OA16404A - Indole derivatives. - Google Patents

Abstract

The present invention relates to the indole derivatives of formula (I), wherein R1- R6 and X are defined in the claims and optical antipodes or racemates and/or salts thereof which are selective antagonists of bradykinin B1 to process for producing these compounds, pharmacological compositions containing them and to their use in therapy or prevention of painful and inflammatory conditions.

Description

The présent invention relates to new indole dérivatives of formula (I) and optical antipodes or racemates and/or salts thereof that serve as sélective bradykinin 1 antagoniste. The invention also relates to the process for producing such compounds. The invention further relates to pharmaceutical compositions comprising such compounds and the use of such compounds in methods for treating or preventing disorders involving pain and inflammation, The invention also provides a method for manufacture of médicaments useful in the treatment or prévention of such disorders.

BACKGROUND OF THE INVENTION

Kinins are endogenous peptides formed in plasma and peripheral tissues following proteolytic cleavage of kininogen precursors by kallikrein enzymes (Bhoola, Pharmacol. Rev. 1992, 44, 1-80). Their biological actions are mediated by two Gprotein coupled membrane receptors, denoted B1 and B2. (Regoli and Barabe, Pharmacol. Rev. 1980,32,1-46, Marceau et al., Pharmacol. Rev. 1998, 50, 357-386).

The first set of kinins, bradykinin (BK) and kallidin (LysBK) involve in acute physiological process of cardiovascular, rénal, nervous and immune System (Calixto et al., Pain, 2000, 87, 1-5). They preferentially act through stimulation of constitutively expressed and rapidly desensitizing B2 receptors, which are widely distributed in many tissues.

On the other hand, the second set of kinins, active carboxypeptidase métabolites of BK and LysBK, desArg⁹BK (DABK) and LysdesArg⁹BK (LysDABK) under pathological conditions activate inducible B1 receptors in several cell types of ectodermal (e.g. neurons, glîas), mesodermal (e.g. endothélial cells, smooth muscle cells, blood cells, stromal cells) and endodermal (e.g. airway épithélial cells) origin (Leeb-Lundberg et al., Pharmacol. Rev. 2005,57, 27-77). Generally B1 receptors which are rarely expressed under non-pathological conditions rapidly appear after injuries of « % various natures (tissue trauma, infections, etc.) but unlike B2 receptors elicit persistent responses due to limited desensitization and internaiization with very low ligand dissociation (Couture et al., Eur.J. of Pharmacol., 2001,429,161-176).

Thus the B1 receptor up-regulation appears to be part of a generalized inflammatory and pain responses that includes the local co-expression (eventually upregulation) of enzymes, receptors, autacoids, cytokines and chemokines that notoriously play key rôles in the early and late responses of tissues to various types of injury. In animal models it has been demonstrated that there is a switch in dominance of fonction from B2 to B1 receptor in chronic inflammatory pain states. While the B2 receptor is implicated in the acute phase of the inflammatory and pain response, the B1 receptor is involved in the chronic phase of this response.

The involvement of kinin receptors in inflammation and pain transduction has been supported by the results of studies on mice lacking bradykinin B1 receptors. B1 receptor déficient mice are different from wild-type mice in sensory fonctions, exhibiting increased analgésie thresholds to noxious chemical and heat stimuli, drastic réduction in the accumulation of polymorphonuclear leukocytes at sites of inflammation, as well as réduction in spinal reflex (Pesquero et al., PNAS, 2000, 97, 8140-8145). Reduced nerve injury-induced neuropathie pain was also confinmed in bradykinin B1 receptor knockout mice (Ferreira et al., J. Neuroscience, 2005, 25, 24052412). Furthermore B1 receptor KO mice developed hyperglycemia but not hyperalgesia in response to STZ administrazion (Gabra, Reg. Pept., 2005, 127, 245248).

Growing evidence supported a critical rôle of bradykinin B1 receptors in pathological states like inflammations (e.g. oedema formations, leukocyte trafïicking), infections, ischemia-reperfosion lésions, cancer growth and metastasis. Involvement of B1 receptors in centrally and peripherally mediated pain like acute, chronic, neuropathie and cancer pain was also confirmed (Calixto et al., Br.J.of Pharmacol., 2004, 143, 803818, Conley et al., Eur. J. Pharmacol,. 2005, 527, 44-51, Sevcik et al., J. Pain, 2005, 6, 771-775). The bradykinin B1 receptor provides a strategie rôle in development and maintenance of chronic inflammatory diseases such as asthma, diabètes, rheumatoid arthritis (Couture et al., Eur. J. Pharmacol. 2001, 429, 161-176, Gabra et al., Biol.Chem., 2006, 387, 127-143, Cassim et al., Rheumatology, 2009, 48, 490-496).

Bradykinin Bl receptors could be therapeutic targets for neurological disorders like epilepsy, multiple sclerosis, Parkinson disases and Alzheimer disease (Rodi et al., Cur. Pharm. Design 2005, 11, 1313-1326, Prediger et al., Neuroscience, 2008,151,631-643)

Several patents and patent applications describe bradykinin Bl receptor antagonists which hâve different chemical structures. International patent application WO09124733 relates to substîtuted sulfonamide dérivatives. In WO09036996 and WO09013299 disclose wide variety of small molécules with different chemical structures which hâve valuable properties. International patent application W007101007 discloses aryl sulfonyl heterocycles and variables thereof. In accordance with the international patent application W005004810 some N-arylsulfonamide dérivatives are also known as bradykinin antagonists or inverse agonists useful in the treatment or prévention of symptoms such as pain and inflammation associated with the bradykinin Bl biological pathway. WO04054584 discloses 2-quinoxalinone dérivatives and WO02099388 relates to benzodiazépine compounds. WO02076964 describes dérivatives of N-(arylsulfonyl)beta-aminoacids comprising a substîtuted aminomethyl group. The compounds referred in these référencés may be used to modulâtes bradykinin receptor activity in vivo and in vitro and are useful in the treatment of conditions responsive to Bl modulation in mammals involving pain and inflammation. But neither of these prior art référencés discloses any compound with the scope of the class of compounds described herein beiow.

SUMMARY OF THE INVENTION

We hâve identifled a class of indole dérivatives which hâve high affinity for bradykinin Bl receptors and selectivity over bradykinin B2 receptors providing unique rôle in the treatment of chronic painful and inflammatory processes and disorders. Furthermore targeting inducible receptor, which has no or minor physiological rôle in the homeostasis guarantees exemption from undesired side effects related to constitutive B2 receptors. The présent invention relates to compounds being sélective bradykinin Bl receptor antagonists and the synthesis thereof. Compounds of the présent invention are useful for the treatment of disorders involving inflammation and pain.

W'L

The présent invention relates to the indole dérivatives of formula (I)

wherein

R'

R²

R³ is hydrogen atom, halogen atom or Ci-C^alkoxy group;

is hydrogen atom, halogen atom, Ci-C4-alkyl group or cyano group;

is selected from (l) -COOR; (2) -CN; (3) -CONR^aR^b;

is hydrogen atom or halogen atom;

is hydrogen atom or Ci-C₄-alkyl group;

is selected from

R⁴

R⁵

R⁶ (1) Cj-Cô-cycloalkyl;

(2) optionally substituted five- or sîx-membered aromatic ring with two nitrogen atoms;

(3) optionally substituted pyridyi;

(4) optionally substituted five-membered aromatic ring with one heteroatom selected from O or S;

(5)-CF₃; (6) -CH2-CF3; (7) -CII₂-CH₂-C=CH; (8) -CH₂-CH₂-CH(CH₃)₂ ;

(9)

(ÎO)

(Π)

(27) nc'

X is -CH- or nitrogen atom;

R is C1-C4 alkyl group;

R^a and R^b are independently from each other hydrogen atom; C]-C₄ alkyl group or pyrrolidin-l-yl group;

R^c is hydrogen atom; C1-C4 alkyl or C1-C4 alkoxy group;

R^d is hydrogen atom; C[-C4 alkyl or C3-C6 cycloalkyl group;

R^c and R^f are independently from each other hydrogen atom; halogen atom; C|-C₄ alkyl group; C1-C4 alkoxy; -CF3; -CN or -NH₂ group;

and optical antipodes or racemates and/or salts thereof.

The invention also relates to the pharmaceutical compositions containing the compounds of formula (I) or optical antipodes or racemates and/or salts thereof as active ingrédient.

Furthermore the présent invention relates to the synthesis of the compounds of formula (I) and optical antipodes or racemates and/or salts thereof, the pharmaceutical compositions comprising thereof and the chemical and pharmaceutical manufacture of médicaments containing these compounds, as well as the methods of treatment with these compounds, which means administering to a mammal to be treated - including human — suffering from disorders involving pain and inflammation effective amount of compounds of formula (I) and optical antipodes or racemates and/or salts thereof of the présent invention as such or as médicament.

DETAILED DESCRIPTION OF THE INVENTION wherein

R²

R³

The présent invention relates to the indole dérivatives of formula (I) c

(I) is hydrogen atom, halogen atom or Ci-C4-alkoxy group;

is hydrogen atom, halogen atom, Ci-C4-alkyl group or cyano group;

is selected from (1) -COOR; (2) -CN; (3) -CONR^aR^b;

H.

is hydrogen atom or halogen atom; is hydrogen atom or Ci-C₄-alkyl group; is selected from

R⁴

R⁵

R⁶ (1) C3-Câ-cycloalkyl;

(2) optionally substituted five- or six-membered aromatic ring with two nitrogen atoms;

(3) optionally substituted pyridyl;

(4) optionally substituted five-membered aromatic ring with one heteroatom selected from O or S;

(5)-CF₃; (6) -CH2-CF3; (7) -CH₂-CH₂-OCH; (8) -CH₂-CH₂-CH(CH₃)₂ ;

8
	/=\	/1
N—/
(24) H O ;	(25) \=n ;	(26)	CH3 and

(27) NC '‘j

X is -CH- or nitrogen atom;

R is C1-C4 alkyl group;

R^a and R^b are independently from each other hydrogen atom; C1-C4 alkyl group or pyrrolidin-l-yl group;

R^c is hydrogen atom; C1-C4 alkyl or C1-C4 alkoxy group;

R^d is hydrogen atom; C1-C4 alkyl or C3-C6 cycloalkyl group;

R^c and R^f are independently from each other hydrogen atom; halogen atom; C1-C4 alkyl; C1-C4 alkoxy; -CF3; -CN 0Γ-ΝΗ2 group;

and optical antipodes or racemates and/or salts thereof.

When the meaning of R⁶ is optionally substituted six-membered aromatic ring with two nitrogen atoms the term “optionally substituted” means that the ring may be substituted by one substituent selected from halogen atom, C1-C4 alkyl, -CF3 or -SCH3 groups.

When the meaning of R⁶ is optionally substituted five-membered aromatic ring with two nitrogen atoms the term “optionally substituted” means that the ring may be substituted by C1-C4 alkyl group.

When the meaning of R⁶ is optionally substituted five-membered aromatic ring with one heteroatom selected from O or S the term “optionally substituted” means that the ring may be substituted by one substituent selected from C]-C4-alkyl or S-(Ci-C4)alkyl group.

When the meaning of R⁶ is optionally substituted pyridyl group the term “optionally substituted” means that it may be substituted by one or two substituent selected from halogen atom, Ci-C4-alkyl or -CF3 group.

The term “halogen” or “halo” as used herein alone or as a part of another group refers to chlorine, bromine, fluorine and îodine.

w «

The term C 1-C4 alkyl as used herein refers to branched or straight chain alkyl groups comprising one to four carbon atoms, including methyl, ethyl, propyl, normaland isopropyl and different butyl groups.

The term “C3-C6 cycloalkyl” as used herein refers to carbocyclic groups of 3 to 6 carbons, respectively; for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term C1-C4 alkoxy as used herein refers to branched or straight chain alkyl groups comprising one to four carbon atoms bonded through an oxygen atom, including but not limited to, methoxy, ethoxy, propoxy and t-butoxy.

As used herein, the term “sélective Bradykinin l antagonist” refers to a substance for example an organic molécule that is a potent full antagonist of human Bl receptor and shows at least 50 fold selectivity over B2 receptors.

The term “mammal” as used herein refers to any members of the class “Mammalia” including, but not limited to human.

The term “sait” means nontoxic acid addition salts of the compounds of the invention which are generally prepared by reacting the base with a suitable organic or inorganic acid. Typically the salts of the présent invention are pharmaceutically acceptable salts including e.g. the hydrochloride, hydrobromide salts.

Inciuded within the scope of the présent invention are ail stereoisomers, géométrie isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolaton of individual enantiomers include chiral synthesis fforn the suitable optically pure precursor or resolution of the racemate (or racemate of a sait or dérivative) using, for example chiral high pressure liquid chromatography (HPLC).

The term pharmaceutically acceptable describes an ingrédient that is useful in preparing a pharmaceutical composition and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.

ιο

The term pharmaceutically effective amount shall mean that amount of active ingrédient that will eiicit the biological or medical response of a tissue, System or animal that is being sought by a researcher or clinician.

The term pharmaceutical composition refers to a mixture of a compound of the invention with other chemical components, such as pharmaceutically acceptable auxiliary materials, e.g. diluents or carriers. The pharmaceutical composition facilitâtes administration of the compound to the subject.

The term auxiliary material defines a chemical compound that facilitâtes the incorporation of a compound into cells or tissues.

As used herein, the term treatment means using an effective therapy to reduce, alleviate or eliminate the symptoms associated with disorders involving pain and inflammation.

As a further aspect of the présent invention there is provided the synthesis of compounds of formula (I)

Compounds in accordance with the présent invention were synthesized in line with the synthetic routes and schemes described below.

Accordingly, the compounds of formula (I) of the invention can be synthesized by one of the following methods:

Reacting an indole dérivative of formula (II)

R¹ (Π) i 0 i

- wherein the meaning of R , R and R is as described above for the formula (I) - with a boronic acid of formula (III)

OH (III)

- wherein the meaning of R⁴ and R⁵ is as described above for the formula (I) - then the so obtained indole dérivative of formula (IV)

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described above for the formula (1)

- is deprotected to yield an amine dérivative of formula (V)

- wherein the meaning of R¹, R², R³, R⁴ and R^s is as described above for the formula (I)

- fînally the latter is reacted with an acid dérivative of formula (VI)

(VI)

- wherein the meaning of R⁶ is as described above for the formula (I) - and the obtained indole dérivative of formula (I) and optical antipodes or racemates and/or salts thereof in given case can be transformed into an other compound of formula (1) and optical antipodes or racemates and/or salts thereof by introducing new substituents and/or modifying or removing the existing ones.

Method b)

Reactîng an indole dérivative of formula (II)

(Π)

- wherein the meaning of R¹, R² and R³ is as described above for the formula (I) - with

(VII) then the so obtained indole dérivative of formula (VIII)

(VIII) l *1 1 , _a

- wherein the meaning of R , R and R is as described above for the formula (I) — is reacted with hydroxylamine hydrochloride to yield the indole dérivative of formula (IX) (LL·.

(IX)

- wherein the meaning of R¹, R² and R³ is as described above for the formula (I) - the latter is hydrogenated to fumish an amine dérivative of formula (X)

I Π 1

- wherein the meaning of R , R and R is as described above for the formula (I) fïnally the latter is reacted with an acid dérivative of formula (VI)

O

(VI)

- wherein the meaning of R⁶ is as described above for the formula (I) - and the obtaîned indole dérivative of formula (I) and optical antipodes or racemates and/or salts thereof in given case can be transformed into an other compound of formula (I) and optical antipodes or racemates and/or salts thereof by introducing new substituents and/or 15 modifying or removing the existing ones.

Method c)

The amine dérivatives of formula (V) or formula (X) - obtained according to the method described in method a) and method b) - are reacted with the amino acid dérivative of formula (XI)

(XI) and the so obtained indole dérivative of formula (XII)

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described above for the formula (I)

- is deprotected to yield an amine dérivative of formula (XIII) «A16404

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described above for the formula (I)

- finally the latter is reacted with an acid dérivative of formula (XIV)

O (XIV)

- wherein the meaning of R⁶ is as described above for the formula (I) - and the obtained indole dérivative of formula (I) and optical antipodes or racemates and/or salts thereof in given case can be transformed into an other compound of formula (I) and optical antipodes or racemates and/or salts thereof by introducing new substituents and/or modifying or removing the existing ones.

The reaction of an indole dérivative of formula (II) with a boronic acid of formula (III) or a boronic acid of formula (VII) is preferably carried out in a proper solvent, preferably in the presence of a copper(Il) sait. The reactions are followed by thin layer chromatography. The necessary reaction time is 20-70 h. The work-up of the reaction mixture can be carried out by the following methods:

The reaction mixture is filtered through Celite and the product is isolated from the filtrate by extraction or column chromatography. The column chromatography is carried out on normal phase using Kieselgel 60 as adsorbent and different solvent Systems, e.g. n-hexane/ethyl acetate, chloroform/methanol/acetic acid, dichloromethane/ethyl acetate or chloroform/acetone as eluents.

