Title of Invention

INDOLE DERIVATIVES

Abstract

This invention provides non-steroidal compounds with affinity for the androgen receptor and utility for androgen-receptor related treatments, having a structure according to the formula (1) wherein X is S,SO or S02; R<1 >is a 5- or 6-membered monocyclic, hetero- or homocyclic, saturated or unsaturated ring structure optionally substituted with one or more substituents selected from the group consisting of halogen, CN, (lC-4C)fluoroalkyl nitro, (lC-4C)a!kyl, (1C-4C)alkoxy or (lC-4C)fluoroalkoxy; R<2> is 2-nitrophenyl, 2-cyanophenyl, 2-hydroxymethyl-phenyl, pyridin-2-yl, pyridin-2-yl-N-oxide, 2-benzamide, 2-benzoic acid methyl ester or 2-methoxyphenyl; R<3> is H, halogen or (1C-4C)alkyl; R<4> is H, OH, (lC-4C)alkoxy, or halogen; R<4> is H, OH, (1C-4C)alkoxy, NH2, CN, halogen, (lC-4C)fluoroalkyl, N02, hydroxy(lC-4C)alkyl, C02H, C02(lC-6C)alkyl, or R<5> is NHR<6>, wherein R<6> is (lC-6C)acyl optionally substituted with one or more halogens, S(0)2( 1 C-4C)alkyl, or S(0)2aryl optionally substituted with (lC-4C)alkyl or one or more halogens, or R<5> is C(0)N(R<8>,R<9>), wherein R<8> and R<9> each independently are H, (3C-6C)cycloalkyl, or CH2R<10>, wherein R<10> is H, (lC-5C)alkyl, (1C-5C)alkenyl, hydroxy(lC-3C)alkyl, (lC-4C)alkylester of carboxy(lC-4C)alkyl, (lC-3C)alkoxy(lC-3C)alkyl, (mono- or di(lC-4C)alkyl)aminomethyl, (mono- or di(lC-4C)alkyl)aminocarbonyl, or a 3-, 4-, 5- or 6-membered monocyclic, homo-or heterocyclic, aromatic or non-aromatic ring, or R<8> and R<9 >form together with the N a heterocyclic 5- or 6-membered saturated or unsaturated ring optionally substituted with (lC-4C)alkyl; or a salt or hydrate form thereof.

Full Text

INDOLES USEFUL IN THE TREATMENT OF ANDROGEN-RECEPTOR RELATED DISEASES The invention relates to indole derivatives, their preparation and their use for the treatment of androgen-receptor related conditions, disorders or diseases and other androgen related treatments. Compounds possessing androgenic activity are useful in the treatment of men with low endogenous levels of circulating androgenic hormones or men with suppressed androgenic effects. Such treatments are prescribed to older men, to hypogonadal men or men treated with progestagens for male contraception. In addition, potent androgens suppress spermatogenesis and can be used as male contraceptives. It is thus important to obtain compounds with high affinity for the androgen receptor. Non-steroidal compounds with high affinity for the androgen receptor are particularly useful since they may have different tissue distribution characteristics than steroidal androgens and can be designed by proper choice of substituents to be more or less selective for certain tissues. For example, an action in the brain is usually prevented when compounds are strongly hydrophilic or carry an ionic charge. The subject invention provides non-steroidal compounds with affinity for the androgen receptor. These compounds are potentially useful for the treatment of androgen-receptor related disorders or disorders which can be treated with androgens. The compounds of the subject invention have a structure according to formula I: R is a 5- or 6-membered monocyclic, hetero- or homocyclic, saturated or unsaturated ring structure optionally substituted with one or more substituents selected from the group consisting of halogen, CN, (lC-4C)fluoroalkyl, nitro, (lC-4C)alkyl, (1C- 4C)alkoxy or (lC-4C)fluoroalkoxy; R is 2-nitrophenyl, 2-cyanophenyl, 2-hydroxymethyl-phenyl, pyridin-2-yl, pyridin-2- yl-N-oxide, 2-benzamide, 2-benzoic acid methyl ester or 2-methoxyphenyl; R3 is H, halogen or (lC-4C)aikyl; R4 is H, OH, (lC-4C)alkoxy, or halogen; R5 is H, OH, (lC-4C)alkoxy, NH2, CN, halogen, (lC-4C)fluoroalkyl, N02, hydroxy(lC-4C)alkyl, C02H, C02(lC-6C)alkyl, or R5 isNHR6, wherein R6 is (1C- 6C)acyl optionally substituted with one or more halogens, S(0>2(lC-4C)alkyl, or S(0)2aryl optionally substituted with (lC-4C)alkyl or one or more halogens, or R5 is C(0)N(R8,R9), wherein R8 and R9 each independently are H, (3C-6C)cycloalkyl, or CH2R10, wherein R10 is H, (lC-5C)alkyl, (lC-SC)alkenyl, hydroxy(lC-3C)alkyl, (lG-4C)alkylester of carboxy(lC-4C)alkyl, (lC-3C)alkoxy(lC-3C)alkyl, (mono- or di(lC-4C)alkyl)aminomethyl, (mono- or di(lC-4C)alkyl)aminocarbonyl, or a 3-, 4-, 5- or 6-membered monocyclic, homo- or heterocyclic, aromatic or non-aromatic ring, or R8 and R9 form together with the N a heterocyclic 5- or 6-membered saturated or unsaturated ring optionally substituted with (lC-4C)alkyl; or a salt or hydrate form thereof. In one embodiment R1 is a 5- or 6-membered monocyclic, hetero- or homocyclic, saturated or unsaturated ring structure optionally substituted with one or more substituents selected from the group consisting of halogen, CN, CF3, nitro, methoxy, trifluoromethoxy or methyl; R2 is 2-nitrophenyl, 2-cyanophenyl, 2-hydroxymethyl-phenyl, pyridin-2-yl, pyridin-2-yl-N-oxide, 2-benzamide, 2-benzoic acid methyl ester or 2-methoxyphenyl; R3 is H, halogen or (lC-2C)alkyl; R4 is H or F. In another embodiment R5 is H, OH5 (lC-4C)alkoxy, CN, halogen, (lC-4C)fluoroalkyl, N02, hydroxy(lC-4C)alkyl, C02(lC-6G)alkyl, or R5 isNHR6, wherein R6 is (1C-6C)acyl optionally substituted with one or more halogens, S(0)2(lC-4C)alkyl, or S(0)2aryl optionally substituted with (!C-4C)alkyl or one or more halogens, or In yet another embodiment R1 is 3,5-difluorophenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrimidin-4-yl, or pyrazin-2-yl; R2 is 2-nitrophenyl, or 2-hydroxymethyi-phenyl; R5 is OH, (lC-2C)alkoxy, CN, hydroxy(lC-4C)alkyI, or NHR6, wherein R6 is formyl, acetyl, fluoroacetyl, difluoroacetyl, or trifluoroacetyl. In yet another embodiment R] is 3,5-difluorophenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, or pyrimidin-4-yl; R2 is 2-nitrophenyl; R5 is OH, (lC-2C)allcoxy, CN, or NHR , wherein R6 is formyl, acetyl, fluoroacetyl, difluoroaceiyl, or trifluoroacetyl. In a specific embodiment the subject invention provides the compounds 6-Methox^/-3-(2-nitro-phenylsulfanyl)-l-pyrimidin-5-ylmethyl-li7-indole, 3-(2-Nitro-phenylsulfanyl)-l-pyridin-2-ylmethyl-l//-indole-6-carbonitrile, 3-(2-Nitro-phenylsulfanyl)-l-pyridin-2-ylmethyl-l/f-indole-6-carbonitrile-hydrochloride, 3-(2-Nitro-phenylsulfanyI)-l-pyrimidin-5-ylmethyI-lflr-indole-6-carbonitrile, 3-(2-Nitro-phenylsulfanyO-l-pyrimidin^-ylmethyl-l/Z-indole^-carbonitrile, A^fl^^-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-liif-indol-6-yl]-2-fluoro-acetamide, andA/-[3-(2-Nitro-phenylsulfanyl)-l-pyrimidin-5-ylmethyI-l//-indol-6-yl]-form amide. In another embodiment X is S; R1 is 3,5-difluorophenyl, pyridin-2-yl, pyridin-3-yl, 3-fluorophenyl, 3-cyanophenyI, or 3-nitrophenyI; R2 is 2-nitrophenyl, 2-hydroxymethyI-phenyl, 2-methoxyphenyl, 2-cyanophenyl or pyridin-2-yl; RJ is H; R5 is C(0)N(R8,R9), wherein RS is H, and R9 is H, or CH2R,0? wherein R10 is H, (1C-2C)alkyl, hydroxy(lC-2C)a!kyl, or methoxy(lC-2C)alkyi. In yet another embodiment R1 is 3,5-difluorophenyl, pyridin-2-yl, or pyridin-3-yl; R2 is 2-nitrophenyl, or 2-hydroxymethyl-phenyl; R5 is C(0)N(Rs,R9), wherein R8 is H, and R9 is CH2R10, wherein R10 is H, or (lC-2C)alkyl. In a specific embodiment the subject invention provides the compound l-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-li7-indole-6-carboxylic acid methylamide. In yet another embodiment X is S; R1 is 3,5-difluorophenyl, pyridin-2-yl, pyridin-3-yl, 3-fluorophenyl, 3-cyanophenyl, or3-nitrophenyl; R2 is 2-nitrophenyl, 2-hydroxymethyl-phenyl, 2-methoxyphenyl, 2-cyanophenyl or pyridin-2-yl; R3 is H; R5 is C(0)N(R8,R9), wherein R8 and R9 each independently are H or CH2R10, wherein R10 is H, (1C-5C)alkyl, (!C-5C)alkenyI,.hydroxy(1C-3C)alkyI, (lC-3C)alkoxy(lC-3C)aIkyl, or (mono- or di(lC-4C)alkyI)aminomethyl. In yet another embodiment R1 is 3,5-difluorophenyl, pyridin-2-yl, or pyridin-3-yl; R2 is 2-nitrophenyl, or 2-hydroxymethyl-phenyl; R5 is C(0)N(Rg,R9), wherein R8 and R9 each independently are H, or CH2R10, wherein R10 is H, (1 C-5C)aIkyi, hydroxy(lC-3C)aikyl, or (lC-3C)alkoxy(lC~3C)alkyl. In a specific embodiment the subject invention provides the compound l-(3,5-Difluoro-benzyl)-3-(2-nitro-phenyIsu!fanyl)-l//-indole-6-carboxylic acid dimethylamide. In those cases that a compound of the invention contains a basic amine function, the compound may be used as a free base or as a pharmaceuticaliy acceptable salt such as hydrochloride, acetate, oxalate, tartrate, citrate, phosphate, maleate or fumarate. A compound according to the invention is a compound as defined above, a salt thereof, a hydrate thereof or a prodrug thereof. The terms used in this description have the following meaning; alkyl is a branched or unbranched alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl, and the like; fluoroalkyl is an alkyl group substituted with one or more fluorine atoms; cycloalkyl is a cyclized unbranched alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and the like; alkenyl is a branched or unbranched alkenyl group, such as ethenyl, 2-butenyl, etc.] alkoxy is a branched or unbranched alkyloxy group, for example methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, sec-butyloxy, tert-butyioxy and the like; fluoroalkoxy is a alkoxy group substituted