CA2240115A1 - Antagonists of gonadotropin releasing hormone - Google Patents

Abstract

There are disclosed compounds of formula (I) and pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related and other conditions in both men and women.

Description

CA 0224011~ 1998-06-09 WO 97t21435 PCT/US96/20004 TITLE~ OF THE INVENTION
~ AN7rAGONISTS ~F GONADOTROPIN RELEASING HORMONE

BACKGROUN~ OF THE INVENTION
The gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in hllm~n reproduction. The hormone is released from the hypoth~l~mus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females. GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH/FSH release. In particular, GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary. GnRH agonists and antagonists have also been utili~ed in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women. They have also shown possible utility in the treatment of pituitary gonadotrophe adenomas, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism, as an adjunct to growth hormone therapy in growth hormone deficient children, and in murine models of lupu.s. The compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g. MK-0677, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH
antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
Additionally, a compound of the present invention may be co-aclminixtered with a Soc-reductase 2 inhibitor, such as finasteride or epristeride; a So~-reductase 1 inhibitor such as 4,7,B-dimethyl-4-aza-5Oc-cholestan-3-one, 3-oxo-4-a~;a-4,7,B-dimethyl- 16,~-(4-chlorophenoxy)-5Oc-androstane, and 3-oxo-4-aza-4,7,B-dimethyl-16,B-(phenoxy)-5~-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of So~-reductase 1 and Soc-reductase 2 such as 3-oxo-4-aza-17,13-(2,5-trifluoromethylphenyl-carbamoyl)-Sa-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha-l blockers such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin.
Further, a compound of the present invention may be u.sed in combination with growth hormone, growth ho~none releasing horrnone or growth hormone secretagogues, to delay puberty in growth hormone de~lcient children, which will allow thern to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
Current GnRH antagonists are GnRH-like decapeptides which are generally ?~flministered intravenously or subcutaneously presumably because o~ negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
Non-peptide GnRH an~agonists offer the possible advantage of oral ~lm;n.~tration. Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J.
~ed. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
Substituted indoles known in the art include those described in the ~ollowing patents and patent applications. US Patent No.
5,030,640 discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potent r3-agonists. US Patent No. 4,544,663 discloses indolamine derivatives which are allegedly useful as male anti-i~ertility agents. WO
90/05721 discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents. French patent CA 0224011~ 1998-06-09 2,181,559 discloses indole derivatives with .sedative, neuroleptic, analgesic, hypotensive, an~iserotonin and adrenolytic activity. Belgian patent 8793~1 discloses 3-aminoalkyl-lH-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.

SUMMARY OF THE INVENTION
The present invention relates to compounds which are non-peptide antagonists of GnRH which can be used to treat a variety of sex-hormone related conditions in men and women, to methods for their preparation, and to methods and pharmaceutical compositions cont~ining said compounds for use in m~mm~
Because of their activity as antagonists of the hormone GnRH, the compounds o~ the present invention are useful to treat a variety of se~-hormone related conditions in both men and women.
These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia.s such as cancers of the prostate, breast and ovaly, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertophy.
They are also useful as an adjunct to treatment of growth horrnone deficiency and short stature, and for the treatment of systemic lupus erythematosis. Further, 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 contraception. They may also be useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive. The compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Fn~l~pril or Captopril, an angiotensin II-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids. Additionally, the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, for ~e treatment and the prevention of dis~urbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
Additionally, a compound of the present invention may be co~ mini~tered with a So~-reductase 2 inhibitor, such as finasteride or epristeride; a So~-reductase 1 inhibitor such as 4,7,3-dimethyl-4-aza-50~-cholestan-3-one, 3-oxo-4-aza-4,7,B-dimethyl-16,13-(4-chlorophenoxy)-Sa-androstane, and 3-oxo-4-aza-4,7~-dimethyl-1613-(phenoxy)-Soc-androstane as disclosed in WO 93/23420 and WO 9S/1 1254; dual inhibitors of Sa-reductase 1 and Sa-reductase 2 such as 3-oxo-4-aza-17,3-(2,5-trifluoromethylphenyl-carbamoyl)-50c-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha-1 blockers such as prazosin, terazo.sin, doxazosin, tamsulosin, and alfuzosin.
Further, a compound of the present invention may be used in combination with growth horrnone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth honnone deficient children, which will allow them to continue to gain height be~ore fusion of the epiphyses and cessation of growth at puberty.

DETAILED DESCRIPTION OF THE l~VENTION
The present invention relates to compounds of the general formula ~8 R~N- (A)--R6 Ro /~\'J R3 R~; R4 (1) wherem A is Cl-C6 alkyl, substituted C1-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloaLkyl, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-c6 alkynyl, substituted C3-c6 alkynyl, Cl-C6 alkoxy, or Co-C~ aLkyl-S(O)n-Co-cs alkyl, Co-Cs alkyl-O-Co-Cs alkyl, Co-Cs alkyl-NR1g-Co-Cs alkyl where R1g and the Co-Cs alkyl can be joined to form a ring, ~ ,~N-(cH2)p-R16 ' or a single bond;
Ro is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, wherein the substituents are as defined below; aryl, substituted aryl, araLkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and Rs;
Rl is ~/'~ ~R-~

wherein:

Y is B, C or a bond;
B is 0, S(O)n, C(O), NRls or C(R1 lRl2)p C is B(CH2)p-;
R2 is hydrogen, Cl-C6 alkyl, substituted C1-C6 alkyl, aralkyl, substituted araLkyl, aryl, substituted aryl, alkyl -ORl 1, Cl-C6(NRl lRl2), Cl -c6(coNR l lRl2) or C(NRl lRl2)NH;
R2 and A taken together form a ring of 5-7 atoms;
R3, R4 and Rs are independently hydrogen, C1-C6 alkyl, substituted Cl-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, Cl-C3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, Rl IO(CH2)p-~R1 1C(O)O(CH2)p-, Rl lOC(O)(CH2)p-, -(cH2)ps(o)nRl7~
-(CH2)pC(O)NRI lR12 or halogen; wherein R17 is hydrogen, Cl-C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl;
R3 and R4 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring con~ining 1-3 heteroatoms selected from N, O and S;
R6 is hydrogen, C1-C6 alkyl, substituted Cl-C6 aLkyl, aryl, substituted aryl, Cl-C3 perfluoroalkyl, CN, N02, halogen, lR 1 lO{CH2)p-, NR 12c(o)Rl 1, NR 12c(o)NR 1 l R 12 or SOnRl l;
R7 is hydrogen, Cl-C6 alkyl, or substituted Cl-C6 alkyl, unless X
is hydrogen or halogen, then R7 is absent;
R8 is hydrogen, C~O)ORg, C(O)NRl lRl2, NR1 lRl2~ C(O)Rl 1, NR12C(O)Rl 1, NR12C(O)NR1 13? l2, NR12S(0)2Rl 1, NR12S(0)2NR1 lRl2, OC(O)Rl 1, OC(O)NR1 lR12, ORl 1, SOnRl 1, S(O)nNR 1 IR12, Cl-c6 aLlcyl or substituted Cl-C6 alkyl, unless X is hydrogen or halogen, then Rx is absent; or R7 and R8 taken together form a carbocyclic ring of 3-7 atoms;
Rg and Rga are independently hydrogen, C1-C6 alkyl, substituted Cl-C6 alkyl; aryl or substituted aryl, aralkyl or substituted araLkyl when m~O; or Rg and R~a taken together form a carbocyclic ring of 3-7 atoms or when m~O;

CA 0224011~ 1998-06-09 ~g and A taken toget~er form a heterocyclic ring cont~ining 3-7 carbon atoms and one or more heteroatoms when m~0; or Rlo and R10a are independently hydrogen, C1-C6 alkyl, substituted Cl-C6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or Rlo and Rloa taken together form a carbocyclic ring of 3-7 atoms or ll Rg and Rlo taken together folm a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m~O; or Rg and R2 taken together form a heterocyclic ring cont~ining 3-7 carbon atoms and one or more heteroatoms when m~0; or Rlo and R2 taken together form a heterocyclic ring con1zlining 3-7 carbon atoms and one or more heteroatoms;
Rlo and A taken together fo~n a heterocyclic ring cont~ining 3-7 carbon atoms and one or more heteroatoms; or R 1 1 and R 1 2 are independently hydrogen, C 1 -C6 alkyl, substituted C 1 -C6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms;
Rl 1 and Rl2 taken together can fonn an optionally substituted ring of 3-7 atoms;
R 13 is hydrogen, OH, NR7R~, NR 1 1 SO2(C 1 -C6 alkyl), NR1 1SO2(substituted Cl -C6 alkyl), NRl ISO2(aryl), NRl 1SO2(substituted aryl), NRI 1SO2(Cl-C3 perfluoroalkyl); S02NR 1 1 (C 1 -C6 alkyl), SO2NR 1 1 (substituted C 1 -C6 alkyl), SO2NR 1 1 (aryl), SO2NR 1 1 (substituted aryl), SO2NR 1 1 (C 1 -C3 perfluoroalkyl); SO2NR 1 1 (C(O)C 1 -C6 aLkyl);
SO2NR 1 1 (C(O)-substituted C l -c6 alkyl); SO2NR ~ l (C(O)-aryl); SO2NRIl(C(O)-substituted aryl); S(O)n(C1-C6 alkyl);
S(O)n (substituted Cl-C6 alkyl), S(O)n(aryl), S(O)n(substituted aryl), Cl-C3 perfluoroalkyl, Cl-C3 perfluoroalkoxy, Cl-C6 alkoxy, substituted C1-C6 alkoxy, COOH, halogen, NO2 or CN;
R14 and Rls are independently hydrogen, Cl-C6 aLkyl, substituted Cl-C6 alkyl, C~2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, Cl-C3 perfluoroalkyl, Cl-C3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R1 IO(CH2)p-, R 11 C(O)O(CH2)p-, R 1 l OC(O)(CH2)p-, -(CH2)pS(O)nR 17, -(CH2)pC(O)NR 1 1 R 1 2 or halogen; wherein R 17 is hydrogen, C~ 6 alkyl, Cl-C3 perfluoroalkyl, aryl or substituted aryl;
R16 is hydrogen, Cl-C6 alkyl, substituted Cl-C6 alkyl, or N(R1 1R12);
R1g is hydrogen, C1-(~6 alkyl, substituted Cl-C6 aLkyl, C(O)ORg, C(O)NRl lRl2, C(O)R~ (O)nRl l;
X is hydrogen, halogen, N, O, S(O)n~ C(O), (CR1 lRl2)p; C2-c6 alkenyl, substituted C2-C6 alkenyl, C2-C6 aLkynyl, or substituted C2-C6 aLkynyl; when X is hydrogen or halogen, R7 and R8 are absent; when X is O, S(O)n, C(O), or CR 1 I R 12 only R7 or R8 is possible;
m is 0-3;
n is 0-2;
p is 0-4; and the aLkyl, cycloalkyl, alkenyl and aLkynyl substituents are selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted araLkyl, hydroxy, oxo, cyano, (~ 6 alkoxy, fluoro, C~O)ORI 1, aryl Cl-C3 alkoxy, substituted aryl C~ 3 alkoxy, and the aryl substituents are as defined for R3, R4 and Rs, or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and claims.

CA 0224011~ 1998-06-09 When any variable (e.g., aryl, heterocycle, Rl, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The tersn "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.
The term "halogen" or "halo" is intended to include fluorine, chlorine, bromine and iodine.
The term "heterocycle" or "heterocyclic ring" is defined by all non-aromatic, heterocyclic rings of 3-7 atoms con~ining 1-3 heteroatoms selected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts In addition, it is well known to those skilled in the art that many of the foregoing heterocyclic groups can exist in more than one tautomeric form. It is intended that all such tautomers be included within the ambit of this invention.
The optical isomeric forms, that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included.

CA 0224011~ 1998-06-09 These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof. These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
The individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering ~e desired isomer. In addition, the individual optical isomers may be prepared by asymmetric synthesis.
Additionally, a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
The compounds of the present invention, while effective themselves, may be formulated and administered in the for~n of their pharmaceutically acceptable addition salts for purposes o~ stability, convenience of crys~ tion, increased solubility and other desirable properties.
The compounds of the present invention may be ~mini~tered in the form of pharmaceutically acceptable salts. The telm "pharmaceutically acceptable salt" is intended to include all acceptable salts. Examples of acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetiG, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like which can be used as a dosage folln for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug form~ ions. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, çthylenediamine, N-methyl-glllt~mine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenedi~mine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and CA 0224011~ 1998-06-09 tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base, or alternatively by reacting a free base with a suitable ~ organic or inorganic acid.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g.
methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
The compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
The compounds of the invention are prepared by the following reaction schemes. All substituents are as defined above unless indicated other~,vise.

Scheme A

I ~ ~ NH2 Ro OEt R ~ ~ ~ 3 pyridine HBr;Br2 R--THF/CHCI3 R6 R10 R10aO

B(~H)2 3 R¢6~R--4R3~ ~
Na2CO3, LiCI R6 ll R
Pd(PPh3)4 ~ N ~1 0aO
toluene/EtOH Ro 11/ \,J R3 Rs R4 H2NNH2 ~ R ~,X~NH2 THF/EtOH R6 5 Reaction Scheme A
As shown in reaction Scheme ~, treatment of tryptamine (1) with N-carboxyphth~limide in an inert organic solvent such as tetrahydrofuran at a temperature of 20-65~C, preferably 65~C, for a period of 12-48 hours gives the corresponding N-phthalimidotryptamine derivative (2). The N-phthalimidotryptamine (2) could be further modified by treatment with a bromin~ting agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0-25~C for a period of 30 minutes to 4 hours to provide the 2-bromotryptamine (3). Bromide (3) may be reacted with an arylboronic acid (prepared essentially as described in:
Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Scr. 1986, 26, 311-314.) with palladium (0) catalysis, a weak base such as aqueous sodium carbonate or the like, and a chloride source such as lithium chloride in an inert solvent like toluene, benzene, ethanol, propanol or mixtures thereof at a temperature of 25~-100~C, preferably 80~C, for a period of 1-6 hours to give the 2-aryltryptamine derivative (4~. Finally, the phth~limido group may be removed by treatment of (4) with aqueous hydrazine in an inert solvent such as methanol or ethanol at a temperature of 0~-25~C for a period of 4-24 hours to give tryptamine (~)- .

Scheme B

HO~(A~ R

EDC, HO~
~8 NMM, CH2C12 R ~X~NHR2 R8 Rg Rg R2 S ~/~ J R~A) R

X~(A)R / R~ R4 triethylamine Reaction Scheme B
As shown in reaction Scheme B, the 2-aryltryptamine may be condensed with a carboxylic acid of type (6) using the coupling reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without l-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorphol~ne (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours to provide the corresponding amide derivative (7). Alternatively, 2-aryltrypt~mine (5) can be treated with an active ester or acid chloride of type (8) in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0~-25~C for 30 minutes to 4 hours to give (7).
Scheme C

R ,~ _ 7 Ro /~\~J 3 or R ,X~ Rs~N~(A) R
LiAlH4, TH F g ~/~\J

Rs R4 Reaction ~cheme C
As shown in reaction Scheme C, the amide carbonyl of (7) can be reduced by treatment with borane, lithium aluminllm hydride, or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at 25~-100~C, preferably 65~C, for a period of 1-8 hours to give the corresponding amine compound (9).

Scheme D

P'8 R9a~ NHR2 s~ ~\'RJ1~R3 Rs R4 TFA 3 A s, ~es~ Rs~20~A)--R1 NaCNBH3 MeOH11 Ro /~\'J R3 R~ R4 Reaction Scheme D
As shown in reaction Scheme D, the 2-aryltryptamine (5) can be modi~led by treatment with an aldehyde or ketone of type (10) in the presence of a weak acid such as trifluorfoacetic acid (TFA~, acetic acid or the like, with or without a dessicant such as 3A molecular sieves or magnesium sulfate, and a hydride source such as sodium borohydride or sodium cyanoborohydride, in an inert organic solvent such as methanol, ethanol, isoprop~nol, tetrahydrofuran, dichloromethane, chloroform, or mixtures thereof at a temperature of 0~-25~C for a period of 1-12 hours to give the corresponding secondary or tertiary amine derivative ( 1 1).

Scheme E
~, o ~HCI R ~3~,9R9 13 R8 NHNH2 R5 R10 RlOa R7~X Rg Rg n-butanol ~ ~NH2 R6 or- R6 ~--NJ~l Oa 12 R4~0 RlOa 5 H ~ J R3 methanol/t-butanol Reaction Scheme E
As shown in reaction Scheme E, treatment of an arylhydrazine or arylhydrazine hydrochloride (12) with an arylcyclopropyLketone of type (13) in a polar organic solvent such als methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol, at a temperature of 70~-120~C for a period of 8-24 hours gives 2-aryltryptamine (5). Alternatively, when an arylhydrazine or arylhydrazine hydrochloride (12) is treated with an arylbutyl ketone of type (14) con~:~ining a leaving group (chloride, bromide, iodide, O-methansulfonate, O-trifluoromethansulfonate, or the like) at the 4-position in a polar solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof at room temperature for a period of 30 minutes to 2 hours followed by heating to a temperature of 65~-100~C for 4-24 hours, 2-aryltrypt~mine (5) is produced.

Scheme F

1~ ~ R

6 ~ '~ R6 R6--~, PdCI2, CH3CN
Pd(PPh3)4 ~ ~X~R CuBr, Et3N 16 R7 R8 R ,R8 7 ~ 3 Reaction Scheme F
As shown in reaction Scheme F, iodoanilines of type (15) may be reacted with aryl acetylenes, an appropriate palladium (û) catalyst such as tetrakis(triphenylphosphine)palladium, a copper (I) halide such as cuprous bromide in an inert organic solvent such as triethyl~min~, at a temperature of 50~-88~C for a period of 30 minlltes to 5 hours to provide the diarylacetylene (16). Acetylene (16) may be further modified by treatment with a palladium (II) catalyst such as palladium (II~ chloride or pall~ m (II) acetate in an inert organic solvent such as acetonitrile at a temperature of 50~- 82~C for a period of 30 minutes to 6 hours to give 2-arylindole (17).

CA 02240ll5 l998-06-09 Scheme G

- ' n ~

P'8 HN (A) R ~ N- (A)--Rl THF R6 ~RJ~--R -or-/~\J LiAlH4, TH F

R;~ R1 r~5 ,~4 Reaction Scheme G
As shown in reaction Scheme G, treatment of 2-arylindole (17) with oxalyl chloride neat or in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran or the like at a temperature of 25~-65~C for a period of 3-24 hours gives the acylchloride adduct (18). The crude product (18) may be reacted with an amine of type (19) in an inert organic solvent such as diethylether, tetrahydrofuran, methylene chloride, chloroform or the like and an amine base such as triethylamine, diisopropylethylamine or pyridine at a temperature of 0~C-25~C for a period of 30 minutes to 4 hours to provide the amide derivative (20). Amide (20) may be further modified by treatment with a reducing agent such as borane or lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran at elevated temperatures, preferably reflux, for a period of 1-5 hours to give compound (21).

Scheme H

R8 fAr R ~X~N- (A)--R6~ 'J H2 22a Rs R4Pd(OH)2/C
or R, 8 O~O~Ar R ,X~b ~.N- (A)--R ~ J~10a H ~/ \,J R3 22b R5 R4 R,8 R

Reaction Scheme H
As shown in reaction Scheme H, N-benzyl derivatives of type (22a) or N-benzyloxycarbonyl derivatives of type (22b) may be reduced to provide the secondary almine analogs (7) by treatrnent with hydrogen (1 atm) and an appropriate catalyst such as palladium on WO 97/21435 PCT/US96/200û4 carbon, palladium hydroxide on carbon, or the like in an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereof to which has been added a weak acid such as 30%
aqueous acet~c acid for a period of 10 minlltes to 3 hours or until the aryl group has been removed to give the secondary amine.
Scheme I

02N~ Rg~N-(A)--R1 R6 ~ ~ Oa H2, RtahnaenyO(~) Ni R~)--25R~ / \~ R3 Rs R4 Reaction Scheme I
As shown in reaction Scheme I, treatment of a nitroindole of type (24) with hydrogen (1 atm) and an appropriate catalyst such as Raney(~) Nickel in an inert organic solvent such as ethanol, methanol, or the like at room temperature for a period of 2-12 hours gives the corresponding aminoindole derivative (25).