The structures of the products are determined by IR, NMR and mass spectrometry.

Deprotection of the indole dérivatives of formula (IV) and formula (XII) can be carried out in a proper solvent using organic or inorganic acids, e.g. trifiuoro acetic acid or hydrogen chloride.

The amide bond formations are preferably carried out by preparing an active 5 dérivative from a carboxylic acid of formula (VI), (XI) or (XIV), which is reacted with an amine of formula (V), (X) or (XIII) respectively, preferably in the presence of a base.

The transformation of a carboxylic acid into an active dérivative can be carried out in situ during the amide bond formation in a proper solvent (e.g. NJVdimethylformamide, dimethyl sulfoxide, acetonitrile, chlorinated hydrocarbons or 10 hydrocarbons or the mixture thereof). The active dérivatives can be active esters (e.g. prepared from carboxylic acid with hydroxybenztriazol (HOBt) and JV-(3dimethylaminopropyO-AT-ethylcarbodiimide hydrochloride (EDC) or O-(7azabenzotriazol-l-yl-M/VJV’JV’-tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-l'yl-TVjAaV’j/V’-tetramethyluronium hexafluorophosphate (HBTU) in the 15 presence of a base e.g. triethylamine, AyV-diisopropylethylamine). The active dérivatives can be prepared at a température in the range of 0 °C to room température. A proper amine of formula (V), (X) or (XIII) is added as a base or as a sait formed with inorganic acid to the so obtained solution or suspension in the presence of a base, e.g. triethylamine, 7V,7V-diisopropylethylamine needed for the libération of the amine. The 20 condensation reactions are followed by thin Iayer chromatography. The necessary reaction time is 6-20 h. The work-up of the reaction mixture can be carried out by different methods.

a) The reaction mixture is poured into water and the product is isolated by filtration or extraction with a proper organic solvent and in given case purified by crystallization or column chromatography. The column chromatography is carried out on normal phase using Kieselgel 60 as adsorbent and different solvent Systems, e.g. nhexane/ethyl acetate, toluene/methanol, chloroform/methanol or toluene/acetone, as eiuents.

b) The reaction mixture is directly purified by column chromatography as described 30 above to yield the pure product.

The structures of the products are determined by IR, NMR and mass spectrometry.

The obtained indole dérivatives of formula (I) and optical antipodes or racemates and/or salts thereof - independently from the method of préparation - in given case can be transformed into another compound of formula (I) and optical antipodes or racemates and/or salts thereof by introducing further substituents and/or modifying and/or removing the existing ones.

For instance jV-(Zert-butoxycarbonyl) group can be cleaved by organic or inorganic acids (e.g. trifluoroacetic acid or hydrogen chloride).

Most of the indole dérivatives of formula (II) are either commercially available or can be synthesized by different known methods. The synthèses of some new indole dérivatives of formula (II) are described in the Examples. Following these procedures the other indole dérivatives of formula (II) can also be prepared.

The compounds of the présent invention and optical antipodes or racemates and/or salts thereof can be used as such or suitabiy in the form of pharmaceutical compositions.

The invention also relates to the pharmaceutical compositions containing the compounds of formula (I) or optical antipodes or racemates and/or salts thereof as active ingrédient for the treatment of certain disorders associated with bradykinin Bl receptor actîvity.

Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parentéral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intraarticular, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections and eye drops.

Altematively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly in the rénal or cardiac area, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery System, for example, in a liposome coated with a tissuespecific antibody. The liposomes will be targeted to and taken up selectively by the organ.

The pharmaceutical compositions can be administered variety of routes and dosages forms. The compound of the invention may be administered either alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. The dosage requîred to exert the therapeutical effect can vary within wide limits and will be fitted to the individual requirements in each of the particular case, depending on the stage of the disease, the condition and the bodyweight of the patient to be treated, as well as the sensitivity of the patient against the active ingrédient, route of 5 administration and number of daily treatments. The actual dose of the active ingrédient to be used can safely be determined by the attending physician ski lied in the art in the knowledge of the patient to be treated.

For the sake of a simple administration it is suitable if the pharmaceutical compositions comprise dosage unîts containing the amount of the active ingrédient to be 10 administered once, or a few multiples or a half, third or fourth part thereof. Such dosage units are e.g. tablets, which can be powdered with grooves promoting the halving or quartering of the tablet in order to exactly administer the requîred amount of the active ingrédient.

The pharmaceutical compositions containing the active ingrédient according to 15 the présent invention usually contain 0.01 to 500 mg of active ingrédient in a single dosage unit. It is, of course possible that the amount of the active ingrédient in some compositions exceeds the upper or lower limits defined above.

As a further aspect of the invention there is provided the pharmaceutical manufacture of médicaments containing the compounds of formula (I). or optical 20 antipodes or racemates and/or salts thereof.

The pharmaceutical compositions of the présent invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

Pharmaceutical compositions for use in accordance with the présent invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into préparations which can be used pharmaceutically. Proper formulation is dépendent upon the route of administration chosen. Any of the well30 known techniques, carriers, and excipients may be used as suitable and as understood in the art.

Ÿ L·

Suitable excipients are, in particular, fîllers such as sugars, încluding lactose, sucrose, mannitol, or sorbitol; cellulose préparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the .

cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a sait thereof such as sodium alginate.

The above described ingrédients and different routes of manufacture are merely représentative. Other materials as well as processing techniques and the like well known 10 in the art can also be used.

The compounds of the présent invention are bradykinin receptor antagonists, in particular sélective bradykinin Bl receptor antagonists, consequently are useful in the treatment or prévention of disorders involving pain and inflammation comprising the administration to a mammal to be treated an effective amount of compounds of formula 15 (I) of the présent invention as such or as médicament.

The compounds would be effective in the treatment of somatic musculo-skeletal pain and disorders încluding bone and joint pain and disorders (e.g. arthritis, încluding rheumatoid and other types of inflammatory arthritis, osteoarthritis, spondylitis and infectious arthritis, arthritis due to goût or pseudogout, autoimmune and vasculitic joint 20 disorders as systemic lupus erythematosus, polymyalgia rheumatica, polyarthritis nodosa, osteoporosis), low-back pain, répétitive motion disorders (e.g. tenosynovitis, tendonitis, epicondylitis, bursitis, ganglion cyst, carpal tunnel syndromes, trigger fïnger), myofascial pain syndrome and fibromyalgia. Compounds of the présent invention can additionally be used to treat inflammatory skin disorders, such as 25 psoriasis, dermatitis and eczema, skin injuries încluding buming and sunbuming (e.g.

UV-erythema and pain), pruritus and wound.

The compounds would be effective in the treatment of viscéral pain and disorders of thorax and abdomen (angina, ulcerative colitis, pancreatitis, cholecystitis, liver disease, nephritis, gastritis, appendicitis, irritable bowel syndrome, inflammatory 30 bowel disease, Crohn’s disease), viscéral pain of pelvis (cystitis, hyperactive bladder, menstruation). They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or utérus as well as for spasms and pain originating from ( L· biliary and urinary tracts. Such compounds may be used therapeuticaily to treat inflammatory airways disease e.g. chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ADRS), bronchitis, pneumonia, pleurisy and asthma. They may be used to control, restrict or reverse airways hyperreactivity in asthma, to treat intrinsic and extrinsic asthma including allergie asthma (atopie or nonatopic), occupational asthma, viral or bacteriai exacerbated asthma, other non-allergic asthmas, “wheezy-infant syndrome”, as well as exercise-induced bronchoconstriction. They may be effective against pneumoconiosis, including aluminosis, anthracosîs, asbestosis, chalicosîs, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Moreover the compounds may be used for the treatment of vascular injuries, disorders and inflammatory states such as angioedema, atherosclerosis, septic shock e.g. as antihypovolemic and/or anti-hypotensive agents, ischemia-reperfusion injury. Compounds may be used to treat inflammatory pain of varied origins (e.g. allergie rhinitis, vasomotor rhinitis, uveitis, retinitis, gingivitis,) atopie and allergie disorders. Compounds may be used to alleviate glaucoma, dental pain and fever.

Compounds of présent invention would be useful in the treatment of neuropathie pain (e.g. neuralgia, nerve injury, phantom limb pain, mononeuropathy, polyneuropathy, neuritis, and radiculitis). Compounds would be effective in the treatment of painful peripheral neuropathies like herpes zoster infection (e.g. postherpetic neuralgia), HIV-related neuropathies, nutritional deficiencîes, toxins. Compounds would be effective in the treatment of cancer pain and in side effect of chemotherapy, radiation injury or surgical injury. Compounds may be used in the treatment of fibrotic disease (e.g. pulmonary fibrosis, rénal fibrosis, liver fibrosis), hyperplasia (e.g. bening prostatic hyperplasia) and cancer (e.g. breast cancer). The compounds would be effective in immunological disorders (autoimmune disease, hypersensitivities, transplant rejection, immune deficiencies). Compounds would be effective in the treatment of perioperative pain (e.g. general surgery, gynecological), postoperative pain (postsurgical pain syndrome), posttraumatic pain (e.g. sprains or fracture). Compounds would be also effective in the treatment of traumatic brain injuries. Compounds of présent invention may be useful analgésie agent using during general and monitored anaesthesia. Furthermore compounds would be effective in the treatment of pain and disorders associated with diabètes (e.g. diabethic neuropathy,

L dîabethic nephropathy, diabetic vasculopathy, diabetic rethinopathy, osteopathy, post capillary résistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinurea and increased nitrite and kallikrein urinary excrétion).

Additionally, they may be effective in some neurologicai disorders, e.g. against multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, epilepsy, stroke, cérébral oedema, headache including cluster headache, migraine including prophylactic and acute use, as well as closed head trauma.

Biological évaluation

Functional assay Assessmcnt of antagonist potency at BI receptors in vitro by measurement of cytosolic calcium ion concentration with a plate reader fluorimcter in cells expressing recombinant human BI receptors

Cell culture

Chinese hamster ovary (CHO) cells stably expressing recombinant human Bl (CHO-B1, Euroscreen) receptors were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 10% Fêtai Calf Sérum (FCS), 100 U/ml penicillin, 0.1 mg/ml streptomycin, 0.25 gg/ml amphotericin B, 1% Minimum Essential Medium Eagle (MEM), non essential amino acid solution, 600 pg/ml G418. Cells were kept at 37°C in a humidified incubator in an atmosphère of 5% CO₂/95% air and were passaged 1:4 three times a week. Cells were plated at 1.5-2.5xl0⁴ cell/well on standard 96-well microplates, measurements of cytosolic calcium ion concentration ([Ca²⁺]i ) were carried out 1-2 days after cell plating.

Fluorimetric measurement of cytosolic calcium concentration

Measurements of [Ca²⁺]i were carried out on CHO-B1 cells stably expressing human Bl receptors, respectively. Cells were grown in standard 96-well microplates and before the measurement were loaded with a fluorescent Ca -sensitive dye, fluo4/AM (2 μΜ): after removîng the culture medium the dye was added to the cells (dissolved in assay buffer: 145 mM NaCl, 5 mM K.C1, 2 mM MgCl₂, 2 mM CaCl₂, 10 mM HEPES, 20 mM D-glucose, 2 mM probenecid, 100 μΐ/well) and cells were incubated at 37°C in a humidified incubator in an atmosphère of 5% CO₂/95% air for 40-120 min. To stop dye loading cells were washed twice with assay buffer. After washîng, various concentrations of the test compounds (diluted in extracellular medium from a DMSO stock solution, final DMSO concentration was <0.1%) or buffer were added to each well depending on the experimental setup. After incubation at 37°C for 20-25 min. baseline and agonist-evoked changes of [Ca²⁺]i were measured column by column with a plate reader fluorimeter (Fluoroskan Ascent, Labsystems). Excitation and détection of émission was carried out from the bottom of the plate. Filters used for Fluo4: excitation filter - 485 nm, émission filter - 538 nm. The whole measurement process was performed at 37°C and was control led by custom software. Inhibitory potency of the test compounds was assessed by measuring the réduction in the agonist-evoked [Ca²⁺]j-elevation in the presence of different concentrations of the compounds. The agonist was LysDABK for CHO-B1 cells. Agonist was applied at an ECgo concentration; the ECgo-vaiues were derived from daily determined dose-response curves. Fluorescence data were expressed as AF/F (fluorescence change normalized to baseline). Ail treatments on a single plate were measured in multiple wells. Data from ail wells with the same treatment were averaged and the average values were used for analysis. Inhibitory potency of a compound at a single concentration point was expressed as percent inhibition of the control agonist response. Sigmoidal concentration-inhibition curves were fitted to the data (derived from at least three independent experiments) and ICso-values were determined as the concentration that produces half of the maximal inhibition caused by the compound.

The examined reference compounds measured in fimctional and binding tests are the following:

1) 4-{2-[(2,2-diphenyl-ethyl)-amino]-5-(4-[4-[(4-methyl-l-piperazinyl)-carbonyl]-lpiperidinyl]-sulfonyl)-benzoyl}-morpholine (NVP-SAA164, Br. J. Pharmacol.144 (2005) 889-899); K_; 8 nM; IC₅₀: 33 nM;

2) (R)-JV-[2,3-dihydro-2-oxo-5-(2-phenyl-ethyl)-l-propyl-177-l,4-benzodiazepin-3-ylJN'-{4-[4-(4-pyridinyl)-l-piperazinyl]-phenyl}-urea (J. Med. Chem. 46 (2003) 18031806); Kj 0.59 nM; IC₅₀ 1.9 nM;

3) 4'-bipiperidin)-r-yIphenyl]-N'-[(3R)-2,3-dihydro-5-(4-methyl-phenyl)-2-oxo- l-propyl-l//-l,4-benzodiazepin-3-yl]-urea (J. Med. Chem. 46 (2003) 1803-1806);

Kj 13.4 nM; IC₅₀ 64.5 nM

The K, and IC50 data measured by us for the référencé compounds are in good agreement with the data given in the literature.

In Table I compounds of this invention measured in functional assay are listed 10 below.

Table I

Number of example	B1 func.	Number of example	B1 func.
1	+++	102	1_
2	4-4 1	103	4-H-
3	4-H-	104	4-H-
4	4-H-	105	4-H-
5	|—1·+	106	4-H-
6	++	107	4-H-
7	+++	108	4-H-
8	+Ή-	109	4-4-4-
9	4-H-	110	Ι·Ι·Ι·
10	+++	111	4-H-
11	4-H-	112	4-H-
12	| | |	113
13	4-H-	114	4-H-
14	4-H-	115	4-H-

Number of cxamplc	B1 func.	Number of cxamplc	B1 func.
15	+++	116	++
16	ίΙΙ·	117	+++
17	+++	118	+++
18	+++	119	+++
19	+++	120	+++
20	+++	121	++
21	+-H-	122	++
22	+++	123	I l |·
23	+++	124	++
24	+++	125	-H-+
25		126	++
26	++4-	127	+++
27	+-H-	128	+++
28	+++	129	+++
29		130	+++
30	+-H-	131	-H-
31	+++	132	4-H-
32	1 1 i	133	+++
33	+	134	+++
34	++	135	++
35	++	136	++
36	l-H·	137

Number of example	B1 func.	Number of example	B1 func.
37	+++	138	++
38	++	139	-H-+
39		140	J ι ι ΓΤΓ
40	+-H-	141	+++
41	+++	142	++
42	+-H-	143	+++
43	+4-	144	++
44	+++	145	++
45	+++	146
46	+++	147	++
47	+++	148	++
48	HH	149	++
49	-H-+	150	++
50	+++	151	+
51	4-H-	152	++
52		153	+-H-
53	+++	154	+++
54	+++	155	++
55	II	156	+++
56	4-	157	-H-
57	++	158	+++
58	+-H-	159	4-H-

Number of cxample	B1 func.	Number of example	B1 func.
59	+++	160	φ_|_φ
60	4-H-	161	++
61	II· L	162	4-H-
62	-H-+	163	4-H-
63	4-H-	164	4-H-
64	+++	165	4-H-
65	+++	166	4-H-
66	+++	167	-H-
67	+++	168	++
68	4-H-	169
69	++	170	++
70	4-H-	171	++
71	4-H-	172	4-H-
72	4-4-+	173	++
73	4-H-	174	4-H-
74	4-H-	175	-H-
75	4-H-	176	++
76	4-4-4-	177
77	4-H-	178	4-H-
78	4-H-	179	-H-
79	4-4-+	180	4-H-
80	4-H-	181	4'4· J·

Number of example	B1 func.	Number of exemple	B1 func.
81	444-	182	4-H-
82	+++	183	4-4-
83	ΙΙΙ	184	4-H-
84	444-	185	4-H-
85	444-	186	4-H-
86	444-	187	44-
87	444-	188	4-H-
88	4-H-	189	4-H-
89	4-H-	190	4-H-
90	4-H-	191	4-H-
91	4-H-	192	444-
92	4-H-	193	444-
93	44-	194	444-
94	4-H-	195	444-
95	4-H-	196	44-
96	4-H-	197	444-
97	-H-	198	444-
98	44-	199	i-
99	4-H-	200	444-
100	4-H-	201	444-
101	4-4-4-

+ IC50 >s between 0.1 and 0.5 μΜ ++ ICso is between 20 and 100 nM «

ι ι i IC50 *· 20 πΜ

Receptor Binding assays

Assessment of ligand binding affinity to B1 and B2 receptors in vitro by compétitive radioligand binding assay

1. Human recombinant bradvkinin B1 receptor binding

Binding assays were carried out on human recombinant bradykininl receptors (expressed in CHO cells, hBl-A5) according to the Euroscreen Technical Data Sheet (Cat.No.:ES-091). 20pg protein/tube was încubated with [3,4-prolyl-3,4-³H(N)]-[DesArg¹⁰] Kallidin as radioligand. Non spécifie binding was determined in the presence of 10 μΜ Lys-des-Arg⁹-Bradykinin. The final incubation volume was 250 μΐ. Samples were încubated for 15 min. at 25 °C then were rapidly vacuum filtered through GF/B filters presoaked for at least 1 h in 0.5 % PEI. Radioactivity was determined by liquid scintillation spectroscopy.