with one or more fluorine atoms; aryl is a mono- or polycyclic, homo- or heterocyclic aromatic ring system, such as phenyl, naphtyl or pyridyl; a monocyclic ring with 6 atoms is preferred for use; acyl is a (substituent-)carbonyl group, such as an aroyl or alkanoyl; aroyl is aiylcarbonyl such as a benzoyl group; alkanoyl means a formyl or alkylcarbonyl group such as formyl, acetyl and propanoyl; carboxy is a -COOH substituent, making the compound an organic acid; carboxylate is a salt of a carboxyl substituent. The prefixes (1C-4C), (2C-4C) etc. have the usual meaning to restrict the meaning of the indicated group to those with 1 to 4, 2 to 4 etc. carbon atoms; halogen refers to fluorine, chlorine, bromine and iodine. The androgen receptor affinity and efficacy of the compounds according to the invention make them suitable for use in the treatment of androgen-receptor related disorders, disorders which can be treated with androgens, and in diagnostic methods focussed on the amount and/or location of androgen receptors in various tissues. For the latter purpose it can be preferred to make labelled variants of the compounds according to the invention. Typical androgen receptor-related treatments are those for male contraception and male or female hormone replacement therapy. Thus the invention also pertains to a method of treatment of androgen insufficiency, by administering to a male or female human or animal an effective amount of any of the compounds of the subject invention. The subject invention also lies in the use of any of its compounds for the preparation of a medicine for treating androgen insufficiency. In the context of the invention, the term "androgen insufficiency" is to be understood to pertain to all kinds of diseases, disorders, and symptoms in which a male or a female suffers from too low a testosterone level, such as in hypogonadal men or boys. In particular, the androgen insufficiency to be treated by a compound of the invention is the reduction of the testosterone level which a male individual incurs as a result of age (the compound of the invention is then used for male hormone replacement therapy), or when he is subject to male contraception. In the context of male contraception, the compound of the invention especially serves to neutralise the effect of regimens of male hormone contraception in which a sterilitant such as a progestagen or LHRH (luteinizing hormone releasing hormone) is administered regularly, e.g. daily, or it is used as the sole male contraceptive substance. Thus, the subject invention provides any one of the compounds of the subject invention for use in therapy. The subject invention iurther encompasses a pharmaceutical composition comprising a compound of the subject invention and a pharmaceutically acceptable carrier. In an embodiment of the subject invention, the pharmaceutical composition is for the treatment of a disorder selected from the group consisting of an androgen-receptor related disorder, an androgen related disorder and androgen insufficiency. The subject invention further provides a use of a compound of the invention for the manufacture of a medicament for the treatment of androgen-receptor related disorders, androgen related disorders and androgen insufficiency. The subject invention further envisions a method of treating a disorder selected from the group consisting of an androgen-receptor related disorder, an androgen related disorder and androgen insufficiency comprising administering a pharmaceutically effective amount of a compound according to the invention to a subject in need thereof. The compounds of the invention may further be useful for the treatment of osteoporosis, as well as other bone disorders, bone fraction repair, sarcopenia, frailty, skin aging; * male hypogonadism, female sexual dysfunction, postmenopausal symptoms, atherosclerosis, aplastic anemia, muscular atrophy, lipodystrophy, reduced muscle strength and function, side effects of chemotherapy, chronic fatigue syndrome, benign prostate hyperplasia (BPH)3 cachexia, chronic catabolic state, cognitive impairment, male contraception, and others. The compounds of the invention may be administered in conjunction with estrogens, progestogen and other androgens. The compounds of the invention can be produced by various methods known in the an of organic chemistry in general. More specifically the routes of synthesis as illustrated in the following schemes and examples can be used. In the schemes and examples the following abbreviations were used; DMF = dimethylformamide mCPBA = meta chloro perbenzoic acid THF = tetrahydofuran TBTU = 2-(lH-benzotriazoI-l-yl)-l,l,3,3-tetramethyIuronium tetrafluoroborate DIPEA = diisopropylethylamine EDCI = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt = 1-hydroxybenzotriazole NMM = N-methylmorpholine SPE = solid phase extraction RP-SPE = reversed phase solid phase extraction DMSO = dimethylsulfoxide DCM = dichloromethane DHT = 5a-dihydrotestosterone NMP = l-methyl-2-pyrrolidinone DMS = dimethyl sulfide In each of the Schemes I-VII the meanings of the symbols correspond to the definitions given in the previous paragraphs. Substituted indole compounds of structure 3 were prepared in two steps from the correctly substituted indoles of strucrure 1, via two different routes. In the first route a correctly substituted indole of structure 1 isN-alkylated with a halide of type R CH:Y, where Y is a halogen, mesylate or tosylate, with NaH or CS2CO3 as a base in DMF or NMP at 0°C to room temperature, to give a compound of structure 2. Structure 2 is then sulfanylated at the C-3 position of the indole ring by reaction with a sulfenyl chloride in either CH2CI2 or diethyl ether at room temperature, to give structure 3. In the second route the two steps of the first route are reversed: the correctly substituted indole of structure 1 is first sulfanylated at the C-3 position of the indole to give structure 4; followed by N-alkylation with R^CHiY to 'give structure 3 (Scheme I). (Structure 8), C02H (Structure 9), CONHMe (Structure 10), CONH2 (Structure 11) or CN (Structure 12). In the first step a substituted indole of structure 6 is sulfanylated at the 3-position with 2-(carboxymethyl)-phenylsulfenyl chloride, which was prepared from methylthiosalicyiate and chlorine gas. to give a compound of structure 7. Reduction of the methyl ester moiety of compounds of structure 7 with LiAlH4 gave the corresponding hydroxymethyl compounds of structure 8. Saponification of the methyl triethylamine in CH2CI2 afforded the corresponding benzonitrile compound of structure 17 (Scheme IV). Scheme V describes the synthesis of compounds of structure 22 containing an acylated amine functionality on the 6-position of the indole ring. These compounds can be synthesised from 6-nitro indoles of structure 18 in 4 steps. In the first step the indole of structure 18 is alkylated on the nitrogen atom by reaction of a halide of type lOCHsY, in which Y is halogen, mesylate or tosylate, with NaH as a base in DMF to give compounds of structure 19. In the second step the nitro group of structure 19 is reduced to an amine group by SnCl2 to give structure 20. Subsequent acylation of the amine group with an acid chloride of type ZCOC1 afforded structure 21, which was then sulfanylated at the 3-position of the indole ring by reaction with a sulfenyl chloride in either CH2CI2 or Et20 as a solvent, at room temperature, to give compounds of structure 22. Direct sulfanylation of a compound of structure 20 with a sulfenyl chloride afforded structure 23 In Scheme VI is decribed how methyl ethers of structure 24 can be cleaved with e.g. BF3DMS in THF at room temperature to hydroxy compounds of structure 25. Scheme VII describes the synthesis of compounds containing either an acylated amine functionality (structure 28) or a sulfonamide functionality (structure 29) at the 6-position of the indole ring. These compounds can be prepared from 6-nitro indoles of structure 18 in 6 steps. In the fust step the indole of structure 18 is alkylated on N-l by reaction of a halide of type RlCH2Y, in which Y is a halogen, mesylate or tosylate. with NaH or CS2CO3 as a base in either NMP or DMF to give compounds of structure 19. In the second step the nitro group of structure 19 is reduced to an amine group with Fe and NH4CI in an ethanol/water mixture to give structure 20. Subsequent acylation of the amine group with di-/er/-butyl dicarbonate afforded structure 26 which was then sulfanylated at the 3-position of the indole ring by reaction with a sulfenyl chloride in either CH2CI2 or Et20 to give compounds of structure 27. Then the amide functionality at the 6-position of the indole was cleaved with trifluoroacetic acid or HCOOH to give amines of structure 23. These amines can be converted into amides of structure 28 by reaction with either triethyiamine and an acid chloride in CH2CI2 (method a) or an acid, TBTU and DIPEA in CH2C12 (method b). Sulfonamides of structure 29 can be prepared by reaction of amines of structure 23 with sulfonyl chlorides (method c). The present invention also relates to a pharmaceutical composition comprising the nonsteroidal compound according to the invention mixed with a pharmaceutical!