N, 8.73%. Found: C, 67.31; H, 5.43; N, 8.67%.

EXAMPLE 17

2-(3-Hydroxy-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0307]

[0308] Method as for Example 13. Chromatography on normal phase silica using 40% EtOAc in heptane as the eluent and subsequent removal of the solvent under reduced pressure gave pure product as a glass (94 mg, 45%); IR (film): 3317, 3059, 2975, 2926, 1645, 1589, 1520, 1456, 1266, 1159, 743 cm−1; NMR (CDCl3): δ1.40 (3H, d, J=7.1 Hz); 1.70-1.90 (1H, br.s); 2.89 (1H, d.d, J=14.5 and 9.4 Hz); 3.33 (1H, d.d, J=14.7 and 4.2 Hz); 3.49-3.54 (1H, m); 3.53 (1H, d, J=13.9 Hz); 3.69 (1H, d, J=13.9 Hz); 5.00-5.20 (2H, m); 6.28 (1H, d, J=1.7 Hz); 6.60 (1H, d, J=7.6 Hz); 6.65 (1H, d.d, J=7.9 and 2.0 Hz); 6.89 (1H, d, J=2.2 Hz); 7.06 (1H, t, J=7.8 Hz); 7.09-7.13 (1H, m); 7.19-7.52 (7H, m); 7.54 (1H, d, J=8.5 Hz); 7.64 (1H, d, J=8.5 Hz); 8.05 (1H, m); MS m/e (ES+): 415.4 (30%), 414.4 (100%, M++H); Analysis calculated for C26H27N3O2: C,75.52; H, 6.58; N, 10.16%. Found: C, 75.28; H, 6.61; N, 10.03%.

EXAMPLE 18

2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0309]

[0310] To a stirred solution of 2-benzofurancarboxaldehyde (3.19 g, 21.8 mmol) in 1,2-dichloroethane (150 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (prepared as described by Boyle S. et al., Bioorg. Med. Chem. 2:357, 1994) (5 g, 15.6 mmol), followed by sodium triacetoxyborohydride (6.6 mg, 31.2 mmol). After stirring over night the reaction was cautiously quenched with 2N NaOH (150 mL) and extracted with CH2Cl2 (3×200 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 30% EtOAc in heptane as eluent and then on reverse phase silica using 70% MeOH in H2O as eluent. Crystallization from ether gave pure product (5.55 g, 79%); mp 118-121° C.: [α)D20=+12.5° (c=1, MeOH); IR (film): 3329, 3059, 2975, 2926, 1652, 1506, 1455, 1371, 1354, 1342, 1255, 1170, 1105, 1010, 938, 743 cm−1; NMR (CDCl3): δ1.47 (3H, s); 1.47 (3H, d, J=6.8 Hz); 1.89 (1H, s); 3.16 (2H, s); 3.78 (1H, br.d, J=12.9 Hz); 3.86 (1H, d, J=14.4 Hz); 5.05-5.13 (1H, m); 6.43 (1H, s); 6.87 (1H, d, J=2.2 Hz); 7.09-7.40 (11H, m); 7.47-7.50 (1H, m); 7.65 (1H, d, J=7.8 Hz); 7.92 (1H, d, J=7.8 Hz); 7.96 (1H, s); MS m/e (ES+): 453.1 (30%), 452.1 (100%, M++H), 393.2 (15%); Analysis calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.30%. Found: C, 77.14; H, 6.42; N, 9.36%.

EXAMPLE 19

2-[(Benzofuran-3-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0311]

[0312] To a stirred solution of 3-benzofurancarboxaldehyde (146 mg, 1 mmol) (Ind. J. Chem., Vol. 31B, 1992, 526) in 1,2-dichloroethane (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (321 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. The reaction was heated to reflux for 4 h. Cooled to room temperature and cautiously quenched with saturated NaHCO3 (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 25% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (232 mg, 51%); mp 104-106° C.: [α]D23=−13.4° (c=1, MeOH); IR (film): 3418, 3314, 3058, 2976, 2927, 1652, 1505, 1452, 1371, 1354, 1341, 1279, 1266, 1186, 1095, 1010, 858, 743 cm−1; NMR (CDCl3): δ1.40 (3H, d, J=6.8 Hz); 1.52 (3H, s); 1.71 (1H, s); 3.15 (1H, d, J=14.4 Hz); 3.27 (1H, d, J=14.4 Hz); 3.80 (1H, d, J=13.2 Hz); 3.88 (1H, d, J=13.2 Hz); 5.01-5.09 (1H, m); 6.79 (1H, d, J=2.2 Hz); 7.07-7.40 (12H, m); 7.44 (1H d,d, J=8.3 and 0.7 Hz); 7.65 (1H, d, J=7.8 Hz); 7.68 (1H, d, J=8.1 Hz); 7.93 (1H, s); MS m/e (ES+): 452.1 (100%, M++H); Analysis calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.30%. Found: C, 76.91; H, 6.39; N, 9.26%.

EXAMPLE 20

3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(1H-pyrrol-2-ylmethyl)-amino]-propionamide, [R—(R*,S*)]

[0313]

[0314] To a stirred solution of 2-pyrrolecarboxaldehyde (71 mg, 0.75 mmol) in 1,2-dichloroethane (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night at room temperature the reaction was cautiously quenched with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 40% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (50 mg, 25%); mp 123-133° C.; [α]D23=(c=1, MeOH); IR (film): 3314, 2976, 2926, 2852, 1651, 1511, 1455, 909, 736 cm−1; NMR (CDCl3): δ1.41 (3H, d, J=6.8 Hz); 1.45 (3H, s); 3.14 (1H, d, J=14.4 Hz); 3.29 (1H, d, J=14.4 Hz); 3.70 (1H, d, J=13.1 Hz); 3.76 (1H, d, J=12.9 Hz); 5.02-5.10 (1H, m); 5.97 (1H, s); 6.07-6.09 (1H, m); 6.58-6.60 (1H, m); 6.74 (1H, d, J=2.2 Hz); 7.10-7.35 (8H, m); 7.41 (1H d, J=7.6 Hz); 7.65 (1H, d, J=7.8 Hz); 7.89 (2H, s); MS m/e (ES+): 423.2 (20%, M++Na); 402.2 (30%); 401.2 (100%, M++H); 322.2 (40%); Analysis calculated for C25H28N4O: C, 74.97; H, 7.05; N, 13.99%. Found: C, 74.83; H, 7.05; N, 13.95%.

EXAMPLE 21

3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(2H-pyrazol-3-ylmethyl)-amino]-propionamide, [R—(R*,S*)]

[0315]

[0316] To a stirred solution of pyrazole-3-carboxaldehyde (96 mg, 1 mmol, supplied as dimer) in pyridine (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (848 mg, 4 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. After stirring over night at room temperature the pyridine was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL) and saturated NaHCO3. The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was initially purified by chromatography on normal phase silica using 95% EtOAc in heptane as eluent. The solvent was removed under reduced pressure and the residue was dissolved in aqueous acetonitrile and acidified using formic acid. Purification by chromatography on reverse phase silica using 25% CH3CN in H2O (0.1% formic acid in mobile phases) as eluent gave pure product. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (20 mg, 10%); IR (film): 3260, 3059, 2979, 2927, 1651, 1515, 1456, 1374, 1266, 1105, 1048, 1011, 932, 741 cm−1; NMR (DMSO-d6): δ1.22 (3H, s); 1.35 (3H, d, J=6.8 Hz); 2.26 (1H, s); 2.96-3.05 (2H, m); 3.50-3.75 (2H, m); 4.93 (1H, s); 6.10 (1H, s); 6.89-6.93 (2H, m); 7.00-7.04 (1H, m); 7.18-7.32 (6H, m); 7.35 (0.5H, s); 7.52 (1H, d, J=7.8 Hz); 7.60 (0.5H, s); 8.05-8.20 (1H, m); 10.82 (1H, s); 12.52 (0.5H, s); 12.73 (0.5H, s); MS m/e (ES+): 424.1 (27%); 402.1 (100%, M++H).

EXAMPLE 22

2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]

[0317]

[0318] Step 1

[0319] To a stirred solution of potassium hydroxide (6.6 g, 100 mmol, 85%) and hydroxylamine (3.66, 52.5 mmol) in EtOH (100 mL, 95%) and water (100 mL) was added 2-benzofurancarboxaldehyde (7.34 g, 50 mmol). Stirred for 48 h before removing the EtOH under reduced pressure. The aqueous phase was saturated with NaCl and then extracted with EtOAc (2×300 mL). The combined organic phases were dried (MgSO4) and the solvent removed under reduced pressure. Crystallization from ether gave pure oxime (7.2 g, 89%). To an ice-cold solution of the oxime (3.22 g, 20 mmol) in THF (150 mL, anhydrous) was added dropwise a solution of lithium aluminum hydride (20 mL, 20 mmol, 1M in THF) under an atmosphere of nitrogen. Reaction mixture allowed to reach room temperature and stirred over night. Reaction mixture cautiously quenched using water. Added 5N NaOH, and aqueous phase extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using EtOAc as eluent to give intermediate IX (1.75 g, 59%).

[0320] Step 2

[0321] A solution of the amine prepared in step 1 (1.358 g, 9.23 mmol) and pyridine (1.46, 18.5 mmol) in CH2Cl2 (20 mL, anhydrous) was added dropwise over 20 min to an ice cooled solution of triphosgene (0.96, 3.23 mmol). Reaction mixture allowed to reach room temperature. After 30 min, solvent removed under reduced pressure. The residue was taken up in EtOAc, filtered, and solvent removed under reduced pressure to give isocyanate (1.60 g, 100%). IR (film): 2256 cm−1. A solution of the isocyanate (1.038 g, 6 mmol) and 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (1.926 g, 6 mmol) in THF (50 mL, anhydrous) was stirred at room temperature for 5 min. The solvent was removed under reduced pressure. The residue was taken up in EtOAc and washed with 1N HCl (3×20 mL), saturated Na2CO3 (30 mL), brine (30 mL), dried MgSO4, and the solvent removed under reduced pressure. The residue was purified by chromatography on reverse phase silica using 65% MeOH in H2O as eluent. Crystallization from MeOH/H2O gave pure product (1.35 g, 45%). mp 176-178° C.; [α]D22=+30.420 (c=1, MeOH); IR (film): 3321, 3058, 2978, 2932, 1645, 1558, 1506, 1495, 1445, 1253, 741 cm−1; NMR (CDCl3): δ1.35 (3H, d, J=6.8 Hz); 1.61 (3H, s); 3.20 (1H, d, J=14.6 Hz); 3.54 (1H, d, J=14.6 Hz); 4.38 (1H, d.d, J=16.0 and 6.0 Hz); 4.45 (1H, d.d, J=15.9 and 6.1 Hz); 4.78 (1H, t, J=6.0 Hz); 4.97 (1H, s); 4.95-5.05 (1H, m); 6.49 (1H, s); 6.76 (1H, d, J=2.4 Hz); 7.00 (1H, d, J=7.6 Hz); 7.05-7.10 (1H, m); 7.13-7.28 (9H, m); 7.38 (1H, d, J=8.1 Hz); 7.48-7.50 (1H, m); 7.57 (1H, d, J=7.8 Hz); 7.74 (1H, s); MS m/e (APCI+): 496.3 (30%); 495.2 (100%, M++H); 477.2 (7%); 374.2 (7%); 322.3 (17%); Analysis calculated for C30H30N4O3: C, 72.85; H, 6.11; N, 11.32%. Found: C, 73.09; H, 6.08; N, 11.35%.