Scheme J

H~ 11 or EDC, HOBt, Ro /,\,J 3 diisopropyl- NMM, CH2Ci2 RR ethyl amine ~; 4 cH2Cl2 R7 ~/

R ~ (A)--26 R/~\J

Reaction Scheme J
As shown in reaction Scheme J, amino- or hydroxyindole (25) may be modified by acy~ation under a variety of conditions. For example, treatment of (25) with an acid chloride, acid anhydride or active ester and an amine base such as triethylamine, diisopropylethyl~mine, pyridine, or the like in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, or mixtures thereof at 0~C to room temperature for a period of 1 to 12 hours gives the corresponding amide or ester derivatives (26). Alternatively (25) may be coupled with a carboxylic acid by one of the many dehydrating agents commonly employed. For instance, treatment of aminoindole (2~) with an appropriate carboxylic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1-hydroxyben~otriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic WO 97t21435 PCT/US96/20004 solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours provides the corresponding amide or ester derivative (26).
Sch~me K

R6 I~'(A) RR11~NJ~CI R11~ 27b N ~ J~ diisopropyl- ;or diisopropyl- ; or Ro i --R3 ethyl amine ethyl amine ~/ \~ Ctl2C12 CH2CI2 i. triphosgene R12 ~ ~N-(A~--R
ii. R12R11NH 2B J R~1oa Reaction Scheme K
As shown in reaction Scheme K, urea or carbamate derivatives of (25) can be prepared by treatment with a carbamoyl chloride of type (27a), or alternatively with an isocyanate reagent of type (27b), and an amine base such as pyridine, triethylamine, diisopropylethyl~mine, N-methylmorpholine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixture.s thereof at a temperature of 0~-65~C for a period of 1-72 hours to give (28~.
Compound (25) can also be modified by treatment with a - bis(electrophilic) reagent such as phosgene, triphosgene, 1,1'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or the like with or without the addition of an amine base such as pyridine, triethyl~min~, diisopropylethyl~min~, N-methylrnorpholine in an inert solvent such as me~ylene chloride, chloroform, or the like at a temperature of -20~-0~C ~or a period of 20 minutes to 2 hours. After this time, the reaction mixture is treated with an appropriate mono- or disubstituted amine at -20~-25~C for a period of 1-5 hours to give the urea or carbamate ~nalog (28).

Scheme L

R 7 ~;

25/~\'J

O~S"O ~ R~

diisopropyl- 31 /~\R
ethyl amine Rs 4 R N-S-CI 30 R 'N'S~N ~)--R~

diisopropyl- R6 NR --R
ethyl amine ~~/ \,J 3 cH2Cl2 32 Rs R4 Reaction Scheme L
As shown in reaction Scheme L, amine (25) can be modified by treatment with an appropriate sulfonyl chloride of type (29) or sulfamyl chloride of type (30) with an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane or the like at a temperature of -20~-25~(~ for a period of 20 minutes to 2 hours to give the corresponding N-sulfonamide (31) or N-sulfamylamide (32) derivatives, respectively.
Scherne M

R ~ MeOH
R~; R4 R~ ~ ~ rA) R

R~ R4 Reaction Scheme M
As shown in reaction Scheme M, the 2-aryltryptamine (33) can be modified by treatment with an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert-butanol, or mixtures thereof at a temperature of 65~-110~C for a period of 8-20 hours to give the corresponding amino-alcohol derivative (35).

CA 02240ll5 l998-06-09 Scheme N

tlO~(R l2R1 1 C~ Rga~,N~ (A)--Rl Rl2R1 1 NH~
R6~/~ oRa3 PyBOP

R p(R12R11~ ~; )--~eaction Scheme N
As shown in reaction Scheme N, amide derivatives of an acid-cont~inin~ indole derivative such as (36) can be prepared by treatment with an appropriate amine (Rl2R1 1 NH) and a suitable coupling agent such as benzotriazol-l-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), benzotriazol- l -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or wi~out l-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylrnorpholine (NMM), triethylamine or the like in an imert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours provides the corresponding amide derivative (37).

CA 0224011~ 1998-06-09 The compounds of the present invention are useful in the treatment of various sex-hormone related conditions in men and women.
This utility is manifested in their ability to act as antagonists of the neuropeptide hormone GnRH as demonstrated by activity in the following in vitro assays.

Rat pituitary GnR~ receptor bindin~ assay:
Crude plasma membranes prepared from rat pituitary tissues were incubated in a Tris.HCI buffer (50 mM, PH. 7.5) cont~ining bovine serum albumin (.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and the desired concentration of a test compound. The assay mixtures were incubated at 4~C~ for 90-120 minutes followed by rapid filtration and repeated w~hing~ through a glass fiber filter. The radioactivity of membrane bound radioligands was determined in a gamma-counter.
From this data, the ICso of the radioligand binding to GnRH receptors in the presence of test compound was estimated.

Inhibition of LH release assay:
Active compounds from the GnRH receptor binding assay were further evaluated with an in vitro LH release assay to confirm their antagonist activity (blocking GnRH-induced LH release).
1. Sample Preparation The compounds to be assayed were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%.
2. Assay The Wistar male rats (150-200 grams) were obtained from Charles River Laboratories (Wilmington, MA). Rats were m~int~ined at a constant temperature (25~~) on a 12-hr light, 12-hr dark cycle. Rat chow and water were available ad libitum. The ~nim~ls were sacrificed by decapitation and pituitary glands were aseptically removed and placed in Hank's Balanced Salt Solution (HBSS~ in a 50-ml - polypropylene centrifuge tube. The collection tube was centrifuged for 5 min at 250 x g, and HBSS was removed by aspiration. Pituitary glands were transferred to a disposable petri plate and minced with a - 2~ -scalpel. The minced tissue was then transferred to a 50-mL disposable centrifuge tube by suspending the tissue fragments in three successive 10-mL aliquots of HBSS containing 0.2% collagenase and 0.2%
hyaluronidase. The cell dispersion was carried out in a water bath at 37~C with gentle stirring for 30 min. At the end of ~e incubation, the cells were aspirated 20 to 30 times with a pipet and the undigested pituitary fragments were allowed to settle for 3 to 5 min. The suspended cells were removed by aspiration, and then subjected to a 1200 x g centrifugation for 5 min. The cells were then resuspended in C~ulture medium. The undigested pituitary fragments were treated with 30 mL aliquots of the digestion enzymes as above for a total of 3 digestions with the collagenase/hyaluronidase mixture. The resulting cell suspensions were pooled, counted and diluted to a concentration of 3 x 105 cells/ml, and 1.0 ml of this suspension was placed in each well of a 24-well tray (Costar, Cambridge, MA). Cells were m~int~ined in a humidified 5% C02-95% air atmosphere at 37~C for 3 to 4 days. The culture medium consisted of DMEM cont~inin~ 0.37% NaHCO3, 10%
horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% gl~ mine, and 0.1% gentamycin. On the day of an experiment, cells were washed three times 1 1/2 hrs prior to and two more tirnes immediately before the start of the experiment with DMEM cont~ining 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids(lOOX), 1% glllt~mine(lOOX), 1%
Penic;llin/Streptomycin(10,000 Units of Penicillin and 10,000 micrograms of Streptomycin per ml), and 25 mM HEPES, pH 7.4. LH
release was initiated by adding 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicate.
Incubation was carried out at 37~C for 3 hr. After incubation, medium was removed and centrifuged at 2,000 x g for 15 min to remove any cellular material. The supernatant fluid was removed and assayed for LH content with a double antibody RIA procedure using materials obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center, Torrance, CA).

CA 0224011~ 1998-06-09 The compounds of formula I are useful in a number of areas affected by GnRH. They may be useful in sex-hormone related conditions, ,sex-hormone dependent cancers, benign prostatic hypertrophy or myoma of the uterus. Sex-hormone dependent cancers which may bene~lt from the ~lministration of the compounds of this invention include prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. Other sex-hormone dependent conditions which may benefit from the ~lmini~tration of the compounds of this invention include endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty. The compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Fn~l~pril or Captopril, an angiotensin II-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
The compounds of the invention may also be useful for controlling pregnancy, as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and for the treatment of sleep disorders such as sleep apnea.
A ~urther use of the compounds of this invention is as an adjunct to growth hormone therapy in growth hormone deficient children. The compounds may be ~lmini~tered with growth hormone or a compound which increases the endogenous production or release of growth hormone. Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-l (described in U.S. Patent No.
4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub.
No. WO 89/07111) and GHRP-2 - (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest., 15(Suppl 4), 45 (1992)). Other compounds which stimulate the release of endogenous growth hormone are 3!; PCT/US96/20004 disclosed, for example, in the following: U.S. Patent No. 3,239,345;
U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No.
5,206,235; IJ.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S.
Patent No. 5,310,737; U.S. Patent No. 5,317,017; U.S. Patent No.
5,374,721; U.S. Patent No. 5,430,144; U.S. Paten~ No. 5,434,261; U.S.
Patent No. 5,438,136; EPO Patent Pub. No. 0,14~,230; EPO Patent Pub.
No. 0,5I3,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub.
No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT
Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290;
PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO
95/11029, PCT Patent Pub. No. WO 95/1259g; PCT Patent Pub. No.
WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub.
No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; Science.
260, 1640- 1643 (June 11, 1993); Ann. Rep. Med. Chem., 2~, 177- 186 (1993); Bioor~. Med. Chem. Ltrs.,_(22), 2709-2714 (1994); and Proc.
Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).
Representative preferred growth ho~none secretagoues employed in ~e present combination include the following:

1) N-[l(R)-[(1,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin] - 1 '-yl)carbonyl] -2-(1 H-indol-3 -yl)ethyl] -2-amino-2-methyl-propanamide;

2) N-[l(R)-[(1,2-Dihydro-l-methanecarbonylspiro[3H-indole-3,4'-piperidin]- 1 '-yl)carbonyl~ -2-(1 H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

3) N- [1 (R)-~(1,2-Dihydro- 1 -benzenesulfonylspiro~3H-indole-3,4'-piperidin]- 1 '-yl)carbonyl]-2-(1 H-indol-3 -yl)ethyl]-2-amino-2-methyl-propanamide;

CA 0224011~ 1998-06-09 4) N-[l(R)-[(3,4-Dihydro-spiro[2H-1-benzopyran-2,4'-piperidin]-1'-yl) carbonyl]-2-( 1 H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

S) N-[ 1 (R)-[(2-~cetyl- 1,2,3 ,4-tetrahydrospiro[isoquinolin-4,4'-piperidin l- 1 '-yl)carbonyl] -2-(indol-3-yl)ethyl] -2-amino-2-methyl-propanamide;

6) N-[l(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-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-[l(R)-[~1,2-Dihydro-1-methanesulfonylspirol3H-~ndole-3,4;-piperidin] -1 '-yl)carbonyl] -2-(2' ,6'-difluorophenylmethyloxy)ethyl] -2-amino-2-methylpropanamide;

9) N-[ 1 (R)-~( 1 ,2-Dihydro- l -methanesulfonyl-S-fluorospiro[3H-indole-3 ,4'-piperidin] -1 '-yl)carbonyl] -2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

10) N-[ l (S)-[(l ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'-piperidin]- 1 '-yl) carbonyl ~-2-(phenylrnethylthio)ethyl]-2-amino-2-methylpropanamide;
1 1 ) N-~ 1 (R)-[( l ,2-Dihydro- I -methanesulfonylspiro[3H-indole-3 ,4'-piperidinl- l '-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl-propanamide, 12) N-[ 1 (E~ ( l ,2-Dihydro- 1 -methanesulfonylspiro[3~I-indole-3,4'-piperidin~- l '-yl)carbonyll-3-cyclohexylpropyl]-2-amino-2-methyl-propanamide;

_ _ _ _ _ _ 13) N-[l(R)-[(1,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]- 1 '-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl-propanamide;

14) N-~l(R)-[(1,2-Dihydro-l-methanesulfonylspiro~3H-indole-3,4'-piperidin]-1 '-yl)carbonyl]-2-(S-fluoro- 1 H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

l S) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonyl-5-fluorospiro~3H-indole-3 ,4'-piperidin]- 1 '-yl)carbonyl~-2-(S-fluoro- 1 H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

16) N-[ 1 (R)-[(l ,2-Dihydro- 1 -(2-ethoxycarbonyl)methylsulfonylspiro-1 3H-indole-3,4'-piperidin]-1 '-yl)carbonyl]-2-(1 H-indol-3-yl)ethyl~ -2-amino-2-methylpropanamide;

17) N-[ 1 (R)-[( 1 ,2-Dihydro- 1,1 -dioxospiror3H-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, e.g. MK-0677, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the Gn~H antagonist.
Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful for the treatment of bone li~iasis as disclosed in U.S. Patent 4,621,077 to Rosini, et al.

CA 0224011~ 1998-06-09 The literature discloses a variety of bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Patent No. 3,251,907; U.S. Patent N o. 3,422,137; U.S.
Patent No. 3,5~4,125; U.S. Patent No. 3,940,436; U.S. Patent No.
3,944,599; U.S. Patent No. 3,962,432; U.S. Patent No. 4,054,598; U.S.
Patent No. 4,267,108; U.S. Patent N o. 4,327,039; U.S. Patent N o.
4,407,761; U.S. Patent No. 4,578,376; U.S. Patent N o. 4,621,077; U.S.
Patent N o. 4,624,947; U.S. Patent N o. 4,746,654; U.S. Patent No.
4,761,406; U.S. Patent No. 4,922,007; U.S. Patent N o. 4,942,157; U.S.
Patent No. 5,227,506; U.S. Patent No. 5,270,365; EPO Patent Pub. N o.
0,252,504; and J. Or~. Chem., 36, 3~43 (1971).
The preparation of bisphosphonic acids and halo-bisphosphonic acids is well known in the art. Representative examples may be found in the above mentioned references which disclose the compounds as being useful for the treatment of disturbances of calcium or phosphate metabolism, in particular, as inhibitors of bone resorption Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxy-hexylidene-bi.sphosphonic acid, and 1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid;
or any pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is alendronic acid (alendronate), or a pharmaceutically acceptable salt thereof. An especially preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received regulatory approval for marketing in the United States under the trademark FOSAMAX(~).
Additionally, a compound of the present invention may be co-~-1mini~tered with a 5O~-reductase 2 inhibitor, such as finasteride or epristeride; a 5Oc-reductase I inhibitor such as 4,7~ dimethyl-4-aza-5Oc-cholestan-3-one, 3-oxo-4-aza-4,7,~3-dimethyl- 16~-(4-chlorophenoxy)-So~-androstane, and 3-oxo-4-aza-4,7,13-dimethyl-16,(3-(phenoxy)-So~-androstane as disclosed in WO 93/23420 and WO 95/11254; dual CA 0224011~ 1998-06-09 inhibitors of ~(x-reductase 1 and 5cc-reductase 2 such as 3-oxo-4-aza-17,1~-(2,5-trifluoromethylphenyl-carbamoyl)-50~-androstane as disclosed 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, a compound of the present invention may be used in combination with growth hormone, growth hormone releasing ho~none or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
For combination treatment with more than one active agent, where ~e active agents are in separate dosage formulations, the active agents may be zl~lmini~tered separately or in conjunction. In addition, the ~lmini.~tration of one element may be prior to, concurrent to, or subsequent to the ~flmini~tration of the other agent.
The pharmaceutical cornpositions cont~ining the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pha~naceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; bindin~ agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablet,s may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the CA 0224011~ 1998-06-09 WO 97/21435 PCT/[JS96/20004 gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl dis$earate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108;
4,166,452; and 4,~65,874 to forrn osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, CA 0224011~ 1998-06-09 hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for exarnple sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mnnooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be form~ ted with sweetening agents, for exarnple glycerol, propylene glycol, sorbitol or sucrose.
Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in ~e forrn of a sterile injectable aqueous or o~eagenous suspension. This suspension may be forrn~ ted according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation 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-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In CA 0224011~ 1998-06-09 WO 97/21435 PCT/US96/200û4 addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For thi,s purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of Formula I may also be ~clmini~tered in the form of a suppositories for rectal ~1mini~tration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth washes and gargles.) The compounds for the present invention can be ~lmini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be ~lmini.~tered in the form of a transdermal delivery system, the dosage ~lmini.~tration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may al,so be delivered as a suppository employing 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 in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition. Optimal precision in achieving CA 0224011~ 1998-06-09 WO 97/;~1435 PCT/US96/20004 concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimin~tion of a drug. Preferably, doses of the compound of structural formula ~ useful in the method of ~e present invention range from 0.01 to I000 mg per adult h~lm~n per day. Most preferably, dosages range from 0.1 to S00 mg/day. For oral ~(1mini~tration, the compositions are preferably provided in the form of tablets cont:~ining 0.01 to 1000 milligrams of the active ingredient, particularly 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 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/lcg to 1 mg/kg of body weight per day.
Advantageously, the active agent of the present invention may be ~lmini~tered in a single daily dose, or the total daily dosage may be ~1mini.stered in dividend doses of two, three or four times daily.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage forrn will vary depending upon the host treated and the particular mode of :~lmini .~tration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of ~actors including the age, body weight, general health, sex, diet, time of 7l~1mini~tration, route of ~1ministration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The following examples illustrate the preparation of some of the compounds of the invention and are not to be construed as limiting the invention disclosed herein.

,~,OH

Ol~Ae OMe N- r2-r2-~3 .4-dimethoxyphenyl)- 1 H-indol-3 -yllethyll -3 -(4-hydroxyphenyl)propionamide To a stirred ,solution of 3-(4-hydroxyphenyl)propionic acid (80 mg in 4 rnL N,N-dimethylformamide) was added 1-hydroxybenzotriazole (78 mg) and the mixture cooled to 0~(~. After 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg) was added. The mixture was warmed to room temperature and 2-[2-(3,4-dimethoxyphenyl)-lH-indol-3-yl]ethylamine (272 mg) was added. After 17 hours the reaction was quenched by the addition of water and extracted with ethyl acetate. The organic portion was washed with water, 0.5M sodium bisulfate and brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 95:~) gave the title compound (227 mg). m/e = 444 (M) Following a procedure similar to that described in Example 1, the following interrnediates were prepared:

~,~N~f(A) R

H / \,J R3 Rs R4 Example # R1 R3,R4,R5 (CH2)n--~ m/e lA Ph-4-0-CH2-Ph 3,4-OMe 3 505 (M + H) lB Ph-4-OH 3,4-OMe 3 459 (M + H) lC Ph-4-OH 3,4-OMe l 431 (M + H) lD Ph-3,4-Cl,Cl 3,4-OMe 1 4g3 (M) lE Ph-4-F 3,4-OMe 1 433 (1\~ + H) 1 F Ph-4-No2 3,4-OMe 3 --lG Ph-4-NH2 3,4-OMe 3 458 (M + H) lH Ph-4-No2 3,4-OMe 1 --l I Ph-4-NH2 3,4-OMe 1 430 (M + H) lJ Ph-4-OH 3,5-OMe 3 --lK Ph-4-OH 3-Ph 3 475 (M + H) 1 L Ph-4-NH- 3,5-Me 3 526 (M + H) COO-tBu lM Ph-4-NH2 3,5-Me 3 426 (M + H) lN Ph-4-N02 3,5-Me 3 4~6 (M + H) Ph-4-OH 3-SCH3, 3 459 (M + H) lP Ph-4-S02NH2 3,5-Me 0 448 (M + H) EX~MPLE 2 H OH
r ~ ~~~

Me CA 0224011~ 1998-06-09 WO 97/21435 PCT/US96t20004 3-r3-r2-r2-(3.5-dimethylphenyl)- lH-indol-3-yllethylaminol-2-hydroxypropoxylphenol Step 2A 2-12-( lH-indol-3-yl)-ethyll-isoindole- 1 .3-dione To a stirred suspension of 2-(lH-indol-3-yl)ethylamine (2.0 g in 20 mL of dry tetrahydrofuran) was added N-carbethoxyphthalimide (2.85g) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacllo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1) and filtered. Purification of the collected solids by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (3.1 g).

Step 2B 2-r2-(2-bromo- lH-indol-3-yl)-ethyll -isoindole- 1 .3-dione To a solution of 2-[2-(lH-indol-3-yl)-ethyl]-isoindole-1,3-dione (1.0 g in a mixture of 10 mL dry tetrahydrofuran and 10 mL dry chloroform) at 0 ~C was added pyridinium bromide perbromide (1.14 g) and the reaction stirred at 0 ~C. After 50 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3x) and ~).3M sodium bisulfate (3x) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) gave the title compound (1.2 g).

Step 2C 2- ~ 2-r2-(3 .5-dimethylphenyl)- 1 H-indol-3 -yll -ethyl ~ - isoindole- 1 .3-dione To a solution of 2-[2-(2-bromo-lH-indol-3-yl)-ethyl]-isoindole-1,3-dione (150 mg in a mixture of 5 mL toluene and 5 mL
ethanol) was added 3,5-dimethylphenyl boronic acid (85 mg) followed by 1.0 mL of 1~ sodium carbonate. To the stirred solution was added lithium chloride (60 mg) followed by tetrakis(triphenylphosphine) palladium (28 mg) and the mixture heated to reflux on 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:I) gave the title compound (146 mg).