The ligand displacement by the compounds was determined using a minimum of seven concentrations in triplicate, and experiments were repeated at least two tîmes. The spécifie radioligand binding is defined as the différence between total binding and the non-specific binding determined in the presence of an excess of unlabelled ligand. Results are expressed as a percent inhibition of spécifie binding obtained in the presence of RGH-478 or reference drugs. IC50 values (i.e. concentration of compound giving 50% inhibition of spécifie binding) were calculated from concentration-displacement curves by sigmoidal fitting using GraphPad Prism Software 4.0. K, values (i.e. inhibition constants) were calculated using the Cheng-Prusoff équation. Ko was determined from the Scatchard plot. (Editor-in-chief: Enna, S.J. and Williams, M. Current protocols in pharmacology vol.l. John Wiley & sons Inc., 1998)

In Table II compounds of this invention measured in binding assay are listed.

Table II

Number of exemple	B1 binding	Number of example	B1 binding
l	4-H-	102	4-H-
2	4-H-	103	4- 4- -1-
3	4-H-	104	4-H-
4	4-H-	105	4-H-
5	4-H-	106	4-H-
6	-H-	107	4-H-
7	4-H-	108	4-H-
8	4-H-	109	4-H-
9	4-H-	110	4-H-
10	| |	111	4-H-
11	4-H-	112	4-4-4-
12	4-H-	113	4-H-
13	4-H-	114	1 H-
14	4-H-	115	4-H
15	4-H-	116	-H-
16	4-H-	117	4-H-
17	4-H-	118	4-4-4-
18	4-4-4-	119	4-4-4-
19	4-H-	120	4-H-
20		121	| ,| |
21	4-H-	122	4-4-

*

Number of example	B1 binding	Number of example	B1 binding
22	Η-Ή·	123	+++
23	+++	124	++
24	+++	125	+++
25	+++	126	-HH-
26	+++	127	+++
27	+++	128	+++
28	+++	129	+++
29	+++	130	| | |
30		131	-H-l·
31		132	+++
32	+++	133	+++
33	++	134	+++
34	l· 1 1 ·	135	+++
35	+++	136	++
36	+++	137	+++
37	+++	138	+++
38	+++	139	+++
39	+++	140	+++
40	+++	141	+++
41	ΙΙΙ	142	+++
42	+++	143	+++
43	+++	144	++

•v* ’

Number of example	B1 binding	Number of example	B1 binding
44	+++	145	-H-
45	+++	146	4--I-4-
46	+++	147	+
47	4-H-	148	4-H-
48	4-H-	149	4-H-
49	1 t 1	150	4-4-4-
50	-1-+-1-	151	+
51	4-H-	152	4-H-
52	+++	153	4-H-
53	4-H-	154	4--1-1
54	4-1-4-	155	4-4-
55	4-4-4-	156	4-H-
56	+	157	-J__t__l_
57	4-+	158	4-H-
58	4-H-	159	+4-4-
59	-H-+	160
60	4-4-4-	161	4-4-4-
61	4-4-4-	162	4-H-
62	4-4-4-	163	4-H-
63	4-H-	164	4-H-
64	4-1-1	165	4-1-1-
65	4-H-	166	„|,_|,

Number of example	B1 binding	Number of example	B1 binding
66	+++	167	-H-
67	-HH-	168	-HH-
68	-HH-	169	+++
69	-H-	170	-HH-
70	-HH-	171
71	+++	172	+++
72	-HH-	173	-HH-
73	-HH-	174	-HH-
74	-HH-	175	-HH-
75	+++	176	-H-
76	+++	177	-H-
77	+++	178	-HH-
78	-HH-	179
79	-HH-	180	-HH-
80	+++	181	-HH-
SI	-HH-	182	-HH-
82	+++	183	++
83	+++	184	-HH-
84	+++	185	-HH-
85	+++	186	-HH-
86	+!+	187	+
87	-HH-	188	-H-

PM

Number of example	Bl binding	Number of exemple	Bl binding
88	+-H-	189	-HH-
89	+++	190	-HH-
90	-HH-	191	4-H-
91	+++	192	-HH-
92	-HH-	193	4-H-
93	-H-	194	-HH-
94	-HH-	195	4-H-
95	+++	196	-HH-
96	-HH-	197	4-H-
97	-HH-	198	-HH-
98	-HH-	199	4-H-
99	l„ 4·. f	200	-HH-
100	4-H-	201	| ·|· d·
101	4-H-

+ K; is between O.l and 0.5 μΜ ++ K, is between 20 and 100 nM +++ Kj < 20 nM

2. Human recombinant bradykinin B2 receptor binding

Binding assays were carried out on human recombinant bradykinin2 receptors (expressed in CHO-Kl cells) according to the Receptor Biology Technical Data Sheet 10 (Cat.No.: RBHB2M) with minor modifications. 8.4 pg protein/tube was incubated with [2,3,-prolyl-3,4-³H(N)]-Bradykinin as radioligand. Non spécifie binding was determined in the presence of 5 μΜ bradykinin. The final incubation volume was 200 μΐ. Samples

6C were incubated for 90 min. at +4 °C then were rapidly vacuum filtered through GF/B filters presoaked for at least l h in 0.5 % PEI. Radioactivity was determined by liquid scintillation spectroscopy. Compounds were tested in 5 μΜ test concentration.

The spécifie radiolîgand binding is defmed as the différence between total binding and the non-specific binding determined in the presence of an excess of unlabelled ligand. Results are expressed as a percent inhibition of spécifie binding obtained in the presence of RGH-478 or reference drugs. IC50 values (i.e. concentration of compound giving 50% inhibition of spécifie binding) were calculated from concentration-displacement curves by sigmoidal fitting using GraphPad Prism Software 4.0. Kj values (i.e. inhibition constants) were calculated using the Cheng-Prusoff équation. Kq was determined from the Scatchard plot. (Editor-in-chief: Enna, S.J. and Williams, M. Current protocols in pharmacology vol.l. John Wiley & sons Inc.,1998)

The compounds exhibited high affinity and selectivity (>50 fold) for the human B1 receptor over the human B2 receptor according to binding assays.

The présent invention will be now îllustrated by the foliowing not limiting examples.

Reference Example 1

3-Fluoro-4frerf-butoxvcarbonylaminomethvhphenylboronic acid

a) 4-Aminomethyl-3-fluoro-phenylboronic acid

A stirred mixture of 5 g (27.33 mmol) of 3-fluoro-4-(hydroxyiminomethyl)phenylboronic acid (W02006/38100) and 0.6 g of 10% Pd/C in 80 mL of éthanol and 4.6 mL (54.7 mmol) of concentrated hydrochloric acid was hydrogenated at room température for 3 h. Initial exothermic period was controlled by the immersion of the reaction flask into a water bath. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and ethyl acetate, the solid was filtered off, washed with diethyl ether (2x15 mL) and dried to yield 5.47 g (97 %) of the title compound as a white amorphous solid. MS (El) 153.1 ([M-NHf).

b) 3-Fluoro-4-(ter/-butoxycarbonylaminomethyl)phenvlboronic acid

To a solution of 5 g (29.6 mmol) of 4-aminomethyl-3-fluoro-phenylboronic acid in 30 mL of water and 50 mL of tetrahydrofuran a solution of 6.7 g (30.5 mmol) of iîc ditertbutyl-dicarbonate in 15 mL of tetrahydrofuran was added followed by the addition of 15.5 mL (88.8 mmol) of W/V-diisopropylethylamine. The reaction mixture was stirred at room température for 2 h. The pH of the mixture was adjusted to 6 at 0°C by the addition of 2M hydrochloric acid solution and the organic and aqueous phases were separated. The aqueous phase was washed with 3x20 mL of ethyl acetate, the combined organic layers were washed with 10 mL of water and 2x10 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hexane and stirred for 2 h. The solid was filtered off and dried to yield 5.44 g (68 %) of the title compound as a yellow oil. MS (El) 292.1 [M+Na]⁺.

Référencé Example 2 (/?)-4-(l-fgrt-Butoxycarbonylamino-ethvl)phenvlboronic acid

Under argon to a solution of 119.74 g (400 mmol) of [(Æ)-l-(4-bromo-phenyl)ethylj-carbamic acid ferf-butyl ester in 1500 mL of dry tetrahydrofuran 800 mL of 2.5 M n-BuLi in hexane solution (2 mol) was added dropwise at -78°C over a period of 1.5 h. After the mixture was stirred at -78°C for 20 min, 125 mL (545 mmol) of triisopropyl borate was added dropwise over a period of 0.5 h. The so obtained mixture was allowed to warm to -20°C and stirred at this température for 18 h. The reaction mixture was quenched by addition of 500 mL of saturated ammonium chloride solution (pH ~8) and allowed to warm to room température. The reaction mixture was extracted with ethyl acetate, the combined organic layer was washed with water, dried over anhydrous sodium sulfate. filtered and concentrated in vacuo. The residue was stirred with 500 mL of n-hexane ovemight then filtered and dried to yield 65.75 g (62%) of the fille compound as a white solid. MS (El) 288.2 [M+Na] 2

Référencé Example 3

6-(7e/7-butoxvcarbonvlamino-inethvl)-3-nvridineboronic acid

a) Pinacol 6-(fôrr-butoxycarbonylamino-methyl)-3-pyridineboronate

To a solution of 8.7 g (38.7 mmol, dihydrochloride) of pinacol 6-(aminomethyl)3-pyridineboronate (Bioorg. Med. Chem. Lett., 2006, 16, 1277-81) in 45 mL of water and 135 mL of tetrahydrofuran a solution of 8.5 g (38.9 mmol) of ditertbutyldicarbonate in 10 mL of tetrahydrofuran was added followed by the addition of 27 mL (155 mmol) of A^jV-diisopropylcthylaminc. The reaction mixture was stirred at room température overnight. The organic and aqueous phases were separated, the aqueous phase was washed with 3x160 mL of ethyl acetate. The combined organic layers were washed with 80 mL of water and 80 mL of brine, dried over anhydrous sodium sulfate, 5 filtered and concentrated in vacuo to yield 9.64 g (74 %) of the title compound as a yellow oil. MS (El) 253.2 (boronic acid deriv.[252.07]H⁺).

b) 6-(7grr-butoxycarbonylamino-methyl)-3-Dyridineboronic acid

To a solution of 9.64 g (26.26 mmol) of pinacol 6-(Zert-butoxycarbonylaminomethyl)-3-pyridineboronate in 190 mL of acetone a solution of 5.63 g (73 mmol) of 10 ammonium acetate in 90 mL of water was added, followed by the addition of 18.8 g (87.8 mmol) of sodium periodate. The suspension was stirred at room température for 3 h and diluted with 180 mL of ethyl acetate. The liquid phases were decanted from the undissolved residue and the process was repeated with 20 mL of ethyl acetate. The organic and aqueous phases were separated, the aqueous phase was washed with 2x10 15 mL of ethyl acetate. The combined organic layers were washed with 3x30 mL of water, 2x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in 90 mL of water and the pH of the suspension was adjusted to 6 by the addition of IM aqueous sodium hydroxide solution and the so obtained mixture was washed with 150 mL of ethyl acetate. The organic layer was 20 washed with 2x50 mL of water and 2x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The yellow foam obtained was triturated with a mixture of hexane and dîethyl ether and the suspension was stirred overnight. The solid was filtered off, washed with hexane and dried to yield 3.55 g (48 %) of the title compound as an off-white solid. MS (El) 253.2 (MH⁺).

Référencé Example 4 l-Amino-cyclopropanecarboxylic acid 4-|3-chloro-2-(2-methyl-2Z/-tetrazol-5-vl)inclol-l-yll-benzylamide hydrochloride

a) 3-Chloro-l//-indole-2-carboxylic acid

A mixture of 40.0 g (0.248 mol) of lH-indole-2-carboxylic acid, 33.6 g (0.251 mol) of jV-chlorosuccinimide in 800 mL of acetonitrile was refluxed for 5 h. The reaction mixture was cooled, concentrated in vacuo and the residue was stirred with 500 mL of water. The precipitated product was filtered off, washed with water and dried to yield 42.21 g (87.0 %) of the title compound. Mp: 192-193 °C.

b) 3-Chloro-l H-indole-2-carboxylic acid amide

A mixture of 42.2 g (0.215 mol) of 3-chloro-l//-indole-2-carboxylic acid, 42.2 mL (0.580 mol) of thionyl chloride, 0.17 mL of jV,/V-dimcthylformamide in 710 mL of chloroform was refluxed for 3 h. The reaction mixture was cooled to 20 °C, poured into a mixture of 420 mL of 25 % ammonia solution and 1500 g of ice, then stirred for 2h. The precipitated product was filtered off and washed with water to yield 25.29 g (60.2 %) of the title compound. Mp.: 191-192°C.

c) 3-Chloro-lH-indole-2-carbonitrile

A mixture of 28.05 g (144 mmol) of 3-chloro-l//-indole-2-carboxylic acid amide, 67.36 mL (722 mmol) of phosphorus oxychloride and 525 mL of chloroform was refluxed for 3h. The reaction mixture was cooled to 20 °C, poured into a mixture of 40 mL of 37 % hydrochloric acid and 1000 g of ice, then stirred for 2 h. The organic layer was separated and the water phase was extracted with 500 mL of chloroform. The combined organic layers were washed with water and saturated sodium carbonate solution, dried over arihydrous sodium sulfate and concentrated. The residue was crystallized from a 1:1 mixture of 2-propanol and water to yield 20.89 g (82.1 %) of the title compound. Mp.: 150-154°C.

d) 3-Chloro-2-(2-methyl-2H-tetrazol-5-yl)-17/-indole

A mixture of 23.31 g (132 mmol) of 3-chloro-l//-indole-2-carbonitrile, 9.32 g (143 mmol) of sodium azide and 7.95 g (148 mmol) of ammonium chloride in 240 mL of M/V-dimethylformamide was refluxed for 3.5 h. The reaction mixture was cooled to 20 °C, then 12.0 mL (192 mmol) of iodomethan was added and stirred for 16 h. The reaction mixture was poured into 500 mL of water, the precipitated product was filtered off and recrystallized from 2-propanol to yield 13.95 g (45.2 %) of the title compound. Mp.: 197-199°C.

e) {4-[3-Chloro-2-(2-methyl-2H-tetrazol-5-vl)-indol-l-vll-benzv0-carbamic acid tertbutyl ester

A mixture of 5.85 g (25 mmol) of 3-chloro-2-(2-methyl-2//-tetrazol-5-yl)-l/7indole, 9.4 g (37.4 mmol) of 4-(zer/-butoxycarbonylaminomethyl)phenylboronic acid,

7.6 g (50 mmol) of copper(II) acetate, 17.6 mL (100 mmol) of Nfldîisopropylethylamine, 12.2 g of 3Â molecular sieves in 200 mL of Λ^Γ,Αdimethylformamide was vigorously stirred at room température with air bubbling for 24 h, and additional 2.0 g (7.9 mmol) of 4-(tert-butoxycarbonylammomethyl)phenylboronic acid was added. The mixture was stirred at room température with air bubbling for 48 h, then filtered through Celite. The filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.0150.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 11.8 g of the title compound as a yellow oil.

f) 4-| 3-Chloro-2-(2-methvl-2/7-tetrazol-5-yl)-indol-l-γΐΐ-benzylamine hydrochloride

The previously obtained product (~25 mmol) was dissolved in 60 mL of 10 % hydrogen chloride in ethyl acetate and stirred at room température for 16 h. The precipitated product was filtered off and washed with diethyl ether to yield 9.34 g (99%) of the title compound. Mp.: 225-228 °C.

g) l-{4-r3-Chloro-2-(2-methyl-2//-tetrazol-5-vD-indol-l-yl]-benzvlcarbamovl}cyclopropyD-carbamic acid tert-butyl ester

A mixture of 6.0 g (16 mmol) of 4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)indol-l-yi]-benzylamine hydrochloride, 3.3 g (16.4 mmol) of 1-tertbutoxycarbonylamino-cyclopropanecarboxylic acid, 4.8 mL (34.5 mmol) of triethylamine, 6.3 g (16.6 mmol) of HBTU [O-benzotriazol-l-yl-À^M/Vy/V¹tetramethyluronium hexafluorophosphate] and 75 mL of MA-dimethylformamide was stirred at room température for 24 h and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene:methanol = 4:1 as eluent to yield 6.42 g of the title compound as a yellow oil.

h) l-Amino-cyclopropanecarboxvlic acid 4-f3-chloro-2-(2-methyl-2//-tetrazol-5-yl)indol-l-yll-benzylamide hydrochloride

The previously obtained product (—16 mmol) was dissolved in 50 mL of 10 % hydrogen chloride in ethyl acetate and stirred at room température for 6 h. The reaction mixture was concentrated in vacuo, the residue was crystallized from diethyl ether to yield 4.22 g (62.5 %) of the title compound. Mp.: 70-80 °C.