EXAMPLES 23 TO 191

[0322] (See Table 2 Below)

Intermediate VII, N-[b]benzofuranylmethyl-R-α-methyl-tryptophan-N-carboxyanhydride

[0323] Intermediate I (5.23 g, 15 mmol) was stirred in toluene (50 mL) under nitrogen and heated to 55° C. Phosgene in toluene (37 mL, 75 mmol) was added in one portion and as soon as the temperature had returned to 55° C. dry THF (150 mL) was added rapidly dropwise. Stirring was continued for 30 min and the reaction was then cooled, the solvent removed in vacuo. The residue taken up in ether (50 mL) and filtered and evaporated to dryness several times until a solid was obtained; (6.15 g, 100%); IR (film): 3418, 1844, 1771, 1455, 1397, 1251, 986, 746 cm−1; NMR (CDCl3) 1.64 (3H, s); 3.31 (1H, d, J=15 Hz); 3.44 (1H, d, J=15 Hz); 4.45 (1H, d J=16Hz); 4.81 (1H, d, J=16 Hz); 6.77 (1H, s); 6.94 (1H, d J=2.8 Hz); 7.14-7.58 (8H, m); 8.16 (1H, s).

[0324] General Procedure for Array Synthesis of Examples 23 to 191

[0325] A 40-well DTI synthesizer rack (U.S. Pat. No. 5,324,483) was loaded with 40 DTI vials (12 mL). To each vial 0.15-0.21 mmol of an amine or amine HCl salt was added. The rack was placed in a Cyberlab Liquid Handling Robot and to each vial 0.10 mmol N-[b]benzofuranylmethyl-R-α-methyl-tryptophan-N-carboxyanhydride (0.227 M in THF) was added. To those vials that contained amine HCl salts, 0.15 mmol triethylamine (0.254 M in THF) was added, in order to liberate the free amines. THF was then added to each vial to make up the total volume to 3 mL. The vials were placed in a 40-well DTI synthesizer equipped with a heating block, 40 condensers and a nitrogen manifold. The synthesizer was kept under a continuous flow of nitrogen and was shaken at 65° C. on an orbital shaker for 2 days. The reactions were monitored by TLC (10% CH3CN in CH2Cl2). The vials in which the reaction had gone to completion were taken out. To the remaining vials CH3CN (2 mL) was added each and these were shaken at 85° C. for 19 h. The vials in which the reaction had gone to completion were taken out. To the remaining vials pyridine (1 mL) was added each and these were shaken at 105° C. for 6 h followed by 15 h at 65° C. The vials were then concentrated at reduced pressure in a Speedvac and were purified by chromatography over a 12 mL LC-Si SPE cartridge containing 2 g silica (elution with 10% CH3CN in CH2Cl2 followed by 20% CH3CN in CH2Cl2, 5% methanol in CH2Cl2, 10% methanol in CH2Cl2, 20% methanol in CH2Cl2 and 50% methanol in CH2Cl2, depending on the polarity of the products). The products were subjected to LC-MS. Those products which did contain the desired molecular ion, but were not sufficiently pure (typically<85%) were further purified by prep HPLC on a C18 reversed phase preparative column. The HPLC-purified products were re-analyzed by LC-MS to determine the purity. The 40 final products were analyzed by 1H NMR.

EXAMPLES 192 TO 308

[0326] (See Table 3 Below)

[0327] Intermediate II

[0328] Step 1

[0329] The compound was prepared as described for Intermediate I, step 1; (20.5 g, 59%); NMR (CDCl3) 2.10 (1H, s); 3.18 (2H, m); 3.60 (3H, s); 3.80-4.00 (2H, m); 6.43 (1H, s); 7.03-7.60 (9H, m); 8.00 (1H, s).

[0330] Step 2

[0331] The compound was prepared as described for Intermediate I; (7.02 g, 85%); NMR (DMSO-D6) 3.01-3.12 (2H, m); 3.52 (1H, m); 3.80 (1H, d, J=15 Hz); 3.80 (1H, d, J=14.8 Hz); 6.61 (1H, s); 6.93-7.54 (9H, m); 10.82 (1H, s).

[0332] General Procedure for Array Synthesis of Examples 192 to 308 (See Table 4 Below)

[0333] A 40-well DTI synthesizer rack was loaded with 40 Kimble vials (10 mL). To each vial approximately 0.34 g (0.10 mmol) N-[b]benzofuranylmethyl-R-tryptophan was added followed by 1.5 equivalent of an amine or amine HCl salt. The rack was placed in a Cyberlab Liquid Handling Robot and to each vial 1.0 equivalent of HBTU (0.4 M in DMF) was added followed by 1.5 equivalent of diisopropylethylamine (0.5 M in DMF). To those vials, which contained amine HCl salts, an additional equivalent of diisopropylethylamine was added. DMF was added to make the total volume up to 1.5 mL. The vials were capped and the rack was shaken on an orbital shaker at room temperature for 3 h. To each vial, water (1 mL) was added and the mixtures were purified on 3 mL LC-18 reversed phase SPE cartridges containing 500 mg of sorbent, using an ASPEC XL4 robot. The cartridges were conditioned with methanol (4 mL) followed by methanol/water 1:1 (4 mL). Water (1 mL) was loaded onto the cartridges and the crude reaction mixtures were loaded into the water layer. The cartridges were washed with water (4 mL) and methanol/water 1:1 (4 mL) and were eluted with methanol (4 mL). The methanol fractions were concentrated and the products were subjected to LC-MS. Those products which did contain the desired molecular ion, but were not sufficiently pure (typically<90%) were further purified by prep HPLC on a C18 reversed phase preparative column. The HPLC-purified products were re-analyzed by LC-MS to determine the purity. The 40 final products were analyzed by 1H NMR.

EXAMPLES 309 TO 405

[0334] (See Table 5 Below)

[0335] General Procedure for Array Synthesis of Examples 309 to 405

[0336] The N-terminal derivatives where prepared from 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, prepared as described by Boyle S., et al., Bioorg. Med. Chem. 2:357 (1994), or from 2-amino-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide (Intermediate V), using the procedure of Siegel M. G., et al., Tet. Lett. 38: 3357, (1997).

[0337] Because the compounds are potent ligands to the NK1 receptor, they are effective at displacing substance P at that position, and therefore are useful for treating biological conditions otherwise mediated by substance P. Accordingly, compounds capable of antagonising the effects of substance P at NK1 receptors will be useful in treating or preventing a variety of brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, and addiction disorders; inflammatory diseases such as arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis. The compounds of the invention, NK1 receptor antagonists, are also useful as anti-angiogenic agents, for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.

[0338] The compounds of the present invention are highly selective and competitive antagonists of the NK1 receptor. They have been evaluated in an NK1-receptor binding assay which is described below.

[0339] Human lymphoma IM9 cells were grown in RPMI 1640 culture medium supplemented with 10% fetal calf serum and 2 mM glutamine and maintained under an atmosphere of 5% CO2. Cells were passaged every 3-4 days by reseeding to a concentration of 4-8×106/40 ml per 175 cm2 flask. Cells were harvested for experiments by centrifugation at 1000 g for 3 min. Pelleted cells were washed once by resuspension into assay buffer (50 mM Tris HCl pH 7.4, 3 mM MnCl2, 0.02% BSA, 40 mg/mL bacitracin, 2 mg/mL chymostatin, 2 mM phosphoramidon, 4 mg/mL leupeptin) and repeating the centrifugation step before resuspending at a concentration of 2.5×106 cells/mL assay buffer. Cells (200 ml) were incubated with [125I]Bolton-Hunter substance P (0.05-0.1 nM) in the presence and absence of varying concentrations of test compounds for 50 min at 21° C. Non-specific binding (10% of the total binding observed under these conditions) was defined by 1 mM [Sar9, Met(02)11] substance P. Reactions were terminated by rapid filtration under vacuum onto GF\C filters presoaked in 0.2% PEI for 1-2 h, using a Brandel cell harvester. Filters were washed with 6×1 ml ice-cold Tris HCl (50 mM, pH 7.4) and radioactivity bound determined using a gamma counter. Results were analyzed using iterative curve fitting procedures in RS1 or Graphpad Inplot.

3TABLE 1In Vitro Human NK1 Receptor Binding AssayNK1 bindingExample NoIC50 (nM)15912233641213529560.773.382791121051114612141335144.715>10,000169.117344184.4195820815211808222.9

[0340] Similiar binding data are presented in Tables 2-5 for specific invention compounds.

