SK77598A3 - Nonpeptide derivatives, pharmaceutical composition containing them and their use - Google Patents

Description

- 1 - 7 /

Non-Peptide Derivatives, Pharmaceutical Compositions Containing Theirs, and Their Use

The present invention relates to non-peptide compounds and pharmaceutically acceptable salts thereof which are useful as gonadotropin releasing hormone antagonists and are useful for the treatment of a variety of sexually related conditions in men and women and pharmaceutical compositions containing said mammalian compounds.

Background Art

Gonadotropin releasing hormone (GnRH), also referred to as luteinizing hormone releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released from the hypothalamus and causes pituitary gland stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) biosynthesis and secretion. Pituitary LH is primarily responsible for the regulation of steroid production in the gonads of both sexes, where FSH regulates sperm production in men and follicular development in women. GnRH antagonists and agonists have been shown to be effective in treating certain conditions that require inhibition of LH / FSH release. GnRH-based treatment has been shown to be particularly effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, premature puberty, and steroid hormone-dependent sex gland tumors, particularly prostate cancer, mammary glands and ovaries. GnRH agonists and antagonists have also been used in various methods of artificial insemination and have been studied as possible contraceptives in both men and women. They have also been found to be useful in the treatment of pituitary gonadotrophic adenomas, sleep depression, irritable bowel syndrome, pre-menstrual syndrome, benign prostatic hyperplasia, excessive hair, as growth aid hormone adjuvants in growth hormone deficient children and in mice of lupus models. The compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents such as growth hormone secretagogues, such as MK-0677, in the treatment and prevention of calcium, phosphate and bone metabolism disorders, particularly preventing bone loss in treatment with GnRH antagonists, and in combination with estrogens, progestones, antiestrogens, antiprogestins and / or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flushes treated with GnRH antagonists. Further, a compound of the present invention may be administered with a 5α-reductase 2 inhibitor such as finasteride or episterid; 5α-reductase 1 inhibitor such as 5,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy) -5α-α androstane and 3-oxo-4-aza-4,7β-dimethyl-16β- (phenoxy) -5α-androstane, as disclosed in WO 03/23420 and WO 95/11254; double inhibitors of 5α-reductase 1 and 5α-reductase 2 such as 3-oxo-4-aza-17β- (2,5-trifluoromethylphenylcarbamoyl) -5α-androsan as described in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate and alpha-1-blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.

Furthermore, the compound of the present invention may be used in combination with growth hormone, growth hormone secreting or releasing hormone, to delay puberty in growth hormone deficient children, to allow growth to continue prior to pineal closure and growth arrest at puberty.

Common GnRH antagonists are GnRH-like decapeptides, which are usually administered intravenously or subcutaneously due to their poor oral activity. These have amino acids usually substituted at positions 1, 2, 3, 6 and 10.

GnRH antagonizing non-peptide agents offer the advantageous oral administration. Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), WO 95/28405, WO 95/29900 and EP 0679642, all Takeda Chemical Industries, Ltd.

Substituted indoles known in the art include the compounds described in the following patents and patent applications. U.S. Pat. 5,030,640 discloses α-heterocyclic ethanolaminoalkylindoles which are potent β-agonists. U.S. Pat. No. 4,544,663 discloses indolamine derivatives which are said to be useful as a means to reduce male fertility. WO 90/05721 discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, obesity and sclerosis agents. French Patent 2,181,559 describes indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic effects. Belgian Patent 879381 discloses 5-thioamide 3-aminoalkyl-1H-indole and carboxamide derivatives as cardiovascular agents useful for treating elevated blood pressure, Raynaud's disease and migraine.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are non-peptide GnRH antagonists that can be used to treat a variety of sex hormone-related conditions in men and women, a method of making the same, and pharmaceutical compositions containing them useful for treating mammals.

Because of their GnRH hormone antagonist activity, the compounds of the present invention are useful in the treatment of a variety of sex hormone-related diseases in men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, excessive hair, premature puberty, steroid hormone-dependent cancers such as prostate cancer, mammary gland and ovarian cancer, pituitary gonadotrophic adenoma, sleep depression, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertrophy. They are also useful as an additive for the treatment of growth hormone deficiency and low stature and for the treatment of systemic lupus erythematosis. Furthermore, the compounds of the invention may be useful in in vitro fertilization and as contraceptives. The compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids, and in the treatment of contraception. They may also be used in combination with testosterone or other androgens or antiprogestogens in men as contraceptives. These compounds may also be used in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril with an angiotensin II receptor antagonist such as losartan or a renin inhibitor for the treatment of uterine fibroids. In addition, the compounds of the invention can also be used in combination with bisphosphonates (bisphosphonic acids) and other agents for the treatment and prevention of calcium, phosphate and bone metabolism disorders, particularly in preventing bone loss during treatment with GnRH antagonists and in combination with estrogens, progesterones and / or androgens for preventing or treating bone loss or hypogonadal symptoms such as hot flushes during treatment with GnRH antagonists.

In addition, a compound of the invention may be co-administered with a 5α-reductase 2 inhibitor such as finasteride or episterid; a 5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β- (phenoxy) -5α-androstane as is described in WO 93/23420 and WO 95/11254; double inhibitors of 5α-reductase 1 and 5β-reductase 2 such as 3-oxo-4-aza-17β- (2,5-trifluoromethylphenylcarbamoyl) -5α-androstane as described in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha-1-blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin. Further, the compound of the present invention may be used in combination with growth hormone, growth hormone releasing or secreting hormone, to delay puberty in growth hormone deficient children, which will allow them to continue to grow prior to closure of the epiphyses and stop growth at puberty.

The present invention relates to compounds of the general formula

(I) wherein A is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, substituted C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, substituted C 3 -C 6 alkynyl, C 1 -C 6 alkoxy or C 0 -C 5 alkyl-S (O) n -C 0 -C 5 alkyl, C 0 -C 5 alkyl-O-C 0 -C 5 alkyl, C 0 -C 5 alkyl-NR 18 -C 10 -C 5 alkyl wherein R 18 and C 0 -C 5 alkyl may be associated with creating a circle

N- (CH 2) p - or a single bond. R c is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R 3, R 4 and R 5; R1 is

R14 R13

-B- R 2 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-OR 11, C 1 -C 6 (NR 11 R 12), C 1 -C 6 (CONR 11 R 12) or C (NR 11 R 12) NH; R 2 and A together form a ring of 5 to 7 atoms; R3, R4 and R5 are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, substituted aryl , aralkyl, substituted aralkyl, R 10 (CH 2) p -, R 11 C (O) O (CH 2) p -, R 110 C (O) (CH 2) p -, - (CH 2) p S (O) n R 17, - (CH 2) PC ( O) NR 11 R 12 or halogen wherein R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, aryl or substituted aryl; R 3 and R 4 together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; R 6 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, C 1 -C 3 perfluoroalkyl, CN, NO 2, halogen, R 10 (CH 2) p -, NR 12 C (O) R 11, NR 12 C (O) NR 11 R 12 or SO n R 11; R 7 is hydrogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl, when X is hydrogen or halogen, R 7 is absent; R 8 is hydrogen, C (O) OR 9, C (O) NR 11 R 12, NR 11 R 12, C (O) R 11, NR 12 C (O) R 11, NR 12 C (O) NR 11 R 12, NR 12 S (O) 2 R 11, NR 12 S (O) 2 NR 11 R 12, OC (O) R 11, OC (O) NR 11 R 12, OR 11, SO n R 11, S (O) n NR 11 R 12, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl, when X is hydrogen or halogen, R 8 is absent, or R 7 and R 8 taken together form a carbocyclic ring of 3 to 7 atoms; R 9 and R 9a are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl, wherein m * 0; or

R 9 and R 9a together form a carbocyclic ring of 3 to 7 atoms or || where m * 0; R 9 and A together form a heterocyclic ring containing 3 to 7 carbon atoms and one or more heteroatoms wherein m * 0; or R 10 and R 10a are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or -Ι R 10 and R 10a together form a carbocyclic ring of 3 to 7 atoms or || R 9 and R 10 and together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing one or more heteroatoms wherein m is 0; or R 9 and R 2 together form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms wherein m * 0; or R 10 and R 2 together form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; R 10 and A together form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; or R 11 and R 12 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, carbocyclic ring of 3 to 7 atoms, or substituted carbocyclic ring containing 3 to 7 atoms; R 11 and R 12 together may form an optionally substituted ring of 3 to 7 atoms; R 13 is hydrogen, OH, NR 11 R 8, NR 11 SO 2 (C 1 -C 6 alkyl), NR 11 SO 2 (substituted C 1 -C 6 alkyl), NR 11 SO 2 (aryl), NR 11 SO 2 (substituted aryl), NR 11 SO 2 (C 1 -C 3 perfluoroalkyl), SO 2 NR 11 (C 1 -C 6 alkyl), SO 2 NR 11 (substituted C 1 -C 6 alkyl), SO 2 NR 11 (aryl), SO 2 NR 11 (substituted aryl), SO 2 NR 11 (C 1 -C 3 perfluoroalkyl), SO 2 NR 11 (C (O) C 1 -C 6 alkyl), SO 2 NR 11 (C (O) -substituted C 1 -C 6 alkyl), SO 2 NR 11 (C (O) -aryl), SO 2 NR 11 (C (O) -substituted aryl), S (O) "(C 1 -C 6 alkyl), S (O) n - (substituted C 1 -C 6 alkyl), S (O) n ( aryl), S (O) n- (substituted aryl), C 1 -C 3 perfluoroalkyl, C 1 -C 3 perfluoroalkoxy, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, COOH, halogen, NO 2 or CN; R 14 and R 15 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, CN, nitro, C 1 -C 3 perfluoroalkyl, C 1 -C 3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R 110 ( CH2) p-, R11C (O) O (CH2) p-, R11OC (O) (CH2) p-, - (CH2) pS (O) nR17, - (CH2) pC (O) NR11R12 or halogen where R17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, aryl or substituted aryl; R 16 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, or N (R 11 R 12); R 18 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C (O) OR 9, C (O) NR 11 R 12, C (O) R 11, S (O) n R 11; - R 19 is as defined for R 13 or R 14; X is hydrogen, halogen, N, O, S (O) n, C (O), (CR 11 R 12) p; C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl; wherein X is hydrogen or halogen, R 7 and R 8 are absent; wherein X is O, S (O) n, C (O), or CR 11 R 12 is only R 7 or R 8; Z is O, S or NR 11; m is 0 to 3; n is 0 to 2; p is 0 to 4 and the alkyl, alkenyl and alkynyl substituents are selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C 1 -C 6 alkoxy, fluoro, C (O) OR 11, aryl C 1 -C 3 alkoxy, substituted aryl C 1 -C 3 alkoxy and aryl substituents are defined as for R 3, R 4 and R 5; or a pharmaceutically acceptable addition salt or hydrate thereof, or, where applicable, a geometric or optical isomer or racemic mixture.

Unless otherwise indicated or indicated, the following definitions will apply in the description and claims.

When any variable (e.g., aryl, heterocyclyl, R1 and the like) occurs more than once in any component of Formula I, its definition at each occurrence is independent of its definition at each other occurrence. Combinations of substituents and / or variables are permissible only if these combinations produce stable compounds.

The term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, for example, methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl and isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane and the like.

The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.

The term "halogen" or "halo" is intended to refer to fluorine, chlorine, bromine and iodine.

As used herein, the term "composition" is intended to encompass a product comprising specific ingredients in the specified amounts, as well as any product that is produced, directly or indirectly, from a combination of specific ingredients in the specified amounts.

It is contemplated that linker group A may be attached to any of the available carbon atoms or heteroatoms of the heteroaromethyl groups R 1, including both rings on the benzene ring of the fused heterocyclic groups, and the like R 13, R 14 and R 15 may be attached to any of the available carbon atoms, heteroaromatic groups R1.

In addition, it is known to those skilled in the art that many of the aforementioned heterocyclic groups may exist in more than one tautomeric form. It is believed that all these tautomers are included within the scope of the invention. Included within the scope of the invention are these optical isomeric forms, i. mixtures of enantiomers or diastereomers, for example racemates, as well as individual enantiomers or diastereomers of said compounds. These individual enantiomers are commonly referred to by the optical rotation caused by them by the symbols (+) and (-), (L) and (D), (I) and (d) or combinations thereof. These isomers may also be labeled according to their absolute spatial configuration by the letters (S) and (R), meaning sinister and rectus.

The individual optical isomers can be prepared using conventional resolution procedures, for example by treatment with a suitable optically active acid, separation of the diastereomers, and recovery of the desired isomer. In addition, individual optical isomers can be produced by asymmetric synthesis.

Moreover, a given chemical formula or name will include pharmaceutically acceptable addition salts and solvates, such as hydrates.

The compounds of the present invention, when effective alone, can be administered in the form of their pharmaceutically acceptable addition salts to provide stability, ease of crystallization, increased solubility, and other desirable properties.

The compounds of the invention may be administered in the form of pharmaceutically acceptable salts. The term " pharmaceutically acceptable salt " it is intended to include all acceptable salts. Examples of salts-forming acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic, and the like, which can be used as a dosage form to modify the solubility or hydrolysis characteristics or may be used to obtain delayed release or to obtain precursors. Depending on the particular functional groups present in the compounds of the present invention, pharmaceutically acceptable salts of the compounds of the invention include salts formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and bases such as ammonium ion, ethylenediamine, N-methylglutamine , lysine, arginine, ornithine, choline, N, N'-dibenzyl ethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane and tetramethylammonium hydroxide. These salts can be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base or alternatively by reacting the free base with a suitable organic or inorganic acid. When an acid group (-COOH) or an alcohol is also present in the compound, pharmaceutically acceptable esters, for example, methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl and the like, and esters known in the art for modifying solubility or hydrolysis characteristics for use in delayed release compositions or precursors.

The compounds of the present invention may be chiral centers other than centers whose stereochemical state is shown in Formula I and therefore may exist in the form of racemates, racemic mixtures and as single enantiomers or diastereomers, all of which isomeric forms are equally included within the scope of the invention. as mixtures thereof. In addition, some crystalline forms of the compounds of the present invention may exist as polymorphs and as such are also encompassed by the present invention. In addition, some of the compounds of the present invention may form solvates with water or with conventional organic solvents. These solvates are also encompassed by the invention.

The compounds of the invention are prepared according to the following reaction schemes. All substituents are as defined above unless otherwise indicated. -11 -

Scheme A

ABOUT

pyridine · 2γ · γ 2 -> f · thf / chci 3

Na 2 CO 3, LiCl Pd (PPh 3) 4 toluene / EtOH H 2 NNH 2 - ►

THF / EtOH

5 -12-

Reaction Scheme A

As shown in Reaction Scheme A, treatment of N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at 20-65 ° C, preferably 65 ° C, for 12-48 hours, to tryptamine (1) affords the corresponding N-phthalimidothryptamine derivative (2). N-phthalimidothryptamine (2) can be further modified by treatment with a brominating agent such as pyridine perbidine pyridine, pyrrolidone tribromide and the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform or mixtures thereof at 0 to 25 ° C hours to give 2-bromotryptamine (3). Bromide (3) can be reacted with aryl boronic acid (prepared as described in Gronowitz, S .; Hornfeldt, A, B; Yang, A, H; Chem. Scr. 1986, 26, 311-314) with palladium catalysis, weak a base such as aqueous sodium carbonate and the like and a source of chloride ions such as lithium chloride in an inert solvent such as toluene, benzene, ethanol, propanol or mixtures thereof at 25 to 100 ° C, preferably 80 ° C, for 1 to 6 hours to provide a 2-aryltryptamine derivative (4). Finally, it is possible to remove the phthalimide group by treatment with aqueous hydrazine in an inert solvent such as methanol or ethanol at 0 to 25 ° C for 4 to 24 hours to give (4) tryptamine (5).

Scheme B hoy (A) .r, O 6

O 8: triethylamine CH 2 Cl 2 - 1i 3 -

Reaction Scheme B

As shown in Reaction Scheme B, a 2-aryltryptamine may be fused to a carboxylic acid of type (6) using a 1- (3-dimethylaminopropyl) -3-ethylcarbodimide (EDC), 1,3-dicyclohexylcarbodiimide (DCC) coupling agent. ) and the like with or without the presence of 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine and the like. In an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof at room temperature or similar temperature for 3 to 24 hours to provide the corresponding amide derivative (7). Alternatively, the 2-aryltryptamine (5) is treated with an active ester or acid chloride of type (8) in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether and the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine and the like at 0 to 25 ° C for 30 minutes to 4 hours to give substance (7).

Scheme C

BH 3, THF or

LiAlH4, THF - 14-

Reaction Scheme C

As shown in Reaction Scheme C, the amide carbonyl of (7) can be reduced by treatment with borane, lithium aluminum hydride or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane and the like at 25-100 ° C, preferably 65 ° C for 1 to 8 hours to provide the corresponding amine compound (9).

Scheme D

Reaction Scheme D

As seen in Reaction Scheme D, the 2-aryltryptamine (5) may be modified by treatment with an aldehyde or ketone of type (10) in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid and the like in the presence or absence of a drying agent such as molecular sieves of 0.3 nm or magnesium sulfate and hydride sources such as borohydride or sodium cyanoborohydride in an inert organic solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dichloromethane, chloroform or mixtures thereof at 0 to 25 ° C for -15- up to 12 hours to provide the corresponding secondary or tertiary amine derivative (11).

Scheme E

ABOUT

R5 14 methanol / t-butanol

Reaction Scheme E

As shown in Reaction Scheme E, treating the arylcyclopropyl ketone type (13) in a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol, at 70-120 ° C providing 2-aryltryptamine (5) for 8-24 hours to arylhydrazine or arylhydrazine chloride (12). Alternatively, if the arylhydrazine or arylhydrazine chloride (12) is treated with an arylbutyl ketone of the type (14) containing a leaving group (chloride, bromide, iodide, O-methanesulfonate, O-trifluoromethanesulfonate and the like) in position 4 in a polar solvent such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, t-butanol or mixtures thereof at room temperature for 30 minutes to 2 hours, and then the mixture is heated to 65 to 100 ° C for 4 to 24 hours to give 2- aryltryptamine (5). -16-

Scheme F R3

Reaction Scheme F

As shown in Reaction Scheme F, type (15) iodoanilines can be reacted with arylacetylenes, a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium, a cuprous halide such as copper (I) bromide in an inert organic solvent such as triethylamine at 50-88 ° C for 30 minutes to 5 hours to give diarylacetylene (16). The acetylene (16) can be further modified by treatment with a palladium catalyst such as palladium (II) chloride or palladium (II) acetate in an inert organic solvent such as acetonitrile at 50 to 82 ° C for 30 minutes to 6 hours to give the 2-arylindole (17). -17-

Scheme G

Reaction Scheme G

As shown in Reaction Scheme G, by treatment with oxalyl chloride alone or in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran and the like, at 25 to 65 ° C for 3 to 24 hours, the acyl chloride adduct (18). The crude product (18) can be reacted with an amine of type (19) in an inert organic solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform and the like and an amine base such as triethylamine, diisopropylethylamine or pyridine at 0 to 25 ° C for 30 minutes to 4 hours to provide the amide derivative (20). The amide (20) can be further modified by treating with a reducing agent such as borane or -18-lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran at elevated temperatures, preferably reflux, for 1 to 5 hours to provide compound (21).