Référencé Example 5

4-l2-(2-MethyI-277-tetrazol-5-yl)-indoIe-vl]-benzylamine hydrochloride

a) 2-(2/7-Tetrazol-5-yl)-lff-indole

A mixture of 1.0 g (7.04 mmol) of l/Z-indole-2-carbonitrile (I. Borza at al. Bîoorg. Med. Chem. Lett. 2005, 15, 5439-5441), 1.5 g (7.28 mmol) of trimethyitin azide, and 50 mLof toluene was refluxed for 3 h. The reaction mixture was cooled to 20 °C and the precipitated product was filtered off to yield 2.22 g of tin complex of the title compound. Mp.: 236-240 °C.

b) 4-i2-(2//-Tetrazol-5-vi')-indole-vl |-benzaldehyde

A mixture of 0.4 g (1.4 mmol) of 2-(2/7-tetrazol-5-yl)-l/f-indole, 0.31 g (2.06 mmol) of 4-formyl-phenylboronic acid, 0.42 g (2.77 mmol) of copper(II) acetate, 0.98 mL (5.6 mmol) of JV^V-diisopropylethylamine, 0.7 g 3Â molecular sïeves in 15 mL of AUV-dimethylformamide was vigorously stirred at room température with air bubbling for 14 h. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and chloroform:methanol:acetic acid = 10:1:0.1 as eluent to yield after crystallization from 2-propanol 0.12 g (19 %) of the title compound. Mp.: 210-212 °C.

c) 4-f2-(2-Mcthvl-2//-tctrazol-5-vl)-indole-vH-bcnzaldehyde

A mixture of 0.7 g (2.4 mmol) of 4-[2-(2Z/-tetrazol-5-yl)-indole-yl]benzaldehyde, 0.2 mL (3.2 mmol) of iodomethane, 1.0 g (7.2 mmol) of potassium carbonate, and 50 mL of acetonitrile was refluxed for 0.5 h. The reaction mixture was cooled to 20 °C, filtered, and the filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene :methanol = 4:1 as eluent to yield 0.238 g (32.4 %) of the title compound (Rfi 0.8), and 0.21 g (28.6 %) of 4-[2-(l-methy-2//-tetrazol-5-yl)-indoleyl]-benzaldehyde (Rf: 0.7).

d) 4-r2-(2-Methly-2//^,-tetrazol-5-yl)-indole-y 11-benzaldehyde oxime

A mixture of 0,238 g (0.78 mmol) of 4-[2-(2-methyl-2/7-tetrazol-5-yl)-indoleyl]-benzaldehyde, 0.07 g (1.0 mmol) of hydroxylamine hydrochloride, 0.09 mL (1.1

4l mmol) of pyridine and 10 mLof éthanol was refluxed for 1 h. The reaction mixture was cooled to 20 °C, concentrated in vacuo and the residue was treated with water. The precipitated product was filtered off to yield 0.19 g (75.6%) of the title compound. Mp.: 159-161 °C.

e) 4-r2-(2-Methvl-2/7-tetrazol-5-yl)-indole-yl1-benzylamine hydrochloride

A mixture of 0.19 g (0.59 mmol) of 4-[2-(2-methlyl-2H-tetrazol-5-yl)-indoleyl]-benzaldehyde oxime, 20 mL of methanol, 1 mL of 36 % hydrochloric acid and 0.05 g of 10 % Pd/C catalyst was hydrogenated for 6 h. The catalyst was filtered off, the filtrate was concentrated in vacuo and the residue was treated with diethylether to yield 0.192 g (94.5 %) of the title compound. Mp.: 289-290 °C.

Reference Example 6

4-13-Chloro-2-f2-methvl-2//-tetrazol-5-yl)-indol-l-yll-2-fluoro-benzvlamine hydrochloride

The title compound was prepared from 3-chloro-2-(2-methyl-2//-tetrazol-5-yl)lW-indole (Reference Example 4d) and 3-fluoro-4-(/er/-butoxycarbonylaminomethyl)phenyl-boronic acid (Reference Example 1) according to the methods described in Reference Example 4e and 4f. Mp.: 268-269 °C,

Reference Example 7

4-f3-Chloro-2-(5-methvl-U3,41oxadiazol-2-vi)-indol-l-yll-benzvlamine_____hydro- chloride

a) 3-Chloro-l//-indole-2-carboxvlic acid Y-acetyl-hydrazide

A mixture of 1.5 g (0.76 mmol) of 3-chioro-l/7-indole-2-carboxylic acid (Reference Example 4a), 0.6 g (0.81 mmol) of acethydrazide, 1.2 mL (0.86 mmol) of triethylamine, 3.0 g (0.79 mmol) of HBTU and 45 mL of IVTV-dimethylformamide was stirred at room température for 24 h, then concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene:methanol = 4:1 as eluent to yield after crystallization &om 2-propanol 1.1g (57.0 %) of the title compound. Mp.: 253-255 °C.

b) 3-Chloro-2-(5-methyl-r 1,3,41oxadiazol-2-vl)-17/-indole

Ab

A mixture of l.l g (4.37 mol) of 3-chloro-l//-indole-2-carboxylic acid N*acetyl-hydrazide and 13.19 mL of phosphorus oxychloride was refluxed for 1 h. The reaction mixture was cooled to 20 °C, poured into 100 g of ice, stirred for 2h, then extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene:methanol = 4:1 as eluent to yield after crystallization from diethyl ether 0.38 g (37.0 %) of the title compound. Mp.: 267-268 °C.

c) 4-r3-Chloro-2-(5-methvl-n.3,41oxadiazol-2-vl)-indol-l-vll-benzvlamine hydrochloride

The title compound was prepared from 3-chloro-2-(5-methyl-[l,3,4]oxadiazol-2yl)-l //-indolc according to the methods described in Reference Example 4e and 4f. Mp.: 265-272 °C.

Reference Example 8

4-12-(l-Methyl-2ff-tetrazol-5-yl)-indole-yl]-benzylamine hydrochloride

The title compound was prepared from 4-(2-(1-methy-2H-tetrazol-5-yl)-indoleyl]-benzaldehyde (Reference Example 5c) according to the methods described in Reference Example 5d and 5e. Mp.: 91-107 °C.

Reference Example 9

1-Amino-cyclopropanccarboxylic acid 4-[3-chloro-2-(5-methyl-|l,2,41oxadiazol-3vD-indol-l-yll-benzylamide

a) 3-Chloro-jV-hydroxy-1 //-indole-2-carboxamidine

A mixture of 14.95 g (84.65 mmol) of 3-chloro-177-indole-2-carbonitrile (Reference Example 4c), 7.65 g (110.04 mmol) of hydroxylamine hydrochloride, 11.38 g (135.44 mmol) of sodium hydrogencarbonate and 440 mL of methanol was stirred at room température for 24 h. The reaction mixture was poured into 300 mL of water and stirred for 1 h, the precipitated product was filtered off, washed with water and dried to yield 17.19 g (96.8%) of the title compound as a white powder.

b) 3-Chloro-2-(5-methyI-f l ,2,4]oxadiazol-3-vD-l//-indole

A mixture of 15.19 g (72.46 mmol) of 3-chloro-7V-hydroxy-l//-indole-2carboxamidine, 306 mL of acetic acid and 17.07 mL (180 mmol) of acetic anhydride was stirred at 90°C for 10 h. The reaction mixture was concentrated in vacuo and the residue was recrystallized from a 1:1 mixture of methanol and water to yield the crude product, which was recrystallized from 2-propanol to yield 12.29 g (72.6%) of the title compound.

c) 4-f3-Chloro-2-(5-methyl-[l,2,41oxadiazol-3-yl)-indol-l-vll-benzvlamine hvdrochloride

To a stirred mixture of 10.0 g (42.7 mmol) of 3-chloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-l//-indole, 21.49 g (85.5 mmol) of 4-(/ert-butoxycarbonylaminomethyl)phenylboronic acid and 12.98 g (85.5 mmol) of copper(II) acetate in 520 mL of DMSO 29.8 mL (310 mmol) of MA-diisopropylethylamine and 20 g of 3 Â molecular sieves were added. The reaction mixture was vigorously stirred at room température with air bubbling for 6 days. The mixture was filtered through Celite. The Citrate was diluted with 1000 mL of ethyl acetate and washed with 2 x 500 mL of 25% ammonium hydroxide solution. The organic layer was washed with 500 mL of IM citric acid, diied <ov<ea· amihydnouis sodium sulfate. filtered and concentrated in vacuo. The residue was dissolved in 350 mL of 10 % hydrogen chloride in ethyl acetate and stirred at room température for 2 h. The precipitated crude product was filtered off, washed with cold ethyl acetate and recrystallized from 2-propanol to yield 14.2 g (88.7%) of the title compound.

d) ( 1 - f 4- Γ3 -Chloro-2-( 5 -methyl- fl ,2,41 oxadiazol-3-yl)-indol-1 -yl 1-benzylcarbamoyl f cvclopropvD-carbamic acid tert-butvl ester

A mixture of 14.0 g (37.3 mmol) of 4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylamine hydrochloride, 200 mL of DMSO, 9.0 g (44.8 mmol) of 1tert-butoxycarbonylamino-cyclopropanecarboxylic acid, 19.0 g (44.8 mmol) of HBTU and 13.0 mL (74.6 mmol) of M/V-diisopropylethylamine was stirred at room température for 2 h. The reaction mixture was poured into 2000 mL of water and stirred for 1 h. The precipitated product was filtered off, washed with water and recrystallized from a 1:1 mixture of 2-propanol and water to yield 13.2 g (67.7%) of the title compound. .

e) 1-Amino-cvclopropanecarboxvlic acid 4-[3-chloro-2-(5-methyl-IL2.41oxadiazol-3vD-indol-l -vll-benzvlamide

A mixture of 29.5 g (56.5 mmol) of (l-{4-[3-chloro-2-(5-methyl- [1,2,4] oxadiazol-3 -yl)-indol-1 -y 1] -benzylcarbamoyI ) -cyclopropyl)-carbam ic acid tertbutyl ester and 450 mL of 10 % hydrogen chloride in ethyl acetate was stirred at room température for 12 h. The reaction mixture was cooled and 500 mL of 20% sodium hydroxide solution was added. After stirring for 20 min the organic layer was separated, dried ονσ anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 23.5 g (98%) of rtflae itStÜLe compound. M.S (El) 422.2 (MH⁴)·

Référencé Examplc 10

4-[3-Chloro-5-fluoro-2-(2-methvI-2/f-tetrazol-5yl)-indoI-l“Vl]-benzvlamine hydrochloride

The title compound was prepared from 5-fluoro-177-indole-2-carboxylic acid according to the methods described in Reference Example 4a-f. Mp.: 216-220 °C.

Reference Example 11 4-[3,5-Dichloro-2-(2-methyl-2£f-tetrazol-5-yl)-indol-l-yl|-benzylamine______hydrochloride

The title compound was prepared from 5-chloro-17/-indole-2-carboxylic acid according to the methods described in Reference Example 4a-f. Mp.: 267-270 °C.

Reference Example 12 4-[3-Chloro-5-fluoro-2-(2-methvl-2ZMetrazol-5-vl)-indol-l-yl]-2-fluorobenzylamine hydrochloride

The title compound was prepared from 5-fluoro-17/-indole-2-carboxylic acid and 3-fluoro-4-(/er/-butoxycarbonylaminomethyl)phenylboronic acid (Reference Example 1) according to the methods described in Reference Example 4a-f. Mp.: 176178 °C.

Reference Example 13

M.

4- [3,5-Dich loro-2-(2-mcth yl-2H-tet razoI-5-γ l)-indol-1 -yll -2-fluoro-be nzylam i n e hydrochloride

The title compound was prepared from 5-chloro-l/f-indole-2-carboxylic acid and 3-fluoro-4-(/er/-butoxycarbonyIaminomethyl)phenylboronic acid (Reference 5 Example I) according to the methods described in Reference Example 4a-f. Mp.: 186189 °C.

Reference Example 14 l-(4-Aminomethvl-phenvl)-3-chloro-lZZ-indole-2-carbonltrile hydrochloride

a) r4-(3-Chloro-2-cyano-ïndol-l-vl)-benzyll-carbamic acid tert-butyl ester

To a stirred mixture of 0.353 g (2.0 mmol) of 3-chloro-l/Aindole-2-carbonitrile (Reference Example 4c), 0.753 g (3 mmol) of 4-(/erZ-butoxycarbonylaminomethyl)phenylboronic acid and 0.606 g (4 mmol) of copper(II) acetate in 24 mL of DMSO 1.4 mL (8 mmol) of WJV-diisopropylethyiamine was added. The reaction 15 mixture was vigorously stirred at room température with air bubblîng for 6 days. The mixture was diluted with 60 mL of ethyl acetate and washed with 2 x 50 mL of 25% ammonium hydroxide solution. The organic layer was washed with 50 mL of IM citric acîd, dried over anhydmus sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) 20 as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 0428 g (56 %) of the title compound. MS (El) 404.1 [M+Na]⁺.

b) 1 -(4-Aminomethyl-phenvl)-3-chloro-l /7-indole-2-carbonitrile hydrochloride

To a mixture of 0.428 g (1.121 mmol) of [4-(3-chIoro-2-cyano-indol-l-yl)benzylj-carbamic acid /ert-butyl ester in 12 mL of ethyl acetate 24 mL of 10 % 25 hydrogen chloride in ethyl acetate was added and the reaction mixture was stirred at room température for 2 h. The mixture was diluted with diethyl ether, the precipitated product was filtered off, washed with diethyl ether and dried to yield 0.32 g (90%) of the title compound. MS (El) 282.1 (MH*).

Reference Example 15 (g)-l-{4-|3-Chloro-2-(5-methvl-[1^.41oxadiazol-3-vl)-indol-l-vlÎ-phenvl}ethylamine hydrochloride

a) C/?Wl-MT3-Chloro-2-i5-methyl-[l ,2,41oxadia2ol-3-vl)-indol-l-yll-phcnvn-ethyBcarbamic acid tert-butyl ester

The title compound was prepared from 3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-l/7-indole (Référencé Example 9b) and (7f)-4-(l-tert-butoxycarbonylamino-ethyl)phenylboronic acid (Référencé Example 2) according to the method described in Example le. MS (El) 475.2 [M+Na]⁺.

b) __________i7?)-l-(4-r3-Chloro-2-(5-methvl-ri,2.41oxadiazol-3-yD-indol-l-vl1-phenyn- ethylamine hydrochloride

The title compound was prepared from (7ï)-(l-{4-[3-chloro-2-(5-methyl|l,2,4]oxadiazol-3--yl)-indol-l-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester according to the method described in Référencé Example 14b. MS (El) 353.1 (MH⁺).