Step 2D 2-1 2-(3.5-dimethylphenyl)- lH-indol-3-yll-ethylamine To a solution of 2-{2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl}-ethyl}-isoindole-1,3-dione (~7 mg in a mi~ture of 4 rnL
tetrahydrofuran and 4 mL ethanol) was added 0.6 mL of 95% aqueous hydrazine and the reaction stirred at room temperature. After 18 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 9:6:1) to provide the title compound (54 mg).

Step 2E 3-r3-r2-r2-(3.5-dimethylphenyl)- 1 H-indol-3-yllethylaminol- 2-hydro~ypropoxylphenol (benzyl ether) To a solution of 2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl~-ethylamine (25.5 mg in 5 mL dry methanol) was added 12.1 mg of 1-[3-(benzyloxy)phenoxy]-2,3-epoxypropane and the mixture heated to reflux on an oil bath. After 7 hours the reaction mixture was cooled to room temperature, concentrated in vacuo and the product prified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give ~e ti~le compound (13.3 mg).

Step 2F 3-r3-r2-12-(3.5-dimethylphenyl)-lH-indol-3-yllethylaminol-2-hydroxypropoxylphenol To a solution of 3-[3-[2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]ethylamino]-2-hydroxypropoxy]phenol (benzyl ether) (11 mg in l mL ethanol) was added 10 mg of 10% palladium hydroxide on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 2 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel ~methylene chloride:methanol, 95:5) to provide the title compound (2.3 mg~. m/e = 431 (M+H) Following a procedure similar to that described in Exarnple 2, the following compounds were prepared:
H
~N~J~(A) R

Example#Rl R3,R4,R5 A m/e 2A Ph-4-OH 3,4-OMe (S) CH2-0 2B Ph-4-OH 4-OMe (S) CH2-0 2C Ph 3,4-OMe (S) CH2-0 2D Ph-4-OH 3,4-OMe(S) CH2-CH2 2E Ph-4-OH 3,4-OMe (R) CH2 2FPh-3-F, 4-NH2 3,4-OMe (S) CH2-0 2G Ph-4-NHAc 3,4-OMe (S) CH2-0 2H Ph-4-NH2 3,4-OMe (S) CH2-0 21 Ph-4-OH 3,4-OMe (R) CH2-0 2J Ph-4-F 3,4-OMe (S) CH2-0 465 (M +H) 2KPh-4-Cl, 3- 3,~0Me (S) CH2-0 496 (M +H) 2L Ph-4-0-CH2- 3,4-OMe (S) CH2-0 ~~
Ph, 3-NH-2MPh-4-OH, 3- 3,4-OMe (S) CH2-0 520 (M + H) 2N Ph-3-CN 3,4-OMe (S) CH2-0 472 (M + H) 20Ph-3-CH20H 3,4-OMe (S) CH2-0 477 (M + H) 2P Ph-3-F 3,4-OMe (S) CH2-0 465 (M +H) 2QPh-3-CH2NH2 3,4-OMe (S) CH2-0 476 (M + H) 2R Ph-2-F 3.4-OMe (S) CH2-0 465 (M +H) 2S Ph-3-OCH2-Ph 3,5-Me (R,S) CH2-O 521 (M +H) 2T Ph-4-OH 3,5-Me(R,S) CH2-O431 (M + H) 2U Ph-3-C1 3,5-Me(S) CH2-O449 (M +H) 2V Ph-3-CN 3,5-Me(S) CH2-0440 (M +H) 2WPh-3-CH20H 3,5-Me(S) CH2-~445 (M +H) H OH

~; ~ ~~
Me OMe OMe (S)-4-r3-r2-r2-(3.5-dimethylphenyl)- l -methyl-lH-indol-3-yllethylaminol -2-hydroxypropoxylphenol Step 3A r2-r2-(3 .4-dimethoxyphenyl)- 1 H-indol-3-yllethyll carbamic acid benzyl ester To a su~pension of 2-[2-(3,4-dimethoxyphenyl)-lH-indol-3-yl]ethylamine (150 mg in 1.5 mL methylene chloride) at -78~C was added benzyl chloroformate (O.OP~ mL) and diisopropylethyl amine (0.093 mL) and the mixture walmed to 0 ~C. After 40 minutes, the reaction was quenched by the addition of saturated ammonium chloride, extracted with ethyl acetate and the organic portion dried over sodiurn sulfate. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) gave the title compound (220 mg).

Step 3B 2-r2-(3.4-dimetho~yphenyl)- l -methyl- 1 H-indol-3-yllethylamine To a solution of [2-[2-(3,4-dimethoxyphenyl)-lH-indol-3-yl]ethyl]carbamic acid benzyl ester ~lO0 mg in 1.5 mL N,N-dimethylformamide) at 0~ C was added sodium hydride (9 mg) and the mixture allowed to s~ir at 0~ C. After 10 mimltes, iodomethane (0.016 mL) was added followed by warming to room temperature for 20 minlltes and quenching by the addition of water. The mixture was extracted with ethyl acetate, washed with water and the organics dried over sodium sulfate to give the crude N-methylated product.
Hydrogenolysis of the crude product by a method similar to that described in EXAMPLE 7.1 Step J gave the title compound.

Step 3C ~S)-4-r3-~2-r2-(3 ~S-dimethylphenyl)- 1 -methyl- 1 H-indol-3-yllethylaminol -2-hydroxypropoxylphenol The title compound was prepared following a procedure similar to that described in Example 2 Step F. m/e - 477 (M + H~

Following a procedure similar to that described above, the following compounds were prepared:
OH

0~ ~N~ A)' R 1 Me / \,J R3 Example # R~ R3,R4,R5 R2 m/e 3A Ph-4-0CH2-Ph 3,4-OMe Me 3 B Ph-4-OCH2-Ph 3,4-OMe H
3C Ph-OH 3,4-OMe Me 491 (M + H) CA 02240ll5 l998-06-09 EXAMPLE3 4.1 H J[ ~ NO2 OMe OMe r2- r2-(3 ~4-dimethoxyphenyl)- I H-indol-3 -yllethyll -r2-(4-nitrophenyl )ethyll arnine ~tep 4.1 A /V-r2-r2-(3 ~4-dimethoxyphenyl)- 1 H-indol-3-yllethyll-2-(4-nitrophenyl)acetamide To a stirred solution of 4-nitrophenylacetic acid (lû0 mg in 2.5 mL N,N-dimethylformamide) was added 1-hydroxybenzotriazole (90 mg) and the mixture cooled to 0~C. After 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg) was added. The mixture was warmed to room temperature and 3-(2-aminoethyl)-2-(3,4-dimethoxyphenyl)indole (316 mg) was added. After 17 hours the reaction was quenched by the addition of water and extracted with ethyl acetate. The organic portion was washed with water, 0.5M sodium bisulfate and brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound ~116 mg).
~tep 4.1 B 1 2-r2-(3 .4-dimethoxyphenyl)- I H-indol-3-yllethyl 1 -r2-(4-nitrophenyl)ethyllamine To a stirred solution of N-[2-[2-~3,4-dimethoxy-phenyl)-lH-indol-3-yl]ethyl~-2-(4-nitrophenyl)acetamide (90 mg in 3 mL dry tetrahydrofuran) was added 0.79 mL of a lM solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath.
A~ter 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (0.60 mL) and heated to reflux on an oil bath.
After 3 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 96:4) gave the title compound (79 mg).

EXAMPLE 4.2 C~, ~ NH2 OMe OMe 1 2-r2-(3 .4-dimethoxyphenyl)- 1 H-indol-3-yllethyll -r2-(4-aminophenyl)ethyll amine To a stirred solution of [2-[2-(3,4-dimethoxyphenyl)-l~I-indol-3-yl]ethyl~-[2-(4-nitrophenyl)ethyl]amine (45 mg in 4 mL
methanol) was added 2N hydrochloric acid (0.020 mL) and 18 mg of 10% pal}adium hydroxide on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 40 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to provide the title compound (32 mg). m/e = 416 (M + H) l~ollowing a procedure similar to that described in EXAMPLES 4.1 and/or 4.2, the following compounds were prepared:

H

O~ ~ N ~ R
N~
H ~ ~J R3 Example # R I R3,R4,R5 m/e 4A Ph-3-F,4-OH 3,4-OMe 435 ~M + H) 4B Ph-4-OH 3,4-OMe 417 (M ~ H) 4C Ph-3,4-C1 3,4-OMe 469 (M + H) 4D Ph-4-F 3,4-OMe 419 (M + H) 4E Ph-4-C~1 3,4-OMe 435 (M + H) 4F Ph-4-OH 3,5-Me 385 (M + H) EXAMPLE S.l ~ Br ~;
OMe OMe r3-(4-bromophenyl)allyll-r2-r2-(3~4-dimethoxyphenyl)- 1~1-indol-3-yllethyllamine To a stirred solution of 2-[2-(3,4-dimethoxyphenyl)-lH-indol-3-yl]ethyl~mine (261 mg in a mixture of 3 mL N,N-dimethylformamide and 8 mL methylene chloride) at 0~ C was added a solution of 81 mg of 4-bromocinnamyl bromide in 2 mL methylene chloride and the mixture allowed to warm to room temperature. After 27 hours the reaction was quenched by the addition of water followed by extraction with ethyl acetate. The organic portion was dried over over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (93 mg).
m/e = 491 (M) EXAMPLE 5.2 OMe OMe 4-r3-r2-rr2-(3.4-dimethoxyphenyl)-lH-indol-3-yllethvll aminolpropyl)phenol To a stirred solution of N-12-[2-(3,4-dimethoxyphenyl)-lH-indol-3-yl]ethyl]-3-(4-hydroxyphenyl)propionamide (50 mg in 1.5 mL
dry tetrahydrofuran) was added 0.45 mL of a lM solution of borane in tetrahydrofuran and the mi~ture heated slowly to reflux on an oil bath.
After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (0.34 mL) and heated to reflux on an oil bath.
After 4 hours the mixture wa.s cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 90:10) gave the title compound (47 mg). m/e = 431 (M ~ H) Following a procedure similar to that described in EXAMPLES 5.1 and 5.2, the following compounds were prepared:

, N ~., R 1 ,~ R3 Example ~ R 1 R3,R4,R5 rn/e 5A Ph-3-NH2~4-OH 3,4-OMe 446 (M + H) SB Ph-4-OH 3~5-Me 399 (M + H) ~C Ph-4-so2NH2 3,5-Me 462 (M + H) 5D Ph-4-CH20H 3,5-Me 413 (M + H) 5E Ph-4-COOMe 3,5-Me 441 (M + H) 5F Ph-4-NHSO2Me 3~5-Me 476 (M + H) EX~MPLE 6.1 ~NH2 ' ~ --~OH

Me 2-rr2-r2-(3 ~S-dimethylphenyl)- 1H-indol-3-vllethyll-14-(4-hydroxyphenyl)-butyll aminol acetamide CA 0224011~ 1998-06-09 WO 97/21435 PCT/US96t20004 To a solution of 4-[4-[[2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]ethyl]amino]butyl]phenol (15 mg in a mixture of 0.7 mL
acetonitrile and 0.2 mL N,N-dimethylformamide) was added 0.015 mL
of diisopropylethyl amine followed by 8 mg of iodoacetamide and the mixture stirred at room temperature. After 4.5 hours the crude reaction mixture was applied to a silica gel preparative TLC plate and eluted with (methylene chloride:methanol, 93:7). Isolation of the desired band was followed by extraction with methylene chloride:methanol (95:5) and further purification of this material by flash chromatography on silica gel (hexane:ethyl acetate, 2:5) to give the title compound (16 mg). m/e = 470 (M + H) EXAMPLE 6.2 r~~ NH2 ~; ~OH

Me 4-r4-r (2-aminoethyl)-1 2-r2-(3 .5-dimethylphenyl)- l H-indol-3 -yllethyllaminolbutyllphenol Following a procedure similar to that in Example 5.2, the title compound was prepared from 2-[[2-[2-(3,5-dimethylphenyl)-lH-indol-3 -yl] ethyl] -[4-(4-hydroxyphenyl)-butyl] amino] acetamide . m/e =
456 (M + H) WO 9712143~; PCT/US96/20004 EXAMPLE 6.3 HNq~ NH2 ~, Mo --~OH
H

Me and EXAMPLE 6.4 H
HNq~N~NH

OH

Me N-r2-r2-(3~5-dimethylphenyl)- lH-indol-3-yllethyll-N-1 4-(4-hydroxyphenvl)butyll~uanidine and N-r2-r2-(3.5-dimethylphenyl)- 1~-indol-3-yllethyll-N-1 4-(4-hydroxyphenyl)butyllguanidino-~uanidine To a solution of 4-[4-[[2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]ethyl]amino]butyl]phenol (15 mg in 0.50 mL ethanol) in a thick-walled vial was added 50 mg of cyanamide followed by 0.30 mL of triethylamine. The vessel was flushed with nitrogen, sealed and heated to 70~ C on an oil bath. After 17.5 hours the mixture was cooled to room temperature, concentrated in vacuo and purified by ~ash chromatography on silica gel - (methanol:chloroform:water:trifluoroacetic acid, 20:100:3:0.3; then repurified with methylene chloride:methanol:ammollium hydroxide, 83:17:1) to give title compounds (12 mg and 5 mg, respectively). m/e =
455 (M + H), 497 (M + H) EXAMPLE 6.5 Me ~, M~OH
H

Me 4-r4-rr2-r2-(3~5-dimethylphenyl)- lH-indol-3-yllethyllmethylaminolbutyllphenol To a solution of 4-[4-[~2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]ethyl]amino]butyl]phenol (19 mg in 1 mL methanol) was added 0.020 mL of a 37% solution of formaldehyde in water followed by 0.010 mL acetic acid and 16 mg of sodium cyanoborohydride and the mixture stirred at room temperature. After 26 hours the reaction was quenched by the addition of acetic acid, concentrated in vacuo and the excess acetic acid removed by toluene azeotrope. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 93.5:6.5; ~en methylene chloride:methanol:ammonium hydroxide, 90:10:1) gave the title compound (20 mg). m/e = 427 (M + H) WO 97~21435 PCT/US96/20004 ~XAMPLE 6.6 ~'--OH

~M- '--~OH
H

Me 4-14-rr2-r2-(3.5-dimethylphenyl)-1~-indol-3-yllethyll-(4-hydroxybutyl)aminolbutvllphenol To a solution of 4-~4-[[2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]ethyl3amino]butyllphenol (18 mg in 2 mL tetrahydrofuran) was added 0.050 mL of 2-ethoxytetrahydrofuran followed by 0.25 mL of 30% aqueous acetic acid and the mixture stirred for 30 minutes. At this time 0.35 mL triethylamine was added followed by 10% palladium hydroxide on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 23 hours ~e reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo and partially purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8). Repurification by HPLC (C8 methanol:water, 55:45 = 0.1% trifluoroacetic acid) gave the title compound (2.8 mg). m/e = 485 ~M + H) lFollowing a procedure similar to that described in EXAMPLES 6.5 or 6.6, the following compounds were prepared:

OH

_ 55 _ Example # R2 R3-Rs m/e ..
6A c~3 3,4-OMe459 (M + H) 6B ((:~H2)4-Ph(4-oH) 3,5-Me561 (M + H) EXAMPLE 7.1 H H
M ~ N~O ~ ~l3~OH

Me Propylcarbamic acid 2-(3~5-dimethylphenyl)-3-r2-r4-(4-hydroxyphenyl)butylaminolethyll-1H-indol-5-yl ester Step 7.1 A 2-r2-(5-benzyloxy- 1 H-indol-3-yl)ethyllisoindole- 1 .3-dione To a stirred suspension of 5-benzyloxytryptamine hydrochloride (1.0 g in 10 mL of dry tetrahydrofuran) was added triethylamine (O.SO mL) followed by N-carbethoxyphth~limide (750 mg) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1, 50 mL) and filtered to give the title compound (1.3 g).
Step 7.1B 2-r2-(5-benzyloxy-2-bromo-lH-indol-3-vl)ethyllisoindole-1 ,3-dione To a solution of 2-[2-(5-benzyloxy-lH-indol-3-yl)ethyl]isoindole-1,3-dione (~00 mg in a mixture of dry 25 mL
tetrahydrofuran and 25 mL dry chloroform) at 0~ C was added pyridinium hydrobromide perbromide (666 mg) and the mixture stirred at 0~ C. After 23 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3x) and 0.3M sodium bisulfate (3x~ then dried over magnesium sulfate.
Purification of the concentrate by flash chromatography on silica gel (hexane:e~yl acetate, 7:2) followed by repurification by flash chromatography on silica gel (methylene chloride) gave the title compound (632 mg).
~tep 7.1 C 2-r2-r5-benzyloxy-2-(3~5-dimethylphenyl)- lH-indol-3-yllethyllisoindole- 1 .3 -dione To a solution of 2-[2-(5-benzyloxy-2-bromo-lH-indol-3-yl)ethyl]isoindole-1,3-dione (500 mg in a mixture of 6 mL ethanol and 16 mL toluene) was added 3,5-dimethylphenyl boronic acid (205 mg) followed by 2.7 mL of l!M sodium carbonate. To the stirred solution was added lithi~n chloride (156 mg) followed ~y tetrakis(triphenylphosphine)palladium (78 mg) and the mixture heated to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (he~ane:methylene chloride:ethyl acetate, 15:8:1 then 12:8:1) gave the title compound (479 mg).
~tep 7.1 D 2-r2-r2-(3 .S-dimethylphenyl)-S-hydroxy- 1 H-indol-3-yllethyllisoindole- 1 .3-dione To a stirred solution of 2-[2-r5-benzyloxy-2-(3,~-dimethylphenyl)-lH-indol-3-yl]ethyl]isoindole-1,3-dione (S10 mg in 20 mL dry ethyl acetate was added 197 mg o~ 10% palladium on carbon catalyst. The reaction fla,sk was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 37 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo to provide the crude title compound (41~ mg).
Step 7.1 E 3-(2-aminoçthyl)-2-(3.5-dimethylphenyl)- 1 H-indol-5-ol CA 0224011~ 1998-06-09 To a solution of 2-[2-[2-(3,5-dimethylphenyl)-S-hydroxy-lH-indol-3-yl]ethyl]isoindole-1,3-dione (41~ mg in a mixture of 7 mL
ethanol and 7 mL tetrahydrofuran) was added 2.5 mL of 95% aqueous hydrazine and the reaction stirred at room temperature. After 12 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:arnmonium hydroxide, ~9: 11: 1) to provide the title compound (228 mg).

Step 7.1 F 4-(4-benzyloxyphenyl)-N- f 2-r2-(3.5-dimethylphenyl~-5-kydroxy-lH-indol-3-yllethyllbutyramide To a stirred solution of 4-benzyloxyphenylbutyric acid (159 mg in a mixture of 2 mL methylene chloride and 0.5 mL N,N-dimethylformamide) was added l-hydroxybenzotriazole (110 mg) and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg) and the reagents allowed to mix for 30 mimltes. At this time a solution of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-ol (144 mg in 4 mL N,N-dimethylformamide) was added and the reaction stirred at room temperature. After 6 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 4:5) to give the title compound (241 mg).

Step 7.1 G 3-12-r4-(4-benzyloxyphenyl)butylaminolethyll -2-(3.5-dimethylphenyl)- lH-indol-5-ol To a stirred solution of 4-(4-benzyloxyphenyl)-N-{2-[2-(3,5-dimethylphenyl)-S-hydroxy- 1 H-indol-3 -yl]ethyl]butyramide(241 mg in 10 mL dry tetrahydrofuran) was added 4 mL of a 1~ solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane ~uenched by the careful addition of methanol.
The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (1.4 mL) and heated to reflux on an oil bath.
- After 3 hours the mixture wa~ cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 92:~S) gave the title compound (234 mg) Step 7.1H r4-(4-benzyloxyphenyl)-butyl~-r2-r2-(3.5-dimethylphenyl)- -5-hydroxy-lH-indol-3-yllethyllcarbamic acid benzyl ester To a solution of 3-[2-[4-(4-benzyloxyphenyl)butylamino3 ethyl~-2-(3,5-dimethylphenyl)-lH-indol-5-ol (234 mg in 5 mL of dry methylene chloride) at -7~~ C was added benzyl chloroformate (0.082 mL) and diisopropylethylamine (0.104 mL) and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted wi~ ethyl acetate. The organic portion was washed with saturated ammonium chloride, dried over magnesium sulfate and concentrated in vacuo.
Purification by flash chromatography on silica gel (hexane:ethyl acetate, 3:1 then 2:1) gave the title compound (lL55 rng).
~tep 7.1I Propylcarbamic acid 3-(2-rbenzyloxycarbonyl-~4-(4-benzyloxyphenyl)butyllaminol-ethyl~-2-(3~5-dimethylphenyl)- I H-indol -S-yl ester To a stirred solution of [4-(4-benzyloxyphenyl)-butyl]-[2-[2-(3,5-dimethylphenyl)-5-hydroxy-lH-indol-3-yl]ethyl]carbamic acid benzyl ester (20 mg in 3 mL dry methylene chloride) at 0~ C was added triphosgene (4.9 mg) and pyridine (0.037 mL of a 10% solution in methylene chloride) and the reagents allowed to mix for 30 minutes. At this time, propylamine (0.040 mL) was added and the mixture allowed to walm to room temperature. After 30 minutes, the reaction was quenched by the addition of 0.3M sodium bisulfate and extracted with ethyl acetate. The organic portion was washed with 0.3M sodium bisulfate (3x) and brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (~exane:methylene chloride:ethyl acetate, 4:5:1) gave the title compound (17 mg).