Scheme H

Reaction Scheme H

As shown in Reaction Scheme H, N-benzyl derivatives of type (22a) or N-benzyloxycarbonyl derivatives of type (22b) can be reduced to provide secondary amine analogs (7) by treatment with hydrogen (0.1 MPa) and a suitable catalyst such as palladium on charcoal, palladium hydroxide on carbon and the like, in an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol or mixtures thereof, to which a weak acid such as 30% aqueous acetic acid is added for 10 minutes up to 3 hours or until the aryl groups have been removed to form a secondary amine.

Scheme I

R1 H2, Raney Ni Ni -►-

Reaction Scheme I

As shown in Reaction Scheme I, treatment of the nitroindole of type (24) with hydrogen (0.1 MPa) in the presence of a suitable catalyst such as RaneyR Nickel in an inert solvent such as ethanol, methanol, and the like at room temperature for 2-12 hours results the corresponding aminoindole derivative (25), -20-

Scheme J -20- R7

Reaction Scheme J

As shown in Reaction Scheme J, amino- or hydroxyindole (25) can be modified by acylation under various conditions. For example, treatment with an acid chloride, an acid anhydride, or an active ester and an amine base such as triethylamine, diisoproylethylamine, pyridine, and the like (25) in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, or mixtures thereof at 0 ° C at room temperature. The corresponding amide ester derivatives are formed for 1 to 12 hours (26). Alternatively, compound (25) can be reacted with a carboxylic acid by treating one of the many commonly used dehydrating agents. For example, treatment with the appropriate carboxylic acid and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and the like to aminoindole (25) with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine and the like, in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at room temperature for 3 to 24 hours to give the corresponding amide or ester derivative (26). -21 -

Scheme K

Reaction Scheme K

As shown in Reaction Scheme K, urea or carbamate derivatives of compound (25) may be prepared by reaction with a carbamoyl chloride of type (27a) or alternatively with an isocyanate reagent of type (27b) and an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine and similarly in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at 0 to 65 ° C for 1 to 72 hours to give compound (28). Compound (25) can also be modified by treatment with a bis (electrophilic) agent such as phosgene, triphosgene, 1,1'-carbonylimidazole, N, N'-disuccinimidyl carbonate and the like with or without the addition of an amine base such as pyridine, triethylamine, diisopropylethylamine, N -methylmorpholine in an inert solvent such as methylene chloride, chloroform and the like at -20 to 0 ° C for 20 minutes to 2 hours. After this time, the reaction mixture is treated with a suitable mono- or disubstituted amine at a temperature of -20 to -25 ° C for 1 to 5 hours to give an analog or carbamate (28). -22-

Scheme L -22- R7 · HNR6 -f-

R1 'R * R! X ^ -fAJ-R '\ _ in »R " b'Cl 1 diisopropyl ethylamine CH 2 Cl 2 r! 31 R11 R7 a, p r-'n ^ -ci 30 R *' V > 0 0 Ϋ., 7- R3 R5 R4 diisopropyl-ethylamine CH2Cl2 r8 \ t

Reaction Scheme L

As shown in Reaction Scheme L, the amine (25) can be modified by treating the appropriate sulfonyl chloride (29) or sulfamyl chloride (30) with an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane and the like at -20 to -25 ° C for 20 minutes to 2 hours to give the corresponding N-sulfonamide (31) or N-sulfamylamide (32). -23-

Scheme M -23-

Reaction Scheme M

As shown in Reaction Scheme M, 2-aryltryptamine (33) can be modified by treatment with an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropyl alcohol, butanol, tert-butanol or mixtures thereof at 65-110 ° C for 8 to 20 hours to provide the corresponding aminoalcohol derivative (35).

Scheme N

R12, R11 NH

PyBOP CH2Cl2 / THF - > 36 -24- -24- 12

R N R R " -κ, Λ

Reaction Scheme N

As shown in Reaction Scheme N, amide derivatives of an indole derivative containing an acid such as (36) can be prepared by treatment with an appropriate amine (R 12 R 11 NH) and a suitable coupling agent such as benztriazol-1-yloxy-tris (pyrrolidino) foafonium hexafluorophosphate (PyBOP), benztriazol-1-yloxy-tris (dimethylamino) phosphonium. hexafluorophosphate (BOP), 1- (3-dimethylethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and the like with or without 1-hydroxybenzotriazole (HOBt) steric amine base such as N-methylmorpholine (NMM), triethylamine and the like in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof at or near room temperature for 3 to 24 hours to give the corresponding amine derivative (37).

The compounds of the present invention are useful in the treatment of various sex hormone-related conditions in men and women. This is reflected in their ability to act as antagonists of the neuropeptide hormone GnRH, as shown by the activity in the following in vitro assays.

Rat Pituitary GnRH Receptor Binding Assay

Crude plasma membranes prepared from rat pituitary tissues were incubated in Tris.HCI buffer (50 mM, pH 7.5) containing bovine serum albumin (0.1%), [125-Dt-Bu-Ser6-Pro9-ethylamide]. GnRH and the desired concentration of test compound. The test mixtures were incubated for 90-120 minutes at 4 ° C and then quickly filtered and repeatedly washed on a -25-glass fiber filter. The radioactivity on membrane-bound radioligands was determined by gamma counter. From these data, the IC 50 of the radioligand binding to GnRH receptors was estimated in the presence of the test compound.

LH release inhibition assay

GnRH receptor binding assay active compounds were further evaluated in an LH release assay in vitro to confirm their antagonistic activity (blocking GnRH-induced LH release).

Sample preparation

Test compounds were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%.

Test

Male Wistar rats (150-200 g) were obtained from Charles River Laboratories (Wilmington, MA). Rats were kept at a constant temperature (25 ° C) in a 12 hour light and 12 hour dark cycle. Food and water were available at will. The animals were sacrificed by decapitation and the pituitary glands were aseptically removed and placed in Hank's Balances Salt Solution (HBSS) in a 50 ml polypropylene centrifuge tube. The cuvette was centrifuged at 250 x g for 5 minutes and HBSS was removed by aspiration. The pituitary glands were transferred to a disposable Petri dish and finely chopped with a scalpel. The cut tissue was then transferred to a 50 ml disposable centrifuge tube by suspending tissue fragments three times in 10 ml HBSS containing 0.2% collagenase and 0.2% hyaluronidase. The cell dispersion was transferred to a 37 ° C water bath with gentle agitation for 30 minutes. At the end of the incubation, the cells were aspirated 20 to 30 X with a pipette and the undigested pituitary fragments were allowed to settle for 3 to 5 minutes. Suspended cells were removed by aspiration and then centrifuged for 5 minutes at 12,000 g. The cells were then resuspended in culture medium. Uncut cleavages of the pituitary glands were digested with 30 ml aliquots of cleavage enzymes as above three times with -26- f collagenase / hyaluronidase. The resulting cell suspensions were pooled, counted and diluted to 3 x 10 5 cells / mL and 1.0 mL of this suspension was placed in each well of a 24-well dish (Costar, Cambridge, MA). Cells were kept under humid 5% CO 2 -95% air at 37 ° C for 3-4 days. The culture medium consisted of DMEM containing 0.37% NaHCO 3 1 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% glutamine and 0.1% gentamycin. On the day of the experiment, the cells were washed three times 1.5 hours before the experiment and two more times immediately before the start of the DMEM experiment containing 0.37% NaHCO3.10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids (100x) , 1% glutamine (100 x), 1% penicillin / streptomycin (10,000 penicillin units and 10,000 pg streptomycin per ml) and 25 mM HEPES pH 7.4). LH release was initiated by the addition of 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicates. Incubation was performed at 37 ° C for 3 hours. After incubation, the medium was removed and centrifuged for 15 minutes at 2000 x g to remove all cell material. The supernatant was removed and tested for the presence of LH by a double antibody RIA procedure using materials obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center, Torrance, CA).

The compounds of formula I are useful in a variety of regions affected by GnRH. They can be used to treat sex hormone-related conditions, sex hormone dependent cancers, benign prostate hypertrophy, or uterine fibroid. and

Sex hormone dependent cancers that can be successfully treated by administering the compounds of this invention include prostate, uterine, mammary gland and gonadotrophic pituitary gonadotrophic cancer. Other sex hormone-dependent conditions that may be improved when administering the compounds of the present invention include endometriosis, polycystic ovarian disease, uterine fibroids, and premature puberty. The compounds may also be used in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril or an angiotensin II receptor antagonist such as losartan or a renin inhibitor to treat uterine fibroids. - 27 -

The compounds of the invention may also be useful for controlling pregnancy, as a contraceptive for men and women, for in vitro fertilization, for the treatment of premenstrual syndrome, for the treatment of lupus erythematosis, for the treatment of excessive hair, irritable bowel syndrome, and sleep disorders such as breathing interruption. sleep.

Another use of the compounds of the invention is as adjuvants for growth hormone treatment in growth hormone deficient children. The compounds may be administered with a growth hormone or a compound that increases endogenous growth hormone production or release. Certain compounds have been developed that stimulate the release of endogenous growth hormone. Peptides known as stimulating endogenous growth hormone release include growth hormone releasing hormone, GHRP-6 peptides and growth hormone releasing GHRP-1 peptides (described in U.S. Patent No. 4,411,890, PCT Patent Application Publication No. WO 89/07110 and PCT Patent Application Publication No. WO 89/07111) and GHRP-2 (described in PCT Patent Publication No. WO 93/04081) as well as hexarelin (J. Endocrinol. Invest., 15 (Appendix 4), 45, (1992)). For example, other compounds that stimulate the release of endogenous growth hormone are described in the following literature: U.S. Pat. 3,239,345; U.S. Pat. 4,036,979; US

no. 4,411,890; U.S. Pat. 5,206,235; U.S. Pat. 5,283,241; US

no. 5,284,841; U.S. Pat. 5,310,737; U.S. Pat. 5,317,017; US

no. 5,374,721; U.S. Pat. 5,430,144; U.S. Pat. 5,434,261; U.S. Pat. 5,438,136; EPO patent publication no. 0,144,320; EPO Patent Publication 0,513,974; PCT patent publication no. WO 94/07486; PCT patent publication no. WO 94/08583; PCT patent publication no. WO 94/11012; PCT patent publication no. WO 94/13696; PCT patent publication no. WO 94/19367; PCT patent publication no. WO 95/03289; PCT patent publication no. WO 95/03290; PCT patent publication no. WO 95/09633; PCT patent publication no. WO 95/11029; PCT patent publication no. WO 95/12598; PCT patent publication no. WO 95/13069; PCT patent publication no. WO 95/14666; PCT patent publication no. WO 95/16675; PCT patent publication no. WO 95/16692; PCT patent publication no. WO 95/17422; PCT patent publication no. WO 95/17422; PCT patent publication no. WO 95/17423; Science, 260, 1640-1643 (Jun. 11, 1993); Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4, (22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).

Examples of preferred growth hormone secretagogues used in the present combination include: I) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [H] -indole-5'-piperidin-1-yl) -yl) carbonyl] - and 2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 2) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1 H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 3) N, N -RH4-dihydro-1-benzenesulfonylspiro [2H-indole-5'-piperidin-1'-y-O-carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2 methylpropanamide; 4) N-N, N, N'-N-dihydro-spiro [1H-1-benzopyran-4'-piperidin-1'-O-carbonyl] -1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 5) N- [1 (R) - [(2-acetyl-1S, 5H-tetrahydro-spiro-isoquinoline-2,4'-piperidin-1-yl) -carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; 6) N-phenyl-4-dihydro-1-methanesulfonylspiro [2H-indole-5'-piperidin-1'-yl-carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 7) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate; 8) N -PRH 4 H -dihydro-1-methanesulfonylspiroISH-indole-5'-piperidin-1'-O-carbonyl] -2- (2 ', 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 9) N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- ( phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 10) N- [1 (S) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin-1'-yl) carbonyl] -2- (phenylmethylthio) ethyl] 2-amino-2-methylpropanamide; II) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3-phenylpropyl] -2 amino-2-methylpropanamide; -29- 12) N- [1 (R) - [(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -3- cyclohexyl propyl] -2-amino-2-methylpropanamide; 13) N - (1 R, 4 R) -dihydro-1-methanesulfonylspiro [OH] -indole-5 '- piperidin-1'-y-O-carbonyl] -4-phenylbutyl] -2-amino-2-methylpropanamide; 14) N, N'H-N-dihydro-1-methanesulfonylspiro [2H-indole-5'-piperidin-1'-y-O-carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2- amino-2-methylpropanamide; 15) N -R 5 R 4 -dihydro-1-methanesulfonyl-5-fluorospiro-5H-indole-5 '- piperidin-1'-yl) carbonyl] -2- (5-fluoro-1 H -indol-3-yl) ethyl] 2-amino-2-methylpropanamide; * 16) N- [1 (R) - [(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (1 H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide; d 17) N- [1 (R) - [(1,2-dihydro-1,1-dioxospiro [3 H -benzothiophene-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; and pharmaceutically acceptable salts thereof.

The compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents such as growth hormone secretagogues, such as MK-0677, for the treatment and prevention of calcium, phosphate and bone metabolism disorders, in particular for the prevention of bone loss during treatment with GnRH antagonists and in combination with estrogens, progesterones and / and androgens to prevent and treat bone loss or hypogonadal symptoms such as hot flushes during treatment with a GnRH antagonist.

Bisphosphonates (bisphosphonic acids) are known as bone resorption inhibiting compounds and are useful for treating bone stone as described in U.S. Patent 4,621,077 Rosini et al.

A number of bisphosphonic acids useful in the treatment and prevention of bone resorption diseases are described in the literature. Representative examples can be found in the following references: U.S. Pat. 3,251,907; U.S. Pat. 3,422,137; U.S. Pat. 3,584,125; U.S. Pat. 3,940,436; U.S. Pat. 3,944,599; U.S. Pat. 3,962,432; U.S. Pat. 4,054,598; U.S. Pat. 4,267,108; US

no. 4,327,039; U.S. Pat. 4,407,761; U.S. Pat. 4,578,376; US

no. 4,621,077; U.S. Pat. 4,624,947; U.S. Pat. 4,746,654; US - 30 - Patent No. 4,761,406; U.S. Pat. 4,922,007; U.S. Pat. 4,942,157; U.S. Pat. 5,227,506; U.S. Pat. 5,270,365; EPO publication no. 0.252,504 and J. Org. Chem., 36, 3843 (1971). The production of bisphosphonic and halobisphosphonic acids is well known in the art. Examples can be found in the above references which describe these compounds as useful in the treatment of calcium or phosphate metabolism disorders, particularly as bone resorption inhibitors. Preferred bisphosphonates are selected from the group consisting of alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidenebisphosphonic acid, and 1- * hydroxy-3- (methylpentylamino) -propylidene-bisphosphonic acid; and pharmaceutically acceptable salts thereof. A particularly preferred bisphosphonate is alendronic acid (alendronate) or a pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has been marketed in the United States under the trademark FOSAMAXR.

In addition, the compounds of the present invention may be administered with a 5α-reductase 2 inhibitor such as finasteride or episterid; a 5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one; 3-oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy) -5α-androstane and 3-oxo-4-aza-4,7β-dimethyl-16β- (phenoxy) -5α-androstane, as described in WO 93/23420 and WO 95/11254, with double inhibitors of 5α-reductase 1 and 5α-reductase 2 such as 3-oxo-4-aza-17β- (2,5-trifluoromethylphenylcarbamoyl) -5α-reductase 2 androstane, described in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate and alpha-1-blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.

Furthermore, the compounds of the present invention may be used in combination with growth hormone, a growth hormone releasing hormone, or growth hormone secretagogues to delay puberty in growth hormone deficient children, allowing them to grow further prior to closure of the epiphyses and arrest of growth in puberty. - 31 -

For combined treatment with more than one active ingredient, where the active ingredients are in separate dosage forms, the active ingredients may be administered separately or together. In addition, administration of one component may be effected prior to, simultaneously with, or after administration of the other component.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, pills, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared by any method known in the art, and the compositions may contain one or more selected from the group of sweeteners, flavoring agents, coloring agents and preservatives to provide pharmaceutical elegant and patient-acceptable pharmaceutical compositions. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch or alginic acid, binding agents such as starch, gelatin or acacia and glidants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action over a longer period. For example, delaying agents such as glycerol monostearate or glycerol distearate may be used. the compositions may also be coated by the methods described in US Patent 4,256,108, 4,166,452 and 4,265,874 to form controlled release osmotic therapeutic tablets.

Compositions for oral use may also be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily environment , for example, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are -32- suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersing or wetting agents which may be naturally occurring phosphatides, for example lecithin, or condensation products alkylene oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecethyleneoxycethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty ester partial esters hexitol acids and anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, solid paraffin or cetyl alcohol. * ≫ sweeteners such as those mentioned above and flavoring agents. These compositions can be protected by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for the manufacture of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting and suspending agents are exemplified above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring phosphatides, such as soybean, lecithin and esters or partial esters derived from -33- fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated using sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. These compositions may also contain a quenching agent, preservative, and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the knowledge of the art using such dispersing or wetting agents and suspending agents as mentioned above. sterile

The injectable composition may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in injectables.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating carrier that is solid at normal temperatures but liquefied at the rectal temperature and will therefore melt to release the drug. Suitable materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions, and the like, containing a compound of Formula I are used. (For the purpose of this application, topical application will include mouthwashes and gargles).

The compounds of the present invention may be administered in intranasal form by topical use of a suitable intranasal carrier or transdermally using such forms of transdermal skin patches as are known in the art. Of course, for administration in the form of a transdermal system, administration will, of course, be more than -34 intermittent during the dosage regimen. The compounds of the present invention may also be provided in the form of suppositories using bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. The dosage regimen utilizing the compounds of the present invention is selected according to a variety of factors including the type, species, age, weight, sex and health of the patient; the severity of the condition being treated; routes of administration, renal and hepatic function of the patient; and the particular compound employed. A physician or veterinarian of ordinary skill in the art will readily determine and prescribe the effective amount of drug required to prevent, prevent, arrest, or prevent the progress of the condition being treated. Optimal accuracy in achieving drug concentration within an effective range without toxic action requires a regimen based on the kinetics of drug availability to target sites. This requires consideration of the distribution, balance and excretion of the drug. Preferably, the doses of the compound of formula I of the present invention will range from 0.01 to 1000 mg per adult human per day. More preferably, the doses will be from 0.1 to 500 mg / day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 mg of active ingredient, in particular 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10. , 0, 15.0, 25.0, 50.0, 100 and 500 mg of the active ingredient for symptomatic dose adjustment in the treated patient. The effective amount of the drug is usually administered at a dose of from about 0.0002 mg / kg to about 50 mg / kg of body weight per day. In particular, the range is from about 0.001 to 1 mg / kg body weight per day. Preferably, the active agent of the present invention is administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

The amount of active ingredient may be combined with the carrier materials to form a single dosage form that will vary depending upon the patient being treated and the route of administration used.