Référencé Example 16 l-(4-Aminomethvl-phenyl)-5-chloro-ltf-indole-2-carbonitrile hydrochloride

a) [4-(5-Chloro-2-cyano-indol-1-y l)-benzyl]-carbamic acid tert-butyl ester

The title compound was prepared from 5-chloro-l/7-indole-2-carbonitrîle (I. Borza at al. Bioorg. Med. Chem. Lett. 2005, 75, 5439-5441) according to the method described in Référencé Example 14a. MS (El) 404.1 [M+Na]⁺.

b) 1 -i4-Aminomethyl-Dhenyl)-5-chloro-l 77-indole-2-carbonitri!e hydrochloride

The title compound was prepared from [4-(5-chloro-2-cyano-indol-l-yl)benzyl]-carbamic acid tert-butyl ester according to the method described in Reference Example 14b.

Reference Example 17 l-Amino-cyclopropanecarboxylic_____acid_____4-(2-cya no-5-meth oxy-ind ol-1 -yllbenzylamide hydrochloride

a) 1 -(4-Aminomethvl-phenvD-5-methoxy- 17/-indole-2-carbonitrile hydrochloride

The title compound was prepared from 5-mcthoxy-l/7-indole-2-carbonitrile (I. Borza at al. Bioorg. Med. Chem. Lett. 2005, 75, 5439-5441) according to the methods described in Reference Example 14a and 14b. MS (El) 261. [(M-NIDf.

b) l-Amino-cyclopropanecarboxylic acid 4-(2-cyano-5-methoxy-indol-l-yl)- benzylamide hydrochloride

The title compound was prepared from l-(4-aminomethyl-phenyl)-5-methoxyl/7-indole-2-carbonitrile hydrochloride according to the method described in Reference Example 4g and 4h. MS (El) 361.2 (MIT¹).

Réference Examplc 18 l-Amino-cyclopropanecarboxylic acid 4-(2-cyano-5-fluoro-indol-l-yl)-benzylamide hydrochloride

a) 1 -(4-Aminomethvl-phenyl)-5-fluoro-1 //-indole-2-carbonitrile hydrochloride

The title compound was prepared from 5-fluoro-l H-indole-2-carbonitrîle (I. Borza at al. Bioorg. Med. Chem. Lett, 2005,15, 5439-5441) according to the methods described in Reference Example 14a and 14b. MS (El) 249.1 [(M-NFh)]*.

b) l-Amino-cyclopropanecarboxylic acid 4-(2-cyano-5-fluoro-indol-l-vl)-benzvlamide hydrochloride

The title compound was prepared from l-(4-aminomethyl-phenyl)-5-fluoro-l/findole-2-carbonitrile hydrochloride according to the methods described in Reference Example 4g and 4h. MS (El) 349.2 (MH⁺).

Reference Example 19 l-Amino-cyclopropanecarboxylic acid 4-[5-fluoro-2-(5-methyl-H^,4]oxadiazol-3yD-indol-l-yll-benzylamide hydrochloride

a) 5-Fluoro-2-(5-methvl-n.2,41oxadiazol-3-vl)-l//-indole

The title compound was prepared from 5-fluoro-177-indole-2-carbonitrile (I. Borza at al. Bioorg. Med. Chem. Lett. 2005, 15, 5439-5441) according to the methods described in Reference Example 9a and 9b.

b) 1-Amino-cvclopropanecarboxvlic acid 4-i5-fluoro-2-(5-methvl-il.2.41oxadiazol-3vD-indol-1 -yll-benzylamide hydrochloride

The title compound was prepared from 5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-17/-indole according to the methods described in Reference Example 9c-e. MS (El)

406.2 (MH*).

Reference Example 20

1- Amino-cvcloDropanccarboxylic acid 4-[3-chIoro-5“methoxv~2-(3-mcthyl- |l,2,4|oxadiazol-5-vl)-indoI-l-yl1-benzvlamidc hydrochloride

a) 3-Chloro-5-methoxy-lff-indole-2-carboxylic acid

The title compound was prepared from 5-methoxy-l//-indole-2-carboxylic acid 5 according to the method described in Reference Example 4a.

b) 3-Chloro-5-methoxv-lJ7-indole-2-carboxvlic acid methyl ester

To a stirred mixture of 24.63 g (109.3 mmol) of 3-chloro-5-methoxy-l//-indole-

2- carboxylic acid in 1200 mL of methanol 20 mL of concentrated sulfuric acid was added and the reaction mixture was refluxed for 40h. The reaction mixture was concentrated to 300 mL and 38 g of sodium carbonate was added portion-wise to the mixture while it was cooled with ice-water. Then the mixture was diluted with 300 mL of ethyl acetate, the pH of the mixture was adjusted to 8 by addition of 40% sodium hydroxide solution. The phases were separated, the water phase was extracted with 3x100 mL of ethyl acetate, the combined organic layers were washed with water and 15 dried over anhydrous magnésium sulfate, filtered and concentrated to yield 23.68 g (90.4%) of the title compound.

c) 1 -r4-(rer/-Butoxvcarbonvlamino-methYl)-phenyl]-3-chloro-5-methoxv-l /f-indole-2carboxvlic acid methyl ester

To a stirred mixture of 4.8 g (20 mmol) of 3-chloro-5-methoxy-l//-indole-220 carboxylic acid methyl ester, 7.53 g (30 mmol) of 4-(ter/-butoxycarbonylaminomethyl)phenylboronic acid and 6.0 g (40 mmol) of copper(II) acetate în 150 mL of N,Ndimethylfonnanùde 14 mL (80 mmol) of M/V-diisopropylethylamine and 10 g of 3 Â molecular sieves were added. The reaction mixture was vigorously stirred at room température with air bubbling for 6 days. The mixture was filtered through Celite. The 25 filtrate was diluted with 500 mL of ethyl acetate and washed with 2 x 200 mL of 25% ammonium hydroxide solution. The organic layer was washed with 200 mL of water, dried w®r anhydrous m^nerium sulfate, filtered and concentrated in vacua. Oie residue was Iriituraled with 2-propanoL the crystalline solid was filtered off and dried to yield 4_28 g (48%) of the title compound. MS (El) 467.2 [M+Na]⁺.

d) {4-[3-Chloro-5-methoxv-2-(3-methyl-i 1,2.41oxadiazol-5-yl)-indol-1 -vll-benzyl 1 carbamic acid tërt-butvl ester ήΕ

A stirred mixture of 4.28 g (9.6 mmol) l-[4-(ferf-butoxycarbonylamino-methyl)phenyl]-3-chloro-5-methoxy-lH-indole-2-carboxylic acid methyl ester, l .07 g (14.4 mmol) H-hydroxy-acetamidine, 3.58 g (25.9 mmol) potassium carbonate and 100 mLof toluene was refluxed for 20 h, then filtered and the filtrate was concentrated to yield 4.23 g (94%) of the title compound. MS (El) 491.1 [M+Na]⁺.

e) 4-r3-Chloro-5-methoxv-2-i3-methyl-|l ,2.41oxadiazol-5-yl)-indol-l -yll-benzylamine hydrochloride

The title compound was prepared from {4-[3-chloro-5-methoxy-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indoI-l-yl]-benzyl}-carbamic acid ferf-butyl ester according to the method described in Reference Example 14b. MS (El) 352.1 [(M-NH2)]⁺.

f) ___________( 1 -{4-[3-Chloro-5-methoxv-2-(3-methvl-[ 1.2,41oxadiazol-5-vD-indol-l-yl1- benzvIcarbamoyll-cycloDropyD-carbamic acid ferf-butyl ester

A mixture of 3.94 g (9.7 mmol) of 4-[3-chloro-5-methoxy-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-benzylamine hydrochloride, 2.93 g(14.7 mmol) of 1ferf-butoxycarbonylamino-cyclopropanecarboxylic acid, 4.43 g (11.4 mmol) of HATU [0-(7-azabenzotriazol-l-yl-A^r,N7V’,A^p-tetramethyluronium hexafluorophosphate], 7.6 g (43.7 mmol) of JVJV-diisopropylethy lamine, 70 mL of dichloromethane and 2 mL of Ν,/V-di methyl form ami de was stirred at room température for 1.5 h, then diluted with 100 mL of water and the phases were separated. The water phase was extracted with dichloromethane, the combined organic layers were dried over anhydrous magnésium sulfate, filtered and concentrated. The residue was triturated with 2-propanol, the crystalline solid was filtered off and dried to yield 4.22 g (79%) of the title compound. MS (El) 574.2 [M+Na]⁺.

g) l-Ammo-cyclopropanecarboxylic acid 4-r3-chloro-5-methoxv-2-(3-methyl[ 1,2,41oxadiazol-5-y!)-indol-l -yll-benzvlamide hydrochloride

The title compound was prepared from (l-(4-[3-chloro-5-methoxy-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-carbamic acid ferfbutyl ester according to the method described in Reference Example 14b. MS (El) 452.2 (MH⁺).

Reference Example 21

F l-id-Aminomethyl-phenyll-S-chloro-S-methoxy-l/f-indole-Z-carbonitrile hydrochloride

a) 3-Chloro-5-methoxv-l//-indole-2-carbonitrile

The title compound was prepared from 5-methoxy-177-indole-2-carboxyIic acid according to the methods described in Reference Example 4a-c.

b) 1 -(4-Aminomethyl-phenyl)-3-chloro-5-methoxy-l J/-indole-2-carbonitrile hydrochloride

The title compound was prepared from 3-chloro-5-methoxy-l/7-indole-2carbonitrile according to the methods described in Reference Example 14a and 14b. MS (El) 295.1 [(M-NH₂)]⁺.

Reference Examplc 22 4-[5-Chloro-2-(5-mcthyl-H,2,41oxadiazol-3-vB-indol-l-yl|-bcnzylamine_____hydrochloride

The title compound was prepared from 5-chloro-lf/-indole-2-carbonitrile (I. Borza at al. Bioorg. Med. Chem. Lett. 2005, 15, 5439-5441) according to the methods described in Reference Example 9a-c. MS (El) 322.1 [(M-NH2)]⁺.

Reference Example 23 l-(4-Aminomethvl-3-fluoro-phenvl)-3-chloro-l/f-indoIe-2-carboxylic acid methyl ester hydrochloride

The title compound was prepared from 3-chloro-17ï-indole-2-carboxylic acid methyl ester and 3-fluoro-4-(/erZ-butoxycarbonylaminomethyl)phenylboronic acid (Reference Example 1) according to the method described in Reference Example 9c. MS (El) 333.1 (MH*)Reference Example 24

4-[3-Chloro-5-methoxv-2-(5-mcthvl-lL2.41oxadiazol-3-vl)-indol-l-yll-benzylamine

a) 5-Methoxv-l//-indole-2-carboxylic acid amide

To a suspension of 10 g (52.3 mmol) of 5-methoxy-l/7-indole-2-carboxylic acid in 300 mL of dichloromethane and 1 mL of /VX-dimethylformamide 8.85 mL (104.6 mmol) of oxalyl chloride was added dropwise. The reaction mixture was stirred at room température for 3 h, than cooled in ice-bath and 56 mL of concentrated aqueous ammonium hydroxide solution was added slowly. The resulted mixture was stirred at room température o verni ght, the precipitated product was filtered off, washed with water and dried in vacuo to yield 9.8 g (98.5%) of the title compound. MS (El) 191.1 (MH*).

b) 3-Chloro-5-methoxy-l/7-indole-2-carboxylic acid amide

To a stirred suspension of 9.9 g (52.3 mmol) of 5-methoxy-l/f-indole-2carboxylic acid amide in 500 mL of acetonitrile 7.68 g (57.5 mmol) of Nchlorosuccinimide was added. The reaction mixture was refluxed for 3 h, then cooled to room température. The separated crystalline solid was filtered off, washed with acetonitrile and recrystallized from 2-propanol to yield 7.96 g (68%) of the title compound. MS (El) 225.1 (MH*).

c) 3-Chloro-5-methoxv-127-indole-2-carbonitrile

To a stirred suspension of 5.5 g (24.2 mmol) of 3-chloro-5-methoxy-l//-indole2-carboxylic acid amide in 200 mL of 1,4-dioxane 17 mL (183 mmol) of phosphorus oxychloride was added. The reaction mixture was refluxed for 3 h. The resulted dark solution was cooled to room température and poured to crushed ice. The icy mixture was stirred for 30 min and extracted with dichloromethane. The combined organic phases were extracted with water, 10% aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo to yield 3.33 g (66.6%) of the title compound. MS (El) 207.1 (MH⁺).

d) 3-Chloro-jV-hydroxv-5-methoxv-l/7-indole-2-carboxamidine

To a stirred solution of 2.2 g (10.6 mmol) of 3-chloro-5-methoxy-l/f-indole-2carbonitrile in 50 mL of éthanol a solution of 1.5 g (21.2 mmol) of hydroxylamine hydrochloride in 30 mL of water and a solution of 2.4 mL (17 mmol) of triethylamîne in 20 mL of éthanol were added dropwise and simultaneously. The resulted mixture was refluxed 3 h, cooled to room température, then concentrated in vacuo. The residue was triturated with water, the crystalline solid was filtered off and the obtained crude product was recrystallized from a 1:1 mixture of 2-propanol and water to yield 1.6 g (63%) of the title compound. MS (El) 241.1 (MIT*).

e) 3-Chloro-5-methoxv-2-(5-methyl-[ 1,2,41oxadiazol-3-yl')-l /f-indole

V? G

To a solution of 1.6 g (6.7 mmol) of 3-chloro-JV-hydroxy-5-methoxy-l//-indole2-carboxamidine in 40 mL of dichloromethane 2 mL (13.4 mmol) of TVJVdimethylacetamide dimethyl acetal was added and the reaction mixture was stirred at room température for 1 h. The reaction mixture was diluted with dichloromethane and extracted with water, dried over anhydrous magnésium sulfate, filtered through a plug of silica, the filter cake was washed with chloroform and the filtrate was concentrated in vacuo. The resîdue was recrystallized from ethyl acetate to yield 1.37 g (81%) of the title compound. MS (El) 264.1 (MH⁺).

f) 14-r3-Chloro-5-methoxv-2-(5-methvM 1,2,41oxadiazol-3-yl)-indol-l-vl1-benzyl)carbamic acid tërf-butvl ester

To a solution of 1 g (3.79 mmol) of 3-chloro-5-methoxy-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-l//-indole in 50 mL of M/V-dimethylformamide 1.14 g (4.55 mmol) of 4-(/eri-butoxycarbonylaminomethyl)phenyiboronic acid, 1.2 g (7.58 mmol) of copper(n) acetate, 2.6 mL (15.2 mmol) of /V,W-diisopropylethylamine and 2 g 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 6 h. The mixture was filtered through Celite. The filter cake was washed with Λ/,/V-dimethylformamide and chloroform, the combined filtrâtes were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane:ethyl acetate = 2:1 as eluent to yield 0.98 g (57.6%) of the title compound. MS (El) 491.1 (M+Na)⁺.

g) 4- [3 -Chloro-5-methoxy-2-( 5-methyl- (1,2,4]oxadiazol-3-yl)-indol -1 - yl] -benzylamine

To an ice-cooled solution of 0.9 g (1.9 mmol) of (4-[3-chloro-5-methoxy-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzyl}-carbamic acid ie/7-butyl ester in 20 mL of dichloromethane 2 mL (27 mmol) of trifluoroacetic acid was added. The reaction mixture was allowed to warm to room température and stirred for 48 h. The reaction mixture was concentrated in vacuo and the residue was taken up dichloromethane and extracted with saturated aqueous sodium carbonate solution and brine, dried over magnésium sulfate, filtered and concentrated in vacuo to yield 0.467 g (67%) of the title compound. MS (El) 369.1 (MH*).