Step 7.1J Propylcarbamic acid 2-(3.5-dimethylphenyl)-3-r2-r4-(4-hydroxyphenyl)-butylaminolethyll - l H-indol-5-yl ester t To a stirred solution of propylcarbamic acid 3-(2-~benzyloxycarbonyl-~4-(4-benzyloxyphenyl)butyl]amino] -ethyl)-2-(3 ,5-dimethylphenyl)-lH-indol-5-yl ester (17 mg in a mixture of 1.5 mL
tetrahydrofuran and 0.5 mL methanol) was added 16 mg of 10%
palladium on carbon catalyst followed by acetic acid (0.010 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo.
Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:6:1) gave the title compound (1 1 mg). m/e--514 (M + H) PREPARATION OF SYNTHETIC INTERMEDIATES
4-(4-benzyloxyphenyl)butyric acid Step A: 4-(4-benzyloxyphenyl)butyric acid benzyl ester To a stirred solution of ~-hydroxyphenylbutyric acid (810 mg in 8 mL N,lV-dimethylformamide) at 0~ C was added sodium hydride (290 mg of an 80% dispersion in mineral oil) and the mixture allowed to warm to room temperature. Benzyl bromide (1.2 mL) was added after 20 minutes and the mixture stirred at room temperature.
After 13 hours the reaction was quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic portion was washed with water (4x), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 13:1) gave the title compound (1.45 g) Step B: 4-(4-benzvloxyphenyl)butyric acid To a stirred solution Or 4-(4-benzyloxyphenyl)butyric acid benzyl ester (277 mg in a mixture of 3 mL methanol and 1 mL
methylene chloride) at 0~ C was added 1.5 mL of 5M sodium hydroxide and the mixture warmed to room temperature. After 2 hours the mixture was acidified to pH 2 by the addition of aqueous hydrochloric acid, the aqueous portion extracted with ethyl acetate (5x) and the resulting organics concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 94:6 then 96:4 + 0.25% TFA) gave the title compound (196 mg).

3~5-dimethylphenylboronic acid To a solution of S-bromo-m-xylene (1.~ g in lS mL of dry tetrahydrofuran) at -78~ C was added 6.4 mL of a 1.4M solution of butyllithium in hexane and the mixture stirred for 20 minutes. At this time triisopropyl borate (2.8 mL) was added and the mixture allowed to warm to room temperature. After 1.5 hours the reaction was concentrated in vacuo to 1/3 volume then cooled to 0~ C and treated with 2N hydrochloric acid (9 mL) followed by warming to room temperature. After 4 hours the mixture was made basic by the addition of 2.5M sodium hydroxide and partitioned between ethyl ether (75 mL) and 1.25M sodium hydroxide. The organic layer was extracted with 1.25M sodium hydroxide (2x) and the aqueous portion then cooled to 0~
C and acidified to pH 3 by the dropwise addition of conc. hydrochloric acid. The white slurry was dissolved in methylene chloride, the organic portion dried over magnesium sulfate and concentrated in vacuo to provide the title compound (960 mg).

CA 0224011~ 1998-06-09 EXA~IPLE 7.2 Me~N~O~ ~,N ~~~3~
,~Me OH
H

Me Ethylcarbamic acid 2-(3.5-dimethylphenyl)-3-r2-r4-(4-hydroxyphenyl)butylaminolethyll-lH-indol-5-yl ester ~tep 7.2A Ethylcarbamic acid 3-(2-rbenzyloxycarbonyl-r4-(4-benzyloxyphenyl)butyll aminol -ethyl )-2-(3 .5 -dimethylphenyl)- I H-indol-5-yl ester To a solution of [4-(4-benzyloxyphenyl)-butyl]-r2-[2-(3,5-dimethylphenyl)-5-hydroxy-lH-indol-3-yl]ethyl]carbamic acid benzyl ester (50 mg in 0.5 mL dry tetrahydrofuran) was added 0.035 mL of ethyl isocyanate and the mixture stirred at room temperature. Over the course of 2 weeks, additional ethyl isocyanate was added in portions and the mixture heated to reflux for several days after which time it was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica ~el (hexane:ethyl acetate, 2:1) to give the title compound (20 mg).
~tep 7.2B Ethylcarbamic acid 2-(3.5-dimethylphenyl)-3-r2-r4-(4-hydroxyphenyl)butvlaminolethyll-1H-indol-5-yl ester To a stirred solution of ethylcarbamic acid 3-(2-rbenzyloxycarbonyl-r4-(4-benzyloxyphenyl)butyl~amino] -ethyl)-2-(3 ,5-dimethylphenyl)-lH-indol-5-yl ester (12 mg in a mixture of ~.5 mL
tetrahydrofuran and 0.5 mL methanol) was added 12 mg of 10%
palladium hydroxide on carbon catalyst followed by acetic acid (0.010 mL of a 30% solution in water~. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:rnethanol:arnmonium hydroxide, 90:7:1) gave the title compound (8.2 mg). m/e = 500 (M + H) Following a procedure similar to that described in EXAMPLES 7.1 and 7.2 above, the following compounds were prepared:

~'~ ~ ~OH

Me Example R2 R8 m/e 7A (CH2)4OH -CO-NHEt 572 (M + H) 7B (cH2)4oH-CO-N(CH2CH3)-CO-NCH2CH3 643 (M + H) 7C H-co-N(cH2cH3)-co-NHcH2cH3 571 (M + H) 7D H -CO-OCH2CH3 501 (M + H) 7E H -CO-NH-CH3 4~6 (M + H) 7F H -CO-N-(CH3)2 500 (M + H) 7G H -CO-NH-Ph 548 (M + H) WO 97/Z1435 PCT/US96/20~04 FXAMPLE

Me H H
M ,N~N~ ,~
~N~Me ~N,S~M

Me N-r4-(4- f 2-12-(3 .5-dimethylphenyl)-S-(3 ,3 -dimethylureido)- 1 H-indol-3-yllethylamino ~butyl)phenyllmethanesulfonamide Step 8A 2-(3.5-dimethylphenylethynyl)-4-nitrophenylamine To a solution of 3,5-dimethylphenylethyne (156 mg in 7 mL of dry, nitrogen saturated triethylamine) was added 2-iodo-4-nitroaniline (264 mg, prepared essentially as described in: Toth, I.
Helv. Chim. Acta, 1971, 54, 1486.) followed by tetrakis(triphenylphosphine)palladium (23 mg) and cuprous bromide (10 mg) and the mixture heated to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:methylene chloride:ethyl acetate, 15:8:1) to give the title compound (256 mg).

Step 8B 2-~3.5-dimethylphenyl)-5-nitro-lH-indole To a stirred solution of 2-(3,5-dimethylphenylethynyl)-4-nitrophenylamine (50 mg in 3 mL of dry, nitrogen saturated acetonitrile) was added 5 mg of palladium (rl) chloride and the mixture heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature, concentrated in v~cuo and purified by flash chromatography on silica gel (hexane:methylene chloride:ethyl acetate, 15:8:1) to provide the title compound (46 mg).

WO 97/21435 PCT/lJS96/20004 Step 8C lV-benzyl-2-r2-(3 5-dimethylphenyl)-5-nitro- lH-indol-3-yll -N-~4-(4-methanesulfonylaminophenyl)butyll -2-oxo-acet~mide To a stirred suspension of 2-(3,5-dirnethylphenyl)-5-nitro-lH-indole (59 mg in 6 mL dry dichloroethane) was added oxalyl chloride (0.025 mL) and heated to reflux on an oil bath. After 15 hours the mixture was cooled to room temperature, diluted with benzene and the volatiles removed in vacuo. The resulting solid was dissolved in 3 mL dry tetrahydrofuran and cooled to 0~ C. To ~is a solution of N-[4-(4-benzylaminobutyl)-phenyl]methanesulfonamlde (74 mg in 2 mL dry methylene chloride) was added simlllt~neously with triethylamine (0.047 mL) and the mixture stirred for 20 minutes at 0~ C then warmed to room temperature. After 10 minutes the reaction was quenched by the addition of saturated sodium bicarbonate, extracted with ethyl acetate.
The organic portion was washed with saturated ammonium chloride (2x), dried over magnesium sulfate and concentrated in vacuo.
Purification by flash chromatography on silica gel (hexane:ethyl acetate, 4:5) gave the title compound (127 mg).

Step 8D IV-~4-r4-(benzyl-f2-r2-(3.5-dimethylphenyl)-5-nitro-lH-indol-3-yllethyl ~ amino)butyllphenyl ~ -methanesulfonamide To a stirred solution of N-benzyl-2-[2-(3,5-dimethylphenyl)-5-nitro- lH-indol-3-yl]-N-[4-(4-methanesulfonylaminophenyl)butyl]-2-oxo-acetamide (73 mg in 4 mL
dry tetrahydrofuran) was added 1 mL of a lM solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath.
After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine ~0.35 mL) and heated to reflux on an oil bath.
After 2.5 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 3,2) gave the title compound (59 mg).

Step 8E N- ~ 4-r4-( ~ 2-r5-amino-2-(3 ~-dimethylphenyl)- 1~-indol-3-yllethvl ~benzylamino)butyllphenyl 1 methanesulfon~mi~le To a stirred .solution of N- { 4-[4-(benzyl- { 2-[2-(3,5-dimethylphenyl)-5 -nitro- 1 H-indol-3-yl]ethyl } amino)butyl]phenyl } -methanesulfonamide (S9 mg in 4 mL absolute ethanol) was added ca. 15 mg of Raney(~) nickel. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 3 hours the reaction was flushed with nitrogen, ~lltered over diatomaceous earth and concentrated in vacuo.
Purification by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (42 mg).

Step 8F N- ~4-r4-(benzyl- ~ 2-r2-(3.5-dimethylphenyl)-5-(3.3-dimethylureido)- lH-indol-3-yllethvl ~-amino)butyllphenyl ~ methanesulfonamide To a stirred solution of N-{4-~4-({2-[5-amino-2-(3,5-dimethylphenyl)- 1 H-indol-3 -yl]ethyl } benzylamino)butyl]phenyl } -methanesulfonamide (15 mg in 1.5 mL of dry methylene chloride) at 0~
C was added dimethylcarbamyl chloride (0.03 mL of a 10% v/v solution in methylene chloride) and diisopropylethylamine (0.053 mL of a 10%
v/v solution in methylene chloride) and the mixture warmed to room temperature. After 3 days the reaction was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) to give the title compound (17 mg).

Step 8G N-r4-(4- ~ 2-r2-(3.5-dimethylphenyl)-5-(3.3-dimethylureido)- 1 H-indol-3-yllethylamino ~butyl)phenvllmethanesulfonamide To a stirred solution of N- { 4-[4-(benzyl- ~ 2-[2-(3,5-dimethylphenyl)-5 -(3 ,3-dimethylureido)- 1 H-indol-3 -yl ~ethyl } -amino)butyl]phenyl}methanesulfonamide (17 mg in a mixture of 4 mL
tetrahydrofuran and 1.5 mL methanol) was added 7 mg of 10%
palladium hydroxide on carbon catalyst followed by acetic acid (0.020 mL of a 30% solution m water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stiITed at room temperature. After 45 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:amrnonium hydroxide, 91:9:1) gave the title compound (145 mg). m/e = 576 (M + H) Following a procedure similar to that described above, the following compounds were prepared:

R~ R2 ~~ NH "S~~Me Me Example R6 R2 X-R7R8 m/e 8A H HNH-COOCH2Ph 8B HCH2P NH-COO-Et 677 (M + H) h 8C H H NH-COO-Et 577 (M + H) 8D H HNH-co-N(cH2cH3)2 604 (M + H) 8E H HN(CH2CH3)CO-N(CH2CH3)2 632 (M + H) 8F H HNH-CO-Cyclopropyl 573 (M + H) 8G H H NH-CO-Ph 609 (M + H) 8H H H Me 637 (M + H) H ~h , N ~ Me o SU~ lUTE SHEET(RULE 26) 81 H H CF3 745 (M + H) ~N~CF3 8J H H NH-CO-Me ~47 (M + H) 8K }I H F 645 (M + H) H ~
'N~~'F
o 8L H HNH-CO-CH(Me)-NH-CO-Me 618 (M + H) 8M H H N(Me)-CO-Ph 623 (M + H) 8N H H N(Me)-CO-Me 561 (M + H) H H NH-S02Me 583 (M + H) 8P H H ,N~J~OCH3 639 (M + H) 8Q H H H 1~1 639 (M + H) ~ N ~OCH3 o 8R H HNH-CO-NH(CH2CH3) 576 (M + H) 8S H H NH-CO-CH2CH3 561 (M + H) 8T _ H H NH-CO-NHMe 562 (M + H) 8U H HNH-CO-NH(CH~CH2C1~3) 590(M + H) 8V H HNH-CO-CH(CH3)2 575 (M + H) ~sW H 1~NH-CO-NH-CH(CH3)2 5~0 (M + H) 8X H HNH-CO-NH-(cyclopropyl) 5~" (M + H) ~Y H HNH-S02-(CH2CH2CH3) 61 1 (M + H) 8Z H HNH-S02-NH-(CH2CH3) 612 (M + H) 8AA H H SCH3 536 (M + H) 8BB H H S(O)CH3 552 (M + H) 8CC H H S(0)2CH3 568 (M + H) 8DD H H S~0)2NH2 569 (M + H) 8EE 6-CI H * 569 (M + H) 8F~ 6-CI HNH-CO-NH-(cyclopropyl) 622 (M + H) Sl.~d ~ ~1 1 UTE SHE~T (RULE 26) * = N02 ;~XAMPLE 9 Following a procedure similar to that desc~ibed in EXAMPLES 4.1 and 12.1 the following compounds were prepared:
H

R6~ (A) R~ R4 EX. #Rl R3-R5 R6(CH2)n=(rn/e A) 9APh-4-0-CH2 Ph 3,4-OMe 4 ~~
9B Ph-4-OH 3,4-OMe 4 445 (M +H) 9C Ph-4-OH 3,4-OMe I 403 (M + H) 9D Ph-4-N02 3,4-OMe 4 474 (M + H) 9E Ph-4-NH2 3,4-OMe 4 444 (M + H) 9F Ph-4-OCH3 3-OCH2(Ph- 4 535 (M + H) 3-OMe) 9G Ph-4-OH 3,4-OMe 5 549 (M + H) 9H Ph-4-OH 3,5-CF3 4 521 (M + H) 91 Ph-4-OH 3,4-OMe 6 473 (M + H) 9J Ph-4-OCH3 3,4-OMe 4 459 (M + H) 9K Ph~OH 2-Me 4 399 (M + H) 9L Ph~OH 2,4-C1 4 453 (M) 9M Ph~OH 4-F 4 403 (M + H) 9N Ph-4-OH 4-Me 4 399 (M + H) Ph-4-OH 3-Cl,4-F 4 437 (M+ H) CA 0224011~ l998-06-os wo 97/21435 PCT/US96/20004 9P Ph-4-OH 3,5-C1 4 453 (M) 9Q Ph-4-OH - 4385 (M + H) 9R Ph-4-OH 3,5-Me 4413 (M +H) 9S Ph-4-OH 3-Me 4399 (M + H) 9T Ph-4-OH 2,6-Me 4413 (M + H) 9U Ph-4-OH 3-OMe 4415 (M + H) 9V Ph-4-OH 3,5-OMe 4445 (M + H) 9W Ph-4-OCH3 3,5-Me 4427 (M + H) 9X Ph-4-OH 3,5-Me 5-C1 4447 (M + H) 9Y Ph-4-OH 3,5-Me S-Me 4427 (M + H) 9Z Ph-4-OH 3,5-Me 5427 (M +H) 9AA Ph-4-OH 3,5-Me S-OBn 4519 (M + H) gBB Ph-4-OH 2,3-Me 4413 (M + H) 9CC Ph-4-OH 3-N(Me)2 4428 (M + H) 9DD Ph~OH 3,5-Me 6441 (M + H) 9EE Ph-4-OH 2,5-Me 4413 (M + H) 9FF Ph-4-OH 3,5-Me 7-Me 4427 (M + H) 9GG Ph-4-OH 3,5-Me 1371 (M + H) 9HH Ph-4-OH 3,5-Me S-OMe 4443 (M + H) 9II Ph-4-OH 3-OCH2-Ph 4491 (M+H) 9JJ Ph-4-OH 3-CH(Me) 4519 (M + H) OBn 9KK Ph-4-OH 3-Et 4413 (M + H) 9LL Ph-4-No2 3,5-Me 4442 (M + H) 9MM Ph-4-OH 3-CH(Me) 4429 (M + H) OH
9NN Ph-4-OH 3,5-Me 6-NH- 4 C(O)CH3 9Oo Ph-4-OCH3 3-O-CH2Ph 4505 (M + H) gpp Ph-4-NH2 3,5-Me 4412 (M + H) 9QQ Ph-4-NH- 3,5-Me 4454 (M + H) CA 02240115 l998-06-os Wo 97/21435 PCT/US96/20004 9RRPh-4-NHS02Ph 3,5-Me 4 552 (M + H) 9SS Ph-4-NHSO2Me 3,5-Me 4490 (M + H) 9'rT Ph-4-OMe 3-OCH2(Ph- 4535 (M + H) 3-OMe) 9UU Ph-4-OH 3-SMe 4431 (M + H) 9W Ph-4-OH 3-SMe, 5-Me 4445 (M + H) 9VVW Ph-4-OH 3,5-Me 6-C1 4475 (M) 9XX Ph-4-SO2NH2 3,5-Me 9YY Ph-4-OH 3,5-Me 4-C1 4475 (M) 9Z Ph~OH 3-S~O)Me 4447 (M + H) 9AAA Ph-4-OH 3-S(O)Me, 4461 (M + H) 5-Me 9BBB Ph-4-OH 3-SO2Me 4463 (M + H) 9CCC Ph-4-OH 3-SO2Me, 5- 4477 (M + H) Me 9DDD Ph-NHS02CF3 3,5-Me 4544 (M + H) 9EEE Ph-NHSO2Et 3,5-Me 4504 (M + H) ~ 471 ~M + H) 9FFF ~ ~ 3,4-OMe 0 H

H ~CH 471 (M + H~
9GGG,~ 3,4-OMe 0 H
Me~ 517 (M + H) 9HHHPh-4-OH 3,5-Me 6- ~ 4 Me 9IIl Ph-4-OH3-Me, 5-i-Bu 4 9JJJ Ph-4-OH3-Me, 5-Pr 4 CA 02240115 1998-06-og wo 97/21435 PCT/US96/20004 9KKK Ph-4-NH23,5-Me 5- 4 NHC(O)-NHEt 9LLL Ph-4-NHS02- 3,5-Me 4532 (M + H) iPr 9MMM Ph-4-OH 3,5-Me5-NO2 4 --9NNN Ph-3,4-OMe 3,5-Me 44~7 (M + H) 9OOO Ph-3,4-OH 3,5-Me 4429 (M + H) 9PPP Ph-4-OH 3,5-Me 5-Br 4492 (M + H) 9QQQ 2-naphthyl 3,5-Me 4447 (M +H) 9RRR Ph-4- 3,5-Me 4505 (M +H) NHS02NHMe 9SSS Ph-4-CN 3,5-Me 4422 (M + H) 91~ Ph-4-F 3,S-Me 4415 (M + H) 9UUU Ph-4-OH 3,5-Me 5-Ph 4489 (M + H) 9VVV Ph-3-Br, 4- 3,5-Me 4570 (M ~ H) NHS02-Me 9WWW Ph-4- 3,5-Me 4469 (M + H) NHCONHMe 9XXX Ph-4-OH 3,5-Me 5- 4455 (M +H) CH(Me)2 gyyy Ph-4-S02NH2 3,5-Me 4476 (M + H) 9ZZ l-naphthyl-4- 3,5-Me 4477 (M + H) OMe 9AAAA l-naphthyl-4- 3,5-Me 4463 (M + H) OH
9BBBB Ph-3-F, ~OMe 3,5-Me 4445 (M + H) 9CCCC Ph-3-F, 4-OH 3,5-Me 44310 (M +
H) 9DDDD Ph-4- 3,5-Me 4519 (M + H) - NHS02NHEt 9EEEE Ph-4- 3,5-Me 4483 (M + H) NHCON~HEt WO g7/21435 PCT/US96/20004 9FFFF Ph~NHS02Me 3,5-Me 5-S02Me 5 582 (M + H) 9GGGG Ph-4-NHSO~Me 3,5-C1 5- 4 N(Et)CO-N(Et)2 9HHHH Ph-4-OH 3,5-Me 5-F 4431 (M + H) Following a procedure similar to thrat described in EXAMPLE 9, the following compounds were prepared:

R6~ ~/\~'OH
Rs R4 Example # R3-R5 R6 m/e 10A 2-(CH)4-3 H 435 (M + H) 10B 3-(CH)4-4 H 435 (M + H) 10C 3-(CH-CH-N(Me))-4 H 438 (M+ H) 10D 2-(CH)4-3 5-OBn 541 (M+ EI) lOE 2-(CH)4-3 5-OH 451 (M + H) lOF 2-(CH)4-3 6-F 453 (M + H) 10G 2-(CH)4-3, 5-Me H 449 (M + H) Me H

OH
H

Me 4-(4-r2-r2-(3 .5-dimethylphenyl)- 1 H-indol-3-yll-propvlaminolbutyl)phenol ~tep 1 1 A 2-methylcyclopropanecarboxylic acid N-methoxy-N-methyl-amide To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL benzene and 2 mL N,N-dimethylformamide) at 0~ C was added 10.5 mL of oxalyl chloride and the mixture stirred at 0~
C for 30 minutes then warmed to room temperature for 30 minutes. At this time, 14.6 g of N,O-dimethylhydroxylamine hydrochloride was added followed by 41 mL of triethylamine. The mixture was stirred at room temperature for one hour then quenched by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organics washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillatic~n under reduced pressure to give P,.9 g as an oil.
Step 1 1 B (3 .5-dimethylphenyl)-(2-methylcyclopropyl)methanone To a solution of 5-bromo-mcta-xylene (5.7 mL in 120 mL
of dry tetrahydrofuran) at -7~~ C was added 30.6 mL of a 1.4M solution of n-butyllithium in hexane and the mixture stirred at low temperature.
After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methyl-arnide (5.0 g in 50 mL tetrahydrofuran) was added dropwise over 5 minutes and the mixture then allowed to warm slowly to room temperature. After 1 hour, the reaction was quenched by the addition of 20 mL 2N hydrochloric acid and 40 mL water. Thi.s was extracted with ethyl acetate washed with saturated sodium bicarbonate and brine then dried over sodium sulfate to give 6.95 g of the crude title compound.