}' acceptable auxiliary, such as described in the standard reference Gennaro et ah Remmington: The Science and Practice of 'Pharmacy, (20th ed.? Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing). Suitable auxiliaries are made available in e.g. the Handbook of Pharmaceutical Excipients (2n Edition, Editors A. Wade and PJ. Weller; American Pharmaceutical Association; Washington; The Pharmaceutical Press; London, 1994). The mixture of a compound according to the invention and a pharmaceutically acceptable auxiliary may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutical^ suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. The compounds of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release. Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts. The dosage amounts of the present compounds will be of the normal order for pharmaceutically active compounds, e.g. of the order of 0.001 to 50 mg/kg body weight of the recipient per administration. The recipient can be a human or an animal in need of an androgen receptor-related treatment or an androgen treatment. The invention is illustrated by the following examples. Examples Example 1 W33-Pifluoro-benzylV6-methoxy-3-f2-nitro-phenylsutfanyn-l//-indole (Compound 63, Structure 3 of Scheme I. where R1 = 3.5-difluorophenvl R~ = 2-nitrophenyL R3=R4=H. R^OMel Genera! method 1: N-alkylation of a (un)substituted indole of structure 1 to give N-alkylated indole of structure 2, followed by 3-sulfanyIation to give substituted indoles of structure 3 (Scheme I). (a) l-n,5-Difluoro-benzvn-6-methoxv-177-indole (^Structure 2, of Scheme I. where R1 = 3.5-difluorophenyl, R3=R4=R R5=OMe) Under a nitrogen atmosphere: to a cooled (0°C) solution of 6-methoxyindole (863 mg, 5.86 mmol) in DMF (40 mL) was added NaH (60% in oil; 281 mg, 7.03 mmol) in small portions over a 3 minute period. The resulting green suspension was stirred at 0°C for 10 min. Then 3,5-difluorobenzyl bromide (0.91 mL, 7.03 mmoi) was added. The mixture was stirred at 0°C for 1 h and then at room temperature for another 21 h. Ethyl acetate (50 mL) was added and the mixture was washed with 3% aqueous citric acid (3x50 mL) and brine (50 mL). The organic phase was dried (MgS04) and concentrated in vacuo to give a green oil (1.43 g). The crude product was purified over a 20 g silica SPE cartridge (ethyl acetate/heptane 1:9) to give the title compound as a colourless oil (1.23 g, yield = 77%). LCMS: 4.01 min (96.3%, MK+ = 274); TLC (ethyl acetate/heptane 1:4): Rf = 0.46; !H NMR (CDCb): 5 3.80 (s, 3H, OCH3), 5.24 (s, 2H, NCH2Ar), 6.51 (dd, 1H, Jl = 3.5 Hz, J2 = 0.8 Hz), 6.57-6.60 (m, 2H), 6.65 (d, 1H, J = 3.1 Hz), 6.66-6.72 (m, 1H), 6.81 (dd, 1H, Jl = 8.6 Hz, J2 = 3.1 Hz), 7.01 (d, 1H, J = 3.5 Hz), 7.53 (d, 1H, J = 8.6 Hz). (b) l-(3.S-Difluoro-benzvn-6-methoxv-3-(2-nitro-phenvlsulfanvlVl//"-indole (Compound 63 , Structure 3 of Scheme L where R = 3.5-difluorophenvK R" = 2-nitrophcnyL R3=R4=K R5=OMe) To a solution of l-(3,5-Difluoro-benz>'l)-6-methoxy-177-indoIe (900 mg, 3.29 mmol) in diethyl ether (20 mL) was added dropwise at room temperature a suspension of 2-nitrobertzenesulfenyl chloride (627 mg, 3.31 mmol) in diethyl ether (10 mL) over a period of 2 min. After stirring at room temperature for I h ethyl acetate (50 mL) was added and the mixture was washed with saturated NaHCCh solution (2x50 mL) and brine (50 mL). The organic phase was dried (MgS04) and concentrated in vacuo to give an orange-red oil (1.54 g). The crude product was crystallised from toluene/acetone to give the title compound as orange-red crystalline solid (900 mg, yield = 64%). LCMS: 4.25 min (10*0%, MHT = 427); HPLC: 4.86 min (98.7%); *HNMR(CDCi3): 5 3.82 (s, 3H, OCH3), 5.32 (s, 2H, NCH2Ar), 6.63-6.69 (m, 2H), 6.72-6.79 (m, 1H), 6.75 (d, 1H, J = 2.7 Hz), 6.85 (dd, 1H, Jl = 8.2 Hz, J2 = 2.7 Hz), 6.98 (dd, 1H, Jl - 6.7 Hz, J2 = 1.2 Hz), 7.16-7.20 (m, 1H), 7.26-7.30 (m, 1H) 7.34 (s, 1H), 739 (d, 1H, J = 8.2 Hz), 8.27 (dd, 1H, Jl = 8.2 Hz, J2 = 1.6 Hz). Example 2 H3.5-Difluoro-benzyiy3-(2-^ ester (Compound 31 , Structure 3 of Scheme I, where R1 = 3.5-difluorophenvl. R2 = 2- nitrophenvl. R3=R4=H, R5«CQ2Me) (a) 1 flr-Indole-6-carboxylic acid methvl ester (Structure 1 of Scheme L where R =R -H, R5=CO:Me) To a solution of l#-Indole-6-carboxylic acid (1.500 g, 9.31 mmol) in methanol (50 mL) was added concentrated H2SO4 (550 ^L, 10.24 mmol). The mixture was stirred overnight at reflux temperature. The mixture was then neutralised to pH 7 by addition of saturated aqueous NaHCC>3 and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over NaaSC>4 and concentrated in vacuo to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as green/yellow crystals (688 mg, yield = 53%) lH NMR (CDCI3): 5 3.94 (s, 3H, CH3OCO), 6.60 (m, 1H), 7.37 (t, 1H, J = 4.7 Hz), 7.66 (d, 1H, J = 8.2 Hz), 7.82 (dd, 1H, Jl = 8.2 Hz, J2 = 1.0 Hz), 8.18 (s, 1H), 8.73 (s, 1H, NH) (b) l-(3.5-Difluoro-benzvn-lff-indole-6-carboxvlic acid methvl ester (Structure 2 of Scheme 1. where R1 = 3,5-difluorophenvK R3=R4=H, R5=Cp7Me) Under a nitrogen atmosphere: to a solution of l#-indole-6-carboxylic acid methyl ester (367 mg, 2.09 mmol) in DMF (10 mL) was added NaH (60% in oil, 101 mg, 2.52 mmol) at room temperature. After stirring for 15 min l-brornomethyl-3,5-difluoro-benzene (325"JJL, 2.51 mmol) was added and the mixture was stirred at room temperature for 4 h. The reaction was quenched with 3% aqueous citric acid (10 mL) and ethyl acetate (30 mL) was added. The mixture was washed with 3% aqueous citric acid (3x20 mL) and brine (20 mL). The organic phase was dried (MgS04) and concentrated in vacuo to give a pale yellow oil (702 mg). The crude product was purified over a 20 g silica SPE cartridge (ethyl acetate/heptane 1:9) to give the title compound as a colourless oil, which slowly crystallised on standing (530 mg, yield = 84%). LCMS: 4.08 min (99%, MH+= 302); 'HNMR (CDC13): 5 3.92 (3, 3H, C02CH5), 5.37 (s, 2H, NCH2Ar), 6.54-6.60 (m, 2H), 6.64 (d, 1H, J = 3.1 Hz), 6.67-6.74 (m, 1H), 7.27 (d, 1H, J = 3.1 Hz), 7.68 (d, 1H, J = 8.6 Hz), 7.83 (d, 1H, J= 8.6 Hz), 8.01 (3, IH). (c) 1-(3.5-Difluoro-benzvl')-3-(2-nitro-phenvlsulfanvlVl/f-indole-6-carboxv'licacid methvl ester (Compound 31. Structure 3 of Scheme I, where R! = 3.5-difluorophenvl. R2 - 2-nitrophenvh R3=R4=H. Rs=CO?Me) To a solution of 1 -(3,5-Difiuoro-benzyl)-l//-indole-6-carboxylic acid methyLester (330 mg, 1.10 mmol) in dichloromethane (30 mL) was added at room temperature a solution of 2-nitrobenzenesulfenyl chloride (210 mg, l.l 1 mmol) in dichloromethane (10mL). The mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated and the crude product was purified over a 20 g silica SPE cartridge (ethyl acetate/heptane 1:5 to 1:2) to give the title compound as a yellow solid (392 mg, yield = 78%): HPLC: 4.60 min (97.8%); lH NMR (CDCI3): 5 3.93 (s, 3H, CO2CH3), 5.45 (s, 2H, NCH2Ar), 6.63-6.69 (m, 2H), 6.74-6.80 (m, 1H), 6.88 (dd, IH, Jl = 8.2 Hz, J2 = 1.2 Hz), 7.18-7.23 (m, IH), 7.26-7.30 (m, IH), 7.57 (d, IH, J - 7.S Hz), 7.58 (s, IH), 7.89 (dd, IH, Jl = 7.8 Hz, J2 =1.2 Hz), 8.12 (s, IH), 8.28 (dd, IH, Jl = 7.8Hz, J2 = 1.2 Hz). Example 3 l-n,5-Difluoro-benzvn-3-(2-nitro-phenylsulfanvn-l//-indole-6-carboxvlic acid (Compound 30 , Structure 14 of Scheme IV, where R! = 3,5-difluorophenyl. R^ = 2-nitrophenvl. R3=R4=H~) To a solution of l-(3,5-Difluoro-ben2yl)-3-(2-nitro«phenylsu!fanyl)-li/-JndoIe-6-carboxylic acid methyl ester (150.0 mg5 033 mmol) in dioxane (20 mL) and water (15 mL) was added LiOH.H^O (83.1 mg, 2.0 mmol) in 5 ml water. The reaction mixture was stirred overnight at 60°C. The mixture was then acidified to pH 4 by addition of } 5% aqueous HC1 and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over NaiSO* and concentrated in vacuo to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as yellow/orange crystals (129.3 mg, y = 89%) *H NMR (DMSO): 5 5.62 (s, 2H, CH2Ar), 6.85 (dd, 1H, Jl = 8.6 Hz, J2 - br), 7.05 (m, 2H, br), 7.20 (m, 1H, br), 7.32-7.38 (m, 1H), 7.40 (d, 1H, J = 8.2 Hz), 7.44-7.50 (m, IH), 7.68 (dd, IH, Jl - 8.6 Hz, J2 = br), 7.97 (s, 1H, COOH), 8.20 (s, 1H), 8.26 (s, 1H), 8.28 (d, 1HJ-&2) Example 4 1 -(3,5-DifluorQ"benzvl)-3-(2-nitr0'phenvlsulfanvn- l//-indole-6-carboxyiic acid methylamide ("Compound 47 , Structure 15 of Scheme IV, where R1 = 3,5* difluorophenvU R2 **2-nitrophenyl R3=R4=R8=H, R^Mel General method 2: amidation of 6-carboxyI indoles of structure 14 to give 6-carboxamideindoles of structure 15 (Scheme IV). Under nitrogen atmosphere: to a solution of l-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsuIfanyl)-l//-indole-6-carboxylic acid (25.1 mg, 57.0 jimol) in dry DMF (lOmL) was added NMM (1 mL), HOBt (9.60 mg, 62.7 nmoi), EDCI (12.1 mg, 62.7 jimol), and methylammonium chloride (19.2 mg, 285 jimol). The reaction mixture was stirred overnight at room temperature and then poured into ice water. The resulting precipitate was filtered and the residue was washed with excess water followed by little heptane. The product was dried in vacuo at 40°C to give the title compound as a yellow solid (I5.2mg,y = 60%). LCMS: 4.31 min (100.0%, MH+ = 454); ]H NMR (DMSO): 5 2.80(d, 3H, J = 4.3, CH2NHCO), 5.63 (s, 2H, CtfcAr), 6.86 (dd, IH, Jl - 8.2 Hz, J2 = 1.0 Hz), 7.04 (m, 2H), 7.20 (m, IH), 7.33-7.37 (m, 1H); 7.41 (d, IH, 8.6 Hz), 