Référencé Example 25 l-(4-Aminomcthvl-phenvl)-3-chloro-4-fluoro-l/f-indolc-2-carboxylic acid methyl ester

a) 3-Chloro-4-fluoro-lH-indole-2-carboxvlic acid methyl ester

To a stirred suspension of l.l g (5.7 mmol) of 4-fluoro-l//-indole-2-carboxylic acid methyl ester in 60 mL of acetonitrile 0.836 g (6.26 mmol) of /V-chlorosuccinimide was added. The reaction mixture was refluxed for 6 h, then cooled to room température. The separated crystalline solid was filtered off, washed with acetonitrile and dried in vacuo. The crude product was recrystallized from 2-propanol to yield l.05g (81%) of the title compound.

b) l-[4-(7e/7-Butoxvcarbonvlamino-methYl)-phenyl |-3-chloro-4-fluoro-l//-indole-2carboxylic acid methyl ester

To a solution of 0.75 g (3.3 mmol) of 3-chloro-4-fluoro-l//-indole-2-carboxylic acid methyl ester in 30 mL of X.X-di methyl form amide 1.1 g (4.4 mmol) of 4-(tertbutoxycarbonylaminomethyl)phenylboronic acid, 1.0 g (6.4 mmol) of copper(II) acetate, 2.2 mL (12.7 mmol) of Λζ/V-diisopropylethylamine and 1.4 g of 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 36 h. The mixture was filtered through Celite. The filter cake was washed with N,A-di methyl formamide and chloroform and the combined filtrâtes were concentarted in vacuo. The residue was taken up în chloroform and subsequently washed with concentrated aqueous ammonium hydroxîde solution, water, 10% aqueous citrîc acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane: ethyl acetate = 2:1 as eluent to yield 0.695 g (49%) of the title compound. MS (El) 453.2 (M+Na)*.

c) l-(4-Aminomethyl-phenyl)-3-chloro-4-fluoro-l/7-indole-2-carboxylic acid methyl ester

To an ice-cooled solution of 0.18 g (0.416 mmol) of l-[4-(/ertbutoxycarbonylamino-methyl)-phenyl]-3“ChlorO“4fluoro-l//-indole-2-carboxylic acid methyl ester in 10 mL of dichloromethane 0.8 mL (10.4 mmol) of trifluoroacetic acid was added. The reaction mixture was allowed to warm to room température and stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was taken up in dichloromethane and extracted with saturated aqueous sodium carbonate solution and brine, dried over magnésium sulfate, filtered and concentrated in vacuo to yield 0.138 g (100%) of the title compound.

Référencé Example 26 l-Amino-cyclopropanccarboxylic acid 4-i5-fluoro-2-(3-methyl-[l^,4]oxadiazol-5vl)-indol-l-yll-bcnzylamidc

a) 5-Fluoro-2-i3-methyl-[l .2.4]oxadiazol-5-yl)-l H-indole

To a stirred solution of 2.70g (14.29 mmol) of 5-fluoro-l//-indole-2-carboxylic acid methyl ester in 150 mL of toluene 1.59 g (21.4 mmol) of A-hydroxy-acetamidine and 3.0 g (21.7 mmol) of potassium carbonate were added. The reaction mixture was refluxed for 24 h, then cooled and diluted with 60 mL of ethyl acetate and 60 mL of water. The mixture was separated and the organic layer was washed with water and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo to yield 2.95 (97%) of the title compound as a white solid.

b) (4-r5-Fluoro~2-(3-methvl-[L2,41oxadiazol-5-vl)-indol-l-yll-benzyl}-carbamic acid terf-butyl ester

To a solution of 1.5 g (6.9 mmol) of 5-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5yl)-l/f-indole in 80 mL of A^JV-di methyl form ami de, 2.6 g (10 mmol) of 4-(tertbutoxycarbonylaminomethyl)phenylboronic acid, 2.1 g (13.8 mmol) of copper(Il) acetate, 4.8 mL (27.6 mmol) of Α,Α-diisopropylethylamine and 3 g of 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 120 h. The mixture was filtered through Celite. The fîlter cake was washed with AyV-dimethylformamide and chloroform and the combined filtrâtes were concentrated in vacuo. The residue taken up in ethyl acetate and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous cîtric acid solution, water, saturated aqueous sodium fh C hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane: ethyl acetate as eluent to yield l .456g (50%) of the title compound.

c) ( 1 ~f 4- Γ 5-Fluoro-2-( 3 -methyl- ί 1,2,41 oxadiazol-5-vl)-indol-1 -vil -benzylcarbamo yl} cyclopropyD-carbamic acid fert-butyl ester

To a cooled solution of 1.456 g (3.45 mmol) of {4-[5-fluoro-2-(3-methyl- [l,2,4]oxadiazol-5-yl)-indol-l-yi]-benzyl}-carbamic acid terï-butyl ester in 40 mL of dichloromethane 3 mL (3.9 mmol) of trifluoroacetic acid was added. The reaction 10 mixture was allowed to warm to room température and stirred for 20 h. The réaction mixture was concentrated in vacuo and the residue was taken up in 80 mL of dichloromethane and washed with saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnésium sulfate and filtered. To the resulted stirred solution of 4-[5-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylamine 0.73 15 g (3.63 mmol) of l-ZerZ-butoxycarbonylamino-cyclopropanecarboxylic acid and 0.995 g (5.2 mmol) of EDC were added at 5°C. The reaction mixture was allowed to warm to room température and stirred overnight. The reaction mixture was washed with 15 mL of water, 2x15 mL of 5% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered 20 and concentrated in vacuo to yield 1.54g (88%) of the title compound as a white foam.

d) l-Amino-cyclopropanecarboxylic acid 4-r5-fluoro-2-(3-methvl-IT,2.41oxadiazol-5vl)-indol-l -vll-benzylamide

To a cooled solution of 1.43 g (2.83 mmol) of (l-{4-[5-fluoro-2-(3-methyl[ 1,2,4]oxadiazol-5-yl)-indol-l -yl]-benzylcarbamoyl}-cyclopropyl)-carbamic acid tert25 butyl ester in 50 mL of dichloromethane 6 mL (7.8 mmol) of trifluoroacetic acid was added. The reaction mixture was allowed to warm to room température and stirred for 3 h. The reaction mixture was concentrated in vacuo, the residue was taken up in dichloromethane and washed with saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo to 30 yield 1.06 g (92%) of the title compound.

Reference Example 27

C

1-Amino-cyclopropanecarboxylic________acid________4-|3,5-dichloro-2-(5-methvlm.41oxadiazol-3-vl)-indoll~vll-benzvIamide

a) 4-r3,5-Dichloro-2-f5-methvl-[l,2.41oxadiazol-3-vl)-indol-l-vll-benzvlamine

The title compound was prepared from 5-chloro-lH-îndole-2-carboxylic acid according to the methods described in Reference Example 24a-g. MS (El) 322.1 [(MNH₂)]⁺.

b) 1-Amino-cvclopropanecarboxvlic acid 4-r3.5-dichloro-2-(5-methyl-n.2,41oxadiazol3-yl)-indoM -vll-benzylamide

The title compound was prepared from 4-[3,5-dichloro-2-(5-methyl10 [l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamine according to the methods described in Reference Example 9d and 9e. MS (El) 422.2 (MH*).

Référencé Examplc 28

1-Amino-cyclopropanecarboxylic______acid______4-|3-chloro-5-fliioro-2-(5-methvl15 11,2,41 oxad iazol-3-yl)-indol-1 -yll-benzylamide

a) 4-r3-ChlorO“5-fluoro-2-(5-methyl-n.2.41oxadiazol-3-vl)-indol-l-vn-benzylamine

The title compound was prepared from 5-fluoro-l//-indole-2-carboxy!ic acid according to the methods described in Reference Example 24a-g. MS (El) 357.1 (MH⁺).

b) 1-Amino-cvclopropanecarboxvlic acid 4-r3-chloro-5-fluoro-2-i5-methyl-

Γ1,2,41 oxadiazol-3-vD-indol-1 -yll-benzylamide

The title compound was prepared from 4-[3,5-dichloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yI]-benzylamine according to the methods described in Reference Example 9d and 9e. MS (El) 440.1 (MH⁺).

Reference Examplc 29

1- Amino-cyclopropanecarboxylic acid 4-|5-methoxy-2-(5-methyl-|13,41oxadiazol-

2- yll-indol-l-yll-benzylamide

a)___________4-[5-Methoxv-2-(5-methvl-ri.3.41oxadiazol-2-vl')-indol-l-vl1-benzylamine hydrochloride

The title compound was prepared from 5-methoxy-l//-indole-2-carboxylic acid according to the methods described in Reference Example 7a-c. MS (El) 318.2 [(MNH₂)]⁺.

b) l-Amino-cyclopropanecarboxylic acid 4-r5-methoxy-2-(5-methvl-H.3.4loxadiazol2-yl)-indol-l -yll-benzyl amide

The title compound was prepared from 4-[5-methoxy-2-(5-methyl- [1.3.4] oxadiazol-2-yl)-indol-l-yl]-benzylamine hydrochloride according to the methods described in Reference Example 9d and 9e. MS (El) 418.2 (MH*).

Referencc Example 30 l-Amino-cyclopropanecarboxylic acid 4-|5-mcthoxy-2-(3-methyl-lU,41oxadiazol-

5-yl)-indol-l-yll-benzylamide

a) 5-Methoxv-lH-indole-2-carboxylic acid methyl ester

A mixture of 9.6 g (0.050 mol) of 5-methoxy-l/7-indole-2-carboxylic acid and

4.5 mL of concentrated sulfuric acid in 250 mL of methanol was refluxed for 6 h. The reaction mixture was cooled, concentrated in vacuo and 200 mL of water and 200 mL of dichloromethane was added to the residue. The organic layer was separated and the water phase was extracted with 100 mL of dichloromethane. The combined organic layers were washed with water and saturated sodium hydrogencarbonate solution, dried over sodium sulfate, concentrated and dried to yield 10.17 g (98.7 %) of the title compound. Mp: 178-181 °C.

b) 5-Methoxy-2-(3-methYl-H ,2_t41oxadiazol-5-vl)-l 77-indole

A mixture of 5.5 g (26.8 mmol) of 5-methoxy-l/f-indole-2-carboxylic acid methyl ester, 3.0 g (40.5 mmol) of jV-hydroxy-acctamidinc and 10 g (72.3 mmol) of potassium carbonate in 150 mL of toluene was refluxed for 18 h, then additional 2.0 g (27 mmol) of A-hydroxy-acetamidinc and 5 g (36.1 mmol) of potassium carbonate was added. The reaction mixture was refluxed for 20 h, cooled to 20 °C, filtered, the filtrate was concentrated and dried to yield 5.45 g (98.7 %) of the title compound. Mp: 141-142 °C. MS (El) 230.2 (MH⁺).

c) (l-f4-r5-methoxy-2-(3-methyl-ri.2.41oxadiazol-5-yl)-indol-l-yll-benzyicarbamoyl)cvclopronvD-carbamic acid ferZ-butyl ester

The title compound was prepared from 5-methoxy-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-l/7-indole according to the method described in Reference Example 4e-g. Mp.: 212-214 °C. MS (El) 418.2 [(M-Boc)]⁺.

Ίιϋ

d) 1-Amino-cvclopropanecarboxylic acid 4-[5-methoxv-2-(3-methvl-H.2,4|oxadia7.ol5-yD-mdoi-1 -yll-benzylamide

A mixture of 1.56 g (3.0 mmol) of (l-{4-[5-methoxy-2-(3-methyl- [1,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-carbamic acid tert- butyl ester, 15 mL of trifluoroacetic acid and 25 mL of dichloromethane was stirred at room température for 2 h. The reaction mixture was concentrated and 100 mL of saturated sodium hydrogencarbonate solution and 100 mL of dichloromethane was added to the residue. The organic layer was separated and the water phase was extracted with 50 mL of dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate and concentrated. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene:methanol = 4:1 as eluent. The so obtained product was crystallized from diisopropyl ether to yield 0.99 g (78.9 %) of the title compound. Mp.: 145-146 °C. MS (El) 418.2 (MH*).

Reference Example 31

Methyl_____________144-(aminomethyl)phenvll-3-chloro-lff-indole-2-carboxylate hydrochloride

a) Methyl 3-chloro-l-(4-formylphenvl)-l/f-indole-2-carboxvlate

The title compound was prepared from methyl 3-chloro-l//-indole-2-carboxylate (Zeneca Limited Paient: US6288103 Bl, 2001;) according to the method described in Reference Example 5b. MS (El) 314.1 (MH*).

b) Methyl 3-chloro-l -f4-r(£)-(hvdroxvimino)methvl1phenyl}-l/7-indole-2-carboxylate

The title compound was prepared from methyl methyl 3-chloro-1-(425 formylphenyl)-l//-indole-2-carboxylate according to the method described in Reference Example 5d. MS (El) 329.1 (MH*).

c) Methyl l-|4-(aminomethvl)phcnvll-3-chloro-l/f-indole-2-carboxylate hydrochloride

The title compound was prepared from methyl 3-chloro-l-{4-[(£)(hydroxyimino)methyl]phenyl}-l H-indole-2-carboxyIate according to the method 30 described in Reference Example 5e. MS (El) 315.1 (MH⁺).

Reference Example 32 l-(4-Aminomethvl-phenvD-3-chloro-l/7-indole-2-carboxyIic·______acid______amide hydrochloride

The title compound was prepared from 3-chloro-l/7-indole-2-carboxamide (Reference Example 4b) according to the method described in Reference Example 9c. MS (El) 283.1 [(M-NH₂)]⁺.

Reference Example 33 (lJ?)-l-i4-f3-chloro-2-(5-methyl-l₄2,4-oxadiazol-3-yl)-l/7-indol-l-yll-2-fluorophenyllethanamine hydrochloride

a) 3-Fluoro-4-r(/?)-l -(2-methvl-propane-2-sulfinylamino)-ethyll-phenylboronic acid

Under argon to a solution of 6.42 g (19.9 mmol) of 2-methyl-propane-2-sulfinic acid [(7?)-l-(4-bromo-2-fluoro-phenyl)-ethy]]-amîde (S.D. Kuduk et al. J. Med. Chem., 2007, 50. 272-232) and 4.4 mL (30 mmol) TMEDA (tetramethylethylenediamine) in 520 mL of dry diethyl-ether 38.5 mL of 2.5 M n-butyllithium in hexane solution (39.8 mmol) was added dropwise at -78°C over a period of 1.5 h. After the mixture was stirred at -78°C for 20 min, 125 mL (545 mmol) of triisopropyl borate was added dropwise over a period of 0.5 h. The so obtained mixture was allowed to warm to room température and stirred at this température for 18 h. The reaction mixture was quenched by addition of 500 mL of saturated ammonium chloride solution (pH ~8) and allowed to warm to room température. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with 100 mL of IM citric acid and water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was sfiired with 50 mL of n-hexane overnight, ithen filtered and dried to yield 3.2 g (56%) of the fille compound as a wifite solid. MS (El) 288.1 (MH⁺).

b) ______(!/?)-!-( 4-f3-chloro-2-(5-methvl-1,2,4-oxadiazol-3-vl)-1 /7-indol-1 -νΠ-2-fluoro- phenyllethanamine hydrochloride

The title compound was prepared from 3-fluoro-4-[(Æ)-l-(2-methyl-propane-2sulfinylamino)-ethyl]-phenylboronic acid according to the method described in Reference Example 9c. MS (El) 354.1 [(M-NH₂)]⁺.

Reference Example 34

4U

4-f3-Chloro-2-(5-mcthvl-H_<2,41oxadiazol-3-vl)-indol-l-vl|-2-fluoro-bcnzylamine hydrochloride

The title compound was prepared from 3-fluoro-4“(terHbutoxycarbonylaminomethyl)-phenylboronic acid (Référencé Example 1) according to the method described in Référencé Example 9c. MS (El) 340.1 [(M-NH₂)]*.

Référencé Example 35 l-Amino-cyclopropanccarboxylic acid 4-|3-chloro-2-(3-methvl-|l_t2_<4|oxadiazol-5vl)-indol-l-vl|-benzylamidc

a) 3-Chloro-2-(3-methvl-r 1.2.4]oxadiazol-5-yl)-17/-indole

The title compound was prepared from 3-chloro-l//-indole-2-carboxylic acid methyl ester according to the method described in Référencé Example 20d. MS (El)

234.1 (MH*).

b) 4-r3-Chloro-2-(3-methyl-ri.2.41oxadiazol-5-vl)-indol-l-vll-benzylamine hvdrochloride

The title compound was prepared from 3-chloro-2-(3-methyl-l,2,4-oxadiazol~5yl)-l//-indole according to the method described in Référencé Example 9c. MS (El)

339.1 (MH*).

c) (l-(4-r3-Chloro-2-(3-methvl-n.2,41oxadiazol-5-yl)-indol-l-vl1-benzylcarbamovBcvcloproDvD-carbamic acid terAbutyl ester

The title compound was prepared from 4-[3-chloro-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-benzylamine hydrochloride according to the method described in Référencé Example 9d. MS (El) 422.2 [(M-Boc)]*.

d) 1-Amino-cyclopropanecarboxvlic acid 4-r3-chloro-2-(3-methvl-[L2,41oxadiazol-5vl)-indol-l -yil-benzvlamide

The title compound was prepared from (l-{4-[3-chloro-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-benzylcarbamoyl}-cyciopropyl)-carbamic acid terlbutyl ester according to the method described in Référencé Example 9e. MS (El) 422.2 (MH*).