Step 1 I C 2-r2-(3 .5-dimethylphenyl)- 1 H-indol-3-yllpropylamine To a solution of phenylhydrazine hydrochloride (1.42 g in 24 mL n-butanol) at 95~ C was added a solution of (3,5-dimethylphenyl)-(2-methylcyclopropyl)methanone 2.0 g in 16 mL of n-butanol) and heat at 1 I0~ C for 4 hours. At this tirne the reaction was cooled to room temperature, 25 mL of 1 N sodium hydroxide and the mixture extracted 3x with methylene chloride. The organics were washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (307 mg).
~teps llD, 11E 4-(4-r2-r2-(3.5-dimethylphenyl)-lH-indol-3-yll-propylaminolbutyl)phenol The title compound was prepared essentially as described in EXAMPLES 1 and 5.2 from 2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]propyl~mine.

CA 02240ll5 l998-06-09 Following a procedure similar to that described above, the following compounds were prepared:

R

Me Ex R1 R2 Rg R~a R1o RlOa A

1 lA Ph-4-OH H H H CH3 H 4 I lB Ph-4-OH H Ph H H H 4 I lC Ph-4-OH -CH2CH2- H H H 4 1 lD Ph-4-OH H CH3 H H H 2 1 lE Ph-4- H CH3 H H H 4 NHS02Me I lF Ph-4-OH H H H CH3 H 2 1 lG Ph-4-OH H H H CH3 CH3 4 I lH Ph-4- H CH3 H H H 2 NHS02Me EXAMPLE 12.1 H {~OH

N ~CH3 H 1¦ l 4-(4- ~ 2-r2-(3,5-dimethylphenyl)- lH-indol-3-yllethylamino ~cyclohexyl)-phenol A mixture of 2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]-ethylamine (EXAMPLE 2, Step D, 345 mg) and 4-(4-hydroxyphenyl)cyclohexanone (62 mg) were solvated in 8 rnL dry methanol to which ca. 2 g powdered 3A molecular sieves were added.
The pH of this mixture was adjusted to 6 by the addition of 0.65 mL of a 10% ,solution of trifluoroacetic acid in methanol and then 90 mg sodium cyanoborohydride was added and the mixture atirred at room temperature. After 20 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel I (methylene chloride:methanol:, g2:8) then again (chloroform:methanol, 90:10) to separate the diastereomers~ to give the title compound (isorner A 40 mg, isomer B 36 mg). m/e = 439 (M + H) EXAMPLE 12.2 ¦ I ~ CH30 --\~OH

1 - ~ 2-r2-(3 .5-dimethylphenyl)- 1 H-indol-3 -yllethyl ~ -3-r2-(4-hydroxyphenyl)ethyllurea ~tep 1 2.2A 1 -r2-(4-benzyloxyphenyl)ethyll-3- f 2-r2-(3~5-dimethylphenyl)- lH-indol-3-yllethyl ~urea To a solution of 2-12-(3,5-dimethylphenyl)-lH-indol-3-yl]-ethylamine (EXAMPLE 2 Step D, 39 mg in 1 mL dry methanol) was added 64 mg [2-(4-benzyloxyphenyl)-ethyl]-carbamic acid 4-nitrophenyl ester and the mixture stirred at room temperature. After 24 hours, the mixture was concentrated in vacuo and the residue re-solvated in ethyl acetate. This was washed with saturated aqueous potassium carbonate (3x) and brine, dried over sodium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 5:4; then 1:1) to give the title compound (73 mg).
~tep 1 2.2B 1- ~ 2-r2-(3~5-dimethylphenyl)- 1 H-indol-3 -yll ethyl ~ -3 -r2-(4-hydroxyphenyl)ethyllurea The title compound was prepared essentially as described in EXAMPLE 2 Step B starting from 1-[2-(4-benzyloxyphenyl)ethyl]-3-{2-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]ethyl}urea to give the title compound. m/e = 42~s (M + H) -Following a procedure similar to those described above and in EXAMPLE 4.1, the following compounds were prepared:

~ C H

Example R 1 (A) m/e 12A Ph-4-0-tBu -CH2-CH2-O-CH2-12B Ph-4-OH -(CH2)3-C(cH3)2-Ph-4-oH
1 2C Ph-4-OH -CH2-CH2-CHMe-CH2-12D Ph-4-OH -CH2-CH(CH3)2- 427 (M + H) 12F Ph-4-OH -CNH-NH-(CH2)2-1 2F Ph-4-OH -(CH2)3-CH(O-CH2-CH2-OH)-1 2G Ph-4-OH -(C~2)3-C(O-CH2-CH2-O)-12H l-(naphthyl- -CH2-C(MC)2- 463 (M + H) 4-OH) EXAMPLE 13.1 Me Me~N~ ,N ~ 3~

tl ~Me N ,S~ M

Me CA 0224011~ 1998-06-09 2-(2-(3 ~5-dimethylphenyl)-3- ~ 2-l 4-~4-methanesulfonylaminophenyl)-butylaminol-ethyl ~-1H-indol-5-yl)-N.N-diethylacetamide ~ Step 13.1A r3-(2-aminoethyl)-2-(3~5-dimethylphenyl)-lH-indol-5-yll-acetic acid ethyl ester A mixture of 6.34 g (approximately 29.5 mmol) of ethyl 2-(4-hydrazinophenyl)acetate hydrochloride/2-(4-hydrazinophenyl)acetic acid hydrochloride, 6.22g (29.5 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone, and 120 mL of absolute ethanol was stirred at reflux under nitrogen for 12 hours. The cooled solution was concentrated in vacuo, and the residue was partitioned between 200 mL
of ethyl acetate and 50 mL of saturated aqueous sodium carbonate solution. The organic phase was washed with 25 mL of brine, then dried over sodium sulfate, and filtered. The residue from concentration of the filtrate in vacuo was purified by flash chromatography on silica gel (elution with 95:5 CH2C12-MeOH and then 95:5:0.5 CH2C12-MeOH-concentrated NH40H). Concentration of the product fractions gave 1.13 g (11%) of a stiff foam; nearly homogeneous by TLC in 95:5:0.5 CH2C12-MeOH-concentrated NH40H. 400 MHz lH NMR (CDC13) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI):
m/e = 351 (M + H).

Stepl3.1B (2-(3.5-dimethylphenyl)-3-~2-r4-(4-methanesulfonylamino-phenyl)butylaminolethyl~-lH-indol-S-yl)acetic acid ethyl ester The reductive ~min~tion reaction of [3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-lH-indol-S-yl]-acetic acid ethyl ester and 4-~4-(methanesulfonamido)phenyl]butyraldehyde was accomplished according to the procedure of Example 14.1, Step 14.1B to give the titled compound in 29% yield as a stiff foam; homogenous by TLC in 92.5:7.5 CH2Cl2-MeOH. 500 MHz 1 H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 576 (M + H).

- ~0 -S~ep 13.1 C r3-(2- ~ benzyloxycarbonyl-r4-f4-methanesulfonylamino-phenyl)butyllamino ~ -ethy~)-2-(3.5-dimethylphenyl)- 1 H-indol-5-yll-acetic acid ethyl ester The reaction of (2-(3,5-dimethylphenyl)-3-{2-[4-(4-methanesulfonylaminophenyl)butylamino]ethyl } -1 H-indol-5-yl)acetic acid ethyl ester with benzyl chlorofo~nate was carried out according to the procedure of Example 14.1, Step 14.1C, to give the titled compound in 73% yield as a stiff foam; homogeneous by TL(~ in 95:5 CH2C12-MeOH. 500 MHz lH NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e = 710 (M + H).
~tep 13.1 D r3-(2- f benzyloxycarbonyl-14-(4-methanesulfonylamino-phenyI)butyll amino ~ ethyl)-2-(3 ~5 -dimethylphenyl) - I H-indol-5-yllacetic acid To a solution of 227 mg (0.32 mmol) of [3-(2-{ benzyloxycarbonyl-[4-(4-methanesulfonylamino-phenyl)butyl lamino } -ethyl~-2-(3,5-dimethylphenyl)-lH-indol-5-yl~-acetic acid ethyl ester in 4.0 mL (2.0 mmol) of 0.50 N potassium hydro7~ide in methanol was stirred under nitrogen at 60-65 ~C as 1.0 mL of water was added gradually, resulting in slight cloudines.s. After 3 hours, the homogeneous solution was cooled and concentrated to small volume in vacuo. The residue was partitioned between 10 mL of ethyl acetate and 10 mL of 0.5 N hydrochloric acid. The organic phase was dried (m~gnesium sulfate), filtered, and concentrated in vacuo at room temperature. Trituration of the residue with diethyl ether resulted in solidification of the product. This material was collected on a filter and washed with small volumes of ether. The evaporation residue from the mother liquor was also triturated with some ether to give a solid. After decantation of the ether, the trituration-decantation cycle was repeated twice more. The solids were combined and dried in vacuo to give 205 mg (94%) of a powder, mp 123-125 ~C; virtually homogeneous by TLC
(92.5:7.5 CH2Cl2-MeOH). 500 MHz lH NMR (DMSO-d6) was CA 0224011~ 1998-06-09 complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e = 682 (M + H).
~tep 13.1 E ~ 2-15-diethylcarbamoylmethyl-2-(3 5-dimethylphenyl)- 1 H-indol-3-yllethyl ~-r4-(4-methanesulfonylaminophenyl)butyll-carbamic acid benzyl ester The reaction of 34.1 mg (0.05 mrnol) of r3-(2-{ benzyloxycarbonyl-l 4-(4-methanesulfonylaminophenyl)butyl] -amino}ethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-yl]acetic acid with diethylamine in the presence of PyBOP reagent was accomplished according to the procedure of Bxample 14.1, Step 14.1L. The crude product was purified by preparative TLC on 2 1000-micron silica gel GF plates (20 x 20 cm), which were developed in 92.5:7.5 CH2C12-MeOH. The product bands were isolated and extracted with the same solvent to afford 30.9 mg (84%) of nearly colorless residual glass;
virtually homogeneous by TLC in 92.5:7.5 CH2C12-MeOH. 500 MHz 1H NMR (CDC13) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (E~I): m/e = 737 (M + H).
~tep 13.1 F 2-(2-(3.5-dimethylphenyl)-3- ~ 2-r4-(4-methanesulfonylaminophenyl)-butylaminol-ethyl ~-1~-indol -5 -yl)-N.N-diethylacetamide A mixture of 28.7 mg (0.039 mmol) of {2-[5-diethylcarbamoylmethyl-2-(3,5-dimethylphenyl)- lH-indol-3-yl]ethyl } -[4-(4-methanesulfonylaminophenyl)butyl~-carbamic acid benzyl ester, 20 mg of 20% palladium hydroxide on carbon, and 5 mL of glacial acetic acid was shal~en with hydrogen (50 psig) in a pressure vessel. After 1 day, an additional 20 mg of catalyst was added, and .~h~kin~ with hydrogen was continued for 3 hours more. The catalyst was removed by filtration through Celite under nitrogen, and the filtrate was concentrated in vacuo. The residue was reconcentrated twice from toluene and then purified by preparative TLC on 2 1000-micron silica gel GF plates (20 x 20 cm), which were developed in 92.5:7.5:0.75 CH2C12-MeOH-concentrated NH40H. The product band from each CA 02240ll5 l998-06-09 plate was isolated, combined, and extracted with the same solvent.
Concentration of the extracts in vacuo afforded 15.7 mg (67%) of a glass; virtually homogeneous by TLC in 92.5:7.5:0.75 CH2Cl2-MeOH-concentrated NH40H. 500 MHz lH NMlR (CDC13) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 603 ~M + H).

EXAMP~}~ 13.2 Me ~ Me Me tl Me ~N~"N~ O
~N~Me ~N,S~Me H 1¦ I H

Me 2-(2-(3.5-dimethylphenyl)-3- ~ 2-1 4-(4-methanesulfonylaminophenyl)-butylaminolethyl ~-1H-indol-5-yl)-N.N-diethylisobutyramide Step 13.2A 2-r3-(2-aminoethyl)-2-(3.5-dimethylphenyl)-lH-indol-5-yll-2-methylpropionic acid ethyl ester By the procedure of Example 14.1 ~tep A, ethyl 2-(4-hydrazinophenyl)-2-methylpropionate was reacted with 3-chloropropyl 3,5-dimethylphenyl ketone to afford the titled compound in 16% yield as a stiff foam; virtually homogeneous by TLC in 95:5:0.5 CH2cl2 MeOH-concentrated NH40H. 500 MHz 1 H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI):
m/e=379 (M+H).
~tep 13.2B 2-f2-f3.5-dimethylphenyl)-3- ~ 2-r4-(4-methanesulfonylamino-phenyl)butylaminolethyl ~ - l ~-indol-5-yl)-2-methylpropionic acid ethyl ester CA 0224011~ 1998-06-09 The reductive amination reaction of 2-~3-(2-arninoethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-yl~-2-methylpropionic acid ethyl ester and 4-~4-(methanesulfonamido)phenyl]butyraldehyde was carried out according to the procedure of Example 14.1 Step B to give the titled compound in 43% yield as a stiff foam; virtually homogenous by TLC
in 92.5:7.5 CH2Cl2-MeOH. 500 MHz l H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): mJe = 604 (M ~ H).
~tep 13.2C 2-r3-(2- ~ benzyloxycarbonyl -14-(4-methanesulfonylamino-phenyl)butyllamino ~ethyl)-2-(3~5-dimethyl-phenyl)-l~-indol-5-yll-2-methylpropionic acid ethyl ester The reaction of 2-(2-(3,5-dimethylphenyl)-3-{2-[4-(4-methanesulfonylarninophenyl)butylamino]ethyl }- 1~-indol-5-yl)-2-methylpropionic acid ethyl ester with benzyl chloroformate was carried out according to the procedure of Example 14.1 Step C, to give the titled compound in 72% yield as a stiff foam; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure.
Mass spectrum (ESI): m/e = 738 (M + H).
~tep 13.2D 2-13-(2- f benzyloxycarbonyl-14-(4-methanesulfonylamino-phenyl~butyll amino ~ ethyl )-2-(3.5 -dimethylphenyl)- 1 H-indol-5-yll-2-methylpropionic acid The saponification of 2-[3-(2-{benzyloxycarbonyl-[4-(4-methanesulfonylamino-phenyl)butyl3amino } ethyl)-2-(3,5-dimethyl-phenyl)-lH-indol-5-yl]-2-methylpropionic acid ethyl ester was achieved according to the procedure of Example 14.1 Step D, except that the reaction time was increased to 30 hours, providing a qll~ntit~tive yield of the titled compound as a powder, mp >102 ~C (gradual; paltial decomposition); homogeneous by TLC in 92.5:7.5 C~I2C12-MeOH. 500 MHz lH NMR (DMSO-d6) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e = 710 (M + H).

Step 13 .2E ~ 2-r5-( 1 -diethylcarbamoyl- 1 -methylethyl)-2-(3 .5-(limethylphenyl)- 1 H-indol-3-yllethyl ~ - r4-(4-methanesulfonylaminophenyl)butyllcarbamic acid benzyl ester A solution of of 71.0 mg (0.1 mmol) of 2-[3-(2-{ benzyloxycarbonyl-[4-(4-methanesulfonylamino-phenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-lH-indol-S-yl]-2-methylpropionic acid, 53.0 mg (0.102 mmol) of PyBOP reagent, and 14.2 lmL (10.3 mg; 0.102 mmol) of triethylamine in 400 mL of dry methylene chloride was stirred at room temperature in a stoppered flask. After 25 minutes, 15.5 mL (11.0 mg; 0.15 mmol) of diethylamine was added, followed after 4 hours by an additional 36.2 mL (25.6 mg; 0.35 mmol) of diethylamine. After 1 day, the solution was partitioned between 10 mL of 0.5 N hydrochloric acid. The organic phase was washed with 10 mL of saturated aqueous ~odium bicarbonate solution and then with S mL of saturated aqueous sodium chloride solution. The ethyl acetate phase was then dried (magnesium sulfate), filtered, and concentrated in vacuo at room temperature. The residue was purified by preparative T~C on 4 Analtech tapered silica gel plates (20 x 20 cm), which were developed in 94:6 CH2C12-MeOH.
The product band from each plate was isolated, combined, and extracted with 94:6 CH2C12-MeOH. Concentration of the extracts in vacuo yielded 66.2 mg (87%) of a nearTy colorless glass; virtually homogeneous by TLC ~n 95:5 CH2C12-MeOH. 500 MHz lH NMR
(CDC13) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e = 765 (M + H).
~tep 1 3.2F 2-(2-(3.5-dimethylphenyl)-3- ~ 2-r4-(4-methane.sulfonylaminophenyl)-butylaminolethyl ~ -1 H-indol-S-yl)-N.N-diethylisobutyramide A mixture of 62.7 mg (0.082 mmol) of ~2-~S-(1-diethylcarbarnoyl- 1 -methylethyl)-2-(3 ,5 -dimethylphenyl)- 1 H-indol-3-yl]ethyl~-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid benzyl CA 0224011~ 1998-06-09 WO 97/21435 PCTtlJS96/21)004 ester, 30 mg of 20% palladium on carbon, 10 mL of glacial acetic acid, and 5 mL of absolute ethanol wa,s shaken with hydrogen (48 psig) in a pressure vessel for 2 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 4 Analtech tapered silica gel plates (20 x 20 cm), which were developed in 92.5:7.5:0.75 CH2C12-MeOH-concentrated NH40H. The product band from each plate was isolated, combined, and extracted with 92.5:7.5:0.75 CH2C12-MeOH-concentrated NE~40H. Concentration of the extracts in vacuo yielded 47.2 mg (91 %) of a glass; homogeneous by TLC in 92.5:7.5:0.75 ~H2C12-MeOH-concentrated NH40H. 500 MHz lH NMR (CDC13) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 631 (M + H).

PREPARATION OF SYNTHETIC INTERMEDIATES

Step A 4-chloro-N-methoxy-N-methylbutyramide To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride. The mixture was stirred under nitrogen and maintained below 25 ~C by cooling in an ice bath as necessary while triethylamine (29.1 mL)was added dropwise over about 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 solution. The organic layer was washed with an additiona~ 100 mL of saturated sodium bicarbonate, and the ac~ueous fractions were back-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacllo to give 10.5 g ~90%) of an oil, which had satisfactory purity by ~H NMR (CDC13). Mass spectrum (PB-NH3/CI):
m/e= 166(M+H).