It will be understood, of course, that the specific dose for each patient will depend on a variety of factors including age, body weight, overall health, condition, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, and severity of the particular disease being treated.

The following examples illustrate the production of certain compounds of the invention and are not to be construed as limiting.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 H1

OMe 1- [2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamino] -3- (pyridin-4-yloxy) propan-2-ol To the solution of [2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamine (118 mg in 4 mL dry methanol) was added 20 mg of 4-oxoranylmethoxypyridine and the mixture was heated to 80 ° C in an oil bath. After 6 h, the mixture was concentrated in vacuo and purified by silica gel flash chromatography (methylene chloride: methanol: ammonium hydroxide, 90: 10: 1) to give the title compound (53 mg), m / e = 448 (M + H ).

Following a similar procedure to that described in Example 1, the following compounds were prepared:

-36-

Example no. R 3 R 3, R 4, R 5 A m / e 1A Pyridine: -4-NH-COCH 3 3,4-OMe CH 2 -O-1B Pyridine. -4-NH 2 3,4-OMe CH 2 -O 463 (M + H).

Example 2.1

{2- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl] - (5-pyridin-4-ylpentyl) amine Step 2.1A 2- [2- (1H-indole -3-yl) ethyl] isoindole-1,3-dione To a stirred suspension of 2- (1H-indol-3-yl) ethylamine (2.0 g in 20 mL of dry tetrahydrofuran) was added N-carbethoxyphthalimide (2.85 g) ) and the mixture was refluxed in an oil bath. After 48 hours, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The solid obtained was suspended in hexane / methylene chloride (2.5: 1) and filtered. Purification of the obtained solids by flash chromatography (methylene chloride: methanol, 97: 3) gave the title compound (3.1 g).

Step 2.1 B 2- [2- (2-Bromo-1 H -indol-3-yl) -ethyl] isoindole-1,3-dione -37- To the 2- [2- (1H-indole-3- yl) -ethyl] isoindole-1,3-dione (1.0 g in a mixture of 10 mL of dry tetrahydrofuran and 10 mL of dry chloroform) at 0 ° C was added pyridinium bromide perbromide (1.14 g) and the reaction mixture was stirred at 0 ° C. . After 50 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution (3x) and 0.3M sodium bisulfate (3x) and then dried over magnesium sulfate. The concentrate was purified by silica gel flash chromatography (hexane: ethyl acetate, 3: 1) to give the title compound (1.2 g).

Step 2.1 C 2- {2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl] ethyl} isoindole-1,3-dione To a solution of 2- [2- (2-bromo-1 H- indol-3-yl) ethyl] isoindole-1,3-dione (150 mg in a mixture of 5 ml of toluene and 5 ml of ethanol) was added 3,5-dimethylboronic acid (85 mg) followed by 1.0 ml of 1M sodium carbonate . To the stirred solution was added lithium chloride (60 mg) followed by tetrakis (triphenylphosphine) palladium (28 mg), and the mixture was refluxed in an oil bath. After 4 hours, the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane: ethyl acetate, 5: 1) gave the title compound (146 mg).

Step 2.1 D 2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl] ethylamine To a solution of 2- {2- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] ] -ethyl} isoindole-1,3-dione (87 mg in a mixture of 4 mL of tetrahydrofuran and 4 mL of ethanol) was added 0.6 mL of 95% aqueous hydrazine and the reaction mixture was stirred at room temperature. After 18 hours, the mixture was concentrated in vacuo and purified by silica gel flash chromatography (methylene chloride: methanol: ammonium hydroxide, 9: 6: 1) to give the title compound (54 mg). -38-

Step 2.1 E {2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl] ethyl} - (5-pyridin-4-ylpentyl) amine To a solution of 2- [2- (3, 5-dimethylphenyl) -1H-indol-3-yl] ethylamine (162 mg) and 5- (4-pyridyl) pentanal (100 mg in 2 mL dry chloroform) was added anhydrous magnesium sulfate (735 mg) and the mixture was stirred for 15 hours. minutes at 0 ° C. At the same time, sodium borohydride (92.7 mg) was added followed by 3 mL of dry methanol and the mixture was stirred at 0 ° C. After 1 hour, the reaction was quenched by pouring into water (25 mL), stirred for 30 minutes and then extracted with methylene chloride (4 x 25 mL). The combined organic phases were dried over potassium carbonate, concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to give the title compound (172 mg), m / e = 412 (M + H) . Production of synthetic intermediates

Step A 5- (4-pyridyl) -4-pentin-1-ol

4-Bromopyridine hydrochloride (3.89 g) or dissolved in a mixture of solvents containing triethylamine (25 mL) and water (5 mL). To the pyridine salt was added anhydrous lithium chloride (848 mg), copper (I) bromide powder (30 mg) and 5-pent-4-yn-1-ol (1.68 g), and the mixture was stirred with a stream of nitrogen for about 15 minutes ; then tetrakis (triphenylphosphine) palladium (231.1 mg) was added. The reaction mixture was refluxed under nitrogen and held at this temperature for 2.5 hours. Then the heating was stopped and the reaction mixture was left to stand at room temperature. The reaction products were isolated by partitioning between ether and brine. The aqueous layer was further extracted with ether (4 x 50 mL) and the combined fractions were dried over anhydrous sodium sulfate. The extract was filtered and evaporated under reduced pressure to give a dark brown oil. Column chromatography using pure ethyl acetate as eluent yielded 2.1 g of a yellow oil, 5- (4-pyridyl) -pentin-1-ol, which slowly solidified and slightly darkened on standing at room temperature. -39-

Step B 5- (4-pyridyl) pentan-1-ol 5- (4-pyridyl) -pentin-1-ol (1.5 g) obtained in the previous step was dissolved in methanol (35 ml) in Parr. hydrogenation flask and platinum oxide (Adams catalyst) (0.3 g) was added. The flask was placed in a Parr hydrogenator and the solution was hydrogenated at 10 psi for 5.5 hours, after which the starting material was consumed by TLC analysis. The spent catalyst was removed by filtration through a celite bed, which was carefully washed with additional methanol. The combined filtrates were evaporated under reduced pressure on a rotary evaporator and the oily residues were then purified by short silica gel column chromatography using pure ethyl acetate as eluent to give the title compound (1.4 g).

Step C 5- (4-pyridyl) pentanal

Oxalyl chloride (2 mL of a 2M solution in dry methylene chloride) was placed in a cold oven-dried oven and cooled to -78 ° C using a dry ice-acetone bath and a solution of DMSO (632 mg) in dry methylene chloride was added dropwise over 3 min. (1 mL). The solution was then stirred for an additional three minutes. A solution of 5- (4-pyridyl) -4-pentan-1-ol (0.6 g) in dry methylene chloride (5 ml) was added to the reaction vessel over about 3 minutes and the reaction mixture was stirred for 15 minutes. Anhydrous triethylamine (2.82 mL) was added and the reaction was stirred for an additional 2 hours while the ice bath was warmed to room temperature. The reaction was quenched by addition of a saturated salt solution and the reaction mixture was partitioned with methylene chloride. The aqueous layer was decanted and the methylene chloride extract dried over powdered anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give an oily residue. The product was isolated by silica gel column chromatography using ethyl acetate as eluent (488 mg). -40-

{2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} - [3- (1H-indol-5-yl) propyl] amine Step 2.2A N- {2- [2 - (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} - (3-1H-indol-5-yl) propionamide To a solution of 3- (1H-indol-5-yl) propionic acid (50 mg) in 2.5 ml of N, N-dimethylformamide) 1-hydroxybenztriazole (43 mg) was added at 0 ° C followed by 71 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride and allowed to warm to rooms. After 23 minutes, 155 mg of 2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamine was added and the mixture was stirred for another hour at room temperature. The reaction was then quenched by the addition of water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and the concentrated oil was purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to give the title compound (111 mg).

Step 2.2B {2- [2- (3,4-Dimethoxyphenyl) -1H-indol-3-yl] ethyl} - [3- (1H-indol-5-yl) propyl] amine To the N- { 2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} - (3-1H-indol-5-yl) propionamide (60 mg in 2.0 mL dry tetrahydrofuran) ) 26 Ig of lithium aluminum hydride was added at 0 ° C and the mixture was heated in an oil bath to 77 ° C. After 5.5 hours, the mixture was cooled to 0 ° C and the reaction was quenched by the addition of 0.025 µL of water and stirred vigorously for 30 minutes, then filtered through a pad of sodium sulfate and the filtrate was concentrated in vacuo. Purification by flash chromatography (methylene chloride: methanol, 92: 8) gave the title compound (32 mg), m / e = 454 (M + H).

By following a procedure similar to that described in Examples 2.1 and 2.2, the following compounds were prepared:

Example no. R1. r3, r4, r5; A = (CH 2) nm / e 2A 3-Phenyltriazine 3,4-OMe 1,428 (M + H) 2B 5-indole 3,4-OMe 1,426 (M + H) 2 C 5-benzimidazole 3,4-OMe 1 427 (M + H) 2D 4-indole 3,4-OMe 1,426 (M + H) 2 E 3-pyridyl 3,5-Me 5 412 (M + H) 2 F 4 -pyridyl 3,5-Me 4,498 ( M + H) 2G 2-pyridyl 3,5-Me 4,498 (M + H) 2H 3-pyridyl 3,5-Me 4,498 (M + H) 21 5-pyrimidine 3,5-Me 4,499 (M + H) 2 H H 3.5-Me 4 453 (M + H) 2 K 0 Lanam N Me H 3.5-Me 4 455 (M + H) -42-2 L and " OMe 3.5-Me " (M + H) 2 AO 3.5-Me 4 415 (M + H) 2 · A 3.5 · Me 4 414 (M + H) 20 3.5-Me 4.43 (M + H) 2Ρ ΌΧ. H 3.5-Me 4.491 (M + H) 2 Q 4-pyridyl 3,5-Me 2 370 (M + H) 2 R 3-pyridyl 3,5-Me 2 370 (M + H) 2 S 2-pyridyl 3 5-Me 2 370 (M + H) -2,4-imidazolyl 3,5-Me 2 359 (M + H) 2 4-pyridyl 3,5-Me 1,356 (M + H) 2 V 2-pyridyl 3,5 -Me 1356 (M + H) 2 W 3-pyridyl 3,5-Me 1,356 (M + H) 2X 3-pyridyl 3,5-Me 3,384 (M + H) 2 Y 4-pyridyl 3,5-Me 3,384 (M + H) 2Z 3-quinolinyl 3,5-Me 4,448 (M + H) 2AA ΤΧ, -Β N'N 3.5-Me 4,481 (M + NH 3) 2BB 3.5-Me 4 -43-

Example 3

[3- (3H-benzimidazol-5-yl) allyl] - {2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} amine Step 3A {2- [2- (3 4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} - [3- (1-methanesulfonyl-1 H -benzoimidazol-5-yl) allyl] amine To a solution of 3- (1H-benzimidazol-5-yl) propyl -2-en-1-ol (44 mg) in a mixture of 2 ml of methylene chloride and 0.1 ml of Ν, β-dimethylformamide) at 0 ° C was gradually added 346 mg of tetrabutylammonium bromide, 0.110 ml of diisopropylethylamine and 100 mg of methanesulfonic anhydride and was allowed to warm to room temperature. After 1 hour, this mixture was added to a solution of 2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamine (300 mg in a mixture of 6 ml of methylene chloride and 1.5 ml of Ν, Ν-dimethylformamide) and continuously stirred for 2.5 hours. Then the mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (methylene chloride: methanol, 91: 9) to give the title compound (24 mg).

Step 3B

I

[3- (3-H-benzimidazol-5-yl) allyl] - {2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} amine To the {2- [2- (3,4-Dimethoxyphenyl) -1H-indol-3-yl] ethyl} - [3- (1-methanesulfonyl-1 H -benzoimidazol-5-yl) allyl] amine (24 mg in 1.5 mL methanol) was 0.225 ml of 2N potassium hydroxide solution was added at 0 ° C, and the mixture was allowed to warm to room temperature. After 1.5 h, the reaction was quenched by the addition of 0.30 mL of 1N hydrochloric acid, concentrated in vacuo, and purified by flash chromatography on silica gel (methylene chloride: methanol, 88:12) to give the title compound (12 mg), m / e = 453 (M + H).

Production of synthetic intermediates

Step A, 1H-Benzimidazole-5-carboxylic acid kyseliny-methoxymethylamide To a suspension of 1H-benzimidazole-5-carboxylic acid (500 mg in 7 mL of N, N-dimethylformamide) was added 500 mg of 1-hydroxybenzotriazole (HOBt) at 0 ° C. and then 828 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) chloride and allowed to warm to room temperature. After 42 minutes, 1.05 g of Ν, β-dimethylhydroxylamine hydrochloride and 1.5 ml of triethylamine were added and stirring was continued at room temperature. The reaction was quenched after 1 hour by the addition of water and the product was isolated by extraction with ethyl acetate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol, 90:10) gave the title compound (458 mg).

Step B 1 H-Benzimidazole-5-carboxaldehyde To a solution of 1 H -benzoimidazole-5-carboxylic acid Ν, oxy-methoxymethylamide (458 mg in a mixture of 5 mL of diethyl ether and 10 mL of tetrahydrofuran) was added at -78 ° C. 7 ml of a 1.5 M solution of diisobutylammonium hydride in toluene and the mixture was stirred at low temperature. After 1 hour, the reaction mixture was transferred via needle into sodium potassium tartrate solution at 0 ° C. The resulting slurry was stirred vigorously at room temperature for 2 hours and then extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (250 mg).

Step C

3- (1H-benzimidazol-5-yl) acrylic acid methyl ester To a solution of 1H-benzimidazole-5-carboxaldehyde (250 mg in 12 mL dry tetrahydrofuran) at 0 ° C was added 1.43 g of methyl (triphenylphosphoranylidene) acetate - 45 and the mixture was allowed to warm to room temperature. After 24 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 93: 7) to give the title compound (257 mg).

Step D 3- (1H-Benzimidazol-5-yl) prop-2-en-1-ol To a solution of 3- (1H-benzimidazol-5-yl) acrylic acid methyl ester (50 mg in 1 mL dry tetrahydrofuran) was added. 1.24 ml of a 1M solution of tri-sec-butylborohydride lithium b in tetrahydrofuran was added at -78 ° C, and the mixture was stirred at -78 ° C for 4 hours and then heated at -40 ° C for a further 4 hours. The reaction was quenched by the addition of aqueous methanol, concentrated in vacuo, and purified by flash chromatography on silica gel (methylene chloride: methanol, 87:13) to give the title compound (44 mg).

Following a similar procedure to that described above, the following compound was prepared:

Example no. X-R 7, R 8 .; R 1, R 3, R 4, R 5; m / e 3A H 5-benzimidazole -N-SO 2 Me 3.4-OMe - -46-

Example 4.1

[2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl] - (4-pyridin-4-yl-butyl) amine Step 4.1 A 2- [2- ( 3,5-dimethyl-phenyl) -5-methanesulfonyl-1 H-indol-3-yl] ethylamine

A suspension of 4- (methanesulfonyl) phenylhydrazine (3.0 g, 16.1 mmol) and 3-chloropropyl-3,5-dimethylphenylcatone (3.4 g, 16.1 mmol) in t-butanol (25 mL) was stirred at room temperature for 20 minutes and was rapidly heated in a spar bath. Methanol (250 mL) was added and the mixture was refluxed overnight. Then the mixture was concentrated to a small volume, the crystals were filtered off and washed with cold methanol. The combined filtrates were evaporated to leave a residue which was partitioned between ethyl ether and water. The ether layer was then extracted twice with water and the combined aqueous extracts were washed with ethyl ether and basified with 5N sodium hydroxide. The product was extracted three times with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to a syrup (3.1 g). The crude material was purified by flash chromatography on silica gel (methylene chloride: methanol, 9: 1) to give the title compound (1.99 g, 36%), R f 0.19 (reacted with ninhydrin).

Step 4.1B N- [2- [2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl] -4-pyridin-4-yl-butyryl-amide -47-

A mixture of 2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] ethylamine (1.29 g, 3.77 mmol), 4- (4-pyridyl) butanoic acid (1 , 37 g, 8.29 mmol), 4-methylmorpholine (1.25 mL, 11.33 mmol), 1-hydroxybenzotriazole (1.53 g, 11.33 mmol) and chloride 2: (3-dimethylaminopropyl) -3 ethylcarbodiimide (1.74 g, 9.08 mmol) in η, β-dimethylformamide (10 mL) was stirred at room temperature for 14 hours. Then the solution was co-distilled with n-butanol (3x) to give a residue which was purified by flash chromatography on silica gel (methylene chloride / methanol, 97: 3) to give the title compound (1.45 g, 79%).

Step 4.1 C

[2- (2- (3,5-dimethylphenyl) -5-methanesulfonyl-1 H-indol-3-yl] -ethyl] - (4-pyridin-4-yl-butyl) -amine

Borane-THF mixture (1.0 M solution in tetrahydrofuran, 27 mL) was added dropwise to a solution of N- [2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] ethyl ] -4-pyridin-4-yl-butyrylamide (1.45 g, 2.96 mmol) in dry tetrahydrofuran (20 mL) and reflux for 2 hours. Then methanol was added to remove excess borane and the remaining solution was evaporated to dryness. The residue was dissolved in tetrahydrofuran (20 mL) and N, N-dimethylethanolamine (8.9 mL, 88.86 mmol) was added. The residue was refluxed for 2.5 hours and then concentrated to dryness. The crude material was purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to give the title compound (1.0 g, 71%). m / e = 476 (M + H).

Step 4.1 D 4- [2- [2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] ethyl] - (4-pyridin-4-yl-butyl) -amine (dihydrochloride) To a solution of [2- (2- (3,5-dimethyl-phenyl) -5-methanesulfonyl-1H-indol-3-yl] -ethyl] - (4-pyridin-4-yl-butyl) -amine (300 mg, 0.63 mmol) in dry tetrahydrofuran (20 mL) was added dropwise a solution of hydrogen chloride in ethyl ether (1.0 M, 1.4 mL) dropwise at 0 ° C. After 10 min, excess hydrogen chloride and solvents were evaporated to give 4848- The product was further dried under high vacuum at 50 ° C to give the title compound.

Example 4.2

Me Me '.N

3- [2- (3,5-Dimethyl-phenyl) -3- [2- (5-pyridin-4-yl-pentylamino) -ethyl] -1H-indol-5-yl] -1,1-dimethyl-urea

Step 4.2A 2- [2- (3,5-Dimethyl-phenyl) -5-nitro-1H-indol-3-yl] -ethylamine 1- (4-chloro-1-oxo-butyl) -3,5- dimethylbenzene (2.5 g) was dissolved in 12 ml of t-butanol and stirred at room temperature and then 4-nitrophenylhydrazine (1.65 g) was added. The reaction mixture was stirred at room temperature for 20 minutes, then water (12 mL) and methanol (108 mL) were added and the mixture was refluxed for 17 hours. Then the reaction mixture was cooled to room temperature and the volatile solvents were removed under reduced pressure on a rotary evaporator. The residues were evaporated to dryness using a stream of nitrogen gas overnight. The solid dry residues were triturated with ethyl acetate (about 100 mL) and scraping crystallization was started and the sample was placed in the refrigerator for 8 hours. The obtained solid material was placed in a sintered glass funnel under vacuum and washed with dry ethyl acetate. 1.4 g of solid was obtained.