Référence Examplc 36

H16404

-Amino-cvclopropanccarboxvlic acid 4-I2-(5-methyl-| l^,41oxadiazol-3-yl)-indoll-vll-benzylamidc

a) 2-(5-Methyl-i 1,2,41oxadia7.ol-3-vl)-l 77-indole

The title compound was prepared from 7V-hydroxy-l/7-indole-2-carboxamidine (Merck Sharp and Dohme Ltd. Patent: US4952587 Al, 1990 ;) according to the method described in Example 9b. MS (El) 200.0 (MH*).

b) 442-( 5-Methyl-Γ 1,2,41oxadiazol-3-vl)-indol-l-yll-benzylamine hydrochloride

The title compound was prepared from 2-(5-methyl-[l,2,4]-oxadiazol-3-yl)-l/findole according to the method described in Reference Example 9c. MS (El) 305.2 (MH*).

c) (14442-(5-Methyl41.2.4]oxadiazol-3-vl)-indot-l-yH-benzylcarbamovlÎ-cvclopropyp-carbamic acid ferf-butvl ester

The title compound was prepared from 4-[2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-l-yl]-benzyiamine hydrochloride according to the method described in Reference Example 9d. MS (El) 388.2 [(M-Boc)J*.

d) l-Amino-cyclopropanecarboxylic acid 44245-methyl-11,2,4|oxadiazol-3-vl)-indol1 -yll -benzylamide

The title compound was prepared from (l-{4-[2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-carbamic acid /ert-butyl ester according to the method described in Reference Example 9e. MS (El) 388.2 (MH*).

Reference Example 37

1-Amino-cyclopropanecarboxvlic acid 442-(3-methyl-ll^,4|oxadiazol-5-yl)4ndol1-yll-benzylamide

a) 2-(3-Methyl4 1,2,41oxadiazol-5-vn-1 H-indole

The title compound was prepared from l/7-indole-2-carboxylic acid methyl ester according to the method described in Reference Example 20d. MS (El) 200.0 (MH*).

b) 442-(3-Methyl41.2.41oxadiazol-5-vl)-indol-l-vn-benzylamine

The title compound was prepared from 2-(3-methy 1-1,2,4-oxadiazo 1-5-yl)-1/7indole according to the methods described in Reference Example 9c. MS (El) 288.2 [(M-NH₂)]*.

c) ___( l - i 4-r2-(3-Methyl-[ 1 ,2,41oxadiazol-5-yl)-indol-l -yll-benzylcarbamoyl} -cyclo- pronvD-carbamic acid fer/-butyl ester

The title compound was prepared from 4-[2-(3-methyl-[l,2,4]oxadiazol-5-yl)indol-l-yl]-benzylamine hydrochloride according to the method described in Reference Example 9d. MS (El) 388.2 [(M-Boc)]⁺.

d) l-Amino-cvclopropanecarboxylic acid 4-[2-(3-methvl-[1.2,41oxadiaz.ol-5-yl)-indol1 -yll-benzylamide

The title compound was prepared from (l-(4-[2-(3-methyl-[l,2,4]oxadiazol-5yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-carbamic acid /ert-butyl ester according to the method described in Reference Example 9e. MS (El) 388.2 (MH⁺).

Reference Example 38 l-Amino-cvclopropanecarboxylic acid 4-(2-cvano-indol-l-yl)-benzylamide

a) l-r4-(Aminomethvl)phenvl1-177-indole-2-carbonitrile hydrochloride

The title compound was prepared from l/7-indole-2-carbonitrile (I. Borza at al. Bioorg. Med. Chem. Lett. 2005, 15, 5439-5441) according to the method described in Reference Example 9c. MS (El) 231.1 [(M-NH₂)]⁺.

b) {l-r4-(2-CYano-indol-l-yl)-benzvlcarbamoyl]-cvclopropYl}-carbamic acid tert-butyl ester

The title compound was prepared from l-[4-(aminomethyl)phenyl]-177-indole-2carbonitrile hydrochloride according to the methods described in Reference Example 9d. MS (El) 331.2 [(M-Boc)]⁺.

c) l-Amino-cvclopropanecarboxylic acid 4-(2-cyano-indol-l-yD-benzylamide

The title compound was prepared from {l-[4-(2-cyano-indol-l-yl)benzylcarbamoyl]-cyclopropyl}-carbamic acid /erf-butyl ester according to the methods described in Reference Example 9e. MS (El) 331.2 (MH*).

Reference Example 39 4-I3,5-Difluoro-2-i5-methvl-H,2,41oxadiazol-3-yl)-indol-l-vll-benzvlamine hydrochloride

a) 3,5-Difluoro-2-(5-methyl-n.2,41oxadiazol~3-yl)-l/7-indole

To a mixture of 0.941 g (4.33 mmol) of 5-fluoro-2-(5-methyl-[l,2,4]oxadiazol3-yl)-l/7-indole (Reference Example 19a) and 30 mL of acetonitril 1.535 g (4.33 mmol) of Selectfluor [l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] was added and the reaction mixture was stirred at 60°C for 18 h. The mixture was diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate and concentrated. The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 2:1 as eluent to yield 0.335 g (32.9%) of the title compound as yellow crystalline solid. MS (El) 236.1 (MH⁺).

b) ί 4-Γ3.5-Difluoro-2-( 5-methyl-r 1.2,4]oxadiazol-3-yl)-indoI-1 -yll-benzyl} -carbamic acid tert-butyl ester

The title compound was prepared from 3,5-difluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-lH-indole according to the method described in Reference Example 4e. MS (El) 463.2 [M+Na]⁺.

c) __________4-[3.5-Difluoro-2-(5-methyl-| 1.2,41oxadiazol-3-yl)-indol-l -yll-benzylamine hydrochloride

The title compound was prepared from (4-[3,5-difluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzyl}-carbamic acid tert-butyl ester according to the method described in Reference Example 4f. MS (El) 341.1 (MH⁺).

Example 1 l-(2,2,2-Trifluoro-acetvlamino)-cvcloproDanecarboxylic acid 4-[3-chloro-2-(2methyl-2j7-tctrazol-5-vl)-indol-l-vll-benzylamide

To a stirred solution of 4.0 g (8.7 mmol) of 1-amino-cyclopropanecarboxylic acid 4-[3-chloro-2-(2-methyl-2Z/-tetrazol-5-yl)-indol-l-yl]-benzylamide hydrochloride (Reference Example 4) and 3.6 mL (25.8 mmol) of triethylamine in 180 mL of dichloromethane 1.36 mL (9.8 mmol) of trifluoroacetic anhydride was added dropwise below 20 °C, and the reaction mixture was stirred at room température for 3 h. Then 100 mL of water was added to the mixture, the organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) «L and toluene:aceton = 2:1 as eluent to yield after crystallization from 2-propanol 2.2 g (48.7 %) of the title compound. MS (El) 518.2 (MH⁺).

Example 2

3-Methoxy-isoxazole-5-carboxvlic acid (l-i4-13-chloro-2-(2-methyl-2//-tetrazol-5yl)-indol-l-vll-benzvlcarbamoyl}-cvclopropyl)-amide

A mixture of 0.16 g (0.42 mmol) of 4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)indol-l-yl]-benzylamine hydrochloride (Reference Example 4), 0.107 g (0.47 mmol) of l-[3-methoxy-isoxazole-5-carbonyl)“amino]-cyclopropanecarboxylic acid (P.D. O’Shea et al. J. Org. Chem. 2009, 74,4547-4553), 0.15 mL (1.07 mmol) of triethylamine, 0.192 g (0.5 mmol) of HBTU and 5 mL of JVQV-dimethylformamide was stirred at room température for 24 h, then concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene:methanol = 4:1 as eluent to yield after crystallization from diethylether 0.12 g (51.5 %) of the title compound. MS (El) 548.1 (MH⁺).

Example 3

3-Methoxy-isoxazoIe-5-carboxvlic acid (l-f4-|2-(2-mcthvl-2//-tetrazol-5-yl)-indoll-yll-benzvlcarbamovlÎ-cvclopropyl)-amidç

The title compound was prepared from 4-[2-(2-methyl-2/7-tetrazol-5-yl)-indoleyl]-benzylamine hydrochloride (Reference Example 5) according to the method described in Example 2. MS (El) 513.2 (MH⁺).

Example 4 l-(2,2/2-T rifluoro-acetylaminoï-cyclopropanecarboxylic acid 4-|3-chloro-2-(2methvl-2/7-tetrazol-5-vl)-indol-l-yll-2-fluorobenzylaniide

A mixture of 0.197 g (0.50 mmol) of 4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)indol-l-yl]-2-fluoro-benzylamine hydrochloride (Reference Example 6), 0.105 g (0.53 mmol) of l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid (M. R. Hickey et al. Synlett. 2005, 255-258), 0.15 mL (1.07 mmol) of triethylamine, 0.2 g (0.53 mmol) of HBTU and 4 mL of NJV-dimethylformamide was stirred at room température for 24 h, then concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 0.14 g (52.2 %) of the title compound. MS (El) 536.2 (MH⁺).

Example 5

3-Methoxv-/V-|l-(f4-[3-chloro-2-(5-mcthyl-l,3,4-oxadiazol-2-vl)-î/7-indol-l- yl] benzy Π carbamovDcvclopropyll isoxazole-5-ca r boxam idc

The title compound was prepared from 4-[3-chloro-2-(5-methyl- [l,3,4]oxadiazol-2-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 7) according to the method described in Example 2. MS (El) 547.2 (MH*).

Example 6 l-(2,2,2-Trifluoro-acetvlamino)-cvclopropanecarboxylic acid 4-13-chloro-2-(5methvl-[13,41ôxadiazol-2-vlÎ-indol~l“yll-benzvlamide

The title compound was prepared from 4-[3-chloro-2-(5-methyl- [l,3,4]oxadiazol-2-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 7) according to the method described in Example 4. MS (El) 518.2 (MH*).

Example 7

3-MethoxY-isoxazole-5-carboxylic acid (l-{4-13-chloro-2-(l-methyl-177-tetrazol-5vl)-indol-l-vll-bcnzvlcarbamovll-cyclopropyl)-amide

The title compound was prepared from 4-(2-( l-methyl-2//-tetrazol-5-yl)-indoleyl]-benzylamine hydrochloride (Reference Example 8) according to the method described in Example 2. MS (El) 547.1 (MH*).

Example 8 l-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-13-chloro-2-(lmethvl-l//-tetrazol-5-vb-indol-l-vl|-benzylamide

The title compound was prepared from 4-(2-(1-methyl-2/7-tetrazol-5-yl)-indoleyl]-benzylamine hydrochloride (Reference Example 8) according to the method described in Example 4. MS (El) 518.1 (MH*).

Example 9

H

3-Meth oxy-isoxazole-5-carboxy lie________acid________(l-f4-|3-chloro-2-(5-mcthylil,2,41oxadiazol-3-vl)-indol-l-yl]-bcnzvlcarbamovlÎ-cvclopropyh-amide

A mixture of 23.0 g (54.5 mmol) of 1-amino-cyclopropanecarboxylic acid 4-[3chIoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylamide (Reference Example 9), 350 mL of DMSO, 9.4 g (65.4 mmol) of 3-methoxy-isoxazole-5-carboxylic acid, 24.8 g (65.4 mmol) of HBTU and 11.4 mL (65.4 mmol) of MN-diisopropylethylamine was stirred at room température for 2 h. The reaction mixture was poured into 3000 mL of water and stirred for 2 h. The precipitated product was filtered off, washed with water and recrystallized from 2-propanol to yield 22.5 g (75.4%) of the title compound. MS (El) 547.1 (MH⁺).

Example 10 3-Chloro-l“f4-(ni-i2_t2,2-trifluoro-acetylamino)-cvclopropanecarbonyll-amino}mcthvl)-phenyl|-l//-indole-2-carboxvlic acid methyl ester

The title compound was prepared from methyl l-[4-(aminomethyl)phenyl]-3chloro-l.H-mdole-2-carboxylate hydrochlorîde (Reference Example 31) according to the method described in Example 4. MS (El) 494.1 (MH*).

Example 11 3-Chloro-l-i4-i({l-[(3-methoxv-isoxazole-5-carbonvl)-aminol-cyclopropanecarbonvlÎ-aminoÎ-methyll-phenvB-l//-indole-2-carboxvlic acid methyl ester

The title compound was prepared from methyl l-[4-(aminomethyl)phenyl]-3chloro-17/-indole-2-cafboxylate hydrochlorîde (Reference Example 31) according to the method described in Example 2. MS (El) 523.1 (MH*).

Example 12

1- (2,2.2-Trifluoro-acetvlaminol-cvclopropanecarboxylic acid 4-13-chloro-5-fluoro-

2- (2-methyl-2jff-tctrazol-5-yl)-indol-l-vll-benzvlamide

The title compound was prepared from 4-[3-chloro-5-fluoro-2-(2-methyl-2/ftetrazol-5-yl)-indol-l-yl]-benzylamine hydrochlorîde (Reference Example 10) according to the method described in Example 4. MS (El) 536.2 (MH*).

4L

Example 13

3-Methoxv-isoxazole-5-carboxylic acid (l-i4-13-chloro-5-fluoro-2-(2-methyl-2Htetrazol-5-vlÎ-indol-l-vll-benzvlcarbamoylÎ-cyclopropvh-amide

The title compound was prepared from 4-[3-chloro-5-fluoro-2-(2-methyl-2Htetrazol-5-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 10) according to the method described in Example 2. MS (El) 365.2 (MH*).

Example 14 l-Î4-i(il-i(3-Méthoxy-isoxazole-5-carbonyl)-aminol-cvclopropanecarboiiyBamino)-methvl|-phenvU-Î//-indoIc-2-carboxylic acid methyl ester

The title compound was prepared from l//-indole-2-carboxylic acid methyl ester according to the methods described in Reference Example 5b, 5d, 5e and Example 2. MS (El) 489.2 (MH*).

Example 15

3-Methoxv-isoxazole-5-carboxylic acid (l-i4-f3-chloro-2-(2-methvl-2Zf-tetrazol-5vl)-indol-l-vll-2-fluQrobenzylcarbamovlÎ-cvclopropyl)-amide

The title compound was prepared from 4-[3-chloro-2-(2-methyl-2/Atetrazol-5yl)-mdol-l-yl]-2-fluoro-benzyIamine hydrochloride (Reference Example 6) according to the method described in Example 2. MS (El) 565.2 (MH*).

Example 16

3-Methoxy-isoxazole-5-carboxylic acid (l-14-[3-chloro-2-(13- oxazoI-S-vD-indol-lvll-benzylcarbamoylÎ-cvclopropyl)-amidc

a) 3-Chloro-2-oxazol-5-yl-l 77-indole

A mixture of 1.2 g (6.68 mmol) of 3-chloro-l W-indole-2-carbaldehyde, 1.32 g (6.76 mmol) of toluenesulfonylmethyl isocyanide, 1.2 g (8.69 mmol) of potassium carbonate and 30 mL of methanol was refluxed for 1 h. The reaction mixture was cooled to 20 °C, concentrated in vacuo, the residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and M hexane:ethyl acetate = 2:1 as eluent to yield 1.2 g (82 %) of the title compound. Mp.: 131-134 °C.

b) 4-(3-Chloro-2-oxazol-5-yl-indol-yl)-benzylamine hydrochloride

The title compound was prepared from 3-chloro-2-oxazol-5-yl-l/f-indole according to the methods described in Reference Example 4e and 4f. Mp.: 183-189 °C.

c) 3-Methoxv-isoxazole-5-carboxylic acid (l-(4-[3-chloro-2-(l,3- oxazol-5-yD-indol-ly 11 -benzy lcarbamo yl ΐ -cyclopropyl )-amide

The title compound was prepared from 4-(3-chloro-2-oxazol-5-yl-indol-yl)benzy lamine hydrochloride according to the method described in Example 2. MS (El)

532.2 (MH⁺).

Example 17 l-(2.2,2-Trifluoro-acetylaminol-cyclopropanecarboxylic acid 4-[3,5-dichloro-2-(2m eth yl-2/7-tct razol-5-yl)-ind ol-1 -yll-hcnzylam ide

The title compound was prepared from 4-[3,5-dichloro-2-(2-methyl-277-tetrazol5-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 11) according to the method described in Example 4. MS (El) 552.1 (MH⁺).

Example 18

3-Methoxy-isoxazole-5-carboxylic acid (l-(4-13,5-dichloro-2-(2-methyl-2//-tetrazol-

5-yD-indoI-l-yl]-benzyIcarbamovl}-cyclopropyl)-amide

The title compound was prepared from 4-[3,5-dichloro-2-(2-methyl-2//-tetrazol5-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 11) according to the method described in Example 2. MS (El) 581.1 (MH⁺).