7.46-7.50 (m, IH), 7.64 (dd, IH, Jl = 8.2 Hz, J2 = 1.0 Hz), 8.15 (s, IH), 8.25 (s, IH), 8.27 (dd, IH, Jl = 8.6 Hz, J2 = 1.0 Hz), 8.40 (m, IH, MeNHCO). Example 5 l-f3,5-Difluoro-benzvI)-3-(2-nitro-phenvlsulfanvl)-l//-indole-6-carboxvIic acid amide (Compound 33 . Structure 16 of Scheme IV. where R1 = 3.5-difluorophenvl R2 =2-nitrophenvl. R3=R4=ffl The title compound was prepared according to General method 2, using 51.1 mg (116 umol) carboxylic acid, 19.5 mg (128 umol) HOBt, 24.6 mg (128 umol) EDCI and 31.1 mg (581 umol) ammonium chloride. The title compound was obtained as a yellow solid (9,0 mg; 18%). LCMS: 4.16 min (100.0%, MH+ = 440); lH NMR (CDC13): 5 5.46 (s, 2H, CH^Ar), 6.65 (m, 2H), 6.77 (m, 1H), 6.88 (dd, 1H, Jl = 8.2 Hz, J2 = 1.0 Hz)), 7.21 (m, 1H), 7,29 (m, 1H), 7.51 (dd, 1H, Jl = 7.8 Hz, J2 = 1.0 Hz), 7.57 (d, 1H, J = 7.7 Hz), 7.58 (s, 1H), 8.05 (s, 1H), 8.29 (dd, 1H, Jl = 8.2 Hz, J2 = 1.0 Hz). Example 6 6-Methoxv-3-(2-nitro-phenvlsulfanyi)-l-pvridin-2-ylmethyl-l //-indole (Compound 9 . Structure 3 of Scheme I, where R1 = 2-pvridyl. R2 = 2-nitrophenvl, R3=R4=H. Rs=QMe) General method 3:3-sulfanylation of a (un)substituted indole of structure 1 to give substituted indoles of structure 4, followed by indoIe-iV-alkylation to give N-alkylated indole structure 3 (Scheme I). (a) 6'Methoxv-3-(2-nitro-phenvlsu]fanvl)-l//Lindole (Structure 4 of Scheme I, where R2 = 2-ni:rophenvl. R]=R3=R4=R R5=OMe) To a solution of 6-methoxyindole (1.5 g, 10.2 mmol) in EtiO (100 mL) was added a solution of 2-nitrobenzenesulfenyl chloride (1.93 g, 10.2 mmol) in 50 mL Et:0 dropwise, over a 4 minute period. Tne resulting yellow solution was stirred at room temperature for 1 h. The solvent was evaporated and the crude product was purified over a silica column (heptane/ethyl acetate 9:1) to give the title compound (3.054 g, yield = 97%). HPLC : 3.72 min. purity 96.7%, TLC (heptane/ethyl acetate 1:1): Rf = 0.6; lH NMR (CDCb): 5 3.87 (s, 3H, OCH3), 6,84 (dd, lHf Jl = 7.8 Hz, J2 = 3,13 Hz), 6.97 (in, 2H), 7.16 (t, 1H, J = 7.8Hz), 7.25 (t, 1H, J = 7.8Hz), 7.36 (d, 1H, J = 7.8 Hz), 7.44 (d-1H, J = 2.0 Hz), 8.26 (d, 1H, J = 7.8 Hz), 8.45 (s, 1H, NH). (b) 6-Methoxv-3-(2-nitro-phenvlsulfanvn-l-pvridin*2-ylmethvl-l//-indole (Compound v 9. Structure 3 of Scheme I, where R = 2-pyridyl, R" = 2-nitrophenyL R ~R =H, R5=OMe) To a solution of 6-Meihoxy-3-(2-nitro-phenylsulfanyl)-l//-indole (1.5 g, 5 mmol) in DMF (150 mL) was added NaH (60% in oil; 500 mg, 12.5 mmol) in small portions, over a 4 minute period. The resulting dark solution was stirred for 5 min. at room temperature. Then 2-picoiyl chloride hydrochloride (984 mg, 6 mmol) was added in small portions, over a 2 minute period. During stirring at room temperature (2h) the colour of the solution slightly changed from dark to yellow. Ethyl acetate (100 mL) was added and the mixture was washed with 2% aqueous citric acid (2x100 mL) and water (100 mL). The organic phase was dried (MgS04) and the solvent was evaporated. The crude product was purified by crystallisation (ethyl acetate/heptane) to give the title compound (1.437 g, yield = 74%). HPLC : 10.3 min, purity 99.6%, TLC (heptane/ethyl acetate 1:1): Rf = 0.3; lH NMR (CDC13): 5 3.80 (s, 3H, OCH3), 5.47 (s, 2H, NCH2), 6.82 (m, 2H), 6.88 (d, 1H, J = 7.8 Hz), 7.01 (dd,lH,Jl = -7.3 Hz, J2 = 1,6 Hz), 7.15-7.19 (m, lH),7.25(m, 2H), 7.37 (d, 1H, j = Z.6 Hz), 7.60-7.64 (in, 1H), 8.26 (dd, 1H, II = 7.8 Hz, J2 = 1.6 Hz), 8.63 (d, 1H, J = 5.88 Hz). According to General method 3 the following compounds were prepared: Example 7 W33-Dif]uoro-benzyl)-6-m^ (Compound 65 , Structure 3 of Scheme t where R1 = 3.5-difluorophenyl. R2 = 2 -pyridvK R3=R*=H, R5=OMes? Under a nitrogen atmosphere: to a cooled (-10°C) solution of 2-mercaptopyridine (25 mg, 0.22 mmol) in CC14 (2 mL) was passed C^-gas during a period of 1 minute. The solvent was evaporated and a solution of l-(3,5-Difluoro-benzy])-6-methoxy-l//-indole (25 mg, 0.09 mmol) in Et20 (2 mL) was added dropwise. The reaction mixture was concentrated and the crude product was purified by preparative LCMS to give the title compound (7.77 mg, yield = 23%). LCMS : 3.95 min (100%, MH+ 383); TLC (heptane/ethyl acetate 1:1); Rf= 0.6; 'H-NMR (CDCb) : 5 2.23 (s, IH, NH), 3.82 (s, 1H, OCH3), 6.65 (m, 2H), 6.73 (d, 1H, J = 2.7 Hz), 6.73-6.78 (m, IH), 6.80 (d, IH, J = 7.8 Hz), 6.87 (dd, IH, Jl = 7.8 Hz, J2 = 1.6 Hz), 7.00 (ddd, IH, Jl = 9.8 Hz, J2 = 4.7 Hz, J3 = 0.8 Hz), 7.35 (s, IH), 7.42 (ddd, IH, Jl = J2 = 7.8 Hz, J3 = 1.6 Hz), 7.50 (d, IH, 8.6 Hz), 8.46 (d, IH, J = 4.7 Hz). Example 8 {2-fl-f3.5-Difluoro-benzYl>^^ (Compound 16 , Structure 8 of Scheme in, where R = 3,5-difluorophenvL RJ-R =H. R5=OMe) a) 2-R-(3.5-Dif1uoro-benzyl)-6"methoxy-li7-indol-3-vlsulfanvl1-beazoic acid methyl ester ^Compound 19 , Structure 7 of Scheme III, where R1 = 3,5-difluorophenyh R3=R4^H, Rs=OMe^ Chlorine gas was bubbled through CCU (5 mL) at -10°C for 3 min. Then a solution of methylthiosalicylate (91 pL, 0.66 mmol) in CCI4 (2 mL) was added. The mixture was stirred at -10°C for 5 min and then at room temperature for 15 min. The mixture was concentrated and redissolved in CH2CI2 (5 mL). To this solution a solution of 1 -(3,5-Difluoro-benzyl)-6-methoxy-lF-kidole (121 mg, 0.443 mmol) in CH2CL (3 mL) was added dropwise. The mixture was stirred at room temperature for 2 h and was concentrated. The crude product was purified by column chromatography (ethyl acetate/heptane 1:9) to give the title compound as a white solid (161 mg, 83% yieid). LCMS: 4.72 min (MH+ = 440); 'H-NMR (CDCI3) : 5 3.82 (s? 3H, ArOCH3), 3.99 (s, 3H, CO2CH3), 5.30 (s, 2H, CH2Ar), 6.62-6.69 (m, 2H), 6.71-6.77 (m, 2H), 6.83 (dd, IK; Jl = 8.6 Hz, J2 = 2.4 Hz), 6.87 (dd, 1H, Jl - 8.4 Hz, J2 = 1.2 Hz), 7.06-7.11 (m, 1H, 7.15-7.20 (m, lH),7.30(s, lH),7.44(d, 1H, J = 8.6 Hz), 8.02 (dd, IH, Jl = 8.0 Hz, J2 = 1.2 Hz). b) (2-n- ^Compound 16 , Structure 8 of Scheme III, where R1 =3,5-difluorophenyl R3=R =H. R5=OMe) Under a nitrogen atmosphere: to a solution of 2-[l-(3,5-Difluoro-benzyl)-6-methoxy-l#-indol-3-ylsuIfanyl]-benzoic acid methyl ester (13.5 mg, 0.031 mmol) in THF (2 mL) was added LiAIH4 (1.0 M in THF, 0.040 mL, 0.040 mmol). The mixture was stirred at room temperature for 3 h. Then ethyl acetate (25 mL) was added and the mixture was washed with 3% aqueous citric acid (2x25 mL) and brine (25 mL). The organic phase was dried (MgS04) and concentrated to give a colourless oil (15 mg). The crude product Example 9 2-f 1 'n,5-DifluorQ-benzvn-6-methoxv-l^-indol-3-vlsulfanvn-ben2amide (Compound 18, Structure 11 of Scheme m. where R1 = 3.5-difluorophenvl, R3=R4^H. Rs=OMe) a) 241-r3,5-Difluoro-benzyl)-6-merhoxv-l//-indol-3-ylsu1fanvI]-benzoic acid (Structure 9 of Scheme ML where R1 =3,5-difluorophenvL R3=R4=R R5=OMe) To a solution of 2-[l-(3,5-Difluoro-benzyl)-6-methoxy-li^-indol-3-ylsulfanyl]-benzoic acid methyl ester (97 mg, 0.221 mmol) in THF (10 mL) was added a solution of LiOH-H20 (71 mg, 1.69 mmol) in water (10 mL). The mixture was stirred at room temperature for 17 h and then at 60°C for 24 h and was then acidified with 3% aqueous citric acid. Ethyl acetate (50 mL) was added and the mixture was washed with 3% aqueous citric acid (2x50 mL) and brine (50 mL). The organic phase was dried (MgS04) and concentrated to give a yellow solid (104 mg). The crude product was recrystallised from ethyl acetate/heptane to give the title compound as a yellow powder (49 mg, 52% yield). LCMS: 4.37 min (MH+ = 426); 'H-NMRfCDCb): 5 3.77 (s, 3H, OCH3), 5.51 (s, 2H, CH2Ar), 6.69 (d, 1H, J = 8.0 Hz), 6.76 (dd, 1H, Jl = 8.4 Hz, J2 = 2.4 Hz), 6.98-7.04 (m, 2H), 7.11-7.15 (m, 1H), 7.16-7.25 (m, 4H), 7.83 (s, 1H), 7.92 (dd, 1H, J] = 8.0Hzr J2 = 1.6 Hz). General method 4: Reaction of an amine with a carboxylic acid of structure 9, with TBTU and DIPEA, to give amides of structure 3, in which R2 = phenyl-2-carboxamide , exemplified by compounds of structure 10 and 11 (Scheme HI). - - b^241-r3.5-Difluoro-benzvl)-6-methox^-l/f-indol-3'Vl5ulfanvH-benzarnidc (Compound 18, Structure 11 of Scheme m. where Rl = 3.5-difluorophenyK R3=R4=R R5OMe) Through a solution of 2-[l-(355-Difluoro-benzyI)-6-methoxy-l//"-indol-3-ylsulfanyl]-benzoic acid (36 mg, 0.085 mmol), TBTU (28 mg, 0.087 mmol) and DIPEA (30 jiL, 0.172 mmol) in DMF (1 mL) was bubbled NH3 gas for 10 min. The mixture was then stirred at room temperature for 3 days. Then 3% aqueous citric acid (0.4 mL) was added and the crude reaction mixture was purified over a RP-SPE cartridge (2g sorbent; 25% aqueous methanol to 100% methanol) to give a white solid (34 mg). The crude product was purified by column chromatography (ethyl acetate) to give the title compound as a colourless oil, which solidifies on standing (31 mg, yield: 86%). LCMS: 4.20 min (MH+ = 425); 'H-NMR (CDCU): 5 3.81 (s, 3H, OCH3), 5.39 (s, 2H. CH2Ar), 6.05 (s, br, 1H, NH), 6.28 (s, br, 1H, NH), 6.61-6.67 (m. 2H), 6.70-6.72 (m, 1H), 6.73-6.77 (m, 1H), 6.83 (dd, 1H, Jl = 8.8 Hz, J2 -2.0 Hz). 