Step 4.2B

(2- [2- (3,5-Dimethyl-phenyl) -5-nitro-1H-indol-3-yl] -carbamic acid tert-butyl ester -49-

2- [2- (3,5-Dimethyl-phenyl) -5-nitro-1 H -indol-3-yl] -ethylamine hydrochloride (1 g) was suspended in dry methylene chloride and 0.806 mL of triethylamine was added and the mixture was stirred at room temperature for 5 minutes. rooms. [2- (tert-butoxycarbonyloxyimino) phenylacetonitrile] (890 mg) was added in small portions over 5 minutes to tryptamine and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was partitioned between methylene chloride and 5% citric acid. The methylene chloride layer was partitioned and washed with brine and dried over anhydrous sodium sulfate. The extract was filtered and evaporated to the ear. the product was isolated by column chromatography using silica gel and eluent of ethyl acetate and hexanes (36:65 by volume). The yield of the title compound was 1 g.

Step 4.2C

{2- [5-Amino-2- (3,5-dimethyl-phenyl) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester

{2- [2- (3,5-Dimethyl-phenyl) -5-nitro-1H-indol-3-yl] -carbamic acid tert-butyl ester (0.4 g) was dissolved in methanol (25 mL) and was platinum oxide (40 mg) was added. The mixture was placed in a Parr hydrogenator and hydrogenated at 310 kPa for 4 hours; at that time, the starting material was consumed and converted into product. The catalyst was removed by filtration and the filtrates were evaporated under reduced pressure using a rotary evaporator, and trace amounts of solvents were removed using high vacuum overnight. The amine (338 mg) was obtained as a powder.

Step 4.2D

{2- [2- (3,5-Dimethyl-phenyl) -5- (3,3-dimethyl-urea) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester

[2- [5-Amino-2- (3,5-dimethyl-phenyl) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester in finely divided state (265 mg) was suspended in the dry state - 50 - tetrahydrofuran (5 mL) and diisopropylethylamine (0.146 mL) and dimethylcarbamoyl chloride (0.077 mL) were added. The reaction mixture was stirred at room temperature for 2.5 days. The reaction mixture was concentrated on a rotary evaporator and the residue was loaded onto 4 (20 x 20 cm, 1000 µl) preparative silica gel plates and eluted with a solvent system containing methanol: methylene chloride 1: 9 by volume. The product (299 mg) was isolated as a thick gum which solidified by further standing.

Step 4.2E 3- [3- (2-Aminoethyl) -2- (3,5-dimethyl-phenyl) -1H-indol-5-yl] -1,1-dimethyl-urea

{2- [2- (3,5-Dimethyl-phenyl) -5- (3,3-dimethyl-urea) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester (295 mg) was dissolved in a three-component solvent mixture containing methylene chloride (6 ml), trifluoroacetic acid (2 ml) and anisole (2 ml) for 2.5 hours. The volatile solvent components were removed by rotary evaporation and the residue was taken up in ethanol and purified on four preparative silica gel plates (20 x 20 cm, 1000 µm) and eluted with a solvent system containing methanol: methylene chloride (1: 9). The product (222 mg) was isolated as a foam material.

Step 4.2F 3- [2- (3,5-Dimethyl-phenyl) -3- [2- (5-pyridin-4-yl-pentylamino) -ethyl] -1H-indol-5-yl] -1,1-dimethyl-urea 3- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -1,1-dimethylurea (25 mg) from the previous step was dissolved in tetrahydrofuran (1 mL) and deuterated chloroform (1 mL) at about 0 ° C and 5- (4-pyridyl) pentanal (10.6 mg) was added. The reaction mixture was maintained at this temperature for 15 minutes and then finely powdered sodium borohydride was added followed by anhydrous methanol. The reaction mixture was stirred at about 0 ° C for 15 minutes and then quenched with 20 drops of 2N hydrochloric acid and water (1 mL). I - 51 - ι

The volatiles were removed by rotary evaporation and water using a stream of nitrogen gas. The residues were applied to four preparative silica gel plates (20 x 20 cm, 500 μίτι) and eluted with a solvent system containing methanol and methylene chloride in a ratio of 1: 9. The product (14.2 mg) was isolated as a thick oil.

Following a procedure similar to that described in Examples 4.1 and 4.2, the following compounds were prepared:

Example no. X-Rr, R8A = (CH2) nR1 m / e4A4-4-pyridyl 443 (M + H) 4BBr4-4-pyridyl 476 (M + H) 4C -NH2 4-4-pyridyl 413 ( M + H) 4 D -NH-COCH 3 4 4-pyridyl 455 (M + H) 4 E -NH-CO-N (CH 2 CH 3) 2 4 4-pyridyl 512 (M + H) 4 F -NH-CO-N (CH 2 CH 3) 4 3-pyridyl 512 (M + H) 4 G -NH-CO-N (CH 2 CH 3) 2 4 6-methoxy-3-pyridyl 542 (M + H) 4 H -NH-CO-N (CH 3) 2 5 3- pyridyl 498 (M + H) 41 -NH-CO-N (CH 2 CH 3) 2 3 3-pyridyl 526 (M + H) 4 J -NH-CO-N (CH 2 CH 3) 2 5 4-pyridyl 526 (M + H) 4K -NH-CO-N (CH 3) 2 4 6-methoxy-3-pyridyl 514 (M + H) 4 L -SO 2 -CH 2 -CO-Me 4 4-pyridyl 518 (M + H) 4 M 2 H q. 9 4 '4-pyridyl 520 (M + H) 4 N owo 0 4 4-pyridyl 502 (M + H) -52 * 40 q 0 4 4-pyridyl 504 (M + H) 4 P MeSO 2 - 4 3-pyridyl 518 ( M + H) 4 Q MeSO 2 - 4 6-methoxy-3-pyridyl 506 (M + H) 4 R MeSO 2 - 4,492 (M + H) 4 S MeSO 2 - 5 4-pyridyl 490 (M + H) 4 T MeSO 2 - 5 3 -pyridyl 490 (M + H) 4 U-? ° v ° Me 14 ^ ^ 4 ^ 4-pyridyl 575 (M + H) (*) - R6 = 5-NO2 (**) - R6 = Br

Example 5.1

2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5-carboxylic acid diethylamide dihydrochloride

Step 5.1A

3- (2-Aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester

A mixture of 4-hydrazino-benzoic acid (7.60 g, 50 mmol), 3-chloropropyl-3,5-dimethyl-phenyl ketone (10.55 g, 50 mmol) and absolute ethanol (200 mL) was stirred under nitrogen and refluxed. After 12 hours, the mixture was cooled and -53- filtered. The filter solid was washed with additional small volumes of ethanol. Concentrated sulfuric acid (4 mL) was added to the filtrate, and the mixture was stirred under a nitrogen atmosphere for 4 days. The cooled mixture was stirred in a water bath and a solution of sodium ethoxide (21% in ethanol) was added dropwise until the mixture became alkaline when measuring pH paper. The mixture was filtered and concentrated in vacuo at 30 ° C. The residue was partitioned between diethyl ether and water, and some saturated aqueous sodium chloride solution was added to facilitate separation of the layers. The aqueous phase was washed with an additional 100 mL of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained gum was purified by flash chromatography on silica gel (elution with methylene chloride: methanol: ammonium hydroxide, 97: 3: 0.3) and then 95: 5: 0.5) to give the title compound (4.8 g). 400 MHz 1 H NMR (CDCl 3) was consistent with the desired structure. Mass spectrum (PB-NH 3 / CI): m / e = 337 (M + H).

Step 5.1 B

2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5-carboxylic acid ethyl ester

To a dry flask was added 5.0 g (14.9 mmol) of 3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester, 1.98 g (13%). 5 mmol) of 4- (pyridin-4-yl) butylaldehyde (prepared exactly as described in Example 2.1, diluted with 0.5 ml of CDCl3), 8.12 g (67.7 mmol) of anhydrous sodium sulfate and a magnetic stir bar . The flask was purged with nitrogen, cooled to -10 ° C, and stirred with 11.5 mL of dry CDCl 3 sequentially with a syringe. The septum was then removed and 670 mg (17.6 mmol) of sodium borohydride was added rapidly. The septum was immediately reinserted and the system was purged with nitrogen again. The mixture was stirred under nitrogen at about -5 ° C and 10 mL of dry methanol was gradually added via syringe. After a few minutes at this temperature, the reaction mixture was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. The residue -54- was purified by flash chromatography on silica gel (eluting with a gradient of 4 to 9% methanol in methylene chloride; again using a gradient of 5 to 15% methanol in methylene chloride to give the title compound (3.19 g). Mass spectrum (PB-NH 3 / Cl): m / e = 470.4 (M + H) An additional 1.91 g of less pure material was also isolated.

Step 5.1C

3- [2- [Benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester

A solution of 3.19 g (6.83 mmol) of 2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5-carboxylic acid ethyl ester in 25 ml of dry methylene chloride was stirred under nitrogen and cooled to -78 ° C in a dry ice-acetone bath with the addition of 2.38 ml (1.76 g, 13.7 mmol) of Ν, Ν-diisopropylethylamine and then gradually added 3.4 ml (4.06 g, 23.7 mmol) of benzyl chloroformate by syringe. After about 2.5 hours, the solution from the cooling bath was removed and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% aqueous potassium hydrogen sulfate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5 to 10% methanol in methylene chloride) gave the product as a yellow foam in quantitative yield. 500 MHz 1H NMR was complex due to the existence of rotamers but in accordance with the desired structure. Mass spectrum (PB-NH 3 / CI): m / e = 604.3 (M + H).

Step 5.1 D

3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid chloride.

A solution of 4.11 g (6.83 mmol) of ethyl 3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H- of indole-5-carboxylic acid in 161 mL (80.5 mmol) of 0.5 N potassium hydroxide in methanol was stirred at about 60 ° C with the gradual addition of 19 mL of water. Stirring was continued at reflux overnight. The cooled mixture was concentrated in vacuo to give a yellow solid which was partitioned between 250 mL of ethyl acetate-tetrahydrofuran 1: 1 and 250 mL of 0.5N hydrochloric acid. The organic phase was washed twice with 0.5 N hydrochloric acid, then dried over magnesium sulfate, filtered and concentrated in vacuo. The solid obtained was triturated with diethyl ether and collected on the filter to give (after drying) 3.46 g of yellow solid, mp 133.5-137.5 ° C; the substance is homogeneous by TLC (95: 5: 0.5 CH 2 Cl 2 -MeOH-AcOH). 500 MHZ @ 1 H NMR (DMSO-d6) was consistent with the desired structure. Mass Spectrum (ESI): m / e = 576.4 (M + H).

Step 5.1 E

[2- [5-Diethylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl] - [4- (pyridin-4-yl) butyl] carbamic acid benzyl ester

A mixture of 846 mg (1.38 mmol) of 3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indole chloride chloride -5-carboxylic acid, 862 mg (1.66 mmol) benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP) and 8.5 ml dry methylene chloride were mixed with 1.16 ml (839 mg, 8.29 mmol) triethylamine and 0.715 ml (505 mg, 6.91 mmol) of diethylamine was added after a few minutes. The resulting solution was stirred under nitrogen at room temperature overnight and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution of 1-5% methanol in methylene chloride) gave the desired product in quantitative yield; homogeneous on TLC 95: 5 CH 2 Cl 2 -MeOH. 500 MHz 1 H NMR (CDCl 3) was complex due to the presence of rotamers but in accordance with the desired structure. Mass spectrum (ESI): m / e = 631.5 (M + H).

Step 5.1 F

2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butyl-amino] ethyl] -1H-indole-5-carboxylic acid diethylamide

A mixture of 871 mg (1.38 mmol) of benzyl [2- [5-diethylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl] - [4- (pyridin-4-yl)] benzyl ester butyl] carbamic acid, 300 mg of 20% palladium hydroxide on carbon and 40 ml of 2-methoxyethanol were shaken with hydrogen (about 310 kPa) in a pressure vessel for 2.3 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution 99: 1: 0.1 to 93: 7: 0.7 CH 2 Cl 2 -MeOH-conc. (NH 4 OH) to give 454 mg (66%) of a yellow foam, homogeneous on TLC 95: 5: 0.5 CH 2 Cl 2 -MeOH-conc. NH 4 OH: 500 MHz 1 H NMR (CDCl 3) was consistent with the desired structure: Mass spectrum (ESI): m / e = 497.5 (M + H).

Step 5.1 G

2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5-carboxylic acid diethylamide dihydrochloride To a solution of 452 mg (0.914 mmol) . 2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butyl-amino] ethyl] -1H-indole-5-carboxylic acid diethylamide in 45.1 methanol was added 1, 83 ml (3.66 mmol) of 2N hydrochloric acid. After a few minutes, the solution was evaporated to dryness. The residue was re-concentrated from methanol and then triturated with diethyl ether. The solid was collected on the filter, washed with additional diethyl ether and dried to give 455 mg (87%) of a pale yellow powder, mp 154-157 ° C. 500 MHz 1H NMR (DMSO-d6) was consistent with the desired structure. -57-

Example 5.2

Following the procedure of Example 5, the following compounds were prepared:

Example no. X-R 1, R 8 R 6 R 1 m / e 5A H 4 -pyridyl 470 (M + H) 5 B O H 3 -pyridyl 470 (M + H) 5 O Me Me 3-pyridyl 469 (M + H) 5 O 0 Me H 4 -pyridyl-469 (M + H) 5 E 0 ^ 1 MeN 2 Me 2 H 3 -pyridyl 497 (M + H) -58- 5 FO 2 -fc 3 N 4 H -pyridyl 605 (M + H) 5G H ° -? - Me 3 H 3 -pyridyl 513 (M + H)? H? -n? MeH 4-pyridyl 513 (M + H) 51 O MeO. X MeO 3 H 3 -pyridyl 557 (M + H) + 5H. 3 H-3-pyridyl 557 (M + H) 5 K a Me 3 H 3 -pyridyl 551 (M + H) 5 O a Me 4 H 4-pyridyl 551 (M + H) 5 M CLA Me 2 H 4-pyridyl 551 (M + H) < 5 > XH 3 -pyridyl 553 (M + H) -59 50 ° C = 4H-4-pyridyl 553 (M + H) 5ΡMeO Me 2 N, 3HH 3 -pyridyl 483 (M + H) 5Q Me 0 Me 2; MeH 4-pyridyl 525 (M + H) 5 R MeO Me 2 N 2 N 2 Me 2 H 3-pyridyl 511 (M + H) 5 S q / 3-pyridyl 559 (M + H) 5 C (/ H 4 -Pyridyl 559 (M + H) 5U 0 MeOH NA H 3 -pyridyl 537 (M + H) 5V -CON (Et) 2 H Me " - 551 (M + H) 5W -COOMe 6-Cl 4- pyridyl 490 (M + H) 5 X -CON (iBu) 2 6 -C 4 -pyridyl, 587 (M + H) 5 Y -CON (Et) 2 H -O'-O-Me Me 689 (M + H) + - 60 -

5Z -CON (CH 2 CH 2 CN) -cyclohexyl H 4 -pyridyl] 576 (M + H) 5AA Ga Me H 4-pyridyl 565 (M + H) 5 BB -COOMe 4-C 4 -pyridyl 490 (M H) 5 CC -CON (iBu ) 24-Cl 4 -pyridyl-587 (M + H) 5 -DD-CON (Et) 26-Cl 4-pyridyl 531 (M + HA)

Example 6

2- (3,5-Dimethylphenyl) -3- {2- [4- (3-methylisoxazol-5-yl) butyl-amino] ethyl} -1H-indole-5-carboxylic acid diisobutylamide To a 3- diisobutylamide solution (aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid (produced as described in Example 5.1, 83 mg in 2.5 mL dry CDCl 3) at 0 ° C was added 240 mg magnesium sulfate and the mixture was stirred at low temperature. After 15 minutes, a cold solution of sodium borohydride (30.2 mg in 1.5 mL of methanol) was added and the mixture was stirred for a further 15 minutes. The reaction was quenched with water, extracted with ethyl acetate, and then methylene chloride and the combined organic phases were dried over sodium sulfate. Purification of the concentrate by preparative silica gel TLC (methylene chloride / methanol, 9: 1) gave the title compound (28 mg), m / e = 557 (M + H). -61 - Manufacture of synthetic intermediates

4- (3-methylisoxazol-5-yl) butyraldehyde Step A

Tert-Butylhex-5-ynyloxydimethylsilane To a solution of hex-5-yn-1-ol (1.96 g in 40 ml of dry methylene chloride) at 0 ° C was added 3.48 ml of triethylamine followed by 3.31 g of tert-butyldimethylsilyl chloride and was stirred with gentle warming to room temperature. After 60 hours, the mixture was filtered to remove solids and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate: hexane, 1.9, then 1: 3) gave the title compound (1.62 g).

Step B 5- [4- (tert-Butyldimethylsilanoyloxy) butyl] -3-methylisoxazole To a solution of tert-butylhex-5-ynyloxydimethylsilane (1.0 g in 20 mL of dry toluene) was added 530 mg of nitroethane followed by 1.31 mL of triethylamine and 1.1 g of 4-chlorophenyl isocyanate and the mixture was stirred at room temperature. After 1 hour, the contents of the flask were refluxed in an oil bath for a further 20 hours and then cooled to room temperature and filtered to remove solids. Concentration of the filtrate in vacuo and purification by flash chromatography on silica gel (ethyl acetate: hexane, 1: 9, then 1: 2) gave the title compound (388 mg).

Step C 4- (3-Methylisoxazol-5-yl) butan-1-ol To a solution of 5- [4- (tert-butyldimethylsilanoyloxy) butyl] -3-methylisoxazole (350 mg in 5 mL dry tetrahydrofuran) at 0 ° C was 1.62 ml of a 1M solution of tetra-butylammonium fluoride in tetrahydrofuran was added and the mixture was stirred with heating to -62 ° C. After 16 h, the mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate: hexane, 1.3, then 1: 1) to give the title compound (147 mg).

Step D 4- (3-Methylisoxazol-5-yl) butyraldehyde To a solution of oxalyl chloride (0.40 mL of a 2M solution in methylene chloride in 2 mL of dry methylene chloride) at -78 ° C was added a solution of methyl sulfoxide (126 mg in 1 mL of methylene chloride) and the mixture was stirred at low temperature for 3 minutes. A solution of 4- (3-methylisoxazol-5-yl) butan-1-ol (100 mg in 1 mL of methylene chloride) was added and the reaction was allowed to continue for 15 minutes and then 0.67 mL of triethylamine was added and the mixture was allowed to cool. warmed to room temperature. After 30 minutes, brine was added and the mixture was extracted with methylene chloride. Dry the organic portion over sodium sulfate and concentrate in vacuo. Purification of the residue by flash chromatography on silica gel (ethyl acetate: hexane, 1: 1) gave the title compound (48 mg).