4TABLE 2Examples 23-191YieldMol.Icms %Icms RtIC50 (nM)Ex.Name(mg)ionpurity(min)hNK1232-[(Benzofuran-2-ylmethyl)-amino]-319.74391003.071284(1H-indol-3-yl)-2-methyl-N-pyridin-2ylmethyl-propionamide242-[(Benzofuran-2-ylmethyl)-amino]-23.54391002.65473-(1H-indol-3-yl)-2-methyl-N-pyridin-3-ylmethyl-propionamide252-[(Benzofuran-2-ylmethyl)-amino]-41.94391002.61313-(1H-indol-3-yl)-2-methyl-N-pyridin-4-ylmethyl-propionamide262-[(Benzofuran-2-ylmethyl)-amino]-18.44301005.21011N-cyclohexyl-3-(1H-indol-3-yl)-2-methyl-propionamide272-[(Benzofuran-2-ylmethyl)-amino]-24.64441005.81311N-cyclohexylmethyl-3-(1H-indol-3-yl)-2-methyl-propionamide282-[(Benzofuran-2-ylmethyl)-amino]-26.5438974.644N-benzyl-3-(1H-indol-3-yl)-2-methyl-propionamide292-[(Benzofuran-2-ylmethyl)-amino]-43.1468823.227N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide302-[(Benzofuran-2-ylmethyl)-amino ]-43.3486745.8117N-[1-(4-chloro-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide312-((Benzofuran-2-ylmethyl)-amino]-29.45021006.05>10,0003-(1H-indol-3-yl)-2-methyl-N-(1-naphthalen-1-yl-ethyl)-propionamide322-[(Benzofuran-2-ylmethyl)-amino]-40.15021005.96>10,0003-(1H-indol-3-yl)-2-methyl-N-(1-naphthalen-1-yl-ethyl)-propionamide332-[(Benzofuran-2-ylmethyl)-amino]-44.44701005.119N-[1-(4-fluoro-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide342-[(Benzofuran-2-ylmethyl)-amino]-23.84971005.07143-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide352-[(Benzofuran-2-ylmethyl)-amino]-27.84821004.86313-(1H-indol-3-yl)-N-[1-(4-methoxy-phenyl)-ethyl]-2-methyl-propionamide36N-[1-(2-Amino-phenyl)-ethyl]-2-25.84671004.451620[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide37N-[1-(3-Amino-phenyl)-ethyl]-2-25.54671003.7364[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide38N-[1-(4-Amino-phenyl)-ethyl]-2-22.54671003.2141[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide392-[(Benzofuran-2-ylmethyl)-amino]-48.34951005.26863N-[1-(4-dimethylamino-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide402-[(Benzofuran-2-ylmethyl)-amino]-25.34951005.181065N-[1-(3-dimethylamino-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide412-[(Benzofuran-2-ylmethyl)-amino]-174581004.89193-(1H-indol-3-yl)-2-methyl-N-(1-thiophen-3-yl-ethyl)-propionamide422-[(Benzofuran-2-ylmethyl)-amino]-34.54521005.062613-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide432-{[2-[(Benzofuran-2-ylmethyl)-28.5500109.43613amino]-3-(1H-indol-3-yl)-2-methyl-propionylamino]-methyl }-4-hydroxy-pyrimidine-5-carboxylicacid442-[(Benzofuran-2-ylmethyl)-amino]-43.9453906.851513-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-3-yl-ethyl)-propionamide452-[((Benzofuran-2-ylmethyl)-amino]-43453957.159133-(1H-indol-3-yl)-2-methyl-N-(2-pyridin-2-yl-ethyl)-propionamide462-[(Benzofuran-2-ylmethyl)-amino]-49.55069510.21560N-(2,4-dichloro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide472-[(Benzofuran-2-ylmethyl)-amino]-52.6531956.6676163-(1H-indol-3-yl)-2-methyl-N-[2-(4-sulfamoyl-phenyl)-ethyl]-propionamide48N-(2-Amino-6-fluoro-benzyl)-2-49.3471958.686423[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide492-[(Benzofuran-2-ylmethyl)-amino]-4.9460958.221550N-(2-hydroxy-cyclohexylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide502-[(Benzofuran-2-ylmethyl)-amino]-44.4468957.61333N-(2-hydroxy-2-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide512-[(Benzofuran-2-ylmethyl)-amino]-31.15749510.32179N-(3,5-bis-trifluoromethyl-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide522-[(Benzofuran-2-ylmethyl)-amino]-39.3459959.16>10,0003-(1H-indol-3-yl)-2-methyl-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-propionamide532-[(Benzofuran-2-ylmethyl)-amino]-42452908.92623-(1H-indol-3-yl)-2-methyl-N-phenethyl-propionamide542-[(Benzofuran-2-ylmethyl)-amino]-23.2466909.95834N-(2,3-dimethyl-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide552-[(Benzofuran-2-ylmethyl)-amino]-49468958.956433-(1H-indol-3-yl)-N-(3-methoxy-benzyl)-2-methyl-propionamide56N-[2-(4-Amino-phenyl)-ethyl]-2-49467907.313228[(benzofuran-2-ylmethyl)-amino ]-3-(1H-indol-3-yl)-2-methyl-propionamide572-[(Benzofuran-2-ylmethyl)-amino]74589510.73290N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide582-[(Benzofuran-2-ylmethyl)-amino]-27466909.956243-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide592-[(Benzofuran-2-ylmethyl)-amino]-46522909.61>10,0003-(1H-indol-3-yl)-2-methyl-N-(3-trifluoromethoxy-benzyl)-propionamide602-[(Benzofuran-2-ylmethyl)-amino]-10481909.16964N-(4-dimethylamino-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide612-[(Benzofuran-2-ylmethyl)-amino ]-48.4456908.7461N-(4-fluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide62N-(4-Amino-benzyl)-2-32.3453907.29837[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide632-[(Benzofuran-2-ylmethyl)-amino]-21.6466759.95583-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-propyl)-propionamide642-[(Benzofuran-2-ylmethyl)-amino]-50.2472909.376N-(4-chloro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide652-[(Benzofuran-2-ylmethyl)-amino]-43.9516909.43700N-(2-bromo-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide662-[(Benzofuran-2-ylmethyl)-amino]-40.9522909.6934443-(1H-indol-3-yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)-propionamide672-[(Benzofuran-2-ylmethyl)-amino]-18.8466929.9433-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide682-[(Benzofuran-2-ylmethyl)-amino]-48.9468908.413123-(1H-indol-3-yl)-N-(4-methoxy-benzyl)-2-methyl-propionamide692-[(Benzofuran-2-ylmethyl)-amino]-44.7453957.681123-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-ethyl)-propionamide702-[(Benzofuran-2-ylmethyl)-amino]-38.14589010.45216N-(2-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide712-[(Benzofuran-2-ylmethyl)-amino]-40452909.131443-(1H-indol-3-yl)-2-methyl-N-(4-methyl-benzyl)-propionamide722-[(Benzofuran-2-ylmethyl)-amino]-43.2516909.4318N-(3-bromo-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide732-[(Benzofuran-2-ylmethyl)-amino]-35.2468907.561229N-(2-hydroxy-2-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide742-[(Benzofuran-2-ylmethyl)-amino]-16506909.51123-(1H-indol-3-yl)-2-methyl-N-(3-trifluoromethyl-benzyl)-propionamide752-[(Benzofuran-2-ylmethyl)-amino]-48.15281007.06>10,000N-(1,2-diphenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide762-[(Benzofuran-2-ylmethyl)-amino]-28405502.0136963-(1H-indol-3-yl)-2-methyl-N-(2-methylamino-ethyl)-propionamide772-[(Benzofuran-2-ylmethyl)-amino ]-204721006.1917N-(3-chloro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide782-[(Benzofuran-2-ylmethyl)-amino ]-9.2485501.93>10,0003-(1H-indol-3-yl)-2-methyl-N-(1,3,5-triaza-tricyclo[3.3.1.1 > 3,7]-dec-7-yl)-propionamide792-[(Benzofuran-2-ylmethyl)-amino]-30.15341006.84>10,0003-(1H-indol-3-yl)-2-methyl-N-[1-methyl-2-(3-trifluoromethyl-phenyl)-ethyl]-propionamide802-[(Benzofuran-2-ylmethyl)-amino]-22.45291005.9>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-phenyl-2-pyridin-2-yl-ethyl)-propionamide814-{[2-[(Benzofuran-2-ylmethyl)-37.45261005.59>10,000amino]-3-(1H-indol-3-yl)-2-methyl-propionylamino]-methyl}-3-methoxy-benzoic acid methyl ester822-[(Benzofuran-2-ylmethyl)-amino]-8.54321006.5111443-(1H-indol-3-yl)-2-methyl-N-(1,2,2-trimethyl-propyl)-propionamide832-[(Benzofuran-2-ylmethyl)-amino]-27.54191003.613519N-(2-dimethylamino-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide844-[2-[(Benzofuran-2-ylmethyl)-55441001.62>10,000amino]-3-(1H-indol-3-yl)-2-methyl-propionylamino]-3-(4-chloro-phenyl)-butyric acid852-[(Benzofuran-2-ylmethyl)-amino]-11.34791003.7324433-(1H-indol-3-yl)-2-methyl-N-(3-oxo-2,3-dihydro-1H-isoindol-1-yl)-propionamide862-[(Benzofuran-2-ylmethyl)-amino]-24.74601002.58>10,000oxo-imidazolidin-1-yl)-ethyl]-propionamide872-[(Benzofuran-2-ylmethyl)-amino]-38.95511004.63>10,0003-(1H-indol-3-yl)-2-methyl-N-[3-(4-pyridin-2-yl-piperazin-1-yl)-propyl]-propionamide882-[(Benzofuran-2-ylmethyl)-amino]-33.45151004.58>10,000N-[4-(2.6-dimethyl-piperidin-1-yl)-butyl]-3-(1H-indol-3-yl)-2-methyl-propionamide892-[(Benzofuran-2-ylmethyl)-amino]-21.25271008.8867353-(1H-indol-3-yl)-2-methyl-N-(1-piperidin-1-ylmethyl-cyclohexyl)-propionamide902-[(Benzofuran-2-ylmethyl)-amino]-8.24561003.07>10,000N-[2-(1H-imidazol-4-yl)-1-methyl-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide912-[(Benzofuran-2-ylmethyl)-amino]-28.14731003.07>10,0003-(1H-indol-3-yl)-2-methyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-propionamide922-[(Benzofuran-2-ylmethyl)-amino]-17.63901004.9622853-(1H-indol-3-yl)-N-isopropyl-2-methyl-propionamide932-[(Benzofuran-2-ylmethyl)-amino]-17.64731003.29>10,0003-(1H-indol-3-yl)-2-methyl-N-[1-methyl-2-(2-oxo-pyrrolidin-1-yl)-ethyl]-propionamide942-[(Benzofuran-2-ylmethyl)-amino]-30.65011003.27>10,000N-[4-(2,5-dimethyl-pyrrolidin-1-yl)-butyl]-3-(1H-indol-3-yl)-2-methyl-propionamide95N-[2-(5-Amino-1H-imidazol-4-yl)-19.24711003.5>10,0002-oxo-ethyl]-2-[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide962-[(Benzofuran-2-ylmethyl)-amino]-4.64611002.26>10,0003-(1H-indol-3-yl)-2-methyl-N-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-propionamide972-[(Benzofuran-2-ylmethyl)-amino]-304421002.26>10,000N-[2-(1H-imidazol-4-yl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide982-[(Benzofuran-2-ylmethyl)-amino]-34.55281002.26>10,000N-(2,2-diphenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide992-[(Benzofuran-2-ylmethyl)-amino]-17.94591002.26>10,0003-(1H-indol-3-yl)-2-methyl-N-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-propionamide1002-[(Benzofuran-2-ylmethyl)-amino]-7.24731002.263903-(1H-indol-3-yl)-2-methyl-N-(5-nitro-furan-2-ylmethyl)-propionamide1012-[(Benzofuran-2-ylmethyl)-amino]-19.44561002.27>10,0003-(1H-indol-3-yl)-2-methyl-N-[2-(5-methyl-1H-imidazol-4-yl)-ethyl]-propionamide1022-[(Benzofuran-2-ylmethyl)-amino]-18.9549908.66>10,000N-[1-(3-dimethylamino-phenyl)-cyclopentylmethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1032-[(Benzofuran-2-ylmethyl)-amino]-0.4478770.0574N-(1H-benzoimidazol-2-ylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1042-[(Benzofuran-2-ylmethyl)-amino]-8.34581000.068N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1052-[(Benzofuran-2-ylniethyl)-amino]-13.2510690.05>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-phenyl-[1,3]dioxolan-2-ylmethyl)-propionamide1062-[(Benzofuran-2-ylmethyl)-amino]-5.75071000.0646303-(1H-indol-3-yl)-2-methyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-propionamide1072-[(Benzofuran-2-ylmethyl)-amino]-144641000.0541453-(1H-indol-3-yl)-2-methyl-N-(2-phenyl-cyclopropyl)-propionamide1082-[(Benzofuran-2-ylmethyl)-amino]-0.64931000.0545663-(1H-indol-3-yl)-2-methyl-N-(1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-propionamide1092-[(Benzofuran-2-ylmethyl)-amino]-30.35121000.06279N-(2,5-dichloro-thiophen-3-ylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1102-[(Benzofuran-2-ylmethyl)-amino]-19.74781000.0511413-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-cyclopropylmethyl)-propionamide1112-[(Benzofuran-2-ylmethyl)-amino]-14781000.08>10,0003-(1H-indol-3-yl)-2-methyl-N-(1,2,3,4-tetrahydro-naphthalen-2-yl)-propionamide1122-[(Benzofuran-2-ylmethyl)-amino]-34831000.06123-(1H-indol-3-yl)-2-methyl-N-(3-nitro-benzyl)-propionamide1132-[(Benzofuran-2-ylmethyl)-amino]-10.14641000.05463N-indan-2-yl-3-(1H-indol-3-yl)-2-methyl-propionamide1142-[(Benzofuran-2-ylmethyl)-amino]-2.5472900.051283-(1H-indol-3-yl)-2-methyl-N-(1-thiophen-2-yl-propyl)-propionamide1152-[(Benzofuran-2-ylmethyl)-amino ]-11.5442950.05154N-(2-furan-2-yl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1162-[(Benzofuran-2-ylmethyl)-amino]-5.64601000.05>10,000N-(1-hydroxy-cyclohexylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1172-[(Benzofuran-2-ylmethyl)-amino]-14.24821000.06>10,000N-(1-furan-2-yl-cyclobutylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1182-[(Benzofuran-2-ylmethyl)-amino]-154921000.0645N-[1-(5-chloro-thiophen-2-yl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1192-[(Benzofuran-2-ylmethyl)-amino ]-4.14831000.07893-(1H-indol-3-yl)-2-methyl-N-(4-nitro-benzyl)-propionamide1202-[(Benzofuran-2-ylmethyl)-amino]-0.7506940.062652N-[2-(1H-indazol-3-yl)-1-methyl-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1212-[(Benzofuran-2-ylmethyl)-amino]-154411000.056543-(1H-indol-3-yl)-2-methyl-N-(2-pyrrol-1-yl-ethyl)-propionamide1222-[(Benzofuran-2-ylmethyl)-amino]-8.75261000.08442N-[1-(2,5-dichloro-thiophen-3-yl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1232-[(Benzofuran-2-ylmethyl)-amino]-7.3499630.04>10,0003-(1H-indol-3-yl)-2-methyl-N-[2-(octahydro-indol-1-yl)-ethyl]-propionamide1242-[(Benzofuran-2-ylmethyl)-amino]-2.64971000.07923-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide1252-[(Benzofuran-2-ylmethyl)-amino]-29.5459970.04>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-piperidin-1-yl-ethyl)-propionamide1262-[(Benzofuran-2-ylmethyl)-amino]-28448950.0767943-(1H-indol-3-yl)-2-methyl-N-(2-methyl-[1,3]dioxolan-2-ylmethyl)-propionamide1272-[(Benzofuran-2-ylmethyl)-amino]-23.94271000.05191N-furan-2-ylmethyl-3-(1H-indol-3-yl)-2-methyl-propionamide1282-[(Benzofuran-2-ylmethyl)-amino ]-31.7461950.03>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-morpholin-4-yl-ethyl)-propionamide1292-[(Benzofuran-2-ylmethyl)-amino]-37.74521000.06433-(1H-indol-3-yl)-2-methyl-N-(3-methyl-benzyl)-propionamide1302-[(Benzofuran-2-ylmethyl)-amino]-37.84641000.05163N-indan-1-yl-3-(1H-indol-3-yl)-2-methyl-propionamide1312-[(Benzofuran-2-ylmethyl)-amino]-31.64871000.08>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-methyl-2-piperidin-1-yl-propyl)-propionamide1322-[(Benzofuran-2-ylmethyl)-amino]-24.6476970.0260353-(1H-indol-3-yl)-2-methyl-N-[2-(2-thioxo-imidazolidin-1-yl)-ethyl]-propionamide1332-[(Benzofuran-2-ylmethyl)-amino]-5480870.0644793-(1H-indol-3-yl)-2-methyl-N-(2-methyl-2-phenyl-propyl)-propionamide1342-[(Benzofuran-2-ylmethyl)-amino]-27.34561000.025368N-(3-imidazol-1-yl-propyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1352-[(Benzofuran-2-ylmethyl)-amino]-13.54321000.0312053-(1H-indol-3-yl)-2-methyl-N-(tetrahydro-furan-2-ylmethyl)-propionamide1362-[(Benzofuran-2-ylmethyl)-amino]-26.6446950.02>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-methyl-tetrahydro-furan-2-ylmethyl)-propionamide1372-[(Benzofuran-2-ylmethyl)-amino]-33.6444960.031003-(1H-indol-3-yl)-2-methyl-N-thiophen-2-ylmethyl-propionamide1382-[(Benzofuran-2-ylmethyl)-amino]-25.4432960.0248673-(1H-indol-3-yl)-2-methyl-N-(tetrahydro-furan-2-ylmethyl)-propionamide1392-[(Benzofuran-2-ylmethyl)-amino]-41.7474930.0599N-(2,5-difluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1402-[(Benzofuran-2-ylmethyl)-amino]-31.84661000.05>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-phenyl-propyl)-propionamide141N-(4-Amino-naphthalen-1-11.6503950.032337ylmethyl)-2-[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide1422-[(Benzofuran-2-ylmethyl)-amino]-19.3498960.031961N-(2,3-dimethoxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1432-[(Benzofuran-2-ylmethyl)-amino]-32.9468960.02>10,000N-[2-(4-hydroxy-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1442-[(Benzofuran-2-ylmethyl)-amino]-16.4446940.02>10,000N-(1-hydroxymethyl-cyclopentyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1452-[(Benzofuran-2-ylmethyl)-amino]-35.9453970.0113013-(1H-indol-3-yl)-2-methyl-N-(2-pyridin-3-yl-ethyl)-propionamide1462-[(Benzofuran-2-ylmethyl)-amino]-0.8444900.023587N-[1-(4,5-dihydro-furan-2-yl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1472-[(Benzofuran-2-ylmethyl)-amino]-18.5460980.02>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-piperazin-1-yl-ethyl)-propionamide1482-[(Benzofuran-2-ylmethyl)-amino]-34.7478930.03>10,0003-(1H-indol-3-yl)-2-methyl-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide1492-[(Benzofuran-2-ylmethyl)-amino]-31.8490750.02>10,000N-(2,5-dimethoxy-2,5-dihydro-furan-2-ylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1502-[(Benzofuran-2-ylmethyl)-amino]-32.4466950.0426213-(1H-indol-3-yl)-2-methyl-N-(2-phenyl-propyl)-propionamide1512-[(Benzofuran-2-ylmethyl)-amino]-2.44891000.0212133-(1H-indol-3-yl)-2-methyl-N-quinolin-3-ylmethyl-propionamide1524-[2-[(Benzofuran-2-ylmethyl)-9510940.01>10,000amino]-3-(1H-indol-3-yl)-2-methyl-propionylamino]-3-phenyl-butyricacid1532-[(Benzofuran-2-ylmethyl)-amino]-6.95141000.013555N-[2-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1542-[(Benzofuran-2-ylmethyl)-amino]-6.143150.04>10,0003-(1H-indol-3-yl)-2-methyl-N-pyrrolidin-3-ylmethyl-propionamide1552-[(Benzofuran-2-ylmethyl)-amino]-25.2445930.02>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-pyrrolidin-1-yl-ethyl)-propionamide1562-[(Benzofuran-2-ylmethyl)-amino]-1.444530.05>10,0003-(1H-indol-3-yl)-2-methyl-N-piperidin-4-ylmethyl-propionamide1572-[(Benzofuran-2-ylmethyl)-amino]-38.2452950.024553-(1H-indol-3-yl)-2-methyl-N-(2-methyl-benzyl)-propionamide1582-[(Benzofuran-2-ylmethyl)-amino]-21.4464960.022567N-indan-1-yl-3-(1H-indol-3-yl)-2-methyl-propionamide1592-[(Benzofuran-2-ylmethyl)-amino]-7492920.0137573-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-3-yl-cyclobutylmethyl)propionamide1602-[(Benzofuran-2-ylmethyl)-amino]-6.15111000.03>10,0003-(1H-indol-3-yl)-2-methyl-N-(1-thiophen-2-yl-cyclohexyl)-propionamide1612-[Benzofuran-2-ylmethyl)amino]-12.34841000.01>10,000N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1622-[(Benzofuran-2-ylmethyl)-amino]-8.7466950.02423-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-propyl)-propionamide1632-[(Benzofuran-2-ylmethyl)-amino]-16.9466800.071663-(1H-indol-3-yl)-2-methyl-N-(2-oxo-2-phenyl-ethyl)-propionamide1642-[(Benzofuran-2-ylmethyl)-amino]-5.5542100.06>10,000N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1652-[(Benzofuran-2-ylmethyl)-amino]-38.14561000.08>10,000N-bicyclo[2.2.1]hept-2-ylmethyl-3-(1H-indol-3-yl)-2-methyl-propionamide1662-[Benzofuran-2-ylmethyl)-amino]-41.9456950.0737N-(3-fluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1672-[(Benzofuran-2-ylmethyl)-amino]-23.24741000.0729N-(3,4-difluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1682-[(Benzofuran-2-ylmethyl)-amino]-42.8490950.08230N-(2-chloro-4-fluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1692-[(Benzofuran-2-ylmethyl)-amino]-11.24671000.066016N-(4,6-dimethyl-pyridin-3-ylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1702-[(Benzofuran-2-ylmethyl)-amino]-49.65331000.082384N-(5-bromo-2-hydroxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1714-{[2-[(Benzofuran-2-ylmethyl)-28.7482950.06>10,000amino]-3-(1H-indol-3-yl)-2-methyl-propionylamino]-methyl}-benzoicacid1722-[(Benzofuran-2-ylmethyl)-amino]-36.84581000.071533-(1H-indol-3-yl)-2-methyl-N-(2-thiophen-2-yl-ethyl)-propionamide1732-[(Benzofuran-2-ylmethyl)-amino]-36.3475900.06>10,0003-(1H-indol-3-yl)-2-methyl-N-(2-morpholin-4-yl-2-oxo-ethyl)-propionamide174N-Benzo[1,3 ]dioxol-5-ylmethyl-2-45.74821000.0794[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide1752-[(Benzofuran-2-ylmethyl)-amino]-21.4507900.0896N-(3,4-dichloro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1762-[2-[(Benzofuran-2-ylmethyl)-44.34531000.071763amino]-3-(1H-indol-3-yl)-2-methyl-propionylamino]-3-(1H-imidazol-4-yl)-propionic acid methyl ester1772-[(Benzofuran-2-ylmethyl)-amino]-24.64901000.08444N-(4-chloro-2-fluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide178N-(3-Amino-benzyl)-2-36.24531000.061373[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide1792-[(Benzofuran-2-ylmethyl)-amino]-3.1470560.065917N-(2,4-diamino-pyrimidin-5-ylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1802-[Benzofuran-2-ylmethyl)-amino]-42456950.07266N-(2-fluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1812-[(Benzofuran-2-ylmethyl)-amino]-23.44741000.07269N-(2,4-difluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1822-[(Benzofuran-2-ylmethyl)amino]-4.1470900.06>10,000N-(3,4-dihydroxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1832-[(Benzofuran-2-ylmethyl)-amino]-1.7472330.05>10,000N-[1-hydroxymethyl-2-(1H-imidazol-4-yl)-ethyl]-3-(1H-indol-3-yl)-2-methyl-propionamide1842-[(Benzofuran-2-ylmethyl)-amino]-36.44601000.07>10,000N-(2-hydroxy-cyclohexylmethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1852-[(Benzofuran-2-ylmethyl)-amino]-28.54751000.06>10,0003-(1H-indol-3-yl)-2-methyl-N-(3-morpholin-4-yl-propyl)-propionamide1862-[Benzofuran-2-ylmethyl)-amino]-8.5454810.0784N-(2-hydroxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1872-[(Benzofuran-2-ylmethyl)-amino]-42.24861000.07131N-(3-fluoro-4-methoxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide188N-(2-Amino-methoxy-benzyl)-2-10483960.062282[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-propionamide1892-[(Benzofuran-2-ylmethyl)-amino]-47472940.071129N-(2-chloro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1902-[(Benzofuran-2-ylmethyl)-amino]-41.6474970.073537N-(2,6-difluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide1912-[(Benzofuran-2-ylmethyl)-amino]-24.4490990.0755N-(3-chloro-4-fluoro-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide

[0341]

5

TABLE 3

Examples 192-308

Yield
Mol.
Icms %
Icms Rt
IC50 (nM)

Ex.
Name
(mg)
ion
purity
(min)
hNK1

192
2-[(Benzofuran-2-ylmethyl)-amino]-
26
425
100
3.94
1981

3-(1H-indol-3-yl)-N-pyridin-2-

ylmethyl-propionamide

193
2-[(Benzofuran-2-ylmethyl)-amino]-
27
446
94
1.04
>10,000

3-(1H-indol-3-yl)-N-(2-piperazin-1-

yl-ethyl)-propionamide

194
2-[(Benzofuran-2-ylmethyl)-amino]-
41
464
100
5.63,
703

3-(1H-indol-3-yl)-N-(1,2,3,4-

5.80

tetrahydro-naphthalen-1-yl)-

propionamide

195
2[(Benzofuran-2-ylmethyl)-amino]-
23
450
100
5.39
1750

N-indan-1-yl-3-(1H-indol-3-yl)-

propionamide

196
2-[(Benzofuran-2-ylmethyl)-amino]-
36
458
100
5.67
92

3-(1H-indol-3-yl)-N-(1-thiophen-2-

yl-propyl)-propionamide

197
2-[(Benzofuran-2-ylmethyl)-amino]-
44
488
99
6.77
933

3-(1H-indol-3-yl)-N-(1-naphthalen-

1-yl-ethyl)-propionamide

198
2-[(Benzofuran-2-ylmethyl)-amino]-
31
445
99
2.27
>10,000

3-(1H-indol-3-yl)-N-[2-(1-methyl-

pyrrolidin-2-yl)-ethyl]-propionamide

199
2-[(Benzofuran-2-ylmethyl)-amino]-
39
454
100
5.11
130

3-(1H-indol-3-yl)-N-(4-methoxy-

benzyl)-propionamide

200
2-[(Benzofuran-2-ylmethyl)-amino]-
34
508
96
6.19
355

3-(1H-indol-3-yl)-N-(3-

trifluoromethoxy-benzyl)-

propionamide

201
2-[(Benzofuran-2-ylmethyl)-amino]-
21
442
100
1.22
>10,000

N-(3-imidazol-1-yl-propyl)-3-(1H-

indol-3-yl)-propionamide

202
2-[(Benzofuran-2-ylmethyl)-amino]-
6
417
98
4.3
2184

3-(1H-indol-3-yl)-N-pyrrolidin-3-

ylmethyl-propionamide

203
2-[(Benzofuran-2-ylmethyl)-amino]-
22
431
96
1.26
>10,000

3-(1H-indol-3-yl)-N-piperidin-4-

ylmethyl-propionamide

204
2-[(Benzofuran-2-ylmethyl)-amino]-
18
460
100
5.53
68

N-(2,5-difluoro-benzyl)-3-(1H-indol-

3-yl)-propionamide

205
2-[(Benzofuran-2-ylmethyl)-amino]-
10
475
97
4.27
2315

3-(1H-indol-3-yl)-N-quinolin-3-

ylmethyl-propionamide

206
2-[(Benzofuran-2-ylmethyl)-amino]-
16
428
98
2.31
6681

N-[2-(1H-imidazol-4-yl)-ethyl]-3-

(1H-indol-3-yl)-propionamide

207
2-[(Benzofuran-2-ylmethyl)-amino]-
43
489
98
6.76
591

3-(1H-indol-3-yl)-N-(1-naphthalen-

1-yl-ethyl)-propionamide

208
2-[(Benzofuran-2-ylmethyl)-amino]-
31
458
100
5.94
15

3-(1H-indol-3-yl)-N-[1-(5-methyl-

thiophen-2-yl)-ethyl]-propionalnide

209
2-[(Benzofuran-2-ylmethyl)-amino]-
35
438
100
5.74
82

3-(1H-indol-3-yl)-N-(4-methyl-

benzyl)-propionamide

210
2-[(Benzofuran-2-ylmethyl)-amino]-
36
452
100
5.98
337

3-(1H-indol-3-yl)-N-(1-p-tolyl-

ethyl)-propionamide

211
2-[(Benzofuran-2-ylmethyl)-amino]-
21
432
100
5
>10,000

N-(1-hydroxymethyl-cyclopentyl)-3-

(1H-indol-3-yl)-propionamide

212
2-[(Benzofuran-2-ylmethyl)-amino]-
18
427
96
5.21
658

3-(1H-indol-3-yl)-N-(2-pyrrol-1-yl-

ethyl)-propionamide

213
2-[(Benzofuran-2-ylmethyl)-amino]-
28
447
100
1.39
1256

3-(1H-indol-3-yl)-N-(2-morpholin-4-

yl-ethyl)-propionamide

214
2-[(Benzofuran-2-ylmethyl)-amino]-
39
467
99
4.3
4015

N-(4-dimethylamino-benzyl)-3-(1H-

indol-3-yl)-propionamide

215
2-[(Benzofuran-2-ylmethyl)-amino]-
9
498
97
6.61
70

N-(2,5-dichloro-thiophen-3-

ylmethyl)-3-(1H-indol-3-yl)-

propionamide

216
2-[(Benzofuran-2-ylmethyl)-amino]-
2
459
11
5.07
>10,000

3-(1H-indol-3-yl)-N-(5-nitro-furan-

2-ylmethyl)-propionamide

217
2-[(Benzofuran-2-ylmethyl)-amino]-
44
481
99
4.46,
819

N-[1-(4-dimethylamino-phenyl)-

4.78

ethyl]-3-(1H-indol-3-yl)-

propionamide

218
2-[(Benzofuran-2-ylmethyl)-amino]-
20
560
85
7.14
294

N-(3,5-bis-trifluoromethyl-benzyl)-

3-(1H-indol-3-yl)-propionamide

219
2-[(Benzofuran-2-ylmethyl)-amino]-
17
502
96
6.96
31

N-(3-bromo-benzyl)-3-(1H-indol-3-

yl)-propionamide

220
2-[(Benzofuran-2-ylmethyl)-amino]-
38
452
100
6.16
2

3-(1H-indol-3-yl)-N-(1-p-tolyl-

ethyl)-propionamide

221
2-[(Benzofuran-2-ylmethyl)-amino]-
37
469
100
5.67
23

3-(1H-indol-3-yl)-N-(4-nitro-

benzyl)-propionamide

222
2-[(Benzofuran-2-ylmethyl)-amino]-
30
431
100
1.64
>10,000

3-(1H-indol-3-yl)-N-(2-pyrrolidin-1-

yl-ethyl)-propionamide

223
2-[(Benzofuran-2-ylmethyl)-amino]-
36
418
100
4.65
>10,000

3-(1H-indol-3-yl)-N-(tetrahydro-

furan-2-ylmethyl)-propionamide

224
2-[(Benzofuran-2-ylmethyl)-amino]-
9
450
100
6.05
2902

3-(1H-indol-3-yl)-N-(2-phenyl-

cyclopropyl)-propionamide

225
2-[(Benzofuran-2-ylmethyl)-amino]-
32
458
97
7.07
1341

N-(1-cyclohexyl-1-methyl-ethyl)-3-

(1H-indol-3-yl)-propionamide

226
2-[(Benzofuran-2-ylmethyl)-amino]-
33
430
100
6.23
54

N-cyclohexylmethyl-3-(1H-indol-3-

yl)-propionamide

227
2-[(Benzofuran-2-ylmethyl)-amino]-
41
481
96
5.05,
182

N-[1-(3-dimethylamino-phenyl)-

5.36

ethyl]-3-(1H-indol-3-yl)-

propionamide

228
2-[(Benzofuran-2-ylmethyl)-amino]-
31
492
100
6.63
82

3-(1H-indol-3-yl)-N-(3-

trifluoromethyl-benzyl)-

propionamide

229
2-[(Benzofuran-2-ylmethyl)-amino]-
39
476
98
6.4
33

N-(3-chloro-4-fluoro-benzyl)-3-(1H-

indol-3-yl)-propionamide

230
2-[(Benzofuran-2-ylmethyl)-amino]-
38
441
100
5.54
21

3-(1H-indol-3-yl)-N-[1-(1-methyl-

1H-pyrrol-3-yl)-ethyl]-propionamide

231
2-[(Benzofuran-2-ylmethyl)-amino]-
35
425
100
0.04
790

3-(1H-indol-3-yl)-N-pyridin-3-

ylmethyl-propionamide

232
2-[(Benzofuran-2-ylmethyl)-amino]-
30
430
100
0.06
63

3-(1H-indol-3-yl)-N-thiophen-2-

ylmethyl-propionamide

233
2-[(Benzofuran-2-ylmethyl)-amino]-
37
452
100
0.07
1998

3-(1H-indol-3-yl)-N-(2-phenyl-

propyl)-propionamide

234
2-[(Benzofuran-2-ylmethyl)-amino]-
37
438
100
0.07
75

3-(1H-indol-3-yl)-N-(1-phenyl-

ethyl)-propionamide

235
2-[(Benzofuran-2-ylmethyl)-amino]-
40
456
100
0.07
3

N-[1-(4-fluoro-phenyl)-ethyl]-3-(1H-

indol-3-yl)-propionamide

236
2-[(Benzofuran-2-ylmethyl)-amino]-
41
444
100
0.07
7

3-(1H-indol-3-yl)-N-(1-thiophen-3-

yl-ethyl)-propionamide

237
2-[(Benzofuran-2-ylmethyl)-amino]-
38
435
0
0.10
5341

3-(1H-indol-3-yl)-N-(2-oxo-2-

phenyl-ethyl)-propionamide

238
2-[(Benzofuran-2-ylmethyl)-amino]-
34
442
100
0.07
89

N-(2-fluoro-benzyl)-3-(1H-indol-3-

yl)-propionamide

239
2-[(Benzofuran-2-ylmethyl)-amino]-
36
450
100
0.07
243

N-indan-2-yl-3-(1H-indol-3-yl)-

propionamide

240
2-[(Benzofuran-2-ylmethyl)-amino]-
33
425
100
0.04
196

3-(1H-indol-3-yl)-N-pyridin-4-

ylmethyl-propionamide

241
2-[(Benzofuran-2-ylmethyl)-amino]-
29
444
100
0.07
2

N-(1-cyclohexyl-ethyl)-3-(1H-indol-

3-yl)-propionamide

242
2-[(Benzofuran-2-ylmethyl)-amino]-
39
438
100
0.07
170

3-(1H-indol-3-yl)-N-(2-methyl-

benzyl)-propionamide

243
2-[(Benzofuran-2-ylmethyl)-amino]-
44
478
100
0.07
15

N-[1-(5-chloro-thiophen-2-yl)-

ethyl]-3-(1H-indol-3-yl)-

propionamide

244
2-[(Benzofuran-2-ylmethyl)-amino]-
38
442
100
0.07
12

N-(4-fluoro-benzyl)-3-(1H-indol-3-

yl)-propionamide

245
2-[(Benzofuran-2-ylmethyl)-amino]-
32
483
100
0.07
3

3-(1H-indol-3-yl)-N-[1-(4-nitro-

phenyl)-ethyl]-propionamide

246
2-[(Benzofuran-2-ylmethyl)-amino]-
39
438
100
0.07
77

3-(1H-indol-3-yl)-N-phenethyl-

propionamide

247
2-[(Benzofuran-2-ylmethyl)-amino]-
33
444
100
0.07
56

3-(1H-indol-3-yl)-N-(2-thiophen-2-

yl-ethyl)-propionamide

248
2-[(Benzofuran-2-ylmethyl)-amino]-
37
442
100
0.07
6

N-(3-fluoro-benzyl)-3-(1H-indol-3-

yl)-propionamide

249