WO 97/21"35 PCT/IJS96/20004 ~tep B 3-chloropropyl 3.5-dimethylphenvl ketone A solution of 10.2 mL ~13.9 g; 72 mmol) S-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at -78 ~C as 35.8 mL (84 mmol) of 2.5 M n-butyllithium in tetrahydrofuran was added dropwise. After lS minutes at -78 ~C, a solution of 10.0 g ~60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide (from Step A) in 30 ml of anhydrous tetrahydrofuran was added dropwise over 25-30 minlltes. The resulting solution was maintained at -78 ~C for 45 minutes and then warmed briefly to room temperature. The reaction was quenched by addition of 40 ml of 2 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue afforded 8.91 g (70%) of an oil, which had satisfactory purity by 1H NMR
(CDC13).
Step AA 4-(4-nitrophenyl)butyric acid. N-methoxy-N-methylamide A stirred solution of 6.29 g (30 mmol) of 4-(4-nitrophenyl)butyrIc acid in 90 mL of dry methylene chloride ( m~int~med under nitrogen and cooled in a water bath) was treated with 4.17 rnL (3.03 g; 30 mmol) of triethylamine, followed by 13.26 g (30 mmol) of BOP reagent. After a few minutes, 3.22 g (33 mmol) of N,O-dime~ylhydroxylamine hydrocholoride was added, followed by an additional 4.59 mL (3.33 g, 33 mmol) of triethylamine. After 2.25 hours, the solution was diluted with 200 rnL of diethyl ether and washed successively with 3 x 100 mL of 2 N hydrochloric acid, 1 x 100 mL
and 2 x 50 mL of saturated aqueous sodium bicarbonate solution, and 1 x 50 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vac~;o. Flash chromatography of the residue on silica gel (elution with 2:1 and then 3:2 hexane-EtOAc) afforded 6.27 g (~3%) of crystals, mp CA 0224011~ 1998-06-09 39.5-41.5 ~C; homogeneous by TLC in 1:1 hexane-EtOAc. 500 MHz lH
NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/C~): m/e = 253 (M + H).

Step BB 4-(4-aminophenyl)butyric acid. N-methoxy-N-methylamide A mixture of 6.05 g (24 mmol) of 4-(4-nitrophenyl)butyric acid, N-methoxy-N-methylamide, 50 mg of 10% palladium on carbon, and 200 mL of ethanol was shaken with hydrogen (initial hydrogen pressure 53 psig) for 1.5 hours, by which time hydrogen uptake had ceased and TLC indicated complete reaction. The mixture was filtered through Celite under nitrogen, and the filtrate was concentrated in vacuo to yield 5.29 g of an oil; homogeneous by TLC in 95:5 CH2C12-MeOH. 400 MHz 1 H NMR (CDC13) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e = 223 (M + H).

Step CC 4-r4-(methanesulfonamido)phenyllbutyric acid. N-methoxy-N-methylamide A solution of 5.33 g (24 mmol) of 4-(4-aminophenyl)butyric acid, N-methoxy-N-methylamide in 48 mL of dry pyridine was stirred under nitrogen with cooling in an ice bath as 1.86 mL (2.75 g; 24 mmol) of methanesulfonyl chloride was added dropwise over about 15 minutes. After completion of the addition, the solution was allowed to warm to room temperature. After 1.5 hours, the solution was concentrated in vacuo at room temperature. The residue was diluted with 10 mL of methylene chloride and partitioned between a mixture of 100 mL of ethyl acetate + 100 mL of tetrahydrofuran and 100 mL of 2 N hydrochloric acid. The organic layer was washed with an additional 4 x 100 mL of 2 N hydrochloric acid, then with 50 mL of saturated aqueous sodium bicarbonate solution, and finally with 20 mL
of saturated aqueous sodium chloride solution. The organic phase was diluted with some tetrahydrofuran, dried over magnesium sulfate, and ~ treated with charcoal. The mixture was filtered through Celite, and the filter cake was washed with additional tetrahydrofuran. C oncentration of the filtrate in vacuo gave 4.39 g (61%) of crystals, mp 115-117 ~(~;

homogeneous by TLC in 95:5 CH2C12-MeOH. 400 MHz ~H NM~
(DMSO-d6) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e = 301 (M + H).

Step DD 4-r4-(methanesulfonamido)phenyllbutyraldehyde A mixture of 4.20 g (14 mmol) of 4-[4-(methane-sulfonamido)phenyl~butyric acid, N-methoxy-N-methylamide and 100 mL of anhydrous tetrahydrofuran was stirred under nitogen with cooling in an ice bath as 17.5 mL (17.5 mmol) of 1 M lithium aluminum hydride in tetrahydrofuran was added gradually by syringe. After 0.75 hours, 70 mL of 5% potassium hydrogen sulfate solution (aqueous) was added cautiously by syringe. The mixture was then removed from the ice bath, diluted with 150 mL of water, and shaken with 150 mL of ethyl acetate. The milky aqueous phase was extracted with aIl additional 50 mL of ethyl acetate. The combined organic fractions were washed successive~y with 2 x 100 mL of 1 N hydrochloric acid, then 50 mL of saturated aqueous sodium bicarbonate solution, and finally 50 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography of the residue on silica gel (elution with 3:2 hexane-EtOAc) yielded 2.47 g (73%) of an oil; homogeneous by TLC in 1:1 hexane-EtOAc). Upon storage in the freezer, solidification occurred (mp 41-44 ~C). 400 MHz lH NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/C~): m/e = 259 (M + NH4).
Step AAA Ethyl 2-(4-hydrazinophenyl)acetate hydrochloride and 2-(4-hydrazinophenyl)acetic acid hydrochloride This compound (a mixture of the ethyl ester and the carboxylic acid) was prepared from 13.4 g (75 mmol) of ethyl 2-(4-aminophenyl)acetate, by diazotization and stannous chloride reduction of the diazonium salt, according to the method of L. J. ~treet, et al., J.
Med. Chem.. 36, 1529 (1993). The material was obtained in two crops.
The first crop consisted of 6.40 g of powder, mp >200 ~C. By 400 MHz CA 0224011~ 1998-06-09 lH NMR (DMSO-d6), this material consisted of a mixture of carboxylic acid and ethyl ester in approximately a 4:3 molar ratio. Mass spectrum (PB-NH3/CI): 19~ (arylhydrazonium cation for the ethyl ester). The second crop consisted of 4.60 g of powder, mp >lP~0 ~C. By 400 MHz 1H NMR (DMSO-d6), this material consisted of a mixture of carboxylic acid and ethyl ester in approximately a 7:1 molar ratio. After adiustment for the mixture composition of the two crops, the estimated total yield was 69%. Because esterification of any carboxylic acid occurs in the next step, both the ester and the acid react to give the same product.

Step AAAA Ethyl (+1-)-2-(4-nitrophenyl)propionate To a solution of 9.76 g (50 mmol) of (+/-)-2-(4-nitrophenyl)propionic acid in lS0 mL of absolute ethanol was added 3.0 mL, of concentrated sulfuric acid. The resulting solution was stirred at reflux under nitrogen. After 6 hours, the solution was cooled and stirred vigorously as 250 mL of saturated aqueous sodium bicarbonate solution was added gradually (Caution: foaming). The mixture was then partitioned between 750 mL of ethyl acetate and S00 mL of water.
The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate solution and then with 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 10.86 g (97%) of an oil;
homogeneous by TLC in 9: l hexane-ethyl acetate. 400 MHz 1 H NMR
(CDCl3) was consistent with the assigned structure.

Step BBBB Ethyl 2-methyl-2-(4-nitrophenyl)propionate A suspension of 924 (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry N,N-dimethylformamide was stirred under nitrogen in an ice bath as a solution of 4.6~ g (21 mmol) of ethyl (+/-)-2-(4-nitrophenyl)propionate in 20.5 mL of dry N,N-dimethylformamide was added gradually over about lO minutes. An intense violet color developed during the addition. The mixture was then allowed to warm to room temperature. After about 1 hour, the mixture was again cooled in an ice bath as a solution of 1.44 mL ~3.28 g; 23 mmol) of methyl iodide in 5 mL of dry N,N-dimethylformamide was added dropwise by syringe over about 10 minutes, while m~in~ining the internal temperature at 10-15 ~C. The mi~ture was allowed to warm to room temperature, and the color changed to brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of iodomethane was added. By the next day, the mixture consisted of a suspension of some grayish solid in a golden liquid. It was stirred vigorously and quenched by gradual addition of 10 mL of 5% aqueous potassium bisulfate solution. The mixture was partitioned between 400 mL of diethyl ether and 400 mL
of water. The organic layer was washed with an additonal 3 x 400 mL
of water and then with 50 mL of saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 19:1 hexane-ethyl acetete) yielded 4.31 g (87%) of an oil; homogeneous by TL(: in 9:1 hexane-ethyl acetete. 400 MHz 1 H NMR (CDC13) was consistent with the assigned structure.

Step CCCC Ethyl 2-(4-aminophenyl)-2-methylpropionate A mixture of 4.27 g (18 mmol) of ethyl 2-methyl-2-(4-nitrophenyl)propionate, 200 mg of 10% palladium on carbon, and 120 mL of absolute ethanol was shaken with hydrogen (initial hydrogen pressure 47 psig) in a pressure vessel for 2 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 at up to 50 ~C gave 3.74 g (100%) of an oil; homogeneous by TLC in 4:1 hexane-EtOAc. 400 MHz lH NMR (CDC13) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 208 (M + H).

Step DDDD Ethyl 2-(4-hydrazinophenyl)-2-methylpropionate A solution of 3.725 g (18 mmol) of ethyl 2-(4-aminophenyl)-2-methylpropionate in 18 mL of concentrated hydrochloric acid was stirred at -10 to -5 ~C in an ice-acetone bath as a . =

CA 0224011~ 1998-06-09 solution of 1.29 g (18.7 mmol) of sodium nitrite in 7.5 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. Next, a small amount of 7 insoluble solid was removed by filtration into a cold receiving flask.
The filtrate was then added dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of stannous chloride dihydrate in 14.5 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about -5 ~C. A gummy material separated during the addition. After completion of the addition, stirring was continued at -10 to -5 ~C for 1 hour. The aqueous phase was decanted, and the residual gum was dissolved in 250 mL of ethyl acetate. The ethyl acetate solution was treated cautiously with 250 mL of saturated aqueous sodium bicarbonate solution and shaken in a separatory funnel.
The ethyl acetate layer was washed with 50 mL of saturated aqueous sodium chloride solution. The entire mixture was filtered before separation of the phases. The ethyl acetate phase was dried over magnesium sulfate, filtered, and concentrated i7~ vacuo at room temperature to yield 2.59 g (65%) of an oil. 500 MHz ~H NMR
(CDCl3) was consistent with the assigned structure and indicated that only minor impurities were present.

Following a procedure similar to that described in EXAMPLES 13.1 and 13.2, the following compounds were prepared:

'N' Me Me Exam,~le X-R7R8 rn/e 13A CH2COOEt 576 (M + H) 13B CH2CON(Me)2 575 (M + H) 13C C~(Me)COOEt 59() (M + H) 13D C(Me)2COOEt 604 (M t H) 13E CH(Me)CON(~t)2 617 (M + ~) 13F C(Me)2CON(Me)2 603 (M ~ H) 13G C(Me)2CON(Pr)2 659 (M + H) FXAMPLE 14. 1 Me~N~N ~
MeJ ~J--N~ ~Me ~ ,S~M

Me 2-(3 ,5-dimethylphenyl)-3- f 2-1 4-(4-methanesulfonylaminophenyl)-butylaminolethyl~-lH-indole-S-carboxylic acid diethylamide Step 14.1 A 3-(2-aminoethyl)-2-(3 .5-dimethylphenyl)- 1 H-indole-5-carboxylic acid ethyl ester A mixture of 7.60 g (50 mmol) of 4-hydrazinobenzoic acid, 10.55 g (S0 mrnol) of 3-chloropropyl 3,5-dimethylphenyl ketone, and 200 mL of absolute ethanol was stirred under nitrogen and heated to reflux. After 12 hours, the mixture was cooled and filtered. The solid on the filter was washed with additional small volumes of ethanol. The filtrate was treated with 4 mL of concentrated sulfuric acid and stirred CA 0224011~ 1998-06-09 at reflux under nitrogen ~or 4 days. The cooled mixture was stirred in an ice bath as a solution of sodium ethoxide (21 % w/w in ethanol) was added dropwise under nitrogen until the mixture was basic by pH paper.
The mixture was filtered and concentrated in vacuo at 30 ~C. The residue was partitioned between diethyl ether and water, with some saturated aqueous sodium chloride solution added to assist in 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 residual gum was flash chromatographed on silica gel (elution with 97:3:0.3 and then 95:5:0.5 CH2C12-~eOH-concentrated NH40H). Concentration of the product fractions yielded 4.03 g of pure product as a stiff foam (virtually homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-concentrated NH40H). Concentration of mixed fractions yielded an additional 0.93 g, which was rechromatographed to provide an additional 0.77 g of pure material, for a total yield of 4.80 g (29%). 400 MHz 1 H NMR
(CDCl3) was consistent with the assigned structure. ~ass spectrum (PB-N~3/CI): m/e = 337 (M + H).
~tep 14.1 B ~-~3.5-dimethylphenyl)-3- ~ 2-r4-(4-methanesulfonylamino-phenyl)butylaminolethyl~-lH-indole-5-carboxy}ic acid ethyl ester To a dry flask were added 672 mg (2.0 mmol) of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-lH-indole-5-carboxylic acid ethyl ester, 530 mg (2.2 mmol) of 4-[4-(methanesulfonamido)phenyl]-butyraldehyde, 1.20 g (10 mmol) of magnesium sulfate, and a magnetic stirring bar. The flask wa,s purged with nitrogen, cooled to -10 to -5 ~C
in an ice-methanol bath, and stirred as 4 mL of dry CDC13 was introduced gradually by syringe. The mixture was stirred under nitrogen for 15 mimltes. Next, the septum was removed, and 100 mg (2.6 mmol) of sodium borohydride was added rapidly. The septum was immediately replaced, and the system was again purged with nitrogen.
The mixture was stirred under nitrogen at about -5 ~C as 4 mL of dry methanol was added gradually by syringe. After 20 minutes at this temperature, the reaction was quenched by gradual syringe addition of 1 mL of acetone to destroy excess sodium borohydride. After a few more minutes, the mixture was removed from the cooling bath and partitioned between 25 mL of ethyl acetate and 25 mL of water. The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, ~en dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was flash chromatographed on silica gel (elution with 97:3 and ~hen 95:5 CH2C12-MeOH). Concentration of the pooled product fractions in vacuo yielded 663 mg (59%) of a foam; virtually homogeneous by TLC (92.5:7.5 CH2C12-MeOH). 400 MHz lH NMR
(CDC13 + small arnount of DMSO-d6) was consistent with the assigned structure. Mass spectrum (E~SI): m/e = 562 (M + H).
~tep 14.1C 3-(2-~benzyloxycarbonyl-r4-(4-methanesulfonvlamino-phenyl)butyllamino ~ethyl)-2-(3.5-dimethylphenyl)- lH-indole-5-carboxylic acid ethyl ester A solution of 646 mg (1.15 mmol) of 2-(3,5-dimethylphenyl)-3- { 2-[4-(4-methanesulfonylamino-phenyl)butylamino]ethyl }-1 H-indole-5-carboxylic acid ethyl ester in 5 mL of dry methylene chloride and 5 mL of anhydrous tetrahydrofuran was stirred under nitrogen and coolecl to -78 ~C in a dry ice-acetone bath as 200 mL of N,N-diisopropylethylamine was added, followed by gradual addition of 173 rnL (207 mg; 1.15 mmol, based on 95% purity) of benzyl chloroformate was added gradually by syringe. After 30 minutes, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned be~ween 25 mL of ethyl acetate and 25 mL of 5% potassium bisulfate aqueous solution.
The organic layer was washed with an additional 25 mL of 5%
potassium bisulfate and then with lO mL of saturated aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate).
filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 9~:2 CH2cl2-MeoH) afforded 611 mg (76%) of a foam; homogeneous by TLC in 95:5 CH2cl2-MeoH. 500 MHz lH NMR was complex, owing to the existence of rotamers, but was CA 0224011~ 1998-06-09 _ 95 _ consistent with the assigned structure. Mass spectrum (ESI): m/e = 696 ~ (M~H).

Step 14.1 D 3-(2- ~ benzyloxycarbonyl-r4-(4-methanesulfonylamino-phenyl)butyll amino ~ ethyl)-2-(3 ~5 -dimethylphenyl)- 1 H-indole-5-carboxylic acid A solution of 600 mg (0.862 mmol) of 3-(2-~ benzyloxycarbonyl- [4-(4-methanesulfonylamino-phenyl)butyl]amino }ethyl)-2-(3,5-dimethylphenyl)-lH-indole-5-carboxylic acid ethyl ester in 18 mL (9 mmol) of 0.50 N potassium hydroxide in methanol was stirred at about 60 ~C as 2.0 mL of water was added gradually. Stirring was continued at 60-65 ~C under nitrogen for 10 hours. The cooled mixture, which contained a white precipitate, was concentrated to small volume in vacuo. The residual suspension was partitioned between 25 mL of ethyl acetate and 25 mL of 0.5 N
hydrochloric acid. After the aqueous layer was separated, precipitation began in the ethyl acetate phase. ~ilution with 25 mL of tetrahydrofuran redissolved the precipitate. The aqueous phase was back-extracted with 10 mL of ethyl acetate + 10 mL of tetrahydrofuran.
The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residual solid was triturated with diethyl ether, collected on a filter, and washed with some additional ether to give (after drying) 573 mg (100%) of a powder, mp 211.5-213 ~C; virtually homogeneous by TLC(92.5:7.5 CH2C12-MeOH). 500 MHz lH NMR (DMSO-d6) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 668 (M + H).

Step 14.1E f2-rS-diethylcarbamoyl-2-(3~5-dimethylphenyl)-lH-indol-3-yllethyl ~ -r4-(4-methanesulfonylaminophenyl)-butyllcarbamic acid benzyl ester To a suspension of 668 mg (0.703 mmol) of 3-(2-{ benzyloxycarbonyl-~4-(4-methanesulfonylamino-phenyl)butyl]amino } ethyl)-2-(3,5-dimethylphenyl)- 1 h-indole-5-carboxylic acid in 2.7 mL of dry methylene chloride and 2.7 mL of anhydrous tetrahydrofuran were added 366 mg (0.703 mmol) of PyBOP
reagent and 98 mL (71.0 mg; 0.703 mmol) of triethylamine. The resulting solution was stirred under nitrogen at room temperature for 20 minutes. Next, 109 mL (77.1 mg; 1.05 mmol) of diethylamine was added, and stirring was continued for 4 hours. The solution was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (gradient elution with 1-4% MeOH in CH2C12) afforded 440 mg (87%) of a stiff foam; homogeneous by TLC in 95:5 CH2C12-MeOH. 500 MHz I H NMR (CDC13) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e = 723 (M + H).
~tep 14.1F 2-(3~5-dimethylphenyl)-3-~2-r4-(4-methanesulfonyl-aminophenyl)butylaminolethyl ~ -1 H-indole-5 -carboxylic acid diethylamide A mixture of 435 mg (0.602 mmol) of {2-[5-diethylcarbamoyl-2-(3,5-dimethylphenyl)- lH-indol-3-yl]ethyl } -[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid benzyl ester, 100 mg of 20% palladium hydroxide on carbon, and 50 mL of 2-methoxyethanol was shaken with hydrogen (42 psig) in a pressure vessel for 2.25 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution with 5-10%
MeOH in CH2Cl2) yielded 353 mg (100%) of a stiff foam;
homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-concentrated NH40H.
500 MHz lH NMR (CDCl3) was consistent with the assigned structure.
Mass spectrum (ESI): m/e = 589 (M + H).

CA 0224011~ 1998-06-09 EXAMPLE~ 14.2 Me O H
Me N~N ~
MelMe ~N ~Me ~ 'S'M

Me 2-(3 .5-dimethylphenyl)-3-r2-~4-14-(methanesulfonylamino)phenyll-butylaminolethyll-~H-indole-5-carboxylic acid diisopropylamide Step 14.2A N~N-diisopropyl-4-nitrobenzamide A solution of 3.51 mL (2.53 g, 25 mmol) of diisopropyl~mine and 3.62 mL (2.63 g, 26 mmol) of triethylamine in 50 mL of anhydrous tetrahydrofuran was stirred under nitrogen and maintained at -5 ~C as a solution of 4.1 l g (22.1 mmol) in 10 mL of anhydrous tetrahydrofuran was added dropwise over 15 minutes. The mixture was allowed to warm gradually to room temperature. After 2 hours, the mixture was filtered, and the filtrate was partitioned between diethyl ether and 1 N hydrochloric acid. The organic phase was then washed with saturated sodium carbonate3 solution, then dried over sodium sulfate and ~lltered. The filtrate was concentrated in vacuo, and the res;due was flash-chromatographed on silica gel (gradient elution with 2-5% MeOH in CH2Cl2) to yield 4.77 g (86%) of yellowish crystals, mp 141.5-142 ~C; homogeneous by TLC 2:1 hexane-EtOAc.
500 MHz lH NMR (CDCl3) was consistent with the assigned structure.