Following a similar procedure to that described in Example 6, the following compounds were prepared:

Example no. - A = (CH 2) n R 1 m / e 6A 4 4-pyridyl 553 (M + H) 6B 4 1 3-pyridyl 553 (M + H) -63-6C 4 6-amino-3-pyridyl 568 (M + H) 6 D 4 6-amino-3-pyridyl 583 (M + H) 6 E 4-Methoxy-3-pyridyl; 583 (M + H) 6 F 4 Y V b N 571 (M + H) 6 G 4 X 16 F 5 -N 585 (M + H) 6 H 4 '= SV'C ° 2H On 587 (M + H) 61 4 AVC02Et N < 615 > (M + H) 6 < 4 > O < 0 > C0NE > 2 U ' N 642 (M + H) 6K < 4 > ) 6M 4 COOEt TV-Me U N 629 (M + H) 6 N 4 2- (CH 2 NH-Boc) -4-pyridyl-60 4 2- (CH 2 NH 2) -4-pyridyl 582 (M + H) 6P 4 6 - (SMe) -3-pyridyl 599 (M + H) 6 Q 4 5-carboethoxy-3-pyridyl 625 (M + H) 6 R 4 6- (NHCOOEt) -3-pyridyl - 6 S 4 2,3,5,6 -tetrafluoro-4-pyridyl 625 (M + H) 6 T 3 3-pyridyl-p -64- 6U 4 6- [NHS (O) 2 CF 3] -3-pyridyl "· 6 · 4 6 6- [NHS (0 2CH 3] -3-pyridyl 646 (M + H) 6 W 4 5-cyano-3-pyridyl 6X 4 N < 6 > pyridyl 621 (M + H) 6 Z 4 N Cl 638, (MH),

Example 7.1

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-diethylisobutyramide

Step 7.1 A 2- [3- (2-Aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -N, N-diethylisobutyramide

A solution of 4.85 g (23 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone and 6.87 g (27.6 mmol) of N, N-diethyl-2- (4-hydrazinophenyl) isobutyramide in 92 ml of absolute ethanol was -65. - stirred for 43 hours at reflux. The solution was then cooled and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution of 0 to 5% methanol in methylene chloride followed by 95: 5: 0.5 methylene chloride-methanol-ammonium hydroxide and 92.5: 7.5: 0.75 methylene chloride-methanol-ammonium hydroxide) provided 873 mg (9.4%) of a brick-red solid foam with sufficient purity on TLC 95: 5: 0.5 CH 2 Cl 2 -MeOH-conc. NH 4 OH. 500 MHz 1H NMR (CDCl3) was consistent with the desired structure. Mass spectrum (PB-NH 3 / Cl). m / e = 406 (M + H).

Step 7.1B 2- [2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-diethyl isobutyramide

A mixture of 93.3 mg (0.23 mmol) of 2- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -N, N-diethylisobutyramide, 37.7 mg (0.253 mmol) of 4- (pyridin-4-yl) butyraldehyde and 138 mg (1.15 mmol) of magnesium sulfate were purged with nitrogen and cooled in an ice-methanol bath to about -10 ° C and 0.50 was added via syringe. mICDCb. The mixture was stirred under nitrogen at this temperature for 1 hour. The septum was removed for the time required to add 11.3 mg (0.30 mmol) of sodium borohydride and the solution was purged with nitrogen again. The mixture was stirred at -10 ° C to -5 ° C with 0.5 ml of dry methanol gradually added and stirring continued at this temperature. After 35 minutes, the mixture was partitioned between 5 mL of ethyl acetate and 5 mL of water. The ethyl acetate layer was washed with brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by two stages of preparative TLC on Analtech tapered silica gel plates (first 90: 10: 1 mixture of methylene chloride-methanol-ammonium hydroxide and again in methylene chloride-methanol 90:10). Stripping the product gave 25.7 mg (21%) of a golden shiny residue homogeneous by TLC in 92.5: 7.5: 0.75 CH 2 Cl 2 -MeOH-conc. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the proposed structure. Mass spectrum (ESI): m / e = 539 (M + H). - 66 -

Preparation of Synthetic Intermediates Step A 4-Chloro-N-methoxy-N-methylbutyramide; i ľ

To a solution of 4-chlorobutyryl chloride (10.0 g in 200 ml of dry methylene chloride) was added 10.4 g of Ν, Ο-dimethylhydroxyamine hydrochloride. The mixture was stirred under nitrogen and kept below 25 ° C by cooling in an ice bath as needed, and triethylamine (29.1 mL) was added dropwise over 20 minutes resulting in precipitation. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate solution and the aqueous fractions were back extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 10.5 g (90%) of an oil which was satisfactory purity when measured by 1 H NMR (CDCl 3). Mass spectrum (PB-NH 3 / CI): m / e = 166 (M + H).

Step B 3-Chlorophyll 3,5-dimethylphenyl ketone

A solution of 10.2 mL (13.9 g, 72 mmol) of 5-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at -78 ° C and 35.8 mL (84 mmol) 2 was added dropwise. 5M n-butyllithium in tetrahydrofuran. After 15 minutes at -78 ° C, a solution of 10.0 g (60 mmol) of 4-chloro-N-methoxy-N-methylbutyrylamide in 30 mL of anhydrous tetrahydrofuran was added over 25 to 30 minutes. The resulting solution was kept at -78 ° C for 45 minutes and then briefly warmed to room temperature. The reaction was quenched with 40 mL of 2N hydrochloric acid and then partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. -67-

Flash chromatography of the residue afforded 8.91 g (70%) of an oil which was sufficiently pure when measured by 1 H NMR (CDCl 3).

Step AA

Ethyl 2- (4-hydrazino-phenyl) -acetic acid chloride and 2- (4-hydrazino-phenyl) -acetic acid chloride This compound (mixture of ethyl ester and carboxylic acid) was prepared from 13.4 g (75 mmol) of ethyl 2- (4-aminophenyl) acetate, diazotization and reduction of the diazonium salt with the stannous method of LJ Street et al., J. Med. Chem., 36, 1529 (1993). The material was obtained in two portions. The first portion consisted of 6.40 g of powder, melting point > 200 ° C. As measured by 400 MHz 1 H NMR (DMSO-d 6), this material consisted of a mixture of carboxylic acid and ethyl ester in a 4: 3 molar ratio. Mass spectrum (PB-NH3 / Cl): 195 (aryldrazonium cation for ethyl ester). The second portion consisted of 4.60 g of powder, melting point > 180 ° C. By measuring 400 MHz 1 H NMR (DMSO-d 6), this material consisted of a mixture of carboxylic acid and ethyl ester in about 7: 1 molar ratio. After adjusting the composition of the mixture of these two fractions, the overall estimated yield was 69%. Since the esterification of any carboxylic acid present occurs in the next step, both the ester and the acid react to form the same product.

Step AAA

(+/-) - 2- (4-Nitrophenyl) propionic acid ethyl ester To a solution of 9.76 g (50 mmol) of (+/-) - 2- (4-nitrophenyl) propionic acid in 150 ml of absolute ethanol was added 3, 0 ml of concentrated sulfuric acid. The resulting solution was stirred under nitrogen at reflux. After 6 hours, the solution was cooled and stirred vigorously with the gradual addition of 250 mL of saturated aqueous sodium bicarbonate (alert to severe foaming). The mixture was partitioned between 750 mL of ethyl acetate and 500 mL of water. Wash the organic layer with 100 mL of saturated aqueous sodium bicarbonate solution and then 100 mL of saturated aqueous chloride solution | : - 68-

Sodium. Dry the organic phase over magnesium sulfate, filter, and concentrate in vacuo to give 10.86 g (97%) of an oil which was homogeneous by TLC 9: 1 hexane-EtOAc. 400 MHz 1H NMR (CDCl3) was consistent with the proposed structure.

Step BBB

2-Methyl-2- (4-nitrophenyl) propionic acid ethyl ester

A suspension of 924 mg (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry

The Ν, Ν-dimethylformamide was stirred under nitrogen in an ice bath and a solution of 4.68 g (21 mmol) of (+/-) - 2- (4-nitrophenyl) propionic acid ethyl ester in 20.5 ml of dry Ν, Ν was added. dimethylformamide over 10 minutes. During

Addition also developed an intense violet color. The mixture was then allowed to warm to room temperature. After about 1 hour, the mixture was again cooled in an ice bath and a solution of 1.44 ml (3.28 g, 23 mmol) of methyl iodide in 5 ml of dry Ν, Ν-dimethylformamide was added dropwise via syringe over 10 minutes while maintaining the internal temperature at 10-15 ° C. The mixture was allowed to warm to room temperature and the color turned brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of methyl iodide was added. The next day, the mixture consisted of a suspension of a certain amount of light gray solid in a gold colored liquid. The mixture was stirred vigorously and the reaction was quenched by the gradual addition of 10 mL of a 5% aqueous potassium hydrogen sulfate solution. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. The organic layer was washed again with 3 x 400 mL of water and then with 50 mL of saturated aqueous sodium chloride. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (eluting with hexane-EtOAc 19: 1) gave 4.31 g (87%) of an oil which was homogeneous by TLC 9: 1 hexane-EtOAc. 400 MHz 1 H NMR (CDCl 3) was consistent with the desired structure.

Step-CCC

2-Methyl-2- (4-nitrophenyl) propionic acid -69-

A solution of 11 g (24 mmol) of 2-methyl-2- (4-nitrophenyl) propionic acid in 1 L of 0.5 M potassium hydroxide in methanol was stirred under nitrogen and heated to about 50 ° C where 111 mL of water was gradually added. The resulting solution was stirred at reflux overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate - tetrahydrofuran and 0.5N hydrochloric acid. The aqueous layer was also repeatedly extracted with chloroform. The organic fractions were dried over magnesium sulfate and concentrated in vacuo to give 9.4 g (94%) of an amorphous yellow-brown solid homogenous by TLC 95: 5: 0.5 CH 2 Cl 2 -MeOH-AcOH. 500 MHz 1H NMR (CDCl3) was consistent with the desired structure.

Step DDD N, N-Diethyl-2- (4-nitrophenyl) isobutyramide

To 8.36 g (40 mmol) of 2-methyl-2- (4-nitrophenyl) propionic acid was added 18 mL of cyclohexane and 9 mL of thionyl chloride. The mixture was stirred under nitrogen and heated to reflux. The solid dissolved gradually and gas evolution was observed. After 20 hours, the solution was cooled and evaporated in a stream of nitrogen and then dried in vacuo. The remaining pale orange solid was dissolved in 50 mL of anhydrous tetrahydrofuran and added dropwise to a solution of 9.10 mL (6.43 g, 88 mmol) of diethylamine in 100 mL of anhydrous tetrahydrofuran, and the mixture was stirred in an ice-methanol bath at about -10 to about. High: -15 ° C. After the addition was complete, the mixture was allowed to gradually warm to room temperature. After two days the mixture was concentrated in vacuo and the residue partitioned between 250 mL of ethyl acetate and 200 mL of water. The organic phase was further washed with water, then with saturated aqueous sodium bicarbonate solution and finally with brine. The ethyl acetate solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate 6: 1 then 5: 1) to give 9.45 g (85%) of a light yellow solid, mp 59.5-61 ° C homogeneous on TLC 2: 1 hexane-EtOAc. 500 MHz 1H NMR, -70-

I (CDCl 3) was consistent with the desired structure. Mass spectrum (PB-NH 3 / CI): m / e = 265 (M + H).

Step EEE 2- (4-aminophenyl) -N, N-diethylisobutyramide

A mixture of 9.38 g (35.5 mmol) of N, N-diethyl-2- (4-nitrophenyl) isobutyramide, 400 mg of 10% palladium on carbon and 120 ml of absolute ethanol was shaken with hydrogen (hydrogen pressure at 324 kPa initially). in a pressure vessel for 22 hours. The catalyst was removed by filtration through Celite under nitrogen and the filter cake was washed with additional ethanol. Concentration of the filtrate in vacuo afforded 8.5 g (100%) of an off-white solid, mp 89-90 ° C, homogeneous over TLC 98: 2 CH 2 Cl 2 -MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the desired structure. Mass spectrum (PB-NH 3 / CI): m / e = 235 (M + H).

Step FFF of N, N-Diethyl-2- (4-hydrazinophenyl) isobutyramide To 8.5 g (35.5 mmol) of 2- (4-aminophenyl) -N, N-diethylisobutyramide was added 35.5 ml of concentrated hydrochloric acid and the mixture was stirred until a homogeneous solution was obtained. This was then stirred in an ice-acetone bath at -10 to -5 ° C and a solution of 2.55 g (36.9 mmol) of sodium nitrite in 13.5 mL of water was added dropwise over 25 minutes. Stirring was continued for another hour at this temperature. The mixture was kept cool and added in small portions over 1 hour to a solution of 40.1 g (178 mmol) of tin (II) chloride dihydrate in 28.5 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath (about -10 ° C). . After the addition was complete, stirring in the cooling bath was continued for 1 hour. The mixture was then allowed to warm to near room temperature with vigorous stirring to give a homogeneous solution. The solution was partitioned between 500 mL of ethyl acetate and 50 mL of water. The ethyl acetate layer was washed with an additional 50 mL of water and 500 mL of half-saturated aqueous sodium bicarbonate solution was carefully added. I '- 71 -

The mixture was gently stirred to produce considerable gas and precipitation. The thick mixture was filtered before phase separation. The ethyl acetate phase was washed with 50 mL of brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature. This gave 7.04 g (80%) of somewhat sticky orange solid, which was unclearly defined by TLC, NMR and mass spectroscopy, but suitable for use in the next step.

Example 7.2

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-diethylisobutyramide

Step 7.2A

2- [2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] ethyl] -1H-indol-5-yl] -2-methylpropionic acid ethyl ester

Dry flask containing 3.00 g (7.93 mmol) of 2- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -2-methylpropionic acid ethyl ester ( produced as described in Example 7.1 step A), 4.76 g (39.7 mmol) of anhydrous MgSO 4 and a magnetic stir bar were provided with a whisper and a needle adapter leading to the Firestone valve. The flask was purged thoroughly with nitrogen and the mixture was cooled in an ice-methanol bath to -10 to -5 ° C and stirred vigorously with the addition of 1.32 g (8.88 mmol) of 4- (pyridin-3-yl) butyraldehyde in 15 ml of dry CDCl 3 syringe over 10 to 15 minutes. The resulting mixture was stirred under nitrogen at -10 to -5 ° C for 40 to 45 minutes. The septum was then removed for the time necessary to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under nitrogen at -10 to -5 ° C and dry methanol (10 mL) was added dropwise over a few minutes. After 30 minutes the mixture was removed from the cooling bath and partitioned between 90 mL of EtOAc and 90 mL of H 2 O. The organic layer was washed with 2 x 30 mL of brine and then dried over sodium sulfate. The filtered solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (gradient elution 0-10% MeOH in CH 2 Cl 2). The fractions containing the product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of a pale beige solid which was used directly in the next step without further purification or characterization.

Step 7.2B

2- [3- [2- [Benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indol-5-yl] ethyl ester methyl-propionic

A solution of 3.00 g (theoretical 5.86 mmol) of crude 2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] ethyl] -1H ethyl ester -indol-5-yl] -2-methyl-propionic acid in 30 ml of dry CH 2 Cl 2 was stirred under nitrogen while cooling in a dry ice-acetone bath. To this solution was added 1.106 ml (820 mg, 6.36 mmol) of Ν, β-diisopropylethylamine by syringe. Then 956 μΙ (1.14 g, 6.36 mmol) of benzyl chloroformate was added dropwise via syringe over 5 to 10 minutes. After 20 minutes, the cooling bath solution was removed and allowed to warm to room temperature. After 2 hours, the solution was diluted with 50 mL of CH 2 Cl 2, transferred to a separate flask and shaken with 80 mL of H 2 O. Dry the organic phase over magnesium sulfate, filter, and concentrate in vacuo. Flash chromatography of the obtained gum on silica gel (gradient elution of 0.2 to 2% MeOH in CH 2 Cl 2) afforded 2.81 g (55% overall in steps 1 and 2) of a light golden yellow gum which was homogeneous on TLC 95: 5 CH 2 Cl 2 MeOH. 500 MHz 1H NMR (CDCl3) was complex due to the presence of rotamers, but seemed to correspond to the desired structure. Mass Spectrum (ESI): m / e = 646 (M + H) +. -73-

Step 7.2C

2- [3- [2- [Benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (3,5-dimethyl-phenyl) -1H-indol-5-yl] - 2-methylpropionic acid

A mixture of 2.78 g (4.30 mmol) of ethyl 2- [3- [2- [benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -2-methylpropionic acid in 43.0 mL (21.5 mmol) of 0.5 M KOH in MeOH and 25 mL of THF was stirred under nitrogen and heated to reflux. Water (18 ml) was gradually added to the resulting solution, and the solution was refluxed for 39 hours. It was then cooled and concentrated to a small volume with precipitation. The mixture was mixed with 10.75 mL (21.5 mmol) of 2N HCl and stirred for several minutes. The solid was collected on the filter and washed thoroughly with water. After sieving under nitrogen, the solid was triturated and washed with diethyl ether and dried under vacuum to give 2.43 g (92%) of cream powder, mp 152-154 ° C (partial decomposition) homogeneous on TLC 90:10 CH 2 Cl 2 -MeOH . 500 MHz 1 H NMR (DMSO-d 6) was consistent with the desired structure. Mass Spectrum (ESI): m / e = 618 (M + H) +

Step 7.2D

[2- [5- (1-Dibutylcarbamoyl-1-methylethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] ethyl] - [4- (pyridin-3-yl) butyl] benzyl ester ] -carbamic

A solution of 92.7 mg (0.15 mmol) of 2- [3- [2- [benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (3,5-dimethyl-phenyl) -1H-indol-5-yl] -2-methylpropionic acid, 83.2 mg (0.16 mmol) of PyBOP reagent and 0.151 ml (116 mg, 0.9 mmol) of triethylamine in 0.75 ml of dry CH 2 Cl 2 were stirred at room temperature and sealed in the bank for 2 days. The solution was then partitioned between 10 mL of EtOAc and 10 mL of 0.5 N HCl. The organic phase was washed with 10 mL of saturated aqueous sodium bicarbonate solution and then with 5 mL of saturated aqueous sodium chloride solution. The EtOAc phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature. The residue was purified by preparative TLC on six Analtech tapered silica gel plates (20 x 20) developed in 95: 5 CH 2 Cl 2 - -74-

MeOH. The product strip from each plate was collected, combined and extracted with 95: 5 CH 2 Cl 2 -MeOH. Concentration of the extracts in vacuo gave 85.2 mg (78%) of a light golden yellow gum which was homogeneous on TLC 95: 5 CH 2 Cl 2 -MeOH. 500 MHz @ 1 H NMR (CDCl3) was complex due to the presence of rotamers but corresponded to the desired structure. Mass Spectrum (ESI): m / e = 729.7 (M + H). I

I

Step 7.2E 2- [2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-diethyl isobutyramide

A mixture of 76.5 mg (0.105 mmol) of benzyl [2- [5- (1-dibutylcarbamoyl-1-methylethyl) -2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl] - [4 - (pyridin-3-yl) butyl] carbamic acid, 40 µg of 10% palladium on carbon, 4 ml of absolute EtOH and 4 ml of EtOAc were shaken with hydrogen (about 324 kPa) in a pressure vessel for 6 hours. The catalyst was removed by filtration through celite under nitrogen and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on four Analtech tapered solica gel plates (20 x 20), which were developed with 92.5: 5.5: 0.75 CH 2 Cl 2 -MeOH-conc. NH4OH. The product bands from each plate were collected, combined and extracted with 92.5: 7.5: 0.75 CH 2 Cl 2 -MeOH-conc. NH4OH. Concentration of the extracts in vacuo afforded 51.4 mg (82%) of a light yellow solid, homogeneous by TLC in 92.5: 5.5: 0.75 CH 2 Cl 2 -MeOH-conc. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the desired structure. Mass spectrum (ESI): m / e = 595.6 (M + H) +.