2-[(Benzofuran-2-ylmethyl)-amino]-
43
454
100
0.06
607

N-(2-hydroxy-1-phenyl-ethyl)-3-

(1H-indol-3-yl)-propionamide

250
2-[(Benzofuran-2-ylmethyl)-amino]-
36
464
100
0.05
3413

N-(1H-benzoimidazol-2-ylmethyl)-

3-(1H-indol-3-yl)-propionamide

251
2-[(Benzofuran-2-ylmethyl)-amino]-
4
428
95
0.06
129

N-(2-furan-2-yl-ethyl)-3-(1H-indol-

3-yl)-propionamide

252
2-[(Benzofuran-2-ylmethyl)-amino]-
37
438
100
0.07
33

3-(1H-indol-3-yl)-N-(3-methyl-

benzyl)-propionamide

253
2-[(Benzofuran-2-ylmethyl)-amino]-
25
464
81
0.07
3327

3-(1H-indol-3-yl)-N-(1,2,3,4-

tetrahydro-naphthalen-2-yl)-

propionamide

254
2-[(Benzofuran-2-ylmethyl)-amino]-
37
424
100
0.06
22

N-benzyl-3-(1H-indol-3-yl)-

propionamide

255
2-[(Benzofuran-2-ylmethyl)-amino]-
41
468
100
0.07
9

3-(1H-indol-3-yl)-N-[1-(4-methoxy-

phenyl)-ethyl]-propionamide

256
2-[(Benzofuran-2-ylmethyl)-amino]-
5
440
68
0.05
>10,000

N-(2-hydroxy-benzyl)-3-(1H-indol-

3-yl)-propionamide

257
2-[(Benzofuran-2-ylmethyl)-amino]-
35
466
100
0.07
>10,000

3-(1H-indol-3-yl)-N-(2-methyl-2-

phenyl-propyl)-propionamide

258
2-[(Benzofuran-2-ylmethyl)-amino]-
38
458
100
0.07
46

N-(4-chloro-benzyl)-3-(1H-indol-3-

yl)-propionamide

259
2-[(Benzofuran-2-ylmethyl)-amino]-
39
452
100
0.07
21

3-(1H-indol-3-yl)-N-(1-phenyl-

propyl)-propionamide

260
2-[(Benzofuran-2-ylmethyl)-amino]-
32
469
100
0.06
14

3-(1H-indol-3-yl)-N-(3-nitro-

benzyl)-propionamide

261
2-[(Benzofuran-2-ylmethyl)-amino]-
31
414
100
0.06
406

N-furan-2-ylmethyl-3-(1H-indol-3-

yl)-propionamide

262
2-[(Benzofuran-2-ylmethyl)-amino]-
41
450
100
0.07
86

N-indan-1-yl-13-(1H-indol-3-yl)-

propionamide

263
2-[(Benzofuran-2-ylmethyl)-amino]-
36
458
100
0.07
9

N-(3-chloro-benzyl)-3-(1H-indol-3-

yl)-propionamide

264
2-((Benzofuran-2-ylmethyl)-amino]-
44
472
100
0.07
7

N-[1-(4-chloro-phenyl)-ethyl]-3-

(1H-indol-3-yl)-propionamide

265
2-[(Benzofuran-2-ylmethyl)-amino]-
41
452
96
0.07
328

3-(1H-indol-3-yl)-N-(1-methyl-1-

phenyl-ethyl)-propionamide

266
2-[(Benzofuran-2-ylmethyl)-amino]-
39
442
100
0.07
633

N-bicyclo[2.2.1]hept-2-ylmethyl-3-

(1H-indol-3-yl)-propionamide

267
N-Benzo[1,3]dioxol-5-ylmethyl-2-
40
468
100
0.06
55

[(benzofuran-2-ylmethyl)-amino]-3-

(1H-indol-3-yl)-propionamide

268
2-[(Benzofuran-2-ylmethyl)-amino]-
39
460
91
0.07
10

N-(3,4-difluoro-benzyl)-3-(1H-indol-

3-yl)-propionamide

269
2-[(Benzofuran-2-ylmethyl)-amino]-
9
439
92
0.04
9

3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-

ethyl)-propionamide

270
2-[(Benzofuran-2-ylmethyl)-amino]-
19
432
100
0.04
>10,000

N-(2-hydroxy-cyclohexyl)-3-(1H-

indol-3-yl)-propionamide

271
2-[(Benzofuran-2-ylmethyl)-amino]-
33
468
98
0.05
196

3-(1H-indol-3-yl)-N-[2-(4-methoxy-

phenyl)-ethyl]-propionamide

272
2-[(Benzofuran-2-ylmethyl)-amino]-
42
468
99
0.05
336

N-(1-hydroxymethyl-2-phenyl-

ethyl)-3-(1H-indol-3-yl)-

propionamide

273
2-[(Benzofuran-2-ylmethyl)-amino]-
15
432
99
0.04
>10,000

N-(4-hydroxy-cyclohexyl)-3-(1H-

indol-3-yl)-propionamide

274
2-[(Benzofuran-2-ylmethyl)-amino]-
21
456
97
0.05
264

N-[2-(2-fluoro-phenyl)-ethyl]-3-(1H-

indol-3-yl)-propionamide

275
2-[(Benzofuran-2-ylmethyl)-amino]-
38
514
100
0.05
2157

N-(2-benzylsulfanyl-1-

hydroxymethyl-ethyl)-3-(1H-indol-

3-yl)-propionamide

276
2-[(Benzofuran-2-ylmethyl)-amino]-
10
416
84
0.05
655

N-cyclohexyl-3-(1H-indol-3-yl)-

propionamide

277
2-[(Benzofuran-2-ylmethyl)-amino]-
17
474
96
0.05
2198

N-(2-cyclohexyl-1-hydroxymethyl-

ethyl)-3-(1H-indol-3-yl)-

propionamide

278
2-[(Benzofuran-2-ylmethyl)-amino]-
33
452
88
0.05
2379

3-(1H-indol-3-yl)-N-(3-phenyl-

propyl)-propionamide

279
2-[(Benzofuran-2-ylmethyl)-amino]-
8
493
86
0.06
30

N-(3,4-dichloro-benzyl)-3-(1H-

indol-3-yl)-propionamide

280
2-[(Benzofuran-2-ylmethyl)-amino]-
25
477
97
0.05
2540

3-(1H-indol-3-yl)-N-[2-(1H-indol-3-

yl)-ethyl]-propionamide

281
2-[(Benzofuran-2-ylmethyl)-amino]-
28
483
93
0.05
51

3-(1H-indol-3-yl)-N-[2-(4-nitro-

phenyl)-ethyl]-propionamide

282
2-[(Benzofuran-2-ylmethyl)-amino]-
30
487
98
0.06
833

N-[2-(4-chloro-phenyl)-1-methyl-

ethyl]-3-(1H-indol-3-yl)-

propionamide

283
2-[(Benzofuran-2-ylmethyl)-amino]-
9
492
91
0.06
420

3-(1H-indol-3-yl)-N-(4-

trifluoromethyl-benzyl)-

propionamide

284
2-[(Benzofuran-2-ylmethyl)-amino]-
33
456
98
0.05
62

N-[2-(4-fluoro-phenyl)-ethyl]-3-(1H-

indol-3-yl)-propionamide

285
2-[(Benzofuran-2-ylmethyl)-amino]-
32
483
99
0.05
246

3-(1H-indol-3-yl)-N-[1-(4-nitro-

phenyl)-ethyl]-propionamide

286
4-{[2-[(Benzofuran-2-ylmethyl)-6
474
62
005
>10,000

amino]-3-(1H-indol-3-yl)-

propionylamino]-methyl}-

cyclohexanecarboxylic acid

287
2-[(Benzofuran-2-ylmethyl)-amino]-
36
449
99
0.06
35

N-(cyano-phenyl-methyl)-3-(1H-

indol-3-yl)-propionamide

288
2-[(Benzofuran-2-ylmethyl)-amino]-
32
472
99
0.06
136

N-[2-(4-chloro-phenyl)-ethyl]-3-

(1H-indol-3-yl)-propionamide

289
2-[(Benzofuran-2-ylmethyl)-amino]-
35
468
99
0.05
209

N-(1-hydroxymethyl-2-phenyl-

ethyl)-3-(1H-indol-3-yl)-

propionamide

290
2-[(Benzofuran-2-ylmethyl)-amino]-
37
517
100
0.06
8

N-[1-(4-bromo-phenyl)-ethyl]-3-

(1H-indol-3-yl)-propionamide

291
2-[(Benzofuran-2-ylmethyl)-amino]-
29
468
96
0.05
1337

3-(1H-indol-3-yl)-N-[2-(3-methoxy-

phenyl)-ethyl]-propionamide

292
2-[(Benzofuran-2-ylmethyl)-amino]-
3
492
90
0.06
1126

3-(1H-indol-3-yl)-N-(2-

trifluoromethyl-benzyl)-

propionamide

293
2-[(Benzofuran-2-ylmethyl)-amino]-
33
456
96
0.05
55

N-[2-(3-fluoro-phenyl)-ethyl]-3-(1H-

indol-3-yl)-propionamide

294
2-[(Benzofuran-2-ylmethyl)-amino]-
15
444
86
0.06
58

N-(1-cyclohexyl-ethyl)-3-(1H-indol-

3-yl)-propionamide

295
2-[(Benzofuran-2-ylmethyl)-amino]-
34
482
99
0.06
3531

3-(1H-indol-3-yl)-N-(1-

methoxymethyl-2-phenyl-ethyl)-

propionamide

296
2-[(Benzofuran-2-ylmethyl)-amino]-
16
484
98
0.06
1338

N-(2-benzylsulfanyl-ethyl)-3-(1H-

indol-3-yl)-propionamide

297
2-[(Benzofuran-2-ylmethyl)-amino]-
36
491
100
0.05
3612

3-(1H-indol-3-yl)-N-[2-(1H-indol-3-

yl)-1-methyl-ethyl]-propionamide

298
2-[(Benzofuran-2-ylmethyl)-amino]-
22
458
99
0.06
221

N-(2-chloro-benzyl)-3-(1H-indol-3-

yl)-propionamide

299
2-[(Benzofuran-2-ylmethyl)-amino]-
28
454
93
0.05
4

N-(2-hydroxy-1-phenyl-ethyl)-3-

(1H-indol-3-yl)-propionamide

300
2-[(Benzofuran-2-ylmethyl)-amino]-
10
452
98
0.06
256

3-(1H-indol-3-yl)-N-(2-p-tolyl-

ethyl)-propionamide

301
2-[(Benzofuran-2-ylmethyl)-amino]-
12
460
98
0.06
53

N-(2,4-difluoro-benzyl)-3-(1H-indol-

3-yl)-propionamide

302
2-[(Benzofuran-2-ylmethyl)-amino]-
25
503
98
0.06
174

N-(2-bromo-benzyl)-3-(1H-indol-3-

yl)-propionamide

303
2-[(Benzofuran-2-ylmethyl)-amino]-
7
510
88
0.06
17

N-(3-fluoro-5-trifluoromethyl-

benzyl)-3-(1H-indol-3-yl)-

propionamide

304
[2-[(Benzofuran-2-ylmethyl)-
36
482
100
0.06
43

amino]-3-(1H-indol-3-yl)-

propionylamino]-phenyl-acetic acid

methyl ester

305
2-[(Benzofuran-2-ylmethyl)-amino]-
30
454
99
0.06
400

3-(1H-indol-3-yl)-N-(2-phenoxy-

ethyl)-propionamide

306
N-(4-Amino-benzyl)-2-
32
439
99
0.04
639

[(benzofuran-2-ylmethyl)-amino]-3-