.c Step 14.2B 4-amino-N.N-diisopropylbenzamide A mixture of 4.70 g (18.8 mmol) of N,N-diisopropyl-4-nitrobenzamide, 200 mg of 10% palladium on carbon, and 200 mL of 2-methoxyethanol was shaken with hydrogen at approx. 50 psig for 6.5 hours. The catalyst was removed by filtration through diatomaceous earth under nitrogen. Concentration of the filtrate in vacuo afforded a quantitative yield of a yellow solid, mp 169.5-170 ~C; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz IH NMR (CDC13) was consistent with the assigned structure. Mass spectrum (PB-NH3/~ m/e = 221 (M + H).
Step 14.2C 4-hydrazino-N.N-diisopropylbenzamide Treatment of 4.2 g (19 mmol) of 4-amino-N,N-diisopropylbenzamide with 15 mL of concentrated hydrochloric acid and 10 mL of water was followed by agitation. The resulting solution was m~int~ined at approx. -3 ~C as a solution of 1.32 g (19.1 mmol) of sodium nitrite in 9 mL of water was added dropwise. After being stirred for an additional 30 minutes at this temperature, this solution was added portionwise to a vigorously stirred solution of 15.1 g (66.7 mmol) of stannous chloride dihydrate in 15 mL of concentrated hydrochloric acid, which was m~int~ined at about -10 ~C. After completion of the addition, the mixture was stirred at this temperature for 5 minutes and then allowed to warm to room temperature. At thi.s point, it was again cooled and basified by gradual addition of 25 mL of 50% sodium hydroxide. The resulting precipitate was collected on a filter and partitioned between tetrahydrofuran and S N sodium hydroxide in a 2:1 ratio. The aqueous layer was extracted 3 times with tetrahydrofuran. The combined organic fractions were concentrated in vacuo. The residue was taken up in CH2CI2-EtOAc, dried over sodium sulfate, filtered, and reconcentrated to give 3.55 g (~0%) of semisolid;
homogeneous by TLC in 95:5 CH2C12-MeOH. 500 MHz lH NMR
(CDC13) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e = 236 (M ~ H).

Step 1 4.2D 3-(2-aminoethyl)-2-(3.5-dimethylphenyl)- 1 H-indole-5- h carboxylic acid diisopropylamide A solution of 3.51 g (14.9 mmol) 4-hydrazino-N,N-diisopropylbenzamide (from Step 3) in 18 mL of 2-methoxyethanol was stirred at 100 ~C under nitrogen as 3.77 g (17.P~ mrnol) of 3-CA 0224011~ 1998-06-09 _ 99 _ chloropropyl 3,5-dimethylphenyl ketone in 7 mL of 2-methoxyethanol was added dropwise over 20 minlltes. The solution was stirred at this temperature for 5 hours, then cooled and filtered to remove a solid (a tetrahydropyridazine by-product). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel ~elution with 95:5 CH2C12-MeOH followed by a gradient of 98:2:0.2 to 92:8:0.8 CH2Cl2-MeOH-concd. NH40H) gave 1.78 g (31%) of a brownish, stiff foam, satisfactory purity by TLC in 95:5:0.5 CH2Cl2-MeOH-concd. NH40H. 500 MHz IH NMR (CDC13) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e = 392.2 (M +
H).

Step 14.2E 2-(3~5-dimethylphenyl)-3-r2-14-r~-(methanesulfonylamino)-phenyllbutylaminolethyll-lH-indole-5-carboxylic acid diisopropylamide A mixture of 100 mg (0.25~ mmol) 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-lH-indole-5-carboxylic acid diisopropylamide, 67.7 mg (0.281 mmol) of 4-[4-(methanesulfonamido)phenyl]butyraldehyde, and 153 mg (1.28 mmol) of anhydrous magnesium sulfate was purged with nitrogen and cooled in an ice-methanol bath at about -10 to -5 ~C as 0.60 mL of dry CDCl3 was added gradually by syringe. The mixture was stirred under nitrogen at this temperature for 35 minlltes. The septum was removed just long enough to add 12.5 mg (0.332 mmol) of sodium borohydride, and the solution was repurged with nitrogen. The mixture was stirred at -10 to -5 ~C as 0.40 mL of dry methanol was added gradually, and stirring was continued at this temperature for several minutes. The mixture wa.s partitioned between ethyl acetate and dilute sodium hydroxide (pH 10).
The ethyl acetate phase was dried over sodium sulfate, filtered, and t concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution with 99:1:0.1 to 90:10:1 CH2Cl2-MeOH-concd. NH40H) to give 16.0 mg of a yellow, stiff foam, and an additional 13.8 mg was obtained by preparative TLC of mixed fractions (developed in 95:5:0.5 CH2Cl2-MeOH-concd. NH40H), affording a total of 29.8 mg (19%) of the title compound, homogeneous by TLC in 90:10:1 CH2Cl2-MeOH-concd. NH40H. 500 MHz lH NMR
(CDC13) was consistent with ~he assigned structure. Mass spectrum (ESI): m/e = 617.5 (M + H).

Following a procedure similar to that described above, the following compounds were prepared:

R7'~/ ,N~
H ~Me ~ N' Me Me Example X-R7R8 rn/e 14A COOEt 562 (M + H) 14B CO-N(CH2CH20H) 621 (M + H) 14C CO-NHEt 562 ~M + H) 14D CO-NH-cyclopropyl 573 (M + H) 14E Me'~~ ~~~ 617 (M + H) Me 14F Me o 603 (M + H) Me'~ N
Me 14G [~ ~ 643 (M + H~
N
Me 14H ~ 591(M+H) HO~ IN~
Me 14I M Me ~ ~ 603 (M + H) Me 14J O 617(M+~) Me ~ NJ~
Me ~
14K O 605(M+H) HO ~' N~

Me 14L ~ o 623(M +H) Me 14M ~ 561 (M+ H) Me~N
Me 14N ~ 605 (M + H) MeO~
Me 140 ~ 633 (M + H) Me~~

Me 1 Me 14P 11 ~~
MeO~

Me ~ Me 14Q O 617(M+H) Me~N~
Me~ Me Me 14R Me~MeO 645 (M + H) N J~\
Me~J
Me 14S 11 697 (M + H) F C~N~

Following a procedure similar to that described in EXAMPLES 8 and 11, the following compounds were prepared:

R7~ ~ ~; Me N--Me Bxample X-R7R8 Rg, Rga:Rlo, Rloa (CH2)n t = A

15A NH-coN(Et)2 Me, H:H, H 4 15B NH-CO-Ph Me, H:H, H 4 CA 02240ll5 l998-06-09 lSC NH-CO-N(Me)2 Me, H:H, H 2 lSD NH-CO-N(Me)2 Me, H:H, H 4 15E N(CH2Ph)2 Me, H:Me, H 4 lSF NHC(O)Ph CH2CH20H, H:H, H 4 lSG SO2Me Me, H:H, H 4 lSH NHC(O)Ph CH2CH20Me, H:H, H 4 lSI O-cH2ph H, H:Me, Me 4 Following a procedure similar to that described in EXAMPLE 14.1, the following compounds were prepared:

R ,X,~ N ~
~Me ~OH

Me Example X-R7R8 m/e 16A COO-CH2CH3 485 (M + H) 16B COOH 457 (M + H) 16C CO-N(CH2CH3)2 512 (M + H) 16D CO-NH-CH2Ph 546 (M + H) 16E CO-N(CH3)2 484 (M + H) 16F CO-N(iBu)2 568 (M + H) EXAMPLl~ 17 Following a procedure similar to that described in EXAMPLES 9 and 14.1, the ~ollowing compounds were prepared:

R ~ N~
~N~CH3 t, ,~

Exarnple Rl X-R7R8 R2 m/e 17A Ph-4- NHCOEt 617 (M + H) NH(S02Me)-COEt 17B Ph-4-S02CH2C(O)Me 652 (M + H) C(O)Me 1 7C Ph-4- S02Me NHS02CH2- 610 (M + H) C(O)Me 17D Ph-4- COOEt 562 (M + H) S02NE~e 17E Ph-4-N02 COOEt 514 (M + H) 17F Ph-4- CON(Et)2 Et617 (M + H) NHS02Me 17G Ph-4- CON(Et)2 589 (M + H) S02NHMe "
17H Ph-4- CON(iBU)2 645 (M + H) S02NHMe CA 0224011~ 1998-06-09 17I Ph-4- CON(cyclohexyl)Et 643 (M + H) S02NHMe 17J Ph-4-NO2 CON(iBu)2 597 (M + H) 17K Ph-4-NH2 CON(iBu)2 567 (M + H) 17L Ph-4-SMe COOEt 515 (M + H) 17M Ph-4-SMe CON(Et)2 542 (M + H) 17N Ph-4-S(O)Me CON(:~t)2 558 (M + H) 170 Ph-4- CON(Et)2 574 (M + H) S(~)2Me 17P Ph-4-SMe CON(iBu)2 598 (M + H) 17Q Ph-4-S(O)Me CON(iBu)2 614 (M + H) 171~ Ph-4- CON(iBU)2 630 (M + H) S(0)2Me 17S Ph-4- CON(iBu)2 666 (M + H) NH[C=N(CO
NH2)]NHMe 17T Ph-4- CON(iBu)2 648 (M + H) NH[C=N(CN) ]NHMe 17U Ph-4-F CON(iBu)2 17V Ph-4- COOEt 576 (M + H) SO2N(Me)2 17W Ph-4- CON(iBU)2 659 (M + H) SO2N(Me)2 17X Ph-4- CON(Et)2 603 (M + H) SO2N(Me)2 17Y Ph-4- CON(Et)cyclohexyl 657 (M + H) SO2N(Me)2 Following a procedure similar to that described EXAMPLES 4.1 and 5.1, the following compounds were prepared:

R ,X~ N (A)--R
N ~¢~ Me Me Example R7-X-R8 -(A)-R 1 M/E

,~

~OH
18D NHCO- ~OH
N(Et)2 18E SO2Me OH 569 (M + H) ~, ,Me o 'o CA 02240ll5 l998-06-09 EXAMPLl~ 19 M~

Me 4-(4- ~ 12-(3 .5 -dimethylphenyl)- I H-indol-3-ylmethyllamino ~butyl)phenol Step l9A r2-(3.5-dimethylphenyl)-lH-indol-3-ylmethylldimethylamine To 2.53 g glacial acetic acid was added 2.0 g dimethyl amine (40% aqueous solution) followed by 1.37 g fomalin (37%
solution) then 4.0 g 2-(3,5-dimethylphenyl)-lH-indole and the mixture atirred at 0 ~C. After 15 minutes, 40 mL ethanol was added and the mixture allowed to warm to room temperature. After 1 hour at room temperature, the reaction was quenched by pouring into 50 mL of lN
sodium hydroxide. The resulting mixture was extracted with methylene chloride (4 x 10 mL) and the combined organics dried over potassium carbonate. Concentration in vacuo gave the crude title compound (4.15 g)-Step 19B 12-(3.5-dimethylphenyll-lH-indol-3-ylmethylltrimethylammonium iodide To a solution of [2-(3,5-dimethylphenyl)-lH-indol-3-ylmethyl~dimethylamine (350 mg in 4 mL diethyl ether) was added O.S
mL iodomethane and the mixture stirred at room temperature. After 3 hours, the mixture was filtered and the solids dried in vacuo to provide the crude title compound. (414 mg).

Step 19C 4-(4-~r2-(3~5-dimethylphenyl)-lH-indol-3-ylmethyllamino ~butyl)phenol To a solution of 4-(4-{r2-(3,5-dimethylphenyl)-lH-indol-3-ylmethyl]amino}butyl)phenol (20 mg in l.S mL dry methanol) was added 47 mg 4-(4-aminobutyl)phenol and the mixture stirred at room temperature. After 32 hours, the mixture was concentrated in vacuo and the residue purified by preaparative TLC on silica gel (methylene chloride:methanol, 96:4) to give the title compound (12.3 mg). m/e =
234 (base) Followirlg a procedure similar to that described above, the ~ollowing compounds were prepared:

N J~ S Me Me Example R1 (CH2)n = A m/e l9A Ph-4-OMe 4 234 (base) 1913 Ph-4-OH 3 234 (base) l9C Ph-4-OH 2 234 (base) . .

WO 97/21435 rCT/US96/:;!0004 ~XAMPLE~ 20 ~ '--N~
N~,J
~J!~N~Me H
Me 2-(3 .5-dimethylphenyl)-3-1 2-(4-phenylpiperazin- 1 -yl)ethyll - I H-indole Step 20A 1 -r2-(3.5-dimethylphenyl)- 1 H-indol-3-yll -2-(4-phenylpiperazin- l -yl)ethane- 1 .2-dione To a solution of 2-(3,5-dimethylphenyl)-lH-indole (75 mg in 4 mL dry diethyl ether) was added dropwise 0.032 mL oxalyl chloride and the mi~ture stirred at room temperature. After 45 minute~, the mixture was concentrated in ~acuo and re-solvated in 3 mL
dry tetrahydrofuran then 0.104 mL of l-phenylpiperazine was added dropwise. After 20 minutes, the reaction was quenched by the addition of water and the resulting mixture extracted with ethyl acetate. The organic portion was washed with brine, dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:1 + 1% methanol) to give the title compound ~143 mg).

Step 20B 2-(3.5-dimethylphenyl)-3-r2-(4-phenylpiperazin-l-yl)ethyll - l H-indole To a solution of 1-[2-(3,5-dimethylphenyl)-lH-indol-3-yl]-2-(4-phenylpiperazin-1-yl)ethane-1,2-dione ~57 mg in 2 mL dry tetrahydrofuran) was added 30 mg of lithium aluminum hydrideand the mixture heated to reflux on an oil bath. After 1 hour the mixture was cooled and quenched by the sequential addition of 1 mL water and 4 mL
ammonium hydroxide and 5 mL ethyl acetate. ~e mixture was filtered to remove the solids. The organic portion was washed with brine, dried over magnesium ,sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:5) to give the title compound (38 mg).
m/e = 410 (M+1) Following a procedure similar to that described above, the following compounds were prepared:

R,8 R2 R ~X~ N (A) R1 N J\ ,~ Me Me Example F~2 m/e R7-X-R8 N (A)- R1 20A H / \ /=\ 440 (M + H) --N~N~OMe 2013 H --N~ N H --,~, 20C H ~~S"0 514 (M + H) \ /--N' Me --N~
~ Y

20D H ~ 465 (M + H) --N/~N NH
\ \

20E H / \ H 439 (M + H) --N~ N N H2 20F NHC(O)- / \ /=\
N(Et)2 --N~
COOEt 20G NHC(O)- / \ /=\
N(Et)2 --N~
COOH
20H H--N~ N--CH2~ 635 (M + H~
kl-s=o tBu o

Claims (56)

WHAT IS CLAIMED IS:

1. A compound of the formula wherein A is C1-C6 alkyl, substituted C1-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, C1-C6 alkoxy, or C0-C5 alkyl-S(O)n-C0-C5 alkyl, C0-C5 alkyl-O-C0-C5 alkyl, C0-C5 alkyl-NR18-C0-C5 alkyl where R18 and the C0-C5 alkyl can be joined to form a ring, , or a single bond;
R0 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and R5;
R1 is wherein:
Y is B, C or a bond;
B is O,S(O)n, C(O),NR18 or C(R11R12)p C is B(CH2)p-;
R2 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl -OR11, C1-C6(NR11R12), C1-C6(CONR11R12) or C(NR11R12)NH;
R2 and A taken together form a ring of 5-7 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, R11O(CH2)p-, R11C(O)O(CH2)p-, R11OC(O)(CH2)p-, -(CH2)pS(O)nR17, -(CH2)pC(O)NR11R12 or halogen; wherein R17 is hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl;
R3 and R4 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
R6 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, C1-C3 perfluoroalkyl, CN, NO2, halogen, R11O(CH2)p-,NR 12C(O)R11,NR12C(O)NR11R12 or SOnR11;
R7 is hydrogen, C1-C6 alkyl, or substituted C1-C6 alkyl, unless X
is hydrogen or halogen, then R7 is absent;
R8 is hydrogen, C(O)OR9, C(O)NR11R12, NR11R12,C(O)R11, NR12C(O)R11,NR12C(O)NR11R12, NR12S(O)2R11, NR12S(O)2NR11R12,OC(O)R11, OC(O)NR11R12, OR11, SOnR11, S(O)nNR11R12, C1-C6 alkyl or substituted C1-C6 alkyl, unless X is hydrogen or halogen, then R8 is absent; or R7 and R8 taken together form a carbocyclic ring of 3-7 atoms;
R9 and R9a are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m~0; or R9 and R9a taken together form a carbocyclic ring of 3-7 atoms or when m~0;
R9 and A taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m~0; or R10 and R10a are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R10 and R10a taken together form a carbocyclic ring of 3-7 atoms or ;
R9 and R10 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m~0; or R9 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m~0; or R10 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
R10 and A taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or R11 and R12 are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms;
R11 and R12 taken together can form an optionally substituted ring of 3- 7 atoms;
R13 is hydrogen, OH, NR7R8, NR11SO2(C1-C6 alkyl), NR11SO2(substituted C1-C6 alkyl), NR11SO2(aryl), NR11SO2(substituted aryl), NR11SO2(C1-C3 perfluoroalkyl); SO2NR11(C1-C6 alkyl), SO2NR11(substituted C1-C6 alkyl), SO2NR11(aryl), SO2NR11(,substituted aryl), SO2NR11(C1-C3 perfluoroalkyl); SO2NR11(C(O)C1-C6 alkyl);
SO2NR11(C(O)-substituted C1-C6 alkyl); SO2NR11(C(O)-aryl); SO2NR11(C(O)-substituted aryl); S(O)n(C1-C6 alkyl);
S(O)n (substituted C1-C6 alkyl), S(O)n(aryl), S(O)n(substituted aryl), C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, C1-C6 alkoxy, substituted C1-C6 alkoxy, COOH, halogen, NO2 or CN;
R14 and R15 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, R11O(CH2)p-, R11C(O)O(CH2)p-, R11OC(O)(CH2)p-, -(CH2)pS(O)nR17, -(CH2)pC(O)NR11R12 or halogen; wherein R17 is hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl;
R16 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, or N(R11R12);
R18 is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C(O)OR9, C(O)NR11R12, C(O)R11, S(O)nR11;
X is hydrogen, halogen, N, O, S(O)n, C(O), (CR11R12)p; C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl; when X is hydrogen or halogen, R7 and R8 are absent; when X is O, S(O)n, C(O), or CR11R12 only R7 or R8 is possible;
m is 0-3;
n is 0-2;
p is 0-4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from C1-C6 alkyl, C3-C7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C1-C6 alkoxy, fluoro, C(O)OR11, aryl C1-C3 alkoxy, substituted aryl C1-C3 alkoxy, and the aryl substituents are as defined for R3, R4 and R5;
or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.