6.92 (dd, 1H, Jl = 8.0 Hz, J2 = 1.2 Hz), 7.07-7.17 (m, 2H), 7.31 (s, 1H), 7.45 (d, 1H, J = 8.8 Hz), 7.60 (dd, lH,Jl=8.0Hz,J2=1.2H"z). Example 10 2-ri-('3.5-Difluoro-benzvn-6-methoxv-l/f-indol-3-vlsulfanvll-A-methvl-benzamide (Compound 17, Structure 10 of Scheme III, where R = 3,5-difluorophenyL RJ=R =H. R5=OMe) According to general method 4 compound 17 was synthesised from methylamine. LCMS: 4.07 min (MH+ = 439). Example 11 241-f3,5-Difluoro-ben2^1>6-m (Compound 20, Structure 12 of Scheme IH where R1 = 3.5-difluorophenvL R3=R4=H. R5=OMe) ■ To a cooled (0°C) solution of 2-[l-(3?5-Difluoro-benzyl)-6-methoxy-l//-indol-3-ylsulfanyl]-benzamide (8 mg, 0.019 mmol) and Et3N (10 \iL, 0.072 mmol) in CH2C12 (1.5 mL) was added Tf20 (6 fiL, 0.036 mmol). The mixture was stirred at 0°C for 2 h and then at room temperature for 22 h. Water (25 mL) was added and the mixture was extracted with CH2CI2 (2x25 mL). The combined organic phases were dried (NaaSCU) and concentrated to give a brown oil (25 mg). The crude product was purified by column chromatography (ethyl acetate/heptane 1:2) to give the title compound as a pale pink oil (3 mg, yield: 39%). LCMS: 4.57 min (MH+ = 407); lH-NMR(CDCl3): 3 3.82 (s, 3H. OCH3), 5.30 (s, 2H, CH2Ar), 6.62-6.67 (m, 2H), 6.71-6.73 (m, 1H), 6.74-6.78 (m, 1H), 6.86 (dd, 1H, Jl = 8.8 Hz, J2 = 2.0 Hz), 6.91 (d, 1H, J = 8.4 Hz), 7.11-7.15 (m, 1H), 7.26-7.30 (m, 1H), 7.37 (s, 1H), 7.46 (d, 1H, J = 8.8 Hz), 7.57-7.60 (m, 1H). Example 12 l-(3,5-Difluoro-ben2?/n-3-(2-nitro-phenvlsulfanvl)-liy-indole'6-carbonitrile (Compound 26, Structure 17 of Scheme IV, where R1 = 3.5-difluorophenvl R2 = 2 -nitrophenvh R3=R4=H) To a ccoled (0°C) suspension of l-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-lH-indole-6-carboxyIic acid amide (15 mg, 0.034 mmol) and EuN (10 JIL. 0.072 mmol) in CH2C1: (1.5 mL) was added Tf20 (13 fxL, 0.077 mmol). The mixture was stirred at 0°C for 2 h and then at room temperature for 20 h. Water (25 mL) was added and the mixture was extracted with CH2CI2 (2x25 mL). The combined organic phases were dried (Na2SC>4) and concentrated to give the title compound as a yellow solid (13 mg, yield: 91%). LCMS: 4.55 min (MH+ = not detectable); !H-NMR (CDC15): 5 5.42 (s, 2H, CH2Ar), 6.63-6.69 (m, 2H), 6.78-6.85 (m, 2H), 7.21-7.25 (m, 1H), 7.28-7.33 (m, 1H), 7.44 (dd, 1H, Jl = 8.4 Hz, J2 - 1.2 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.66 (s, 1H), 8.29 (dd, 1H, Jl = 8.4 Hz, J2= 1.6 Hz). Example 13 l-n,5-Difluoro-benzvl)-6'methoxv-3-f2-nitro-benzenesulfinvl)-l//-indole (Compound 64, Structure 5 of Scheme EL where R1 = 3,5-difluorophenvL R2 = 2-nitrophenvU R3=R4=R RsK)Me> To a solution of 1 -(3,5-Difluoro-ben2^'l)-6-methoxy-3-(2-nitro-phenylsuifanyl)-l//-indole (40 mg, 0.09 mmol) in CH2CI2 (4 mL) was added meta-chloroperbenzoic acid (14.5, 0.08 mmol). The solution was stirred at room temperature for 2 h. The solvent was evaporated and the crude product was purified by prep LC-MS to give the title compound (14.3 mg, yield = 34%). HPLC : 4.13 min, purity 100%; TLC (heptane/ethyl acetate 1:1) : Rf = 0.4; !HNMR (CDCl:.): 5 3.66 (s, 3H, OCH3), 5.12 (s, 2H), 6.57 (m, 3H), 6.75 (m, 2H), 7.47 (d, 1H, J = 7.8 Hz), 7.52 (s, 1H), 7.66-7.70 (m, 1H), 8.28-8.32 (m, IK), 8.23 (dd, 1H, Jl - 7.8 Hz, J2 = 1.9 Hz), 8.80 (dd, 1H, Jl = 7.8 Hz, J2 = 3.1 Hz). Example 14 l-f3,5-Difluoro-benzvO-6-methoxv^ 62, Structure 6 of Scheme n. where Rl = 3.5-difIuorophenvl R2 = 2-nitrophenvl R3=R4=H. Rs*OMe^ To a solution ofl-(3,5-Difluoro-benzyl)-6-m indole (40 mg, 0.09 mraol) in CH2CI2 (4 mL) was added meta-chloroperbenzoic acid (46.5 mg, 0.27 mmol). The solution was stirred at room temperature for 6 h. The solvent was evaporated and the crude product was purified by LC-MS to give the title compound (14.5 mg, yield = 34%). HPLC: 4.38 min. purity 100%; TLC (heptane/ethyl acetate 1:1); Rf = 0.6; ]HNMR (CDCb): 5 3.71 (s, 3H, OCH3), 5.25-(s; 2H), 6.58 (d, 1H, J = 3.1), 6.62 (m, IH), 6.07- 6.11 (m, 1H), 6.88 (dd, IH, Jl = 7.8 Hz, J2 = 3.1 Hz), 7.63 (m, 4H), 7.72 (d, IH, J = 7.8 Hz), 7.83 (s, IH), 8.37 (dd, IH, Jl = 7.8 Hz, J2 = 1.9 Hz). « To a solution of 6-Methoxy-3-(2-nitro-phenylsulfanyl)-l-pyridin-2-ylmethyl-lrf-indoie in methylene chloride was passed HCl-gas till the organic salt crystallised. The title compound was isolated by filtration. LC-MS : 4.04 min (MH+ = 392); !H NMR (DMSO): 5 3.78 (s, 3H, OCH3), 5.78 (s, 2H, NCH2), 6.77 (dd, 1H, Jl = 7.8 Hz, J2 = 2.0 Hz), 6.93 (dd, 1H, Jl = 7.8 Hz, J2 = 0.8 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.26 (d, 1H, J = 2.0 Hz), 7.34 (m, 2H), 7.48-7.52 (m, 1H), 7.59 (t, 1H, J = 7.0 Hz), 7.96 (s, 1H), 8.08 (t, 1H, J = 7.0 Hz), 8.2" (dd, 1H, Jl = 7.8 Hz, J2 = 1.6 Hz), 8.74 (d, 1H, J = 6.7 Hz). Example 16 1 -(3,5-Difluoro-benzvlV3-(2-nitro-phenvlsulfanvl)-li:/-indoi-6-ylamine (Compound 57. Structure 23 of Scheme V. where R1 = 3,5-difluorophenvl. R: = 2-nitrophenvl R3=R4=H1 a) l-(3.5-Difluoro-benzvl)-6-nitro-l//-indole (Structure 19 of Scheme V, where R1 = 3.5-difluorophenvl. R3=R4=ffl To a solution of 6-nitroindole (162 mg, 1.0 mmol) in DMF (4 mL) was added NaH (60% dispersion on oil; 80 mg, 2.0 mmol). The resulting dark solution was stirred at room temperature for 15 minutes. 3,5-difluorobenzyl bromide (129 u.L, 1,1 mmol) was added. The reaction mixture was stirred overnight, poured into acidified water and extracted twice with ethyl acetate. The combined organic layers were dried over Na?S04 and concentrated in vacuo. The product was purified over a S1O2 column (heptane/ethyl acetate 9:1) to give the title compound as a yellow solid (270 mg; yield = 94%). LCMS: 5.54 min (100.0%, MH+ = 289); 'HNMRfCDCb): 5 5.40 (s, 2H, CHjAr), 6.58 (m, 2H), 6.71 (d, 1H, J = 3.5 Hz), 6.75 (m, 1H), 7.26 (s, 1H), 7,41 (d, 1H, J = 3.5 Hz), 7.71 (d, 1H, J = 8.3 Hz), 8.05 (dd, 1H,J1 = 8.3 Hz, J2 = 2.0 Hz), 8.21 (d, 1H,J = 2.0 Hz). b) 1-(3.5-Difluoro-benzviyi#-indol-6-ylamine (Structure 20 of Scheme V. where R1 = 3.5-difluorophenvl. R3=R4=H) To a solution of l-(3?5-Difluoro-benzyl)-6-nitro-l//"-indole (144 mg, 0.5 mmol) in ethanol (20 mL) was added hydrochloric acid 37% (80 ^iL) and SnCl2.2H20 (600 mg). The reaction mixture was stirred at 60 °C for 40 h and was then concentrated in vacuo. The residue was poured into ethyl acetate and a concentrated NaHC03-solution was added. The two-layer phase system was filtered over decalite to get rid of the tin salts and the filtrate was twice extracted with ethyl acetate. The combined organic layers were dried over Na2SC>4 and concentrated in vacuo. The product was purified over a Si02 column (heptane/ethyl acetate 9:1) to give the title compound as a colourless oil (89 mg, yield = 69%). LCMS: 3.20 min (97.7%, MH+ = 259); "HNMRCCDCb): 5 5.12 (s, 2H, CH2Ar), 6.52 (m, 2H), 6.56 (d, 1H, J - 3.5 Hz), 6.63 (m, 1H), 7.97 (dd, 1H, Jl = 8.3 Hz, J2 = 2.0 Hz), 7 J 3 (d, IH, J = 3.5 Hz), 7,17 (d, 1H, J = 2.0 Hz), 7.55 (d, IH, J = 8.3 Hz). c) l-(3,5-Difluoro-benzvl)-3-(2-nitro-phenvlsulfanvn-l//-indol-6-vlamine (Compound 57, Structure 23 of Scheme V, where R1 = 3,5-difluorophenyI, R2 = 2-nitrophenyl R3=R4=ffi To a solution of l-(3,5-Difluoro-benz>l)-l//-indol-6-ylamine (25 mg, 0.1 mmol) in DCM (4 mL) was added 2-nitrobenzenesulfenyl chloride. The resulting yellow solution was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and purified over a S1O2 column (heptane/ethyl acetate 9:1) to give the title compound as an orange solid (11.6 mg, yield = 28%). LCMS: 5.11 min (100.0%, MH+ = 412); ]HNMR(CDCl3): 5 5.22 (s, 2H, C&Ar), 6.56 (m, 2H), 6.65 (m, IH), 6.84 (dd, IH, Jl = 8.2 Hz, J2 = 1.2 Hz), 7.00 (dd, IH, Jl - 8.2 Hz, J2= 1.2 Hz ), 7.19 (m, IH), 7.30 (d, IH, J = 1.2 Hz), 7.31 (s, IH), 7.37 (d, IH, J = 8.2 Hz) 7.49 (m, IH), 8.27 (dd, IH, Jl = 8.2 Hz, J2 = 1.2 Hz). Example 17 W'-rH3.5-Difluoro-benzyiy3-(2-nitro-phenyls^^ (Compound 58. Structure 22 of Scheme V, where R1 = 3.5-difluorophenvl. R2 = 2- nitrophenvl. R3=R4=H, Z = methyl) General method 5: Reaction of an acid anhydride with a 6-aminoindole of structure 20 to give compounds of structure 21, followed by sulfanylation of the indole 3-position to give compounds of structure 22 (Scheme V). a) TV-ri-GJ-Difluoro-benzvn -l/f-indol-6-yl]-acetamide (Structure 21 of Scheme V, where R! = 3,5-difluorophenyK R3=R4=R Z = methyl) To a solution of l-(3s5-Difluoro-benzv*l)-li7-indol-6-ylamine (25 mg, 0.1 mmol) in DCM (4 mL) was added pyridine (25 jaL) and acetic anhydride (9.8 \iL, 0.11 mmol) and stirred overnight at room temperature. The reaction mixture was poured into 10 mL of water and neutralised with NaHC03 and extracted twice with DCM. De combined organic layers were dried overNa2SC>4 and concentrated in vacuo to give the crude compound as a off white solid (23.3 mg, yield = 84%). The product was used without further purification. LCMS: 4.10 min (97.4%, MH+ = 301); ^NMRCCDCh): 5 2.18 (s, 3H, CH3CON), 5.28 (s, 2H, CtkAr), 6.53 (d, 1H, J = 3.1), 6.58 (in, 2H), 6.68 (m, 1H), 6.87 (dd, 1H, Jl = 8.3 Hz, J2 = 1.6 Hz), 7.07 (d, 1H, J = 3.1 Hz), 7,55 (d, 1H, J = 8.3 Hz), 7.90 (s, 1H). b)#-ri-(3.5-Difluoro-benzvlV3-(2-n^ (Compound 58, Structure 22 of Scheme V, where R1 = 3.5-difluorophenvl R2 = 2- nitrophenvl R3=R4=H, Z = methyl) To a solution of 7V'-[l-(335-Difluoro-ben2y])-liy-indol-6-yl]-acetamide (23.3 mg, 0.08 mmol) in diethyl ether (4 mL) was added 2-nitrobenzenesulfenyl chloride (14.7 mg, 0.09 mmol). The resulting yellow solution was stirred overnight at room temperature. The mixture was concentrated in vacuo and purified over a SiCh column (heptane/ethyl acetate 9:1) to give the title compound as a yellow solid (35.0 mg, yield = 96%). LCMS: 4.26 min (98.6%, MH+ = 454); ]H NMR (DMSO): 5 2.03 (s, 3H, CH3CON), 5.51 (s, 2H, ClfeAr), 6.89 (dd, 1H, J = 8.3 Hz, J2 = 1.2 Hz), 6.95 (m, 2H), 7.17 (dd, 1H, J\ = 8.3 Hz, J2 = 2.0 Hz), 7.19 (m, 1H), 7.27 (d, 1H, J = 8.3 Hz), 7,34 (m, 1H), 7.49 (m, 1H), 7.97 (d, 1H, J= 1.2 Hz), 8.02 (s, 1H), 8.27 (dd, 1H, Jl - 8.3 Hz, J2 = 1.2 Hz). Example 18 #-ri-(3,5-Difluoro-benzyty3^ acetamide (Compound 59, Structure 22 of Scheme V. v/here R1 = 3,5-difluorophenyl, R2 = 2-nitrophenyl. R3=R4=R Z = trifluoromethyl) According to General method 5, step a): Ar-[l-(3,5»Difluoro-benzyl>l//-indo!