(1H-indol-3-yl)-propionamide

307
2-[(Benzofuran-2-ylmethyl)-amino]-
36
466
99
0.06
392

3-(1H-indol-3-yl)-N-(1-methyl-3-

phenyl-propyl)-propionamide

308
2-[(Benzofuran-2-ylmethyl)-amino]-
6
440
94
0.05
731

N-(3-hydroxy-benzyl)-3-(1H-indol-

3-yl)-propionamide

[0342]

6

TABLE 4

Examples 309-359

Yield
Mol.
Icms %
Icms Rt
IC50 (nM)

Ex.
Name
(mg)
ion
purity
(min)
hNK1

309
3-(1H-Indol-3-yl)-2-methyl-2-
30.51
462
50
6.44
169

[(naphthalen-2-ylmethyl)-amino]-N-

(1-phenyl-ethyl)-propionamide

310
3-(1H-Indol-3-yl)-2-methyl-N-(1-
37.02
413
83
4.74
3325

phenyl-ethyl)-2-[(pyridin-2-

ylmethyl)-amino]-propionamide

311
3-(1H-Indol-3-yl)-2-methyl-N-(1-
31.53
463
84
5.96
88

phenyl-ethyl)-2-[(quinolin-2-

ylmethyl)-amino]-propionamide

312
2-[(Furan-3-ylmethyl)-amino]-3-
28
402
78
4.9
1820

(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

313
3-(1H-Indol-3-yl)-2-methyl-N-(1-
41.02
452
8
6.02
50

phenyl-ethyl)-2-[(pyridin-4-

ylmethyl)-amino]-propionamide

314
2-[(Furan-2-ylmethyl)-amino]-3-
27.6
402
74
4.82
141

(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

315
3-(1H-Indol-3-yl)-2-methyl-N-(1-
3.13
463
12
3.78
1068

phenyl-ethyl)-2-[(quinolin-3-

ylmethyl)-amino]-propionamide

316
2-[(1H-Benzoimidazol-2-ylmethyl)-
58.59
452
16
4.63
>10,000

amino]-3-(1H-indol-3-yl)-2-methyl-

N-(1-phenyl-ethyl)-propionamide

317
3-(1H-Indo1-3-yl)-2-[(5-methoxy-
33.16
482
75
7.29
>10,000

benzofuran-2-ylmethyl)-amino]-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

318
3-(1H-Indol-3-yl)-2-](isoquinolin-4-
8.84
463
55
3.28
1596

ylmethyl)-amino]-2-methyl-N-(1-

phenyl-ethyl)-propionamide

319
3-(1H-Indol-3-yl)-2-](6-methoxy-
5.15
482
65
7.22
2098

benzofuran-2-ylmethyl)-amino]-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

320
3-(1H-Indol-3-yl)-2-methyl-N-(1-
20.2
413
72
2.51
5972

phenyl-ethyl)-2-[(pyridin-3-

ylmethyl)-amino]-propionamide

321
2-{2-[2-(1,3-Dioxo-1,3-dihydro-
20.67
552
96
0.05
3040

isoindol-2-yl)-acetylamino]-

ethylamino}-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

322
2-(3-Furan-2-yl-allylamino)-3-(1H-
2.88
428
47
0.05
91

indol-3-yl)-2-methyl-N-(1-phenyl-

ethyl)-propionamide

323
3-(1H-Indol-3-yl)-2-methyl-N-(1-
28.74
519
69
0.05
3183

phenyl-ethyl)-2-[2-(pyridin-2-

ylmethoxy)-benzylamino]-

propionamide

324
3-(1H-Indol-3-yl)-2-methyl-N-(1-
32.96
519
88
0.04
2971

phenyl-ethyl)-2-[2-(pyridin-3-

ylmethoxy)-benzylamino]-

propionamide

325
3-(1H-Indol-3-yl)-2-methyl-N-(1-
42.66
504
77
0.06
72

phenyl-ethyl)-2-[(5-styryl-furan-2-

ylmethyl)-amino]-propionamide

326
2-(4-Chloro-3-methylsulfamoyl-
8.05
539
83
0.05
4827

benzylamino)-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

327
5-(4-{[2-(1H-Indol-3-yl)-1-methyl-
7.02
556
92
0.05
>10,000

1-(1-phenyl-ethylcarbamoyl)-

ethylamino]-methyl}-phenoxy)-2,2-

dimethyl-pentanoic acid

328
3-(1H-Indol-3-yl)-2-methyl-2-{[4-
17.49
498
86
0.07
>10,000

(4-methyl-pent-2-enyl)-cyclohex-3-

enylmethyl]-amino}-N-(1-phenyl-

ethyl)-propionamide

329
(2-{[2-(1H-Indol-3-yl)-1-methyl-1-
16.92
499
95
0.05
4188

(1-phenyl-ethylcarbamoyl)-

ethylamino]-methyl}-phenyl)-

carbamic acid ethyl ester

330
2-(4-Chloro-2-methylsulfamoyl-
7.56
539
89
0.05
1100

benzylamino)-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

331
2-[4-(2-Dimethylamino-ethoxy)-
24.9
499
65
0.03
>10,000

benzylamino]-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

332
2-(2,3-Diphenyl-propylamino)-3-
10.84
516
98
0.06
4944

(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

333
3-(1H-Indol-3-yl)-2-methyl-N-(1-
16.98
516
98
0.06
3606

phenyl-ethyl)-2-[(1-phenyl-1H-

indol-2-ylmethyl)-amino]-

propionamide

334
3-(1H-Indol-3-yl)-2-methyl-N-(1-
19.88
527
74
0.06
>10,000

phenyl-ethyl)-2-[4-(4-phenyl-

piperidin-1-yl)-benzylamino]-

propionamide

335
3-(1H-Indol-3-yl)-2-methyl-N-(1-
38.16
571
65
0.06
>10,000

phenyl-ethyl)-2-[4-(2-pyrrolidin-1-

yl-ethoxy)-benzylamino]-

propionamide

336
2-(4-Chloro-3-sulfamoyl-
5.2
525
79
0.03
4229

benzylamino)-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

337
4-{[2-(1H-Indol-3-yl)-1-methy1-1-
20.24
525
81
0.04
1920

(1-phenyl-ethylcarbamoyl)-

ethylamino]-methyl}-benzoic acid

methyl ester

338
2-(2,3-Diphenyl-allylamino)-3-(1H-
20.13
470
99
0.05
>10,000

indol-3-yl)-2-methyl-N-(1-phenyl-

ethyl)-propionamide

339
2-(3-Benzo[1,3]dioxol-5-yl-
24.74
514
54
0.06
343

allylamino)-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

340
2-[3-(4-Benzyloxy-phenyl)-
24.64
482
72
0.05
4912

allylamino]-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

341
2-(4-Benzyloxy-benzylamino)-3-
32.02
544
62
0.06
>10,000

(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

342
Toluene-4-sulfonic acid 3-{[2-(1H-
20.65
518
96
0.06
5091

indol-3-yl)-1-methyl-1-(1-phenyl-

ethylcarbamoyl)-ethylamino]-

methyl}-phenyl ester

343
2-[(Benzofuran-2-ylmethyl)-amino]-
23.9
582
93
0.06
13

3-(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

344
2-(3-Benzyloxy-benzylamino)-3-
33.15
518
89
0.06
185

(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

345
3-(1H-Indol-3-yl)-2-methyl-2-(4-
31.61
458
90
0.06
609

methylsulfanyl-benzylamino)-N-(1-

phenyl-ethyl)-propionamide

346
2-[(Anthracen-9-ylmethyl)-amino]-
17.46
512
73
0.07
>10,000

3-(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

347
3-(1H-Indol-3-yl)-2-methyl-2-(4-
36.52
504
95
0.06
3382

phenoxy-benzylamino)-N-(1-phenyl-

ethyl)-propionamide

348
2-[(Biphenyl-4-ylmethyl)-amino]-3-
30.82
488
93
0.06
5562

(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

349
2-[(Benzo[1,3]dioxol-5-y1methyl)-
33.19
456
94
0.06
356

amino]-3-(1H-indol-3-yl)-2-methyl-

N-(1-phenyl-ethyl)-propionamide

350
2-[2-(4-Chloro-phenylsulfanyl)-
21.92
554
90
0.07
>10,000

benzylamino]-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

351
3-(1H-Indol-3-yl)-2-methyl-N-(1-
22.24
514
88
0.07
>10,000

phenyl-ethyl)-2-(4-styryl-

benzylamino)-propionamide

352
2-(2,6-Dimethyl-octa-2,6-
30.03
458
44
0.07
2212

dienylamino)-3-(1H-indol-3-yl)-2-

methyl-N-(1-phenyl-ethyl)-

propionamide

353
3-(1H-Indol-3-yl)-2-methyl-2-{[5-
38.51
523
82
0.06
13

(4-nitro-phenyl)-furan-2-ylmethyl]-

amino}-N-(1-phenyl-ethyl)-

propionamide

354
2-[(9H-Fluoren-2-ylmethyl)-amino]-
27.91
500
92
0.06
1731

3-(1H-indol-3-yl)-2-methyl-N-(1-

phenyl-ethyl)-propionamide

355
3-(1H-Indol-3-yl)-2-[(1H-indol-3-
9.83
451
69
0.06
1047

ylmethyl)-amino]-2-methyl-N-(1-

phenyl-ethyl)-propionamide

356
3-(1H-Indol-3-yl)-2-methyl-2-(2-
33.02
508
86
0.07
>10,000

pentyl-3-phenyl-allylamino)-N-(1-

phenyl-ethyl)-propionamide

357
3-(1H-Indol-3-yl)-2-methyl-N-(1-
18.91
418
97
0.05
548

phenyl-ethyl)-2-[(thiophen-2-

ylmethyl)-amino]-propionamide

358
3-(1H-Indol-3-yl)-2-methyl-N-(1-
18.79
418
99
0.05
598

phenyl-ethyl)-2-[(thiophen-3-

ylmethyl)-amino]-propionamide

359
3-(1H-Indol-3-yl)-2-methyl-N-(1-
7.47
413
79
0.04
3712

phenyl-ethyl)-2-[(pyridin-4-

ylmethyl)-amino]-propionamide

[0343]

7

TABLE 5

Examples 360-405

Yield
Mol.
Icms %
Icms Rt
IC50 (nM)

Ex.