Following the procedure described in Examples 7.1 and 7.2, the following compounds were prepared:

R8 X H N

CH3 -75-

Example No. X-R7, R8, R1 m / e · 7A Me. 1 Me Me 4-pyridyl 539 (M + H) 7A Me. 1 Me Me 3 -pyridyl 539 (M + H) 7 MeOH. Me Me 2 N 3 O 3 -pyridyl 599 (M + H) 7 MeO 2 S Me. Me Me ^ NX 0 4-pyridyl 599 (M + H) 7 Me Me Me Μγ ^ 0 4-pyridyl 511 (M + H) 7E Me Me Me-NX O 3-pyridyl 511 (M + H) 7F Me Me | Me. MeMe 4-pyridyl 595 (M + H) 7 MeOH / Mee. Me r " ^ X o Me Me 3-pyridyl 595 (M + H) -76-7Η 1 Me Me. ^ NX ^ 0 4-pyridyl 595 (M + H) 71 X 1 Me Me Me - 0 3 -Pyridyl 579 (M + H) 7 -I-Me Me Me 2 N 2 X Me 3 3-pyridyl 525 (M + H) 7K MeM Me 3 " 3-pyridyl 511 (M + H) 7 Me Me; 1 Me Me MeN > Me 3 3 -pyridyl 553 (M + H) 7M Me. 1 has Me 3 -pyridyl 593 (M + H) 7 N Me. 1 Mme Me 4-pyridyl 593 (M + H) 70 Me Me H 2 NXX 3 -pyridyl 483 (M + H) 7 P Ε, α-MeO 4-pyridyl .526 (M + H)

{2- [2- (3,5-Dimethyl-phenyl) -1H-indol-3-yl] -ethyl} - (3-pyridin-3-yl-cyclohexyl) -amine To a solution of 3-pyridin-3-yl-cyclohexanone (30 mg in 1.5 mL dry CDCl 3) was added at 0 ° C a solution of 2- [2- (3,4-dimethoxyphenyl) -1 H -indol-3-yl] ethylamine (45 mg in 1 mL dry CDCl 3) then 206 mg of magnesium sulfate and the mixture was stirred at low temperature. After 15 minutes, 26 mg of sodium borohydride was added followed by 1.0 mL of methanol and the mixture was stirred for an additional 30 minutes. Then the reaction was quenched by the addition of 2N hydrochloric acid and evaporated to dryness. Purification of the concentrate by preparative silica gel TLC (methylene chloride: methanol, 9: 1) gave the title compound (8.4 mg). Preparation of Synthetic Intermediates 3-Pyridin-3-yl-cyclohexanone

Step A 3-Pyrid-3-yl-cyclohex-2-enone To a solution of 3-ethoxy-2-cyclohexen-1-one (1.4 g in 10 mL of dry tetrahydrofuran) was added 1.58 g of 4- bromopyridine and the mixture was vigorously stirred at -78 ° C. To this mixture was added dropwise tert-butyl lithium (11.8 ml of a 1.7 M solution in pentane) and the reaction was quenched by the addition of 2N hydrochloric acid and refluxed for 14 hours. The mixture was then cooled and cooled

I - 78 - neutralized to pH 7 by careful addition of 1N sodium hydroxide. The mixture was then extracted with methylene chloride and the organic phase was dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane, 1: 1, 2: 1) gave the title compound (1.37 g).

Step B 3-Pyridin-3-yl-cyclohexanone To a solution of 3-pyridin-3-yl-cyclohex-2-enone (1.25 g in 50 mL of ethanol) was added 164 mg of the platinum oxide catalyst and the mixture was placed in an atmosphere of hydrogen at 276 kPa. After 2 hours, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. Purification of the residue by silica gel flash chromatography (ethyl acetate: hexane, 1: 1) gave the title compound (427 mg).

Following the procedure described in Example 8, the following compounds were prepared: R2

Example 1 (A) R 2 '. R1 m / e, 8A -CH2CH2- - (CH2) 4-4- (phenyl-4- OMe) 4-pyridyl 532 (M + H) -79-8B -CH2CH2- - (CH2) 4- (phenyl- 4- (OH) 4-pyridyl 518 (M + H) 8 C -CH 2 C (Me) 2 CH 2 CH 2 - -H 4-pyridyl 426 (M + H) 8 D (T -H 3-pyridyl 424 (M + H) 8 Ό " -H 3-pyridyl 410 (M + H) 8 F -TH-3-pyridyl 440 (M + H)

Example 9.1

2- (3,5-Dimethylphenyl) -3- [2- (1-methyl-4-pyridin-3-yl-butylamino) ethyl] -1H-indole-5-carboxylic acid diisobutylamide

Step 9.1 A

3- (2-tert-Butoxycarbonylaminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester To a solution of 3- (2-aminoethyl) -2- (3,5-dimethylphenyl) ethyl ester 1 H -indole-5-carboxylic acid (prepared according to the procedure of Example 5.1, 1.5 g in 30 mL of dry tetrahydrofuran) at 0 ° C was added a solution of di-tert-butyl dicarbonate (1.9 g in 3 mL of THF) and then aqueous potassium carbonate solution (1 g in 10 mL of water) and the resulting suspension was vigorously stirred at 0 ° C. After 12 minutes, the reaction was quenched by the addition of excess saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid was washed sequentially with methylene chloride, hexane and ethyl acetate to give the title compound (1.77 g).

Step 9.1 B

3- (2-tert-butoxycarbonylaminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid To a suspension of 3- (2-tert-butoxycarbonylaminoethyl) -2- (3,5 -dimethylphenyl) -1H-indole-5-carboxylic acid (830 mg in 50 mL of methanol) was added with 8 mL of 1.25N sodium hydroxide and the mixture was heated to 75 ° C in an oil bath. After 5.5 hours, another 3 mL of 1.25N sodium hydroxide was added and the reaction allowed to continue for a further 2 hours. At this time, the mixture was cooled to room temperature and quenched with pH 2 buffer. The mixture was extracted with ethyl acetate, washed with saturated ammonium chloride solution, and the organic portion was dried over sodium sulfate. Concentration in vacuo gave the crude acid in quantitative yield.

Step 9.1 C

{2- [5-Diisobutylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethylcarbamic acid tert-butyl ester To a solution of 3- (2-tert-butoxycarbonylaminoethyl) -2- (3,5- of dimethylphenyl) -1H-indole-5-carboxylic acid (200 mg in 12 mL of methylene chloride) was added 104 mg of 1-hydroxybenzotriazole followed by 118 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and stirred at room temperature. room temperature. After 30 minutes, 0.35 ml of diisobutylamine was added and the mixture was stirred at room temperature for 14 hours, then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane: ethyl acetate, 2: 1) to give the title compound (230 mg). = 81-1

Step 9.1 D

3- (2-Aminoethyl) -1- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid diisobutylamide i. To a solution of tert-butyl {2- [5-diisobutylcarbamoyl-2- (3,5-dimethyl-phenyl) -1H-indol-3-yl] ethyl} carbamic acid (230 mg in 12 mL of methylene chloride) at 0 ° C was 0.55 ml of anisole was added followed by 3.4 trifluoroacetic acid and the mixture was stirred at 0 ° C. After 1 hour, the mixture was concentrated in vacuo and the remaining acid was removed by azeotropic toluene distillation. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 8: 1) gave the title compound ("173 mg").

Step 9.1 E

2- (3,5-Dimethylphenyl) -3- [2- (1-methyl-4-pyridin-3-yl-butylamino) -ethyl] -1H-indole-5-carboxylic acid diisobutylamide (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid (142 mg in dry methanol) was added 19 mg of 5-pyridin-3-yl-pentan-2-one and the pH was adjusted to 6 by addition of trifluoroacetic acid. To this mixture was added about 10 mg of molecular sieves 0.3 nm followed by 27 mg of sodium cyanoborohydride. The pH was adjusted occasionally with trifluoroacetic acid for 36 hours to maintain pH 6. The reaction was then quenched by the addition of aqueous potassium carbonate solution and extracted with ethyl acetate. The organic portion was washed successively with aqueous potassium carbonate solution and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 8: 1) gave the title compound (32 mg) [m / e = 567 (M + H)] and unreacted amine (115 mg) . Production of synthetic intermediates

Step A 4- Pyridin-3-yl-butyraldehyde i -82- To a solution of oxalyl chloride (0.74 mL in 5 mL dry methylene chloride) was added a solution of methylene sulfoxide (0.90 mL in 5 mL methylene chloride) at -78 ° C and she was

1 L stirred for 15 minutes at low temperature. A solution of 4-pyridin-3-yl-butan-1-ol (prepared as described in Example 2.1, 820 mg in 10 mL of methylene chloride) was added and the reaction was allowed to proceed for a further 45 minutes and then 4 mL of triethylamine was added. and the mixture was allowed to warm to room temperature. After 35 minutes, saturated sodium bicarbonate solution was added and the mixture was extracted with methylene chloride. The organic portion was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (813 mg).

I

Step B; 5-Pyridin-3-yl-pentan-2-ol To a solution of methylmagnesium bromide (0.75 mL of a 3M solution (diethyl ether) in 3.5 mL of dry tetrahydrofuran) at 0 ° C was added a solution of 4-pyridin-3-yl-butyraldehyde (133 mg in 1 mL of tetrahydrofuran) and the mixture was stirred at low temperature. After 30 minutes, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) gave the title compound (71 mg).

Step C 5-Pyridin-3-yl-pentan-2-one i To a solution of oxalyl chloride (0.060 mL in 1 mL of dry methylene chloride) was added a solution of methyl sulfoxide (0.075 mL in 0.25 mL of methylene chloride) at -78 ° C and was stirred at low temperature for 18 minutes. A solution of 5-pyridin-3-yl-pentan-2-ol (71 mg in 1 mL of methylene chloride) was added and the reaction was allowed to continue for 40 minutes and then 0.35 mL of triethylamine was added and the mixture was allowed to stand. to warm to room temperature. After 35 minutes, water was added and the mixture was extracted with methylene chloride. The organic portion was washed

With saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (methylene chloride: methanol, 96: 4) gave the title compound (61 mg).

1- {2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl] ethyl} -1H-indole-hexahydro-2'-bipyridinyl

Example 9.2

Step 9.2A 1- [2- (3,5-Dimethyl-phenyl) -1H-indol-3-yl] -2- (3,4,5,6-tetrahydro-2H- [4,4 '] bipyridinyl-1-one) yl (ethane-1,2-dione To a solution of 2- (3,5-dimethylphenyl) -1H-indole (200 mg in 2 mL of dry methylene chloride) 0.083 mL of oxalyl chloride was added dropwise and the mixture was stirred at room temperature. After 1 hour, 213 mg of 1,2,3,4,5,6-hexa-hydro- [4,4 '] bipyridine dihydrochloride and then 1.5 ml of methylene chloride and 0.567 ml of triethylamine were added and the mixture was further stirred at room temperature. The reaction mixture was diluted with ethyl acetate for 4 hours and washed successively with water, saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, and the concentrate was purified by flash chromatography on silica gel (methylene chloride: methanol, 96: 4) to give the title compound. compound (148 mg).

Step 9.2B 1- {2- [2- (3,5-Dimethyl-phenyl) -1H-indol-3-yl] -ethyl] -1,2,3,4,5,6-hexahydro [4,4 '] bipyridinyl To a solution of 1- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] -2- (3,4,5,6-tetrahydro-2H- [4,4 '] - bipyridinyl-1) -yl (ethane-1,2-dione (148 mg in dry tetrahydrofuran) was added dropwise 2.71 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran and the mixture was heated to reflux in an oil bath. and quenching the reaction by sequential addition of 30 mL of water and 4 mL of ammonium hydroxide and 25 mL of ethyl acetate The mixture was filtered to remove solids The organic portion was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (71 mg), m / e = 410 (M + H).

Example 9.3

Me

2- [2- (3,5-dimethylphenyl) -3- [2- [methyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -1H-indol-5-yl] -N, N -dibutylizobutyramid

Dry flask containing 67 mg (0.113 mmol) of 2- [2- (3,5-dimethylphenyl) -3- [2- [methyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -1H-indole -5-yl] -N, N-dibutylisobutyramide (prepared according to Example 7.2), 33.9 mg (1.3 mmol) paraformaldehyde and 100 mg powder molecular sieves 0.3 nm were whispered and thoroughly purged with nitrogen. Then, 2.65 ml of MeOH and 65.2 µl (67.8 mg, 1.13 mmol) of glacial acetic acid were added and the mixture was stirred at room temperature for 35 minutes. Sodium cyanoborohydride (28.4 mg, 0.452) was added and 2.5 mL of anhydrous THF was added over a further 20 minutes. After a few minutes, TLC showed complete reaction. Then the mixture was filtered and the filtrate was shaken in a separate brine solution funnel. The aqueous phase was extracted three more times with CH 2 Cl 2. The combined organic fractions were dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution 99: 1: 0.1 to 95: 5: 0.5 CH 2 Cl 2 -MeOH-conc. NH 4 OH) to give 31.1 mg (45%) of the title compound as a glassy solid. homogeneous by TLC 95: 5: 0.5 CH 2 Cl 2 -MeOH-conc. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the desired structure, m / e = 609.5 (M + H).

In a similar manner to the method described in Examples 9.1, 9.2 and 9.3, the following compounds were prepared: R 8 R 2

Example No. -N (R20- (A) - x-r7, r8; r1 m / e 9A) - CO2Et -NH-CO- N (Et) 2 3-pyridyl 596 (M + H) 9B / - CO2H -NH-CO- N (Et) 2 3-pyridyl 568 (M + H) 9 C / -V CO 2 Et -NH-CO- (4-morpholine) 3-pyridyl 610 (M + H) 9 D / - CO 2 H -? - N -? - CO- (4-morpholine 3-pyridyl 582 (M + H) 9 E? -NH-CO- N (Et) 2 3-pyridyl 524 (M + H) -86-9F- 1 H -H-3-pyridyl 425 (M + H) 9 H -H 4 -pyridyl 425 (M + H) 9 -NN-H 4 -pyridyl 411 (M + H) 91 -NHCH 2 CH 2 CH 2 O- -COOEt Pr U ^ fN E1 582 (M + H) 9 J 'C (O) N- (1 Bu) 2 4-pyridyl 595 (M + H) 9 K -NHCH 2 CH 2 CH 2 O - C (O) N- (iBu) 2 3-pyridyl 555 (M + H) 9 L -NHCH (Me) CH 2 CH 2 -C (O) N- (1 Bu) 2 3-pyridyl 553 (M + H) 9 M -NH- CH (Me) CH 2 CH 2 CH 2 -C (O) N- (iBu) 2 4-pyridyl 567 (M + H) 9 N (cis) -NHCH 2 CH = CH- C (O) N- (iBu) 2 3-pyridyl 537 (M + H) 9 N (trans) -nh 2ch = ch-C (O) N- (1 Bu) 2 3 -pyridyl 537 (M + H) 90 -NHCH 2 CH 2 CH (Me) - C (O) N- (1 Bu) 2 4-pyridyl 553 (M + H) 9 P -NHCH 2 CH 2 CH (Me) - C (O) N- (1 Bu) 2 3-pyridyl 553 (M + H) 9 -NHCH 2 CH 2 -O-CH 2 -C (O) N- (iBu) 2 3-pyridyl 555 (M + H) 9 R -N (Et) - CH 2 CH 2 CH 2 CH 2 -C (Me) 2 C (O) N - (B u) 2 4 -pyridyl 4 · 8 -87-9 S -NHCH 2 CH (CH 3) CH 2. ch2-C (O) N- (1Bu) 2-pyridyl 567 (M + H) 9 T -nh2ch2ch2. CH (CH3) - C (O) N- (1Bu) 2-pyridyl 56Ί (M + H) 9U -NHCH 2 CH 2. CH (CH 3) CH 2 --C (O) N- (1Bu) 2 3-pyridyl 567 (M + H) 9 N -NHCH (CH 3) CH 2 --C (O) N- (iBu) 2 3-pyridyl 539 (M + H) 9 W -N (Me) - CH 2 CH 2 CH 2 CH 2 -C (O) N - (Et) 2 4-pyridyl. - 9X -NHC (CH 3) 2 CH 2 CH 2 --CH 2 --C (O) N- (IBu) 2 3-pyridyl 5 S 1 (M + H) 9 Y -NHC (CH 3) 2 CH 2 CH 2 --CH (OH) - C (O) N- ( iBu) 2,3-pyridyl • 597 (M + H) 9 Z -NHC (CH 3) 2 CH = CH-CH (OH) - C (O) N- (iBu) 2 3-pyridyl 595 (M + H) 9 Z - NHC (CH 3) 2 CH 2 CH 2 - C 2 -C (Me) 2 C (O) N- (Et) 2 3-pyridyl 567 (M + H) 9AA -nh 2 2ch 2 -C (O) N- (iBu) 2 3-pyridyl 525 (M + H) 9 BB -nh 2 Ch 2 C 2 -C (Me) 2 C (O) N- (Et) 2 3-pyridyl 511 '(M + H) 9 CC -NHC (CH 3) 2 CH = CH-CH (OH) - C (O) N- (iBu) 2 -pyridyl 595 (M + H) 9DD -NHC (CH 3) 2 CH 2 CH 2 --CH (OH) - C (O) N- (iBu) 2 4-pyridyl 597 (M + H) 9EE -NHC (CH 3) 2 CH 2 CH 2 - ch 2 -C (O) N- (IBu) 2 4-pyridyl 581 (M + H) 9FF -NHC (CH 3) 2 CH = CH-CH (OH) - C (Me) 2-C (O) N- (Et) 4-pyridyl 581 (M + H) -88-9GG -NHC (CH 3) 2 CH 2 CH 2 -CH 2 -C (Me) 2 C (O) N- (Et) 2 4-pyridyl 567 (M + H) 9HH -NHCH 2 CH (CH 3) CH 2 CH 2 -C (O) N- (1 Bu) 2 -pyridyl 567 (M + H) 9 P 1 -nhch 2. CH (CH 2 CH 3) CH 2 CH 2 --C (O) N- (iBu) 2 4-pyridyl-5B1 ((M 4 H > 9 J-nhch 2 ch 2 -C (Me) 2 C (O) N- (Et) 2 4 -Pyridyl in 511. '' cM + h) 9KK -nhch2ch2-C (O) N- (1Bu) 2-pyridyl; ; 525

Example 10

{2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] propyl} - (4-pyridin-4-yl-butyl) amine

Step 10A 2-Methylcyclopropanecarboxylic acid N-methoxy-N-methylamide To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL of benzene and 2 mL of β-dimethylformamide) was added 10.5 mL of oxalyl chloride and the mixture was stirred. 30 min at 0 ° C and then warmed to room temperature over 30 min. Then 14.6 g of Ν, β-dimethylhydroxylamine hydrochloride and 41 ml of triethylamine were added. The mixture was stirred at -89- at room temperature for 1 hour and then quenched with saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo, the product was purified by distillation under reduced pressure to give 8.9 g of an oil.