2. The compound of Claim 1 of the structural formula wherein R1, R3, R4, R5 and A are as indicated in the table below:

R1 R3,R4,R5 (CH2)n = A

Ph-4-O-CH2-Ph 3,4-OMe 3 Ph-4-OH 3,4-OMe 3 Ph-4-OH 3,4-OMe 1 Ph-3,4-C1,C1 3,4-OMe 1 Ph-4-F 3,4-OMe 1 Ph-4-NO2 3,4-OMe 3 Ph-4-NH2 3,4-OMe 3 Ph-4-NO2 3,4-OMe 1 Ph-4-NH2 3,4-OMe 1 Ph-4-OH 3,5-OMe 3 Ph-4-OH 3-Ph 3 Ph-4-NH- 3,5-Me 3 COO-tBu Ph-4-NH2 3,5-Me 3 Ph-4-NO2 3,5-Me 3 Ph-4-OH 3-SCH3, 3 Ph-4-SO2NH2 3,5-Me 0 Ph-4-OH 3,4-OMe 2

3. The compound of Claim 1 of the structural formula wherein R1, R3, R4, R5 and A are as indicated in the table below:

R1 R3,R4,R5 A

Ph-4-OH 3,4-OMe (S)CH2-O
Ph-4-OH 4-OMe (S)CH2-O
Ph 3,4-OMe (S)CH2-O
Ph-4-OH 3,4-OMe (S)CH2-CH2 Ph-4-OH 3,4-OMe (R)CH2 Ph-3-F,4-NH2 3,4-OMe (S)CH2-O
Ph-4-NHAc 3,4-OMe (S)CH2-O
Ph-4-NH2 3,4-OMe (S)CH2-O
Ph-4-OH 3,4-OMe (R)CH2-O
Ph-4-F 3,4-OMe (S)CH2-O
Ph-4-Cl,3-NH2 3,4-OMe (S)CH2-O
Ph-4-O-CH2-Ph, 3,4-OMe (S)CH2-O

Ph-4-OH,3- 3,4-OMe (S)CH2-O

Ph-3-CN 3,4-OMe (S)CH2-O
Ph-3-CH2OH 3,4-OMe (S)CH2-O

Ph-3-F 3,4-OMe (S)CH2-O
Ph-3-CH2NH2 3,4-OMe (S)CH2-O
Ph-2-F 3,4-OMe (S)CH2-O
Ph-3-OCH2-Ph 3,5-Me (R,S)CH2-O
Ph-4-OH 3,5-Me (R,S)CH2-O
Ph-3-Cl 3,5-Me (S)CH2-O
Ph-3-CN 3,5-Me (S)CH2-O
Ph-3-CH2OH 3,5-Me (S)CH2-O

4. The compound of Claim 1 of the structural formula wherein R1, R2, R3, R4 and R5 are as indicated in the table below:

R1 R3,R4,R5 R2 Ph-4-OCH2-Ph 3,4-OMe Me Ph-4-OCH2-Ph 3,4-OMe H
Ph-OH 3,4-OMe Me Ph-OH 3,4-OMe H

5. The compound of Claim 1 of the structural formula wherein R1, R3, R4 and R5 are as indicated in the table below:

R1 R3,R4.R5 Ph-3-F,4-OH 3,4-OMe Ph-4-OH 3,4-OMe Ph-3,4-Cl 3,4-OMe Ph-4-F 3,4-OMe Ph-4-Cl 3,4-OMe Ph-4-OH 3,5-Me Ph-4-NO2 3,4-OMe Ph-4-NH2 3,4-OMe

6. The compound of Claim 1 of the structural formula wherein R1, R3, R4 and R5 are as indicated in the table below:

R1 R3,R4,R5 Ph-3-NH2,4-OH 3,4-OMe Ph-4-OH 3,5-Me Ph-4-SO2NH2 3,5-Me Ph-4-CH2OH 3,5-Me Ph-4-COOMe 3,5-Me Ph-4-NHSO2Me 3,5-Me Ph-4-Br(trans) 3,4-OMe Ph-4-OH 3,5-Me

7. The compound of Claim 1 of the structural formula wherein R2, R3, R4 and R5 are as indicated in the table below:

CH3 3,4OMe (CH2)4-Ph(4-OH) 3,5-Me (CH2)CONH2 3,5-Me (CH2)2NH2 3,5-Me (CNH)NH2 3,5-Me (CNH)NH(CNH)NH2 3,5-Me CH3 3,5-Me (CH2)4OH 3,5-Me

8. The compound of Claim 1 of the structural formula wherein R2 and R8 are as indicated in the table below:

(CH2)4oH -CO-NHCH2CH3 (CH2)4oH -CO-N(CH2CH3)-CO-NH-Et H -CO-N(CH2CH3)-CO-NH-Et H -CO-NH-Me H -CO-N-(CH3)2 H -CO-NH-Ph H -CO-NH-(CH2)2CH3

9. The compound of Claim 1 of the structural formula wherein R2 and XR7R8 are as indicated in the table below:

H H NH-COOCH2Ph H CH2Ph NH-COO-Et H H NH-COO-Et H H NH-CO-N(CH2CH3)2 H H N(CH2CH3)CO-N(CH2CH3)2 H H NH-CO-Cyclopropyl H H NH-CO-Ph H H H H H H NH-CO-Me H H H H NH-CO-CH(Me)-NH-CO-Me H H N(Me)-CO-Ph H H N(Me)-CO-Me H H NH-SO2Me H H H H H H NH-CO-NH(CH2CH3) H H NH-CO-NHMe H H NH-CO-NH(CH2CH2CH3) H H NH-CO-CH(CH3)2 H H NH-CO-NH-CH(CH3)2 H H NH-CO-NH-(cyclopropyl) H H NH-SO2-(CH2CH2CH3) H H NH-SO2-NH-(CH2CH3) H H S(O)CH3 H H S(O)2CH3 H H S(O)2NH2 6-Cl H *
6-Cl H NH-CO-NH-(cyclopropyl) H H NH-CO-N(CH3)2 * = NO2

10. The compound of Claim 1 of the structural formula wherein R1, R3, R4, R5, R6 and A are as indicated in the table below:

R1 R3-R5 R6 (CH2)n=(A) Ph-4-O-CH2-Ph 3,4-OMe 4 Ph-4-OH 3,4-OMe 4 Ph-4-OH 3,4-OMe 1 Ph-4-NO2 3,4-OMe 4 Ph-4-NH2 3,4-OMe 4 Ph-4-OCH3 3-OCH2(Ph- 4 3-OMe) Ph-4-OH 3,4-OMe 5 Ph-4-OH 3,5-CF3 4 Ph-4-OH 3,4-OMe 6 Ph-4-OCH3 3,4-OMe 4 Ph-4-OH 2-Me 4 Ph-4-OH 2,4-Cl 4 Ph-4-OH 4-F 4 Ph-4-OH 4-Me 4 Ph-4-OH 3-Cl,4-F 4 Ph-4-OH 3,5-Cl 4 Ph-4-OH - 4 Ph-4-OH 3,5-Me 4 Ph-4-OH 3-Me 4 Ph-4-OH 2,6-Me 4 Ph-4-OH 3-OMe 4 Ph-4-OH 3,5-OMe 4 Ph-4-OCH3 3,5-Me 4 Ph4-OH 3,5-Me 5-Cl 4 Ph-4-OH 3,5-Me 5-Me 4 Ph4-OH 3,5-Me 5 Ph-4-OH 3,5-Me 5-OBn 4 Ph-4-OH 2,3-Me 4 Ph-4-OH 3-N(Me)2 4 Ph-4-OH 3,5-Me 6 Ph-4-OH 2,5-Me 4 Ph-4-OH 3,5-Me 7-Me 4 Ph-4-OH 3,5-Me 1 Ph-4-OH 3,5-Me 5-OMe 4 Ph-4-OH 3-OCH2-Ph 4 Ph-4-OH 3-CH(Me) 4 OBn Ph-4-OH 3-Et 4 Ph-4-NO2 3,5-Me 4 Ph-4-OH 3-CH(Me) 4 OH
Ph-4-OH 3,5-Me 6-NH- 4 C(O)CH3 Ph-4-OCH3 3-O-CH2Ph 4 Ph-4-NH2 3,5-Me 4 Ph-4-NH- 3,5-Me 4 Ph-4-NHSO2Ph 3,5-Me 4 Ph-4-NHSO2Me 3,5-Me 4 Ph-4-OMe 3-OCH2(Ph- 4 3-OMe) Ph-4-OH 3-SMe 4 Ph-4-OH 3-SMe, 5-Me 4 Ph-4-OH 3,5-Me 6-Cl 4 Ph-4-SO2NH2 3,5-Me 1 Ph-4-OH 3,5-Me 4-Cl 4 Ph-4-OH 3-S(O)Me 4 Ph-4-OH 3-S(O)Me, 5 4 Me Ph-4-OH 3-SO2Me 4 Ph-4-OH 3-SO2Me, 5- 4 Me Ph-NHSO2CF3 3,5-Me 4 Ph-NHSO2Et 3,5-Me 4 3,4-OMe 0 3,4-OMe 0 Ph-4-OH 3,5-Me 4 Ph-4-OH 3-Me, 5-i-Bu 4 Ph-4-OH 3-Me, 5-Pr 4 Ph-4-NH2 3,5-Me 5-NHC(O)- 4 NHEt Ph-4-NHSO2-iPr 3,5-Me 4 Ph-4-OH 3,5-Me 5-NO2 4 Ph-3,4-OMe 3,5-Me 4 Ph-3,4-OH 3,5-Me 4 Ph-4-OH 3,5-Me 5-Br 4 2-naphthyl 3,5-Me 4 Ph-4- 3,5-Me 4 NHSO2NHMe Ph-4-CN 3,5-Me 4 Ph-4-F 3,5-Me 4 Ph-4-OH 3,5-Me 5-Ph 4 Ph-3-Br,4- 3,5-Me 4 NHSO2-Me Ph-4- 3,5-Me 4 NHCONHMe Ph-4-OH 3,5-Me5-CH(Me)2 4 Ph-4-SO2NH2 3,5-Me 4 1-naphthyl-4- 3,5-Me 4 OMe 1-naphthyl-4-OH 3,5-Me 4 Ph-3-F, 4-OMe 3,5-Me 4 Ph-3-F,4-OH 3,5-Me 4 Ph-4- 3,5-Me 4 NHSO2NHEt Ph-4- 3,5-Me 4 NHCONHEt Ph-4-NHSO2Me 3,5-Me 5-SO2Me 5 Ph-4-NHSO2Me 3,5-C1 5-N(Et)CO- 4 N(Et)2 Ph-4-OH 3,5-Me 5-F 4

11. The compound of Claim 1 of the structural formula wherein R3, R4, R5 and R6 are as indicated in the table below:

2-(CH)4-3 H
3-(CH)4-4 H
3-(CH-CH-N(Me))-4 H
2-(CH)4-3 5-OBn 2-(CH)4-3 5-OH
2-(CH)4-3 6-F
2-(CH)4-3, 5-Me H

12. The compound of Claim 1 of the structural formula wherein R1, R2, R9, R9a, R10, R10a and A are as indicated in the table below:

R1 R2 R9 R9a R10 R10a A

Ph-4-OH H H H CH3 H 4 Ph-4-OH H Ph H H H 4 Ph-4-OH -CH2CH2- H H H 4 Ph-4-OH H CH3 H H H 2 Ph-4- H CH3 H H H 4 NHSO2Me Ph-4-OH H H H CH3 H 2 Ph-4-OH H H H CH3 CH3 4 Ph-4- H CH3 H H H 2 NHSO2Me Ph-4-OH H CH3 H H H 4

13. The compound of Claim 1 of the structural formula wherein R1 and A are as indicated in the table below:

R1 (A) Ph-4-O-tBu -CH2-CH2-O-CH2-Ph-4-OH -(CH2)3-C(CH3)2-Ph-4-OH
Ph-4-OH -CH2-CH2-CHMe-CH2-Ph-4-OH -CH2-CH(CH3)2-Ph-4-OH -CNH-NH-(CH2)2-Ph-4-OH -(CH2)3-CH(O-CH2-CH2-OH)-Ph-4-OH -(CH2)3-C(O-CH2-CH2-O)-1-(naphthyl- -CH2-C(Me)2-4-OH) Ph-4-OH Ph-4-OH -CO-NHCH2CH2-

14. The compound of Claim 1 of the structural formula wherein XR7R8 is as indicated in the table below:

CH2COOEt CH2CON(Me)2 CH(Me)COOEt C(Me)2COOEt CH(Me)CON(Et)2 C(Me)2CON(Me)2 C(Me)2CON(Pr)2 CH2CON(Et)2 C(Me)2CON(Et)2

15. The compound of Claim 1 of the structural formula wherein XR7R8 is as indicated in the table below:

COOEt CO-N(CH2CH2OH) CO-NHEt CO-NH-cyclopropyl CO-N(Et)2

16. The compound of Claim 1 of the structural formula wherein X-R7R8, R9, R9a, R10, R10a and A are as indicated in the table below:

X-R7R8 R9, R9a:R10, R10a (CH2)n = A

NH-CON(Et)2 Me, H:H, H 4 NH-CO-Ph Me, H:H, H 4 NH-CO-N(Me)2 Me, H:H, H 2 NH-CO-N(Me)2 Me, H:H, H 4 N(CH2Ph)2 Me, H:Me, H 4 NHC(O)Ph CH2CH2OH, H:H, H 4 SO2Me Me, H:H, H 4 NHC(O)Ph CH2CH2OMe, H:H,H 4 O-CH2Ph H, H:Me, Me 4

17. The compound of Claim 1 of the structural formula wherein X-R7R8 are as indicated in the table below:

COOH
CO-N(CH2CH3)2 CO-NH-CH2Ph CO-N(CH3)2 CO-N(iBu)2

18. The compound of Claim 1 of the structural formula wherein R1, R2 and XR7R8, are as indicated in the table below:

Ph-4- NHCOEt NH(SO2Me)-COEt Ph-4- SO2CH2C(O)Me C(O)Me Ph-4- SO2Me C(O)Me Ph-4- COOEt SO2NHMe Ph-4-NO2 COOEt Ph-4- CON(Et)2 Et NHSO2Me Ph-4- CON(Et)2 SO2NHMe Ph-4- CON(iBu)2 SO2NHMe Ph-4- CON(cyclohexyl)Et SO2NHMe Ph-4-NO2 CON(iBU)2 Ph-4-NH2 CON(iBu)2 Ph-4-SMe COOEt Ph-4-SMe CON(Et)2 Ph-4-S(O)Me CON(Et)2 Ph-4- CON(Et)2 S(O)2Me Ph-4-SMe CON(iBu)2 Ph-4-S(O)Me CON(iBu)2 Ph-4- CON(iBu)2 S(O)2Me Ph-4- CON(iBu)2 NH[C=N(CO
NH2)]NHMe Ph-4- CON(iBu)2 NH[C=N(CN) ]NHMe Ph-4-F CON(iBu)2 Ph-4- COOEt SO2N(Me)2 Ph-4- CON(iBu)2 SO2N(Me)2 Ph-4- CON(Et)2 SO2N(Me)2 Ph-4- CON(Et)cyclohexyl SO2N(Me)2

19. The compound of Claim 1 of the structural formula wherein A, R1 and X-R7R8 are as indicated in the table below:

X-R7R8 -(A)-R1 H H H NHCO- N(Et)2 SO2Me

20. The compound of Claim 1 of the structural formula wherein A and R1 are as indicated in the table below:

R1 (CH2)n = A

Ph-4-OMe 4 Ph-4-OH 4 Ph-4-OH 3 Ph-4-OH 2

21. The compound of Claim 1 of the structural formula wherein A, R1, R2 and X-R7R8 are as indicated in the table below:

X-R7R8 H H H H H NHC(O)- N(ET)2 NHC(O)- N(ET)2 H H

22. The compound as defined in Claim 1 which is a) N-[2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl]-3-(4-hydroxyphenyl)propionamide;
b) 3-[3-[2-[2-(3,5-dimethylphenyl)-1H-Indol-3-Yl]ethylamino]-2-hydroxypropoxy]phenol;
c) (S)-4-[3-[2-[2-(3,5-dimethylphenyl)-1-methyl-1H-indol-3-yl]ethylamino]-2-hydroxypropoxy]phenol;
d) [2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyll-[2-(4-nitrophenyl)ethyl]amine;
e) [2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl]-[2-(4-aminophenyl)ethyl]amine;
f) [3-(4-bromophenyl)allyl]-[2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl]amine;
g) 4-[3-[2-[[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl]amino]
propyl)phenol;

h) 2-[[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-(4-hydroxyphenyl)-butyl]amino]acetamide;
i) 4-[4-[(2-aminoethyl)-[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]amino]butyl]phenol;
j) N-[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-N-[4-(4-hydroxyphenyl)butyl] guanidine;
k) N-[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-N-[4-(4-hydroxyphenyl)butyl] guanidino-guanidine;
l) 4-[4-[[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]methylamino]
butyl]phenol;
m) 4-[4-[[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-(4-hydroxybutyl)amino]butyl]phenol;
n) Propylcarbamic acid 2-(3,5-dimethylphenyl)-3-[2-[4-(4-hydroxyphenyl)butylamino]ethyl]-1H-indol-5-yl ester;
o) Ethylcarbamic acid 2-(3,5-dimethylphenyl)-3-[2-[4-(4-hydroxyphenyl)butylamino]ethyl]-1H-indol-5-yl ester;
p) N-[4-(4-{2-[2-(3,5-dimethylphenyl)-5-(3,3-dimethylureido)-1H-indol-3-yl]ethylamino}butyl)phenyl]methanesulfonamide;
q) 5-[(N,N-Diethylcarbamoyl)methyl]-2-(3,5-dimethylphenyl)-3-[2-[[4-[4-(methanesulfonamido)phenyl]butyl]amino]ethyl]indole;
r) 5-[1-(N,N-Diethylcarbamoyl)-1-methylethyl]-2-(3,5-dimethylphenyl)-3-[2-[[4-[4-(methanesulfonamido)phenyl]
butyl]amino]ethyl]indole;and s) 5-(N,N-Diethylcarbamoyl)-2-(3,5-dimethylphenyl)-3-[2-[[4-[4-(methanesulfonamido)phenyl]butyl]amino]ethyl]indole.

23. A pharmaceutical composition which comprises an effective amount of a compound as defined in Claim 1 and a pharmaceutically acceptable carrier therefor.

24. A method for antagonizing gonadotropin-releasing hormone in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1 to a subject suffering from a gonadotropin-releasing hormone derived disorder.

25. A method according to Claim 24 wherein the gonadotropin-releasing hormone derived disorder is a sex-hormone related condition.

26. A method according to Claim 24 wherein the gonadotropin-releasing hormone derived disorder is a sex hormone dependent cancer, benign prostatic hypertropy or myoma of the uterus.

27. A method according to Claim 26 wherein the sex hormone dependent cancer is selected from the group consisting of prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas.

28. A method according to Claim 25 wherein the sex hormone related condition is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty.

29. A method for preventing pregnancy in a subject in need thereof which comprises administering an effective amount of a compound as defined in Claim 1.

30. A method for treating lupus erythematosis in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.

31. A method for treating irritable bowel syndrome in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.

32. A method for treating premenstrual syndrome in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.

33. A method for treating hirsutism in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.

34. A method for treating short stature or a growth hormone deficiency in a subject in need thereof which comprises administering to said subject an effective amount of a compound which stimulates the endogenous production or release of growth hormone and an effective amount of a compound as defined in Claim 1.

35. A method for treating sleep disorders such as sleep apnea in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.

36. A pharmaceutical composition which comprises an inert carrier and an effective amount of a compound which stimulates the endogenous production or release of growth hormone in combination with a compound as defined in Claim 1.

37. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier therefor.

38. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

39. A use of an effective amount of a compound as defined in claim 1 for antagonizing gonadotropin-releasing hormone in a subject suffering from a gonadrotropin-releasing hormone derived disorder.

40. A use of an effective amount of a compound as defined in claim 1 for the production of a medicament for antagonizing gonadotropin-releasing hormone in a subject suffering from a gonadrotropin-releasing hormone derived disorder.

41. A use according to claim 39 or 40 wherein the gonadotropin-releasing hormone derived disorder is a sex-hormone related condition.

42. A use according to claim 39 or 40 wherein the gonadotropin-releasing hormone derived disorder is a sex hormone dependent cancer, benign prostatic hypertropy or myoma of the uterus.

43. A use according to claim 42 wherein the sex hormone dependent cancer is selected from the group consisting of prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas.

44. A use according to claim 41 wherein the sex-hormone related condition is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty.

45. A use of an effective amount of a compound as defined in claim 1 for treating lupus erythematosis in a subject in need thereof.

46. A use of an effective amount of a compound as defined in claim 1 for the production of a medicament for treating lupus erythematosis in a subjectin need thereof.

47. A use of an effective amount of a compound as defined in claim 1 for treating irritable bowel syndrome in a subject in need thereof.

48. A use of an effective amount of a compound as defined in claim 1 for the production of a medicament for treating irritable bowel syndrome in a subject in need thereof.

49. A use of an effective amount of a compound as defined in claim 1 for treating premenstrual syndrome in a subject in need thereof.

50. A use of an effective amount of a compound as defined in claim 1 for the production of a medicament for treating premenstrual syndrome in a subject in need thereof.

51. A use of an effective amount of a compound as defined in claim 1 for treating hirsutism in a subject in need thereof.

52. A use of an effective amount of a compound as defined in claim 1 for the production of a medicament for treating hirsutism in a subject in need thereof.

53. A use of an effective amount of a compound which stimulates the endogenous production or release of growth hormone and an effective amount of a compound as defined in claim 1 for treating short stature or a growth hormone deficiency in a subject in need thereof.

54. A use of an effective amount of a compound which stimulates the endogenous production or release of growth hormone and an effective amount of a compound as defined in claim 1 for the production of a medicament for treating short stature or a growth hormone deficiency in a subject in need thereof.

55. A use of an effective amount of a compound as defined in claim 1 for treating sleep disorders such as sleep apnea in a subject in need thereof.

56. A use of an effective amount of a compound as defined in claim 1 for the production of a medicament for treating sleep disorders such as sleep apnea in a subject in need thereof.