(mg)
ion
purity
(min)
hNK1

360
2-(3-Furan-2-yl-allylamino)-3-(1H-
12.16
414
59
0.06
>10,000

indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

361
3-(1H-Indol-3-yl)-N-(1-phenyl-
14.01
505
79
0.04
729

ethyl)-2-[2-(pyridin-3-ylmethoxy)-

benzylamino]-propionamide

362
3-(1H-Indol-3-yl)-N-(1-phenyl-
39.92
490
36
0.08
>10,000

ethyl)-2-[(5-styryl-furan-2-

ylmethyl)-amino]-propionamide

363
2-(4-Chloro-3-methylsulfamoyl-
18.8
526
86
0.06
490

benzylamino)-3-(1H-indol-3-yl)-N-

(1-phenyl-ethyl)-propionamide

364
5-(4-{[2-(1H-Indol-3-yl)-1-(1-
12.49
543
79
0.07
1247

phenyl-ethylcarbamoyl)-

ethylamino]-methyl}-phenoxy)-2,2-

dimethyl-pentanoic acid

365
2-{[4-(4-Hydroxy-4-methyl-pentyl)-
31.21
503
42
0.07
5278

cyclohex-3-enylmethyl]-amino}-3-

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

366
3-(1H-Indol-3-yl)-2-{[4-(4-methyl-
38.13
484
65
0.09
4046

pent-2-enyl)-cyclohex-3-

enylmethyl]-amino}-N-(1-phenyl-

ethyl)-propionamide

367
(2-{[2-(1H-Indol-3-yl)-1-(1-phenyl-
4.86
485
82
0.07
236

ethylcarbamoyl)-ethylamino]-

methyl}-phenyl)-carbamic acid ethyl

ester

368
2-(2-Chloro-4-morpholin-4-yl-
14.38
518
84
0.07
2239

benzylamino)-3-(1H-indol-3-yl)-N-

(1-phenyl-ethyl)-propionamide

369
2-(4-Chloro-2-methylsulfamoyl-
53.07
526
83
0.06
450

benzylamino)-3-(1H-indol-3-yl)-N-

(1-phenyl-ethyl)-propionamide

370
2-(2,3-Diphenyl-propylamino)-3-
11.18
502
73
0.08
534

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

371
3-(1H-Indol-3-yl)-2-[(4-oxo-4H-
16.18
466
66
0.07
>10,000

chromen-3-ylmethyl)-amino]-N-( 1-

phenyl-ethyl)-propionamide

372
3-(1H-Indol-3-yl)-2-[(1-oxo-1,2,3,9-
9
523
26
0.08
>10,000

tetrahydro-4-thia-9-aza-fluoren-2-

ylmethyl)-amino]-N-(1-phenyl-

ethyl)-propionamide

373
3-(1H-Indol-3-yl)-2-[(5-methyl-4-
17.38
506
2
0.07
507

oxo-6-phenyl-4H-pyran-3-ylmethyl)-

amino]-N-(1-phenyl-ethyl)-

propionamide

374
4-{[2-(1H-Indol-3-yl)-1-(1-phenyl-
33.82
456
95
0.06
1914

ethylcarbamoyl)-ethylamino]-

methyl}-benzoic acid methyl ester

375
3-(1H-Indol-3-yl)-N-(1-phenyl-
28.55
495
76
0.05
165

ethyl)-2-[(2-propyl-5-pyrrol-1-yl-

3H-imidazol-4-ylmethyl)-amino]-

propionamide

376
2-(2,3-Diphenyl-allylamino)-3-(1H-
14.27
500
76
0.08
>10,000

indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

377
2-(3-Benzo[1,3]dioxol-5-yl-
14.52
468
57
0.07
593

allylamino)-3-(1H-indol-3-yl)-N-(1-

phenyl-ethyl)-propionamide

378
2-[3-(4-Benzyloxy-phenyl)-
8.68
530
64
0.09
932

allylamino]-3-(1H-indol-3-yl)-N-(1-

phenyl-ethyl)-propionamide

379
2-(4-Benzyloxy-benzylamino)-3-
15.05
504
80
0.08
587

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

380
3-(1H-Indol-3-yl)-2-(3-naphthalen-
11.18
476
46
0.08
500

1-yl-propylamino)-N-(1-phenyl-

ethyl)-propionamide

381
Toluene-4-sulfonic acid 3-{[2-(1H-
24.84
568
92
0.08
>10,000

indol-3-yl)-1-(1-phenyl-

ethylcarbamoyl)-ethylamino]-

methyl}-phenyl ester

382
2-(3-Benzyloxy-benzylamino)-3-
44.62
504
91
0.08
>10,000

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

383
3-(1H-Indol-3-yl)-2-(4-
39.33
444
69
0.07
252

methylsulfanyl-benzylamino)-N-(1-

phenyl-ethyl)-propionamide

384
3-(1H-Indol-3-yl)-2-(4-phenoxy-
32.52
490
83
0.08
2350

benzylamino)-N-(1-phenyl-ethyl)-

propionamide

385
2-[(Biphenyl-4-ylmethyl)-amino]-3-
24.28
474
90
0.08
1463

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

386
2.-[(Benzo[1,3]dioxol-5-ylmethyl)-
41.91
442
78
0.06
240

amino]-3-(1H-indol-3-yl)-N-(1-

phenyl-ethyl)-propionamide

387
2-[2-(4-Chloro-phenylsulfanyl)-
48.88
541
96
0.09
201

benzylamino]-3-(1H-indol-3-yl)-N-

(1-phenyl-ethyl)-propionamide

338
3-(1H-Indol-3-yl)-N-(1-phenyl-
12.14
500
66
0.09
>10,000

ethyl)-2-(4-styryl-benzylamino)-

propionamide

389
2-(2,6-Dimethyl-octa-2,6-
50.41
444
5
0.08
2573

dienylamino)-3-(1H-indol-3-yl)-N-

(1-phenyl-ethyl)-propionamide

390
3-(1H-Indol-3-yl)-2-{[5-(4-nitro-
7.86
509
44
0.07
50

phenyl)-furan-2-ylmethyl]-amino}-

N-(1-phenyl-ethyl)-propionamide

391
2-[(9H-Fluoren-2-ylmethyl)-amino]-
37.84
486
85
0.08
846

3-(1H-indol-3-yl)-N-(1-phenyl-

ethyl)-propionamide

392
2-[(2,5-Dimethyl-1-phenyl-1H-
5.27
491
3
0.08
>10,000

pyrrol-3-ylmethyl)-amino]-3-(1H-.

indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

393
3-(1H-Indol-3-yl)-N-(1-phenyl-
03.2
399
71
0.04
802

ethyl)-2-[(pyridin-3-ylmethyl)-

amino]-propionamide

394
3-(1H-Indol-3-yl)-2-[(naphthalen-2-
03.7
448
88
0.06
158

ylmethyl)-amino]-N-(1-phenyl-

ethyl)-propionamide

395
3-(1H-Indol-3-yl)-N-(1-phenyl-
02.9
399
74
0.05
>10,000

ethyl)-2-[(pyridin-2-ylmethyl)-

amino]-propionamide

396
3-(1H-Indol-3-yl)-N-(1-phenyl-
04.3
404
98
0.05
1073

ethyl)-2-[(thiophen-2-ylmethyl)-

amino]-propionamide

397
2-(3,4-Dimethoxy-benzylamino)-3-
03.3
458
65
0.05
>10,000

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

398
2-(3,5-Bis-trifluoromethyl-
04.3
534
94
0.07
>10,000

benzylamino)-3-(1H-indol-3-yl)-N-

(1-phenyl-ethyl)-propionamide

399
2-(3,5-Difluoro-benzylamino)-3-
03.5
434
92
0.06
140

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

400
2-(3-Chloro-benzylamino)-3-(1H-
03.4
432
86
0.06
13

indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

401
2-(3-Fluoro-benzylamino)-3-(1H-
03.4
416
87
0.06
39

indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

402
2-[(Furan-3-ylmethyl)-amino]-3-
03.0
388
84
0.05
881

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

403
3-(1H-Indol-3-yl)-N-(1-phenyl-
0.07
426
85
0.06
3907

ethyl)-2-(3-phenyl-propylamino)-

propionamide

404
3-(1H-Indol-3-yl)-N-(1-phenyl-
03.2
404
81
0.05
2390

ethyl)-2-[(thiophen-3-ylmethyl)-

amino]-propionamide

405
2-[(Furan-2-ylmethyl)-amino]-3-
03.2
388
86
0.06
429

(1H-indol-3-yl)-N-(1-phenyl-ethyl)-

propionamide

[0344] As noted above, the compounds of formula I will be best utilized in the form of pharmaceutical formulations. The following examples further illustrate specific formulations that are provided by the invention.

EXAMPLE 406

[0345]

8

Tablet Formulation

Ingredient
Amount

3-[(benzofuran-2-ylmethyl)-amino]-3 -(IH-indol-3-yl)-2-
50 mg

methyl-N-(1-phenyl-ethyl)-propionamide,[R-(R*, S*)]

potato starch
100 mg

talc
50 mg

magnesium carbonate
20 mg

dextrose
20 mg

240 mg

[0346] The above ingredients are blended to uniformity and pressed into a tablet. Such tablets are administered to human subjects from one to four times a day for treatment of pain, depression and schizophrenia.

EXAMPLE 407

[0347]

9

Capsules

Ingredient
Amount

The compound of Example 5
200 mg

Corn starch
100 mg

Sodium benzoate
10 mg

talc
50 mg

360 mg

[0348] The ingredients are blended to uniformity and encapsulated into gelatin telescoping capsules. The capsules are administered to a human at the rate of one to three each day for treatment of rheumatoid arthritis, atheroclerosis, aberrant neovascularization, and for the inhibition of tumor cell growth.

	Number	Date	Country
Parent	09868449	Jun 2001	US
Child	10267477	Oct 2002	US

NK1 receptor antagonists

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Provisional Applications (1)

Divisions (1)