Step 10B (3,5-Dimethylphenyl) - (2-methylcyclopropyl) methanone To a solution of 5-bromo-meta-xylene (5.7 mL in 120 mL dry tetrahydrofuran) at -78 ° C was added 30.6 mL 1.4M n-butyllithium in hexane and stirred at low temperature. After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methylamide (5.0 g in 50 mL of tetrahydrofuran) was added dropwise over 5 minutes and the mixture was allowed to slowly warm to room temperature. After 1 hour, the reaction was quenched by the addition of 20 mL of 2N hydrochloric acid and 40 mL of water. This mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate to give 6.95 g of the crude title compound.

Step 10C 2- [2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] propylamine To a solution of (4-methanesulfonylphenyl) hydrazine (1.88 g in 20 mL n-butanol) at 95 ° C was added (3,5-dimethylphenyl) - (2-methylcyclopropyl) methanone (2.24 g) and the mixture was heated to 110 ° C in an oil bath. After 16 h, the reaction was cooled to room temperature and poured into 200 mL of diethyl ether and the resulting brown precipitate was collected by filtration. The solids were dissolved in 300 mL of water and extracted with diethyl ether. The aqueous portion was basified by the addition of 1N sodium hydroxide and then extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on -90- silica gel (methylene chloride: methanol, 9: 1) gave the title compound (313 mg).

Step 10D {2- [2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] propyl} - (4-pyridin-4-yl-butyl) amine

A mixture of 4-pyridin-4-yl-butyraldehyde (23 mg), 2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] propylamine (50 mg) and magnesium sulfate (76 mg) was diluted with 1.5 mL of CDCl 3 and stirred at -5 ° C. After 15 minutes, a solution of sodium borohydride (6.8 mg in 1.5 mL of dry methanol) was added and the mixture was stirred at low temperature for a further 20 minutes. After the reaction was quenched by the addition of water, the reaction mixture was extracted with ethyl acetate, and the organic portion was washed successively with water and brine and then dried over sodium sulfate. Purification of the concentrate by preparative silica gel TLC (methylene chloride: methanol, 9: 1) gave the title compound (29 g).

Following a similar procedure to Example 7 and 10, the following compounds were prepared:

Example no. R9 Rsa H X < N-r10-R10a: X-Rr, R8. * (CH 2) n - R 1 m / e 10A MeO 2 x H -NHC (O) Ph 4 4-pyridyl 575 (M + H) 10BH Me Me 4 4-pyridyl 526 (M + H) -91 - 4C-4-pyridyl 553 (M + H) 10 D; Me 4 3-pyridyl 553 (M + H) 10 E Ψ H Me. Me (Et) 2 N 2 X 4 O 4 4-pyridyl 553 (M + H) 10 F Ve H Me. Me (Et) 2N. ≫ 0 4 4-pyridyl ' (M + H) < 10 > Me (BuifeN ^ X ^ 0 4 4-pyridyl-6-fluoro-10H-H-Me-Me; )

Example 11

2- (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1H-indole-5-carboxylic acid diethylamide

Step 11A

2- (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1H-indole-5-carboxylic acid ethyl ester -92- To a solution of ethyl ester 3- (2 -aminoethyl) -2- (3,5-dichloropropyl) -1H-indole-5-carboxylic acid (prepared as described in Example 5.1.100 mg in 7.0 mL of chloroform) at -5 ° C was added 172 mg of magnesium sulfate and then 46.3 mg of 4-pyridin-3-yl-butyraldehyde and the mixture was stirred at low temperature for 15 minutes. A solution of sodium borohydride (13.7 mg in 1.2 mL of dry methanol) was then added and after another 40 minutes the reaction was quenched with water. The mixture was partitioned between ethyl acetate and saturated potassium carbonate, extracted, and the organic phase was washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol, 92: 8) gave the title compound (100 mg).

Step 11B

3- {2- [tert-Butoxycarbonyl- (4-pyridin-3-yl-butyl) -amino] -ethyl] -2- (3,5-dichlorophenyl) -1H-indole-5-carboxylic acid ethyl ester To ethyl ester 2 solution - (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) -ethyl] -1H-indole-5-carboxylic acid (500 mg in 8 mL dry tetrahydrofuran) was added 331 mg tert-butyl dicarbonate at 0 ° C and then aqueous potassium carbonate solution (215 g in 4 mL of water and the resulting suspension was stirred vigorously at 0 ° C. After 1 hour the reaction was quenched with excess aqueous ammonium chloride solution and extracted with ethyl acetate. Dry the organic portion over sodium sulfate and concentrate in vacuo Purify the residue by flash chromatography on silica gel (methylene chloride: methanol, 96.5: 3.5) to give the title compound (472 mg).

Step 11C

3- {2- [tert-butoxycarbonyl- (4-pyridin-3-yl-butyl) amino] ethyl] -2- (3,5-dichloro-phenyl) -1H-indole-5-carboxylic acid K a suspension of 3- {2- [tert-butoxycarbonyl- (4-pyridin-3-yl-butyl) -amino] -ethyl] -2- (3,5-dichlorophenyl) -1H-indole-5-carboxylic acid ethyl ester (65 mg in 4 ml of methanol at 0 ° C was added 1.4 ml of 1.25N sodium hydroxide solution and the mixture was heated to 75 ° C in an oil bath. After 2.5 hours, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with saturated ammonium chloride solution and the organic portion dried over sodium sulfate. Concentration in vacuo afforded the crude title compound (63 mg).

Step 11D

{2- [2- (3,5-Dichlorophenyl) -5-diethylcarbamoyl-1H-indol-3-yl] ethyl} - (4-pyridin-3-yl-butyl) carbamic acid tert-butyl ester To the acid solution 3 - {2- [tert-butoxycarbonyl- (4-pyridin-3-yl-butyl) amino] ethyl] -2- (3,5-dichlorophenyl) -1H-indole-5-carboxylic acid (63 mg in 6 ml of methylene chloride) was added 24.2 mg of 1-hydroxybenzotriazole followed by 26.7 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the mixture was stirred at room temperature. After 30 minutes, 0.06 ml of diethylamine was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride / methanol, 95: 5) to give the title compound (63 mg).

Step 11E

2- (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1H-indole-5-carboxylic acid diethylamide To a solution of tert-butyl acid {2- [2 - (3,5-Dichlorophenyl) -5-diethylcarbamoyl-1H-indol-3-yl] ethyl} - (4-pyridin-3-ylbutyl) carbamic acid (63 mg in 3 mL methylene chloride) at 0 ° C was added 0.15 ml of anisole and then 0.76 ml of trifluoroacetic acid and the mixture was stirred at 0 ° C. After 1.5 hours, another portion of 0.5 mL of trifluoroacetic acid was added and stirring was continued for an additional hour, then the mixture was concentrated in vacuo and the residual acid was removed by azeotropic distillation with toluene. Purification of the concentrate by flash chromatography on silica gel -94- (1-methylene chloride: methanol: ammonium hydroxide, 90: 6.5: 1) gave the title compound (38 mg), m / e = 537 (M).

Following a similar procedure to that described in Example 11, the following compounds were prepared:

Example No. x-r7, r8 R1 m / e 11A Me ^ Me ^ ΜΚ ^ 3 3-pyridyl 582 (M + H) 11B -COOEt 3-pyridyl 510 (M) 11C -CON (iBu) 2 3 -Pyridyl 593 (M) 11D -CON (nBu) 2 3-pyridyl 593 (M) 11E -CON (Et) 2 ON 541 (M)

Example 12.1

-95-

1- {2- (3,5-Dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone Step 12.1A

3- {2- [tert-Butoxycarbonyl- (4-pyridin-4-yl-butyl) -amino] -ethyl] -2- (3,5-dimethyl-phenyl) -1H-indole-5-carboxylic acid ethyl ester

Prepared as described in Example 9.1, Step A starting from 3- (3,5-dimethyl-phenyl) -3- [2- [4- (pyridin-4-yl) -butylamino] -ethyl] -1H- ethyl ester. indole-5-carboxylic acid (Example 5.1, Step B) to give the title compound.

Step 12.1 B

3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl] -2- (3,5-dimethyl-phenyl) -1H-indole-5-carboxylic acid

Prepared as described in Example 9.1, Step B starting from 3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl] -2- (3,5-dimethylphenyl) ethyl ester -1H-indole-5-carboxylic acid and lithium hydroxide is used to give the title compound.

Step 12.1 C

{2- [2- (3,5-Dimethylphenyl) -5- (methoxymethylcarbamoyl) -1H-indol-3-yl] ethyl} - (4-pyridin-4-yl-butyl) carbamic acid tert-butyl ester To the solution 3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl] -2- (3,5-dimethyl-phenyl) -1H-indole-5-carboxylic acid (1.44 g in N, N-dimethylformamide (25 mL) at 0 ° C was added 540 mg (1-hydroxybenzotriazole (HOBt) followed by 0.44 mL of 4-methylmorpholine and 365 mg of Ν, Ο-dimethylhydroxylamine hydrochloride. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and allowing the mixture to warm to room temperature After the three days of reaction, another portion of 540 mg of HOBt, 0.44 ml of 4-methylmorpholine, 365 mg of Ν , Ο-dimethylhydroxylamine hydrochloride and 815 mg of EDC The reaction was assembled after four days by concentration in vacuo and re-concentration of -96- from toluene to remove all volatiles The residue was dissolved in ethyl acetate and washed successively with saturated aqueous m sodium bicarbonate solution and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane: ethyl acetate, 30:70, then 20:80, then 0: 100) gave the title compound (1.4 g).

Step 12.1 D

Tert-Butyl 3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl] -2- (3,5-dimethylphenyl) -5- (methoxymethylcarbamoyl) -1H-indole- 5-carboxylic acid

Prepared as described in Example 9.1 step A starting from tert-butyl {2- [2- (3,5-dimethylphenyl) -5- (methoxymethylcarbamoyl) -1H-indol-3-yl] ethyl} - (4-pyridin-4-yl-butyl) carbamic acid (1.4 g) to give the title compound (1.55 g).

Step 12.1 E

5-Acetyl-3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) -amino] -ethyl] -2- (3,5-dimethyl-phenyl) -1H-indole tert-butyl ester 5-carboxylic acid To a solution of 3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl] -2- (3,5-dimethylphenyl) -5- (methoxymethylcarbamoyl) tert-butyl ester -1H-indole-5-carboxylate (0.069 g in 3 mL dry tetrahydrofuran) at -10 ° C was added 0.20 mL of a 1.5 M solution of methyl lithium in ether and the mixture was stirred at low temperature. After 45 minutes, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, and the concentrate was purified by preparative silica gel TLC (hexane: ethyl acetate, 2: 3) to give the title compound (58 mg).

Step 12.1 F 1- {2- (3,5-Dimethyl-phenyl) -3- [2- (4-pyridin-4-yl-butylamino) -ethyl] -1H-indol-5-yl} -ethanone -97-

Prepared in the same manner as described in Example 9.1, Step D starting from tert-butyl 5-acetyl-3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) -amino] -ethyl ] -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid (120 mg) to give the title compound (82 mg), m / e = 440 (M + H).

Example 12.2

1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanol To a solution of 1- {2- ( 3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone (45 mg in 2 mL dry tetrahydrofuran) at 0 ° C was added 0.30 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran and the mixture was stirred at low temperature. After 45 minutes, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Wash the organic portion with brine, dry over sodium sulfate, and purify by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 10: 0.25) to give the title compound (40 mg), m / e = 442 ( M + H).

Example 12.3

-98- O-methyloxime 1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl] -ethanone To a solution of 1- { 2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone (22 mg in 0.50 mL methanol) ) 102 mg of sodium acetate trihydrate and 63 mg of methoxylamine hydrochloride were added and the mixture was stirred at room temperature. After 20 hours, the mixture was concentrated in vacuo and the residue was suspended in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine. Dry the organic portion over sodium sulfate and concentrate the concentrate by preparative silica gel TLC (methylene chloride: methanol: ammonium hydroxide, 90: 10: 0.25) to give the title compound (23 mg), m / e = 469 (M + H).

Following the procedures similar to those in Examples 12.1, 12.2 and 12.3, the following compounds were prepared. R7

Example no. x-r7, r8 m / e 12A O440 (M + H) 12BO2502 (M + H) +, AS, UF U -99- 12C01 α 4,504 (M + H) 12D (xr1 520 ( M + H) 12E 0.Me 1 1 1 I .i 468 (M + H) 12F Ofrl Μβ Χ Me 1 L 470 (M + H) 12G 0 Me JJ Μβ-η Me 1 jl \ t H) 12H MeOH-MV 482 (M + H) + 121 Me 1 482 (M + H) +, 12 I, 482 (M + H) +.

Example 13

Following procedures similar to those described in Examples 1 to 12, the following compounds are prepared: t

J

-101 - 13G Me 1 Me Me Me NLX ^ 0 Me Me 13 Me Me Me Me \ t Me Me | l ^ 131 Me. 1 Me. Me 0 H '^ Xn' - ^^ Ní ^ n Me Me [i J 13J Me. 1 Me Me 0 iX ~ Ti 13Κ Me 1 Me. Me 0 Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me \ t

J

I

13P Me 1 Me Me ^^ Nv ^ JX ^ 0 Xb ^ X * " 13Q Me Me Me 3 O 13R Me 1 Me Me 0 " HFVF O 13S Me Me Me Me NLX ^ 0 H F. F: ^ 13T Me 1 Me Me ^ N0 < ^ 0 H F. FX ^ O &o; F F. F -N 13V HF2C ^ 1 Me. Me HF2C ^ N.X ^ 0H 13W HF2CX 1 Me. Me hf2c ^, n 0 ^ H 13X H2FCX 1 Me. Me h2fc ^ n.X ^ 0 H 13Υ h2fcn; 1 Me. Me 2 H 2 R 4 is N, X 1, O H; L.N 13Ζ f3cn 1 Me. Me F3C N0 <. H 13ΑΑ F3Cv. 1 Me. N / ^ ν ^Χ le le í le leΒΒΒΒΒΒΒΒΒΒ 13ΒΒ F3C ^ FaCs / Nys 0 H 0 13CC F3C ^ FaCv / Nys 0 Ψ H 13DD Me 1 1 Mev Me 0 13 Me 1 Me Me 0 N 13GG Me 1 Mev Me MvN &X;

13ΗΗ Me. 1 Me Me 0 H LJ 13Π Me 1 Me Me 0 H 13JJ Me 1 Me Me Me NLX ^ 0 13 ΚΚ Me. 1 Me Me MV ^ X 0 Xr '-' O 13LL Me 1 Me Me ^ Ns ^ 0 Me t H F \ t 1 Me Me ^ N ^ > 0 Me 13 Me Me Me Me 0 Me H Cl ^ 0 NH 1300 Me. ^ Me Me ^ J Me H Cl rv0 NH

I - 105-

Claims (24)