-6-yl]-2,2,2-trifluoro-acetamide was prepared using l-(3,5-Difluoro-benzyl)-li7-indol-6-ylamine (17.7 mg, 69 jamol), pyridine (17 jiL) and trifluoroacetic anhydride (9,68 ^L, 70 |xmol). The compound was purified over a SiCh column (heptane/ethyl acetate 9:1) to give the title compound as a white solid (10.9 mg, yield = 61%). LCMS: 4.41 min (82.1%, MH+ = 355) According to General method 5, step b): Ar-[l-(355-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyI>lF-indol-6-yl]-2?2,2-trifluoro-acetamide was prepared using //-[l-(3,5-Difluoro-benzyO-liZ-indol-e-ylj^^^-trifluoro-acetamide (10.9 mg, 31 jimol) and 2-nitrobenzenesulfenyl chloride (5.7 mg, 37 (imol). The compound was purified over an HPLC column (MeCN/H20) to give the title compound as a yellow solid (10.2 mg, yield = 65%). LCMS: 4.65 min (89.0%, MH+ = 508j; *H NMR (DMSO): 5 5.56 (s, 2H, CHAr), 6.87 (dd, 1H, J = 8.3 Hz, J2 « 1.2 Hz), 7.01 (m, 2H)3 7.20 (m, 1H), 7.35 (m, 1H), 7.37 (dd, 1H, JI = 8.3Hz,J2=2.0Hz),7.39(d, 1H, J = 8.3 Hz), 7.49 (m, lH),'f9$vifl, IH,J = 2,0 Hz), 8.15 (s, 1H), 8.28 (dd, 1H, Jl = 83 Hz, J2 = 2.0 Hz). Example 19 Compound 97; iV4H3>Pifluoro4)enzv^^ fluoro-acctamide, structure 28 of Scheme VII. where R1 = 3.5-difluorophenvt, R2 = 2- nitrophenyl R3=R4=H, Z1== monofluoromethyl. a) 1 -(3.5-Difluoro-benzvlV6-nitro-l J7-indole, structure 19 of Scheme VII, where Rl = 3.5-difluorophenyL R2=R3=R4=H. To a solution of 6-nitro-lF-indole (19.5 g, 120 mmol) in NMP (500 mL) was added at 0 °C cesium carbonate (39.1 g, 120_mmol). After stirring for 30 min at 0 °C 3,5-difluorobenzyl bromide (30.0 g, 144 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 18 hrs. The mixture was poured into saturated aqueous ammonium chloride (1 L) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with H2O (2 x 500 mL) and brine (500 mL) and dried (Na2S04) and concentrated to give the title compound (65 g, yellow solid) which was used without fiirter purification. b) 1 -r3.5-Difluoro-benzvn-l//-indol-6-ylamine, structure 20 of Scheme VCL where R1 = 3.5-difluorophenvU R2=R3=R4=H. EtOH 96% (1L) was added to 1 -(3,5-difluoro-benzyl)-6-nitro-l //-indole and the mixture was stirred at 60 °C until al! material was dissolved. 37% HC1 (37 mL) was added followed by tin(H)chloride dihydrate (268 g, 1.19 mol) and stirring was continued at 60 °C for 18 hrs. After the mixture was cooled to room temperature the solvent was removed under reduced pressure. Ethyl acetate (800 mL) was added and the . mixture was poured into saturated aqueous NaHCC>3 (1 L) and filtered over kieselguhr. The layers were separated and the organic layer was washed with H2O (2 x 500 mL) and brine (500 mL), dried (Na2S04) and concentrated to afford the the title compound (54 g, brown oil/solid) which was used without further purification. c) ri-r3,5-Difluoro-benzvn-l//"-indol-6-vl1-carbamic acid tert-butvl ester, structure 26 of Scheme VEL where R1 =3,S-difluorophenYK R2=R3=R4=H. l-(3,5-Dif]uoro-benzyl)-l#-indol-6-ylamine was dissolved in NMP (1 L) and triethylamine (34 mL, 242 mmol) was added followed by di-terr-butyl dicarbonate (53 g, 242 mmol) and the mixture was stirred at room temperature for 18 hrs. The mixure was poured into saturated aqueous NaHCOs (1.5 L) and extracted with ethyl acetate (3 x 750 mL). The combined organic layers were washed with H2O (1 L) and brine (1 L), dried (Na2S04) and concentrated. The crude product was purified using column chromatography (heptane/ethyl acetate 4:1) to afford the title compound (39 g. 109 mmol, 91% (three steps), white solid). d) fl-r3,5-Difluoro-benzvn'3-f2-mtro-phenvlsulfanvlVl/f-indol"6-yl]-carbajnicacid tert-butvl ester, structure 27 of Scheme VII, where R! = 3,5-difluorophenvl. R = 2-nitrophenvl R3=R4=H. To a solution of [l-(3,5-difluoro-benz\'l)-l/7-indol-6-yl]-carbamic acid tert-butyl ester (39 g, 109 mmol) in diethylether (750 mL) was added 2-nitrobenzenesulfenyl chloride (20.4 g, 109 mmol) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was poured into saturated aqueous NaHCCh (1 L) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with H2O (400 mL) and brine (400 mL), dried and concentrated to afford the title compound (56 g, yellow solid) which was used without further purification. e) l-G.5-Difluoro-benzvn-3-f2-nitro-Dhenvlsulfanvn-l//'-indol-6-vlamine, structure 23 of Scheme VIL where R1 = 3,5-difluorophenvl, R2 = 2-nitrophenvl, R3=R4=H. [l-(3,5-Difluoro-ben2yl)-3-(2-nitro-phenylsuIfanyl)-l//-indol-6-yl]-carbamic acid tert- butyl ester was dissolved in CH2Cl2 (1 L) and under nitrogen atmosphere trifluoroacetic acid (48 mL, 624 mmol) was added dropwise at room temperature. After stirring for 1 h another portion of trifluoroacetic acid (48 mL, 624 mmol) was added and the reaction mixture was stirred for an additional hour. The mixture was diluted with CH2CI2 (500 mL) and H20 (1 L) and 3N NaOH solution was added until the pH of the mixture was 11-12. The layers were separated and the organic layer was washed with H2O (500 mL) and brine (500 mL), dried (Na2S04) and concentrated to afford the crude product. The product was purified using column chromatography (heptane/ethylacetate 1:1) to give the title compound (28 g, 68 mmol, 63 % (two steps), red/brown solid). General method 6: Reaction of an acid chloride (method a), carboxylic acid (method b) or sulfonyl chloride (method c) with a 6-aminoindole of structure 23 to give compounds of structure 28 and 29 (Scheme VII). Method a, b and c can all be carried out using the same procedure which is examplified below for method a. To a solution of l-(3,5-difluoro-benzyl)-3-(2-nitTO»phenylsulfanyl)-l//-indol-6-yiamine (300 mg, 0.73 mmol) in CH2C12 (7 mL) was added at 0 °C triethylamine (0.12 mL, 0.87 mmol). Subsequently monofluoroacetyl chloride (50 \xL, 0.73 mmol) was added and the mixture was stirred at room temperature for 18 hrs. The mixture was concentrated and purified using flash column chromatography (CftCb/MeOH 99:1) to afford compound 97 (317 mg, 0.67 mmol, 92%, yellow solid). 'HNMR (DMSO) 5 4.82 (s, 1H), 5.03 (s, 1H), 5.52 (s, 2H), £89 (dd, 1H, Jl -= 7.6 Hz, J2 = 1.1 Hz), 6.98-7.01 (m, 2H), 7.20 (tt, 1H, Jl = 9.5 Hz, J2 = 3.0 Hz), 7.28-7.32 (m, 2H), 7.33-7.37 (m, 1H), 7.46-7.51 (m, 1H), 7.98 (s, 1H), 8.08 (s, 1H), 8.27 (dd, 1H, Jl = 7.6Hz, J2= 1.1 Hz), 10.15 (s, 1H). Compound 61:1 -f3 To a solution of compound 63 (240 mg, 0.56 mmol) in CH2C12 (10 mL) was added at 0 °C boron trifluoride-methyl sulfide complex (2.37 mL, 22.5 mmol). After stirring for 2 hrs at 0 °C the reaction mixture was allowed to warm to room temperature and stirring was continued for another 4 hrs. The reaction mixture was poored into ice water (20 mL) and after addition of ethyl acetate (10 mL) the layers were separated. The organic layer was washed with saturated aqueous NaHC03 (20 mL) and brine (20 mL) and dried over Na2SC>4. Concentration gave the crude product which was purified using flash chromatography (heptane/ethylactate 3:2) to afford compound 61 as a yellow oil (87 mg, 0.21 mmol, 38%). lH NMR (CDC13) 5 4.75 (2, 1H), 5.29 (s, 2H), 4.66 (m, 1H), 6.72-6.79 (m, 3H), 6.98 (dd, 1H, Jl = 8.4 Hz, J2 = 1.5 Hz), 7.17-7.21 (m, 1H), 7.27-7.31 (m, 1H), 7.35-7.37 (m, 3H), 8.27 (dd, 1H, Jl = 8.4 Hz, J2 = 1.5 Hz). Example 22 Compound lQ9:3-f2-Nitro-phenvlsu1fanvlVl-pvridin-2-vlmethvl--l//Lindole-6- ■ -) carboxvlic acid dimethvlamide. structure 15 of Scheme IV, where R = 2-pyridvl R~ = 2-nitrophcnvL R3=R4=H, R8=R9=Me. a) l-P\Tidin-2-vlmethyl-1//'-indole--6-carbQxylic acid methvl ester. Under a nitrogen atmosphere: to a solution of lif-indole-6-carboxylic acid methyl ester (for synthesis see example 2a), 2.47 g, 14.1 mmol) in NMP (140 mL) was added CS2CO3 (10.1 mg, 31 mmol) at 0 °C. After stirring for 15 min 2-picolyl chloride hydrochloride (2.77 g, 16.9 mmol) was added and the mixture was stirred at room temperature for 18 h. Ethyl acetate (200 mL) was added and the mixture was washed with saturated aqueous ammonium chloride (3x150 mL) and brine (200 mL). The organic phase was dried (Na:S04) and concentrated. The crude product was purified using column chromatography (ethyl acetate/heptane 1:3) to give the title compound as a colourless oil, which slowly crystallised .on standing (2.72 g, 10.2 mmol, 72%). b) 3-r2-Nitro-phenylsulfanvlVl-pyridin-2-ylmethyl-lff-indole-6-carboxvlic acid methvl ester, structure 13 of Scheme IV, where R1 =2-pyridylf R2 = 2-nitrophenyl, R^=R^=H. To a solution of l-pyridin-2-ylmethyl-l#-indole-6-carboxylic acid methyl ester (2.72 g, 10.2 mmol) in dichloromethane (75 mL) was added at room temperature a solution of 2-nitrobenzenesulfenyl chloride (1.93 g, 10.2 mmol) in dichloromethane (75 mL). The mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated and the