1. Non-peptide derivatives of the general formula (1) wherein A is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, substituted C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, substituted C 3 -C 6 alkynyl, C 1 -C 6 alkynyl, C 1 -C 6 alkynyl, C 6 alkoxy or C 0 -C 5 alkyl-S (O) n -C 0 -C 5 alkyl, C 0 -C 5 alkyl-O-C 0 -C 5 alkyl, C 0 -C 5 alkyl-NR 18 -C 0 -C 5 alkyl wherein R 18 and C 0 -C 5 alkyl may be combined to form a circle N- (CH2) p or a single bond. R c is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R 3, R 4 and R 5; R1 is 0 14 -107 - 15 / ^ R y in R14 S '* -' 'y .m R19 Λ- r11y-' 13 R14 (in) R13 I · R ”R13 sĹ · * ^ - | N R 13 R R 2 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-OR 11, C 1 -C 6 (NR 11 R 12), C 1 -C 6 (CONR 11 R 12) or C (NR 11 R 12) NH; R 2 and A together form a ring of 5 to 7 atoms; R 3, R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, CN, nitro, C 1 -C 3 perfluoroalkyl, C 1 -C 3 perfluoroalkoxy, aryl, substituted aryl, aralkyl , substituted aralkyl, R 10 (CH 2) p -, R 11 C (O) O (CH 2) p -, R 110 C (O) (CH 2) p -, - (CH 2) PS (O) n R 17, - (CH 2) PC (0) NR 11 R 12 or halogen wherein R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, aryl or substituted aryl; R 3 and R 4 together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; R 6 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, C 1 -C 3 perfluoroalkyl, CN, NO 2, halogen, R 10 (CH 2) p -, NR 12 C (O) R 11, NR 12 C (O) NR 11 R 12 or SO n R 11 ; -108 - R 7 is hydrogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl, when X is hydrogen or halogen, R 7 is absent; R 8 is hydrogen, C (O) OR 9, C (O) NR 11 R 12, NR 11 R 12, C (O) R 11, NR 12 C (O) R 11, NR 12 C (O) NR 11 R 12, NR 12 S (O) 2 R 11, NR 12 S (O) 2 NR 11 R 12, OC (O) R 11, OC (O) NR 11 R 12, OR 11, SO n R 11, S (O) n NR 11 R 12, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl, when X is hydrogen or halogen, R 8 is absent, or R 7 and R 8 together form a carbocyclic ring 3 to 7 atoms; R 9 and R 9a are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl, wherein m * 0; or R 9 and R 9a together form a carbocyclic ring of 3 to 7 atoms or where m φ 0; R 9 and A together form a heterocyclic ring containing 3 to 7 carbon atoms and one or more heteroatoms wherein m * 0; or R 10 and R 10a are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R 10 and P 10 and SP 10 form a carbocyclic ring of 3 to 7 atoms or || R 9 and R 10 and together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing one or more heteroatoms wherein m * 0; or R 9 and R 2 together form a heterocyclic ring containing 3 to 7 carbon atoms and one or more heteroatoms wherein m φ 0; or R 10 and R 2 together form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; R 10 and A together form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; or R 11 and R 12 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted 1 aryl, aralkyl, substituted aralkyl, carbocyclic ring of 3 to 7 atoms, or substituted carbocyclic ring containing 3 to 7 atoms; R 11 and R 12 together may form an optionally substituted ring of 3 to 7 atoms; > 7d8, 11 < , 11 < R 13 is hydrogen, OH, NR 1 R 0, NR 11 SO 2 (C 1 -C 6 alkyl), NR 11 SO 2 (substituted C 1 -C 6 alkyl), NR 11 SO 2 (aryl), NR 8 SO 2 (substituted aryl), NR 11 SO 2 (CrC 3 > 11 11 < -109 - I perfluoroalkyl, SC 1 NR 6 C 1 -C 6 alkyl), SO 2 NR 11 (substituted C 1 -C 6 alkyl), SO 2 NR 11 (aryl), SO 2 N R 11 (substituted aryl), SO 2 NR 11 (C 1 -C 3 perfluoroalkyl), SO 2 NR 11 (C (O) C 1 -C 6 alkyl ), SO 2 NR 11 (C (O) -substituted C 1 -C 6 alkyl), SO 2 NR 11 (C (O) -aryl), SO 2 NR 11 (C (O) -substituted aryl), S (O) n (C 1 -C 6 alkyl), S (O) " - (substituted C 1 -C 6 alkyl), S (O) n (aryl), S (O) n- (substituted aryl), C 1 -C 3 perfluoroalkyl, C 1 -C 3 perfluoroalkoxy, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, COOH, halogen, NO 2 or CN; R 14 and R 15 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, CN, nitro, C 1 -C 3 perfluoroalkyl, C 1 -C 3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R 110 ( CH 2) p-, R 11 C (O) O (CH 2) p -, R 110 C (O) (CH 2) p -, - (CH 2) p S (O) n R 17, - (CH 2) p C (O) NR 11 R 12 or halogen wherein R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, aryl or substituted aryl; R 16 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, or N (R 11 R 12); R 18 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C (O) R 9, C (O) NR 11 R 12, C (O) R 11, S (O) n R 11; R 19 is as defined for R 13 or R 14; X is hydrogen, halogen, N, O, S (O) n, C (O), (CR 11 R 12) P; C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl; wherein X is hydrogen or halogen, R 7 and R 8 are absent; wherein X is O, S (O) n, C (O), or CR 11 R 12 is only R 7 or R 8; Z is O, S or NR 11; m is 0 to 3; n is 0 to 2; p is 0 to 4 and the alkyl, alkenyl and alkynyl substituents are selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C 1 -C 6 alkoxy, fluoro, C (O) OR 11 , aryl C 1 -C 3 alkoxy, substituted aryl C 1 -C 3 alkoxy and aryl substituents are defined as for R 3, R 4 and R 5; or a pharmaceutically acceptable addition salt or hydrate thereof, or, where applicable, a geometric or optical isomer or racemic mixture. - 110- 2. Non-peptide derivatives according to claim 1 of the formula - 110- wherein R 1, R 3, R 4, R 5 and A are as shown in the following table: R 3 R 3, R 4, R 5 A Pyridine -NH-COCH 3 3,4-OMe CH 2 O Pyridine -NH 2 3,4-OMe CH 2 -O 3. Non-peptide derivatives according to claim 1 of the formula R 5 R 4 wherein R 1, R 3, R 4, R 5 and A are shown in the following table: R 3 R 3, R 4, R 5 A = (CH 2) n 3-Phenyltriazole 3,4-OMe 1 5-Indole 3,4-OMe 1 5-Benzimidazole 3,4-OMe 1 4-Indole 3,4-OMe 1 3-pyridyl 3,5-Me 5 4-pyridyl 3,5-Me 4 2-pyridyl 3,5-Me 4 3-pyridyl 3 5-Me 4 -111-5-pyrimidine. 3.5-Me 4 " " C 3,5-Me 4 N Me H 3.5-Me 4 xx. 3.5-Me 4 N ^ nh 3.5-Me 4 xx x0 3.5-Me 4 Y ^ N ^ nh2 3.5-Me 4 in > ° > ° .s. N Me H 3,5-Me 4 4-pyridyl 3,5-Me 2 3-pyridyl 3,5-Me 2 2-pyridyl 3,5-Me 2 4-imidazolyl 3,5-Me 2 4-pyridyl 3 5-Me 1 2-pyridyl 3,5-Me 1 3-pyridyl 3,5-Me 1 3-pyridyl 3,5-Me 3 4-pyridyl 3,5-Me 3 3-quinolinyl 3,5-Me 4 I , 3,5-Me 4 n-n'N 4-pyridyl 3,5-Me 5 5-indolyl 3,4-OMe 3 YY ^ 3,5-Me 4 Non-peptide derivatives according to claim 1 of the formula Y wherein R 1, R 3, R 4, R 5 and X-R 7 R 8 are shown in the table below: x-r 7, r 8 R 3 R 3, R 4 (R 5 H 5-Benzimidazole -N-SO 1 Me 3.4- OMe H 5-Benzimidazole 3,4-OMe 5. The non-peptide derivatives according to claim 1 of the formula wherein A, R 1, R 5 and X-R 18 are shown in the table below: I -113- x-r7, r8 = CH 2) n R 1 *, 4-pyridyl Br 4-pyridyl -NH 2% 4-pyridyl -NH-COCH 3 4 4-pyridyl -NH-CO-N (CH 2 CH 3) 2 4 4-pyridyl -NH-CO-N (CH 2 CH 3) 2 4 3-pyridyl -NH-CO-N (CH 2CB 3) 2 4 6-methoxy-3-pyridyl -NH-CO-N (CH 3) 2 5 3 -pyridyl -NH-CO-N (CH 2 CH 3) 2 5 3-pyridyl -NH-CO-N (CH 2 CH 3) 2 5 4-pyridyl -NH-CO-N (CH 3) 2 4 6-methoxy-3-pyridyl -SO 2 4-pyridyl O, 4-pyridyl O 4 4-pyridyl MeSO 4 - 4 3-pyridyl Me 2 - 4 6-methoxy-3-pyridyl MeSO 2 - 4 MeSO 2 - 5 4-pyridyl MeSO 2 - 5 3-pyridyl x V 4 4-pyridyl MeSO 2 - 4 4-pyridyl -144 -114- 4-pyridyl -NH-CO-N (CH 3) 2 (*) - R6 = 5-NO2 (**) - R6 = Br 6. Non-peptide derivatives according to claim 1 of the formula wherein R 1, R 7 and R 8 are shown in the table below: x-r 7, r 8 'R 6 R 2 (D) O 4 H -pyridyl s (D > O h 3 H -pyridyl O Me H 3-pyridyl O Me H 4-pyridyl-4-pyridyl-4-pyridyl-15-oxo-3-pyridyl-4-pyridyl-4-pyridyl-3-pyridyl-H-4-pyridyl-4-pyridyl-0 3-pyridyl-3-pyridyl OiA-Me 3 H-3-pyridyl-3-pyridyl-O-Me-4-pyridyl-4-pyridyl-4-pyridyl-116-O-2-H-3-pyridyl; pyridyl O, 4H-pyridyl MeOH, 4H, 3-pyridyl MeOH, MeH 4-pyridyl MeOH, Me 2 H 3-pyridyl (H) 3-pyridyl Cr / H 4-pyridyl H 3 -pyridyl-CON (Et) 2 H -COOMe 6-Cl 4 -pyridyl-CON (iBu) 2 6-Cl 4 -Pyridyl-117--CON (Et) 2 H xx > s, O Me -CON (CH 2 CH 2 CN) - H 4 -pyridylcyclohexyl / H 4 -pyridyl-Uy-Me-COOMe 4-C 4 -pyridyl-CON (iBu) 2 -C 4 -pyridyl- CON (Et) 26-C14-pyridyl 7. Non-peptide derivatives according to claim 1 of the formula wherein R 1 and A are shown in the table below: A = (CH 2) n R 4 4 -pyridyl 4 3-pyridyl 4 6-amino-3-pyridyl 4 6-amino-3-pyridyl-118- 6-methoxy-3- pyridyl 4 U " N 4 ° " N 4 " TV-co2H U " N 4 X ' " and " N 4 TVcONEt, UN 4 2-Cyano-4-pyridyl 4 ' N 4 2- (CH 2 NH-Boc) -4-pyridyl 4 2- (CH 2 NH 2) -4 * pyridyl 4 6- (SMe) -3-pyridyl 4 5-carboethoxy-3-pyridyl 4 6- (NHCOOEt) -3- pyridyl 4 2,3,5,6-tetrafluoro-4-pyridyl 3 3-pyridyl 4 6- [NHS (O) 2 CF 3] -3-pyridyl-119-4 6- [NHS (O) 2 CH 3] -3-pyridyl 4 5-cyano-3-pyridyl 4N-4'-Me-YrN 4 3,5-dichloro-4-pyridyl-4'-N-Cl- 8. Non-peptide derivatives according to claim 1 of the formula wherein R 1, X 1 -R 1 ', R 8 are shown in the table below: X 1 -R 1, R 8 R 1 Me 2 - Me Me, Nv > < 4 > -pyridyl MeOH Me Me 2 N 2 X 3 O 3 -pyridyl-120-MeO Me. Me Me 2 O 3 Y 2 O 3 -pyridyl MeC 1 / MeMe. Me MeO 4 Ny 2 O 4-pyridyl Me-NY 2 O 4-pyridyl MeMe 2 M 8 -NH 2 O 3 -pyridyl Me Me 2 Me. Me-Me-Me-4-pyridyl Me Me-Me. Me r »^ Me Me ^ 3-pyridyl Mevyv] Me Me 0 4-pyridyl Me ^ - I Me Me / v ^ NL ^ 3 3-pyridyl -121 - I Me M0 Me — Ny ^ 0 3- pyridyl HMe Me MeNNTi 'MeO 3 -pyridyl wMe. MeO 3 -pyridyl Me. I Me Me MeNxjX. MeO 3 -pyridyl Me. I Me. Me 3-pyridyl Me. | Mev Me cr 4-pyridyl Me Me 2ΝγΚ, 0 3-pyridyl ΕκΓ > < > 4-pyridyl -122-9: Non-peptide derivatives according to claim 1 of formula -122 - wherein R 1, R 2 and A are shown in the table below: R 2 (A) R 2 R '-CH 2 CH 2 - - (CH 2 M - (phenyl-4-OMe) 4-pyridyl -CH 2 CH 2 - - (CH 2) 4- (phenyl-4-OH) 4-pyridyl -CH 2 C (Me) 2 CH 2 CH 2 - - H 4-pyridyl xr -H 3-pyridyl-H 3-pyridyl-C 3 -C 6 -H 3-pyridyl-123- 10. Non-peptide derivatives according to claim 1 of formula R 8 R 2 where A, R 1, R 2 and X-R 7, R 8 are as shown in the table below: -N (r 2:) - (A), x-r 7, r 8 R 1 / - CO 2 Et Nv / n -NH-CO- N (Et ) 2 3-pyridyl (-) - 2H - N '- (-) -NH-CO- N (Et) 2 3-pyridyl (- CO2Et " VT ") -NH-CO- (4-morpholine) 3-pyridyl (-) - NH - CO - (4 - morpholine) - 3 - pyridyl - O - NH - CO - N (Et) 2 - 3 - pyridyl - 1 - (-) - H 3 -pyridyl-1H-1 H-4-pyridyl-1H-4-pyridyl-1,2,4-NHCH 2 CH 2 CH 2 O--COOEt Pr El 1 O, "C (O) N- ( iBu) 2 4-pyridyl-nh 2 2ch 2ch 2 - C (O) N- (1 Bu) 2 3-pyridyl -NHCH (Me) CH 2 CH 2 - C (O) N- (1 Bu) 2 3-pyridyl -NH- CH (Me) CH 2 CH 2 CH 2 - C (O) N- (iBu) 2 4-pyridyl (cis) -NHCH 2 CH = CH- C (O) N- (iBu) 2 3-pyridyl (trans) -nh 2 ch = ch-C (O) N- ( iBu) 2 3-pyridyl -NHCH 2 CH 2 CH (Me) - C (O) N- (iBu) 2 4-pyridyl -NHCH 2 CH 2 CH (Me) - C (O) N- (iBu) 2 3-pyridyl-nhch 2 ch 2 -o-ch 2 - C (O) N - (Bu) 2 3 -pyridyl -N (Et) - CH 2 CH 2 CH 2 CH 2. C (Me) 2-C (O) N- (1Bu) 4-pyridyl -NHCH 2 CH (CH 3) CH 2. ch 2 -C (O) N- (1 Bu) 2 3-pyridyl -nh 2 ch 2 ch 2. CHCCH 3) - C (O) N- (1Bu) 2 -pyridyl-nhch 2ch 2. CH (CH 3) CH 2 --C (O) N- (iBu) 2 3-pyridyl -NHCH (CH 3) CH 2 --C (O) N- (iBu) 2 3-pyridyl -N (Me) - CH 2 CH 2 CH 2 CH 2 - C (0 ) N- (Et) 2-4-pyridyl-125--NHC (CH 3) 2 CH 2 CH 2 -CH 2 -C (O) N- (1Bu) 2 -pyridyl-NHC (CH 3) 2 CH 2 CH 2 -CH (OH) - C (0 ) N- (1Bu) 2 -pyridyl-NHC (CH 3) 2 CH = CH-CH (OH) - C (O) N- (Bu) 2 -pyridyl -NHC (CH 3) 2 CH 2 CH 2 -CH 2 -C (Me) 2-C (O) N- (Et) 2 -pyridyl-nhch2ch2-C (O) N- (iBu) 2 3-pyridyl-nhch2ch2-C (Me) 2-C (O) N- (Et) 2 3-pyridyl -NHC (CH 3) 2 CH = CH-CH (OH) - C (O) N- (1Bu) 2 -pyridyl -NHC (CH 3) 2 CH 2 CH 2 --CH (OH) - C (O) N- (iBu ) 2 4-pyridyl -NHC (CH 3) 2 CH 2 CH 2 - ch 2 -C (O) N- (1Bu) 2 4-pyridyl -NHC (CH 3) 2 CH = CH-CH (OH) -! C (Me) 2 - C (O) N- (Et) 2 - 4-pyridyl -NHC (CH 3) 2 CH 2 CH 2 -! ch 2 -C (Me) 2 C (O) N - (Et) 2 4-pyridyl -NHCH 2 CH (CH 3) CH 2 - "CH 2 --C (O) N- (1Bu) 2 -pyridyl -nhch 2. CH (CH 2 CH 3) CH 2 CH 2 --C (O) N- (iBu) 2 -pyridyl-nhch 2ch 2-C (Me) 2-C (O) N- (Et) 2 4-pyridyl-nhch 2ch 2-C (O) N- (iBu) 2 4-pyridyl-1 -26- where R1, XR7, R8, R9, R9a, R10 and R10a are shown in the table below: r9 R9a M R10 R103 x-r7, r8 < ca2) a-: - :: - ¾¾¾¾ r1: H -NHC (0) Ph 4 4-pyridyl-H Me Me (X 4) 4-pyridyl-H Me Me (Et) 2 N -X 4 O-4-pyridyl-H Me Me (Et) 2 N -X 4 O-3-pyridyl ^ H Me Me (Et) 2N. ^ 0 4 4-pyridyl f Me Me (Et) 2N ^ X ^ 0 4 4-pyridyl -127- f Me Me (Bui) 2N.X ^ 0 4 4 -Pyridyl-H-Me-Me-4-3-pyridyl-H-amino-Me-Me-3-pyridyl 12. Non-Peptide Derivatives of Claim 1 wherein R1 and XRr, R8 are as shown in the table below: X-R7, R8 R1 Me2 Me2 O3-pyridyl -COOE3 3-pyridyl -CON (IBu) 2 3-pyridyl -CON (nBu) 2 3-pyridyl -CON (Et) 2 ° -N -CON (Et) 2 3-pyridyl Non-peptide derivatives according to claim 1 of the formula where XR7, R8 is shown in the table below: 14. Non-peptide derivatives according to claim 1 of the formula wherein A, R 1, R 2, XR 7, R 8, R 9, R 9a, R 10 and R 10a are shown in the table below:! X-R7, R8 d9 p9a R2 ^ X.Ň— (A) - R1 Me I Mev Me ΧβνΜνΧ 0 / Me Me Me. Me 0 Ψ H Me | Me Me? N? X? O? Me? -130? Me | Me Me Me 2 N 2 X 2 O Me Me; Me. Me Me Me 2 N 2 X 2 O Me Me; Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Mex ^ Nv > < x 0 Me Me! Me Me. Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me \ t γγ Me -131 -: I -132- t. i h2fcx I Me. Me h2fc ^ n ^ X ^ 0 'HaFCX I Me. Me h2fc ^ n. ≫ ^ 0 Φ H f3cn I Me. Me F3C ^ NOX 0 0 f3cn 1 Me. Me F3C > ^ NOX 0 H —0 f3c ^ FaC ^ N ^^ 0 H F3C ^ f Me ^ Me Me 0 l H Me. Me Me Me N 2 X 3 O N -135- Non-peptide derivatives according to claim 1, which are: a) 1- (2- (2- (3,4-dimethoxyphenyl) -1H-indol-3-yl) ethylamino] -3- (pyridin-4-yloxy) propan-2-ol b) [2- (2- (3,5-dimethylphenyl) -5-methanesulfonyl-1 H -indol-3-yl] ethyl] - (pyridin-4-yl-butyl) -amine; 3- (2- (3,5-dimethylphenyl) -3- [2- (5-pyridin-4-ylpentylamino) ethyl] -1H-indol-5-yl] -1,1-dimethylurea. 16. A pharmaceutical composition comprising an effective amount of a non-peptide derivative of claim 1 together with a pharmaceutically acceptable carrier. 17. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound stimulating endogenous growth hormone production or release in combination with a non-polypeptide derivative of claim 1. -136. Non-peptide derivatives according to claim 1 for use in the prevention of pregnancy. Non-peptide derivatives according to claim 1 for use in the treatment of lupus erythematosis. Non-peptide derivatives according to claim 1 for use in the treatment of irritable bowel syndrome. Non-peptide derivatives according to claim 1 for use in the treatment of premenstrual syndrome. The non-peptide derivatives of claim 1 for use in the treatment of excessive hair. The non-peptide derivatives of claim 1 for use in the treatment of sleep disorders such as sleep arrest. Use of the non-peptide derivatives of claim 1 in combination with a compound that stimulates endogenous production or release of growth hormone for the manufacture of a medicament for the treatment of low growth hormone deficiency. Use of a non-peptide derivative according to claim 1 for the manufacture of a medicament for the treatment of gonadotropin releasing hormone disorders. The use of claim 25, wherein the gonadotropin-releasing hormone-derived disorder is a sex hormone-related condition. The use of claim 25, wherein the gonadotropin releasing hormone disorder is cancer, benign prostate hypertrophy, or sex hormone dependent uterine fibroid. -137- Use according to claim 27, wherein the sex hormone dependent cancer is from the group of prostate, uterine, mammary gland and pituitary gonadal adenoma. 1 The use of claim 26, wherein the sex hormone dependent condition is endometriosis, polycystic ovarian disease, uterine fibroid, and premature puberty. i f V i