crude product was purified using column chromatography (ethyl acetate/heptane 1:5 to 1:2) to give the title compound as a yellow solid (3.21 g, 7.65 mmol, 75%). c) 3-r2-Nitro-phenylsulfanvl)-l-pyridin-2-ylmethyl"liy-indole-6-carboxylic acid, structure 14 of Scheme IV. where R! = 2-pyridyl, R2 = 2-nitrophenyL R3=:R4=H. To a suspension of 3-(2-nitro-phenylsulfanyl)-l-pyridin-2-ylmethyl-li7T-indole-6-carboxylic acid methyl ester (3.0 g, 6.58 mmol) in dioxane (65 mL) was added a solution of LiOH.HiO (1.66 g, 39.6 mmol) in water (65 mL). The reaction mixture was stirred overnight at 60°C. The mixture was then acidified to pH 6 by addition of 15% aqueous HC1 and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over Na2S04 and concentrated to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as yellow/orange crystals (2.47 g, 6.09 mmol, 93%) General method 7: amidation of 6-carboxyl indoles of structure 14 to give 6-carboxamideindoles of structure 15 (Scheme IV). Under nitrogen atmosphere: to a solution of 3-(2-nitro-phenylsulfanyl)-l-pyridin-2-ylmethyl-l/f-indole-6-carboxylic acid (700 mg, 1.73 mmol) in dry CH2C12 (70 mL) was added DIPEA (0.9 mL, 5.2 mmol), TBTU (840 mg, 2.6 mmol) and dimethylamine hydrochloride (420 mg, 5.1 mmol). The reaction mixture was stirred overnight at room temperature and then poured into saturated aqueous NaHC03 (100 mL). The organic layer was washed with brine (50 mL), dried (Na2S04) and concentrated. The crude product was purified by column chromatography (ethyl acetate/MeOH 95:5) to afford compound 109 (540 mg, 1.25 mmol, 72%, yellow solid). lH-NMR (CDC13): 8 2.97 (s, 3H), 3.11 (s, 3H), 5.53 (s, 2H), 6.90 (dd, 1H, Jl = 7.6 Hz, J2 = 1.5 Hz), 6.95 (d, 1H, J = 7.6 Hz), 7.17-7.28 (m, 4H), 7.51 (d, 1H, J = 7.6 Hz), 7.54 (s, 1H), 7.61-7.66 (m, 2H), 8.28 (dd, 1H, Jl = 8.4 Hz, J2 = 1.5 Hz), 8.61 (d, 1H, J = 4.6 Hz). Example 23 'Compound 118: jV^f3-(2-Nifro-phenylsulfany^ formamide. structure 28 of Scheme VDL where R1 = 3,5-pyrimidvl R2 = 2-nitrophenvl, R3=R4=R Z = H a) 6-Nitro-l -pyrimidin-5-ylmethyl-\H-indole 5-(Hydroxymethyl)pyrimidine (16.2 g, 147 mmol) was dissolved in 500 mL of CH2CI2 and cooled to -40°C. MsCl (16.0 g, 140 mmol) was added at -40 °C. The mixture was stirred for 1 hour allowing to reach -20°C. The solution was used as such. 6-Nitroindole-liy-indole (35.6 g, 220 mmol) was dissolved in 750 mL of DMF and NaH (50%, 12 g, 250 mmol) was added in portions and the mixture was stirred for 1 hour. The mixture was cooled to -40°C and the solution of the mesylate was added dropwise. The mixture was allowed to reach room temperature overnight The mixture was quenched with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (2x) and brine and dried over Na2S04- After concentration in vacuo the material was purified by means of column chromatography (silica, heptane/ethyl acetate (1 :!)->(! :4)) affording compound the title compound as a yellow solid (14 g, 55 mmol, 39%). b) l"Pvrimidin-5-vimethvl-l/AindoI-6-vlamine. 6-Nitro-l-pyrimidin-5-ylmethyI-l#-indole (4.1 g, 16.1 mmol) was dissolved in 100 mL of THF and 100 mL of isopropanol. Pd/C (2 g) was added and the mixture was stirred under an H2-atmosphere (balloon) for 2 hours. The mixture was filtered over Celite and washed with ethyl acetate affording the title compound after concentration (3.5 g, 15.6 mmol, 97 %). c) l-F^/rimidin-S-vlmethvl-liy-indQl-O'VlVcarbamic acid tert-butyl ester l-Pyrimidin-5-ylmethyl-li7-indol-6-ylamine (5.5 g7 24.6 mmol) was dissolved in 100 mL of NMP and triethylamine (3.5 g, 35 mmol) and di-ferr-butyl dicarbonate (7.0 g, 32 mmol) were added. The mixture was stirred overnight, quenched with NaHC03-sat and extracted with toluene (3x). The combined organic layers were washed with water (4x) and brine and dried overNa2S04. Concentration of the layers afforded the title compound (3.1 g, 39%). d) [3-(2-Nitro-phenylsulfanvn-l-pvrimidin-5-ylmethvl-l//Lindol-6-yl]-carbamicacid tert-butyl ester l-Pyrimidin-5-ylmethyl-li^-indol-6-yl)-carbamic acid tert-butyl ester_(3.1 g, 9.6 mmol) was dissolved in 150 mL of CH2Ch and 2-nitrobenzene sulfenylchloride (1.86 g, 9.8 mmol) was added. The mixture was stirred for 18 hours and quenched with NaHCCh-sat and extracted with ethyl acetate (2x). The combined organic layers were washed with brine and dried over Na2S04. The product was purified by means of column chromatography (silica, heptane / ethyl acetate (1:1) which gave the title compound as a yellow solid (3.8 g, 83 %). e)N-f3-f2-Nitto-phenylsulfany1>l^ [3-(2-Nitro-phenylsulfanyI)-l-pyrimidin-5-ylmethyl-lif-indol-6-yl]-carbamic acid tert-butyl ester (3.8 g, 8.0 mmol) was dissolved in 150 mL of formic acid and stirred for 4 hours. The solution was concentrated in vacuo. NaHCCb-sat was added and the mixture was extracted with CH2CI2 (2x) The combined organic layers were washed with brine and dried over Na2S04. The solution was allowed to stand overnight. The formed solid was filtered affording a mixture of compound 118 and structure 23 of Scheme VII, where R1 = 3,5-pyrimidyl, R2 = 2-nitrophenyl, R3=R4=H (2.4 g). Compound 118: *H NMR (CDC13 + drop MeOD) 5 5.47 (s, 2H): 6.91 (dd, 1H, Jl = 8.4 Hz, J2 = 1.1 Hz), 6.99 (dd, 1H. Jl = 8.4 Hz, J2 = 1.9 Hz), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H), 7.33 (s, 1H), 7.42 (d, 1H, J = 8.4 Hz), 7.49 (s, 1H), 8.22 (d, 1H, J = 1.9 Hz), 8.27 (dd, 1H, Jl = 8.4 Hz, J2 = 1.1 Hz), 8.66 (s, 2H), 9.16 (s, 1H). Example 24 Compound 119: 3-f2-Nitro-phenvlsulfanvD-l -pvridin-2-ylmethvl-lff-indole-6-carbonitrile. structure 3 of scheme I. where R =2-pvridvL R~ - 2-nitrophenvl. RJ = R = ER5 = CN. ■■ a) To a solution of 1 //-indole-6-carbonitrile (1.00 g, 7.04 mmol) in diethyl ether (50 mL) was added at rt 2-nitrobenzenesulfenyl chloride (1.34 g, 7.04 mmol) and the reaction mixture was stirred for 18 hrs. The mixture was concentrated and the crude product was purified using column chromatography (ethyl acetate/heptane 1:4 —► 4:1) to give S^-Nitro-phenylsulfanyO-l/f-indole-e-carbonitrile (1.62 g, 5.49 mmol, 78%). b) To a solution of 3-(2-nitro-phenylsulfanyl)-l/f-indole-6-carbonitrile (200 mg, 0.68 mmol) in DMF (5 mL) was added at 0 °C Cs2C03 (442 mg, 1.36 mmol) and the mixture was stirred for 20 min. Subsequently 2-picolylchloride hydrochloride (112 mg, 0.68 mmol) was added and the mixture was stirred for 18 hrs at room temperature. Aqueous saturated NaHCCb was added and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (Na2S04) and concentrated. The crude product was purified using column chromatography to afford compound 119 (223 mg, 0.58 mmol, 85%). *HNMR (CDC13) 5 5.54 (s, 2H), 6.86 (dd, 1H, Jl = 8.4 Hz, J2 = 1.1 Hz), 7.04 (d, 1H, J = 8.4 Hz), 7.19-7.23 (m, 1H), 7.26-7.31 (m, 2H), 7.40 (dd, 1H, Jl = 8.4 Hz," J2 =1.1 Hz), 7.59 (d, 1H, J = 8.4 Hz), 7.70 (td, 1H, Jl = 8.4 Hz, J2 = 1.9 Hz), 7.76 (s, 1H), 7.78 (s, 1H), 8.29 (dd, 1H, Jl = 8.4 Hz, J2 = 1.1 Hz), 8.63 (d, 1H, J = 3.0 Hz). Concentrated hydrochloric acid (0.0225 ml) was added to a solution of compound 119 (0.093 g) in dioxane. The mixture was stirred for 20 min. and then concentrated under reduced pressure, to give compound 120 (0.096 g). lB NMR (MeOD) 8 6.01 (s, 2H), 6.98 (dd, 1H, Jl = 7.6 Hz, J2 = 1.1 Hz), 7.28 -7.32 (m, 1H), 7.36-7.41 (mf 1H), 7.48 (dd, 1H, Jl * 7.6 Hz, J2 = 1.1 Hz), 7.53 (d, 1H, J = 8.4 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.93 (t, 1H, J = 6.1 Hz), 8.08 (s, 1H), 8.10 (s, 1H), 8.27 (dd, 1H, Jl = 8,4 Hz, J2 = 1.1 Hz), 8.44 (td, 1H, Jl = 8.4 Hz, J2 = 1.1 Hz), 8.85 (dd, 1H, Jl =6.1 Hz, J2 = 1.9 Hz). Compounds were tested for their Androgen Receptor activity in a transactivation assay and in a binding assay. The (anti-)androgenic activity of test compounds (EC50 and intrinsic activity) was determined in an in vitro bioassay of Chinese hamster ovary (CHO) cells stably transfectec with the human androgen receptor expression plasmid and a reporter plasmid in which the MMTV-promoter is linked to the luciferase reporter gene. The cell-line CHO-AR-pMMTV-LUC 1G12-A5-CA is described in Schoonen et ai. (2000), Journal of Steroid Biochemistry and Molecular Biology 74(4):213-222. The antiandrogenic activity of a test compound was determined by the inhibition of the transactivation via the androgen receptor of the enzyme luciferase in the presence of 1 nM DHT(5cc-dihydrotestosterone, 17p-hydroxy-5a-androstan-3~one). Intrinsic activity of antiandrogenic activity was determined in the presence of the reference antiandrogen 2-Hydroxy-2-methyl-A^(4-nitro-3-trifluoromethyl-phenyl)-propionamide (Hydroxyflutamide), and set at 100%. For androgenic activity, maximal intrinsic activity in the presence of 100 nM DHT was set at 100%. The results are presented in Table 4. note 1: EC50 scale: +++ l0000 nM note 2: efficacy scale (maximal intrinsic activity, i.e. intrinsic activity observed in the presence of 100 nM DHT, was set at LOO): -H- >0.80; + between 0.50 and 0.80; ± between 0.20 and 0-50; - The androgenic activity (EC50, potency, and efficacy) of the compounds in Table 5 was determined in an in vitro bioassay of Chinese hamster- ovary (CHO) cells stably transfected with the human androgen receptor expression plasmid and a reporter plasmid in which the MMTV promoter is linked to the luciferase reporter gene. The cell line CHO-AR-pMMTV-LUC 1G12-A5-CA is described in Schoonen et al (J. Steroid Biochem. Molec. Biol. 2002; 74: 213-222). The androgen receptor activity of compounds was determined in the presence of 0.1 jimol/1 onapristone. The maximal efficacy in the presence of 100 nmol/I DHT was set as 100%. The potencies are expressed as percentage of DHT activity. note 1: potency scale: ++ >5%; + between 1 % and 5%; ± between 0.1% and 1 %. note 2: efficacy scale (maximal intrinsic activity, i.e. intrinsic activity observed in the presence of 100 nM DHT, was set at 1.00): ++ >0.80; + between 0.50 and 0.80; ± between 0.20 and 0.50; - Determination of competitive binding to cytoplasmic human androgen receptor from recombinant CHO cells is used to estimate the relative binding affinity (RBA) of a test compound for androgen receptors present in the cytosol prepared of the recombinant CHO cell-line, CHO-AR-pMMTV-LUC 1G12-A5-CA. Compound 63 and compound 92 were tested in this binding assay and both compounds were found to have a relative binding affinity >1% relative to DHT. Claims wherein X is S, SO or SO2; R is a 5- or 6-membered monocyclic, hetero- or hornocyclic, saturated or unsaturated ring structure, optionally substituted with one or more substituents selected from the group consisting of halogen, CN, (lC-4C)fluoroalkyl, nitro, 11 C-4C)alkyl, (1 C-4C)alkoxy or (1 C-4C)fluoroalkoxy; R" is 2-nitrophenyl, 2-cyanophenyl, 2-hydroxymethyl-phenyl, pyridin-2-yl, pyridin- 2-yl-N-oxide, 2-benzamide, 2-benzoic acid methyl ester or 2-methoxyphenyl; R3 is H, halogen or (lC-4C)alkyl; R4 is H, OH, (lC-4C)alkoxy, or halogen; R5 is H, OH, (1 C-4C)alkoxy, NH2, CN, halogen, (lC-4C)fluoroalkyl, N02, hydroxy(lC-4C)aIkyl, C02H, C02(IC-6C)alkyI, or R5 isNHR6, wherein R5 is (lC-6C)acyl optionally substituted with one or more halogens, S(0)2(lC-4C)aIkyl, or S(0)2aryl optionally substituted with (1C-4C)alkyl or one or more halogens, or R5 is C(0)N(R8,R9), wherein R8 and R9 each independently are H, (3C- 6C)cycloalkyl, or CH2R10, wherein R10 is H, (lCoC)alkyl, (lC-5C)alkenyL hydroxy(lC-3C)alkyl, (lC-4C)alkylester of carboxy(lC-4C)alkyl, (!C-3C)alkoxy(lC-3C)alkyl, (mono- or di(lC-4C)alkyl)aminomethyl, (mono- or di(lC-4C)alkyl)aminocarbonyl, or a 3-, 4-, 5- or 6-membered monocyclic, homo- or heterocyclic, aromatic or non-aromatic ring, or R and R form together with the N a heterocyclic 5- or 6-membered saturated or unsaturated ring optionally substituted with (lC-4C)alkyl; or a salt or hydrate form thereof. 2. A compound according to claim 1, characterised in that - R is a 5- or 6-membered monocyclic, hetero- or homocyclic, saturated or unsaturated ring structure optionally substituted with one or more substituents selected from the group consisting of halogen, CN, CF3, niiro, methoxy, tritluoromethoxv or methvl; R~ is2-nitrophenyl, 2-cyanophenyl, 2-hydroxymethyl-phenyl, pyridin-2-yl, pyridin- 2-yl-N-oxide, 2-benzamide, 2-benzoic acid methyl ester or 2-methoxyphenyI; R3 is H, halogen or (lC-2C)alkyl; R4is HorF. 3- A compound according to claim 2, characterised in that R5 is H, OH, (lC-4C)alkoxy, CN, halogen, (lC-4C)fluoroalkyl, NO2> hydroxy(lC-4C)alkyl, CO2(IC-6C)a!kyl, or R5 is NHR6, wherein R6 is (IC-6C)acyl optionally substituted with one or more halogens, S(O)2(lC-4C)alkyl, or S(O)2aryl optionally substituted with (1C-4C)alkyl or one or more halogens, or R5 is C(0)N(R8,R9), wherein R8 and R9 each independently are H, (3C- 6C)cycloalkyl, or CH2R10, wherein R10 is H, (lC-5C)alkyl, (lC-5C)alkenyl, hydroxy(lC-3C)alkyl, (lC-4C)alkylester of carboxy(lC-4C)alkyl, (1C-3C)alkoxy(lC-3C)alkyl, (mono- or di(lC-4C)alkyl)aminomethyl, (mono- or di(lC-4C)alkyl)-aminocarbonyl, or a 3-, 4-, 5- or 6-membered monocyclic, homo- or heterocyclic, aromatic or non-aromatic ring, or R and R form together with the N a heterocyclic 5- or 6-membered saturated or unsaturated ring optionally substituted with (lC-4C)aIkyl. 4. A compound according to claim 3, characterised in that R3 is H or halogen; R4 is H; R5 is H, OH, (1 C-4C)alkoxy, CN, F, CI, CF3, NO2, hydroxy(] CMQalkyl, C02(1 C- 6C)alkyl, or R* is NHR6, wherein R6 is (lC-3C)acyl optionally substituted with one or more halogens or R5 is C(0)N(R8,R9), wherein R8 and R9 each independently are H, (3C-5C)cycloalkyl, or CH2R10, wherein R10 is H, (lC-SC)alkyl, 5. A compound according to claim 4, characterised in that X is S or S02; R2 is 2-nitrophenyl, 2-hydroxymethyl-phenyl, 2-benzamide, 2-methoxyphenyl, 2- cyanophenyl or pyridin-2-yl; R3 is H or F; R5 is H, OH, (lC-2C)alkoxy, CN, F, CI, CF3, N02, hydroxy(lC-4C)alkyl3 C02(1C-4C)alkyl, or R5 is NHR6, wherein R6 is formyl, acetyl, fluoroacetyl, difluoroacetyl, or trifluoroacetyl, or R5 is C(0)N(R8,R9), wherein R8 is H, and R9 is H, cyclopropyi or R9 is CH2R10, wherein R10 is H, (lC-2C)aIkyl, hydroxy (lC-2C)alky I, methoxy(lC-2C)a!kyI, cyclopropyi. 6, A compound according to claim 5, characterised in that XisS; R1 is 3,5-difluorophenyl, pyridin-2-yi, pyridin-3-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyrazin-2-yl, 3-fluorophenyl, 3-cyanophenyl, or 3-nitrophenyl; R2 is 2-nitrophenyl, 2-hydroxymethyl-phenyl, 2-methoxyphenyl, 2-cyanophenyl or pyridin-2-yl; R3 is H; R5 is OH, (I C-2C)alkoxy, CN, CF3, NO2, hydroxy(l C~4C)alkyl, CO2(1 C-4C)a]kyl, or NHR5, wherein R6 is formyl, acetyl, fluoroacetyl, difluoroacetyl, or trifluoroacetyl. 7. A compound according to claim 6, characterised in that Rl is 3,5-difluorophenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yL pyrimidin-4-yl, or pyrazin-2-yl; R2 is2-nitrophenyl, or 2-hydroxymethyl-phenvl; R5 is OH, (IC-2C)alkoxy, CN, hydroxy(lC-4C)alkyl, or NHR6, wherein R6 is forrnyL acetyl, fluoroacetyl, difluoroacetyl. or trifluoroacetyl. 8. A compound according to claim 7, characterised in that R1 is 3,5-difIuorophenyI, pyridin-2-yl, pyridin-3-yI, pyrimidin-5-yl? orpyrimidin-4- R2is2-nitrophenyl; R5 is OH, (lC-2C)alkoxy, CN, or NHR6, wherein R6 is formyl, acetyl, fluoroacetyl, difluoroacetyl, or trifluoroacetyl. 9. A compound according to claim 8 selected from the group consisting of 6- Methoxy-3-(2-nitro-phenylsulfanyl)-l-pyrimidin-5-ylmethyl-5-ylmethyl-1-H-indole 3-(2- Nitro-phenylsulfanyl)-1 -pyridin-2-ylmethyl-1 if-indole-6-carbonitrile, 3-(2-Nitro-phenylsulfanyl)-l-pyridin-2-ylmethyl-lH-indole-6-carbonitrile-hydrochloride, 3-(2-Nitro-phenylsulfanyl)-l-pyrimidin-5-ylmethyl-lH-indole-6-carbonitrile, 3-(2-Nitro-phenylsulfanyl)-l-pyrimidin-4-ylmethyl-lH-indoie-6-carbonitrile, A-[l-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-Ii/-indol-6-yl]-2-fluoro-acetamide, and 7V-[3-(2-Nitro-phenylsulfanyl)-l-pyrimidin-5-ylniethy]-lH-indol-6-yl]-formamide. 10. A compound according to claim 5, characterised in that X is S; R1 is 3,5-difluorophenyUpyridin^-y^pyridin-S-yl^-fludrophenyi, 3-cyanophenyI, or3-nitrophenyl; K2 is2-nitrophenyl, 2-hydroxymethyl-phenyl, 2-methoxyphenyl, 2-cyanophenyl or pyridin-2-yl; R3 is H; R5 is C(0)N(R8,R9), wherein R8 is H, and R9 is H, or CH2R10, wherein R10 is H, (1C-2C)alkyl, hydroxy(lC-2C)alkyi, or methoxy(lC-2C)alkyl. 11. A compound according to claim 10, characterised in that R is 3,5-difluorophenyl, pyridin-2-yl, orpyridin-3-yl; R" is 2-nitrophenyl, or 2-hydroxymethyl-phenyl; R5 is C(0)N(R8,R9), wherein RS is H, and R9 is CH2R10, wherein R10 is H, or (1C-2C)alkyL 12. A compound according to claim 11 which is l-(3,5-Difluoro-benzyl)-3-(2-nitro- phenylsulfanyl)-l#-indole-6-carboxylic acid methylamide. 13. A compound according to claim 4, characterised in that X is S; R is 3,5-difluorophenyl, pyridin-2-yI, pyridin-3-yl, 3-fluorophenyl, 3-cyanophenyl, or3-nitrophenyl; R" is2-nitrophenyl, 2-hydroxymethyl-phenyl, 2-methoxyphenyl, 2-cyanophenyl or pyridin-2-yl; R3 is H; R5 is C(0)N(R8,R9), wherein R8 and R9 each independently are H, or CH2R10, wherein R10 is H, (lC-5C)aIkyl, (lC-5C)alkenyl, hydroxy(lC-3C)alkyl, (]C- 3C)alkoxy(lC-3C)alkyl, or (mono- or di(lC-4C)alkyl)aminomethyl. 14. A compound according to claim 13, characterised in that R1 is 3,5-difluorophenyl, pyridin-2-yl, orpyridin-3-yl; R" is2-nitrophenyl, or 2-hydroxymethyl-phenyl; R' is C(0)N(R*,Ry), wherein R8 and R9 each independently are H, or CH2R10, wherein R10 is H, (lC-5C)alkyl, hydroxy(lC-3C)alkyl, or (lC-3C)alkoxy(lC-3C)alkyl. 15. A compound according to claim 14 which is l-(3,5-Difluoro-benzyl)-3-(2-nitro-pheny]sulfanyI)-lH-indole-6-carboxy!ic acid dimethylamide. 16. The compound of any one of claims 1-15 for use in therapy. 17. A pharmaceutical composition comprising a compound according to any one of claims 1-15 and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition according to claim 17 for the treatment of a disorder selected from the group consisting of an androgen-receptor related disorder, an androgen related disorder and androgen insufficiency. 19. A use of a compound according to any one of claims 1-15 for the manufacture of a medicament for the treatment of androgen-receptor related disorders, androgen related disorders and androgen insufficiency. 20. A method of treating a disorder selected from the group consisting of an androgen-receptor related disorder, an androgen related disorder and androgen insufficiency comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1-15 to a subject in need thereof.

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