Example 19

1- (2.2,2-Trifluoro-acctvIamino)-cyclopropanccarboxvlic acid 4-f3-chlorO“5-fluoro-

2- (2-methvl-2jtf-tetrazol-5-vh-indol-l-yll-2-fluoro-bcnzylamide

The title compound was prepared from 4-[3-chloro-5-fluoro-2-(2-methyl-2Htetrazol-5-yl)-indol-l-yl]-2-fluoro-benzylamine hydrochloride (Reference Example 12) according to the method described in Example 4. MS (El) 554.1 (MH⁺).

V>L

Example 20

3-Methoxv-isoxazolc-5-carboxyIic acid (l-{4-l3-chloro-5fluoro-2-(2-methyl-2/Ztctrazol-5-yl)-indol-lVll-2-fluoro-bcnzyIcarbamoyl}-cyclopropvD-amide

The title compound was prepared from 4-[3-chloro-5-fluoro-2-(2-methyl-2/7tetrazol-5-yl)-indol-l-yl]-2-fluoro-benzylamine hydrochloride (Reference Example 12) according to the method described in Example 2. MS (El) 583.2 (MH*).

Example 21

3-Methoxv-isoxazole-5-carboxylic acid (l-f4-i3-cvano-2-(5-methyl-H,2,41oxadiazol3-vr)-indol-l-vl|-benzvlcarhamovl}-cvcloproDyl)-amide

a) 2-(5-Methvl- ί 1,2,41 oxadiazol-3-yl) -1 H-indole-3 -carbaldehyde

To a stirred mixture of 2 mL of Ν,Ν-dimethylformamide and 10 mL of dichloromethane 0.7 mL (7.5 mmol) of phosphores oxychloride was added dropwise at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. Then 1.0 g (5.0 mmol) of

2- (5-methyl-[l,2,4]oxadiazol-3-yl)-lH-indole (Reference Example 36a) in 25 mL of dichloromethane was added dropwise to the reaction mixture and stirred at room température for 1 h. Then 20 g of ice was added to the mixture and stirred at room température for 3 h. The precipitated product was filtered ofïto yield 1.1g (96.5 %) of the title compound. Mp.: 228-230 °C.

b) 2-(5-Methyi-r 1 ,2,41oxadiazol-3-yl)-1 H-indole-3-carbonitriIe

A mixture of 1.1 g (4.8 mmol) of 2-(5-methyl-[l,2,4]oxadiazol-3-yl)-lH-indole-

3- carbaldehyde, 2.38 g (29.0 mmol) of sodium acetate, 2.6 mL (36.2 mmol) of nitroethane and 8 mL of acetic acid was refluxed for 8 h. The precipitated product was filtered off, washed with water and recrystallized from îsopropanol to yield 0.68 g (62.9 %) of the title compound. Mp.: 209-212 °C.

c) _________1 -(4-AminomethyÎ-phenyl)-2-(5-methyl-i 1,2,41oxadiazol-3-y 1)-1 H-indole-3- carbonitrile hydrochloride

The title compound was prepared from 2-(5-methyl-[i,2,4]oxadiazol-3-yl)-lHindole-3-carbonitrile and 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid according to the method described in Reference Example 4e and 4f. Mp.: 201-204 °C.

H

d)______3 -Methoxy-isoxazoIe-5-carboxy lie______acid______(l-{4-r3-cyano-2-(5-methvl-

Γ1.2.41oxadiazol-3-vD-indol-1 -yll-benzylcarbamoyl ΐ -cvcloproDvl)-amidc

The title compound was prepared from l-(4-aminomethyl-phenyl)-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-lH-indole-3-carbonitrile hydrochloride according to the method 5 described in Example 2. MS (El) 538.2 (MH⁺).

Example 22 l-(2,2,2-Trifluoro-acetvlamino)-cvclopropanccarboxvlic acid 4-[3,5-dichloro-2-(2methvl-2//-tetrazol-5-vl)-mdoI-l-yl|-2-fluoro-benzylamide

The title compound was prepared from 4-[3,5-dichloro-2-(2-methyl-2//-tetrazol5-yl)-indol-l-yl]-2-fluoro-benzylamine hydrochloride (Reference Example 13) according to the method described in Example 4. MS (El) 570.1 (MH*).

Example 23 l-f2,2_<2-Trifluoro-acetvlamino)-cyclopropanccarboxvlic acid 4-[3-chloro-2-(5mcthvl-il,2_t4]oxadiazol-3-yl)-indol-l-vl1-benzvlamide

The title compound was prepared from 4-[3-chloro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 9c) according to the method described in Example 4. MS (El) 518.1 (MH⁺).

Example 24

5-Cvclopropyl-isoxazole-3-carboxvlic acid (l-f4-13-chloro-2-(2-methvl-2/Z-tctrazol-

5-vl)-indol-l-vl|-benzvlcarbamoylÎ-cyclopropyl)-amide

A mixture of 23.0 mg (0.15 mmol) of 5-cyclopropyl-isoxazole-3-carboxylic 25 acid, 30 μΙ (0.21 mmol) of triethylamine, 63.2 mg (0.18 mmol) of 1-aminocyclopropanecarboxylic acid 4-[3-chloro-2-(2-methyl-2Z7-tetrazol-5-yl)-indol-l -yl]benzylamide (Reference Example 4) 60.0 mg (0.16 mmol) of HATU and 1 mL of N.Ndimethylformamide was stirred at room température for 24 h. The reaction mixture was purified by column chromatography using Kîeselgel 60 (Merck) as adsorbent and 30 hexaneæthyl acetate = 4:1 as eluent to yield 26 mg (31 %) of the title compound. MS (El) 557.2 (MH*).

V

7l

Compounds of Table l were prepared from l-amino-cyclopropanecarboxyüc acid 4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)-indol-l-yi]-benzylamide (Reference Example 4) according to the method described in Example 24.

Table 1

Example	Name	MS (El) (MH*)
25	5-Methyl-pyrazine-2-carboxylic acid (l-{4-[3-chloro-2-(2methy l-2//-tetrazol -5 -y l)-indol-1 -y l]-benzy lcarbamoy 1} cyclopropyl)-amide	542.2
26	5-MethyI-isoxazoIe-3-carboxylic acîd (l-(4-[3-chloro-2-(2methyl-2Z/-tetrazol-5-yl)-indol-l -yl]-benzylcarbamoyl} cyclopropy l)-ami de	531.2
27	2-Chloro-2V-(l-{4-[3-chloro-2-(2-methyl-2/f-tetrazol-5-yl)-indol- 1 -yl]-benzylcarbamoyl} -cyclopropyl)-nicotinamide	561.2
28	jV-( 1-(4-(3 -chloro-2-(2-methy l-2//-tetrazol-5-y 1) -i ndol-1 -yl] benzylcarbamoyl} -cyclopropyl)-2-fluoro-isonicotinamide	545.2
29	1 -(3,3,3,-Tri fl uoro-propiony 1 amino)-cy clopropanecarboxy lie acid 4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)-indol-1 -y 1 ]benzylamide	532.2
30	JV-( 1 ~{4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)-indol-l -y 1 ]benzylcarbamoyl} -cyclopropy l)-5-trifluoromethy 1-nicotinamide	595.2
31	JV-(l-{4-[3-chloro-2-(2-methyl-2W-tetrazol-5-yl)-indol-l-yl]benzy lcarbamoy 1}-cyclopropy l)-3-fluoro-benzamide	544.2

Example 32

3-Chloro-l-14-(l-fH-(2.,2_<2-trifluoro-acetylainino)-cvclonroDanecarbonvl|-ammo)ethyl)-phenvl1-lÆ-indole-2-carboxylic acid methylamide

a) 3-Chloro-l//-indole-2-carboxylic acid methylamide

To a stirred suspension of 0.8 g (4.6 mmol) of l/7-indolc-2-carboxylic acid methylamide (W02007/53131 ) in 20 mL of acetonitrile 0.68 g (5 mmol) of Nchlorosuccinimide was added. The reaction mixture was refluxed for 6 h and concentrated in vacuo. The yellowish white residue was crystallised from éthanol to give 0.45 g (47 %) of the title compound as a light beige solid. MS (El) 209.1 (MH⁺).

b) l-(4-Acetvl-phenvl)-3-chloro-lff-indole-2-carboxvlic acid methylamide

To a stirred solution of 0.45 g (2.16 mmol) of 3-chloro-l//-indole-2-carboxylic acid methylamide in 10 mLof A.A-dirnethylformarmde 0.53 g (3.24 mmol) of 4-acetylphenylboronic acid, 0.79 g (4.32 mmol) of copper(II) acetate, 1.5 mL (8.6 mmol) of yVJV-diisopropylethylamine and 1 g of 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 48 h. After the reaction was complété, the mixture was filtered through Celite. The filter cake was washed with chloroform and the combined filtrâtes were concentrated in vacuo. The residue was taken up in chloroform and filtered through a plug of silica (20 g), the filter cake was washed with chloroform and the combined filtrâtes were concentrated in vacuo. The residue was crystallised from 2-propanol to yield 0.42 g (60 %) of the title compound as beige crystals. MS (El) 327.1 (MH⁺).

c) 1-14-(1-Amino-ethvl)-phenvll-3-chloro-l/7-indole-2-carboxylic acid methylamide

To a solution of 0.42 g (1.29 mmol) of l-(4-acetyl-phenyl)-3-chloro-l/7-indole2-carboxylic acid methylamide in a mixture of 3 mL of methanol, 3 mL of dichloromethane and 2 mL of acetonitrile 0.074 mL of acetic acid (1.29 mmol), 0.12 g (1.8 mmol) of sodium cyanoborohydride, 1 g (12.9 mmol) of ammonium acetate and 0.5 g of 3Â molecular sieves were added. The reaction mixture was stirred at room température ovemight when a second portion of sodium cyanoborohydride (0.12 g, 1.8 mmol) was added and the mixture was stirred at room température for 72 h. The pH of the reaction mixture was adjusted to 5 by the addition of 3M aqueous hydrochloric acid solution and the so obtained mixture was concentrated in vacuo. The residue was treated with 50 mLof dichloromethane and extracted with 10 mL of water. The aqueous phase was reextracted with dichloromethane. The combined organic layers were washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.0400.063 mm) as adsorbent (Merck) and chloroform:methanolrammonium hydroxide .

solution (25%) = 95:5:1 as eluent to yield 0.17 g (40 %) of the title compound as white vaxy solid. MS (El) 328.1 (MH⁴).

d) 3 -Chloro-1 -Γ4-( 1 Π -(2,2.2-trifluoro-acetvlaminoÎ-cycloproDanecarbonvn-amino] ethyl)-phenyl1~l/7-indole-2-carboxylic acid methvlamide

To a solution of 0.173 g (0.53 mmol) of l-[4-(l-amino-ethyl)-phenyl]-3-chlorolH-indole-2-carboxyIic acid methylamide in 7 mL of dichloromethane 0.109 g (0.55 mmol) of l-(2,2,2-trifluoro-acetylamino)-cycIopropanecarboxylic acid (M. R. Hickey et al. Synlett. 2005, 255-258), 0.2 g (1 mmol) of EDC [7V-(3-dimethylaminopropyl)-N’ethylcarbodiimîde hydrochloride], 0.004 g (0.03 mmol) of hydroxybenzotriazole monohydrate and 0.44 mL (3.17 mmol) of triethylamine were added. The reaction mixture was stirred at room température ovemight. The mixture was diluted with 100 mL of dichloromethane and washed with 2x20 mL of saturated sodium hydrogencarbonate aqueous solution, 2x20 mL of water and 20 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chloroform:methanol = 95:5 as eluent to yield 0.19 g (73 %) of the title compound as a white amorphous solid. MS (El) 507.1 (MH⁴).

Example 33 l-(2,2,2-Trifluoro-acetvlamino)-cvclopropanecarboxvlic acid (l-f4-13-chloro-2(pvrrolidine-l-carbonvh-indol-l-vl|-phcnvl}-cthyl)-amidc

a) (3-chloro-l/^:7indol-2-yl)-pyrrolidin-l -vl-methanone

To a stirred suspension of 0.89 g (4.15 mmol) of (lf/-indol-2-yl)-pyrrolidin-lyl-methanone (US2007/21463) in 20 mL of acetonitrile 0.6 g (4.6 mmol) of Nchlorosuccînimide was added. The reaction mixture was refluxed for 5 h and allowed to stand at room température ovemight. The separated crystalline solid was filtered off, washed with acetonitrile and dried to give 0.66g (66 %) of the title compound as a yellowish crystalline solid. MS (El) 249.1 (MH⁴).

b) l“M-r3-Chloro-2-(pvrrolidine-l-carbonvD-indol-l-yl1-phenvH-ethanone

To a solution of 0.66 g (2.65 mmol) of (3-chloro-lH-indol-2-vl)-pyrrolidin-l-ylmethanone in 15 mL of AY-dimethylformamide 0.65 g (3.96 mmol) of 4-acetylphenylboronic acid 0.96 g (5.3 mmol) of copper(II) acetate, 1.9 mL (10.6 mmol) of

HjH-diisopropylethylamine and 1.5 g of 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 48 h. The mixture was filtered through Ceiite. The filter cake was washed with N.Ndimethylformamide and the combined filtrâtes were evaporated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chloroform:acetone = 95:5 as eluent to yield after crystallization from 2-propanol 0.33 g (34 %) of the title compound as a yellow crystalline solid. MS (El) 367.1 (MH*).

c) {1 - Γ4-( 1 -Amino-ethyl)-pheny 11-3 -chloro-1 H-indol-2-y 11 -pyrrolidin-1 -yl-methanone

To a solution of 0.32 g (0.87 mmol) of l-{4-[3-chloro-2-(pyrrolidine-lcarbonyl)-indol-l-yl]-phenyl}-ethanone in a mixture of 2 mL of methanol and 2 mL of dichloromethane 0.67 g (8.7 mmol) of ammonium acetate and 0.077 g (1.22 mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at room température overnight. The pH of the reaction mixture was adjusted to 5 by the addition of 3M aqueous hydrochloric acid solution and the so obtained mixture was concentrated in vacuo. The residue was treated with 30 mLof dichloromethane and extracted with 10 mL of water. The aqueous phase was reextracted with 10 mL of dichloromethane. The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chloroform:methanol:ammonium hydroxide solution (25%) = 95:5:1 as eluent to yield 0.15 g (46 %) of the title compound as white foam. MS (El) 368.1 (MH*).

d) l-Î2,2,2-Trifluoro-acetyiamino)-cycIopropanecarboxvlic acid (T-14-[3-chloro-2( pyrrolidine-1 -carbonyll-indol-1 -yll-pheny 1} -ethyD-amide

To a solution of 0.15 g (0.4 mmol) of {1-(4-(1-amino-ethyl)-phenyl]-3-chlorolH-îndol-2-yl}-pyrrolidin-l-yl-methanone in 5 mL of dichloromethane 0.089 g (0.45 mmol) of l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid (M. R. Hickey et al. Synlett. 2005, 255-258), 0.156 g (0.82 mmol) of EDC, 0.003 g (0.02 mmol) of hydroxybenzotriazole monohydrate and 0.34 mL (2.4 mmol) of triethylamine were added. The reaction mixture was stirred at room température overnight. The mixture was diluted with 100 mL of dichloromethane and washed with 2x20 mL of saturated sodium hydrogencarbonate aqueous solution, 2x20 mL of water and 20 mL of brine, ήί.

dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chloroform:methanol = 95:5 as eluent to yield 0.14 g (66 %) of the title compound as an off-white amorphous solid. MS (El) 547.2 (MH⁺).

Examplc 34 3-Chloro-l-i4-ffil-|f3-methoxv-isoxazole-5-carbonvl)-aminol-cvclopropanecarbonyl}-amino)-incthvl|-phcnvl}-17/-indole-2carboxylic acid ethyl ester

a) 3-Chloro-lJ7-indole-2-carboxvlic acid ethyl ester

To a stirred suspension of 3 g (15.86 mmol) of l/7-indole-2-carboxylic acid ethyl ester in 30 mL of acetonitrile 2.33 g (17.44 mmol) of /V-chlorosuccinimide was added. The reaction mixture was refluxed for 6 h and allowed to stand at room température overnight. The separated crystalline solid was filtered off, washed with acetonitrile and dried to give 2.4 g (67 %) of the title compound as a yeilowish crystalline solid. MS (El) 224.1 (MH⁺).

b) 3-Chloro-l-(4-formyl-phenyl)-177-indole-2-carboxylic acid ethyl ester

To a solution of 1.0 g (4.47 mmol) of 3-chloro-l//-indole-2-carboxylic acid ethyl ester în 20 mL of Λ/,/V-dimethylformamide 1.0 g (6.7 mmol) of 4-formylphenylboronic acid, 1.62 g (8.94 mmol) of copper(Il) acetate, 3.1 mL (17.9 mmol) of AyV-diisopropylethylamine and 2.5 g of 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 30 h. The mixture was filtered through Celite. The filter cake was washed with N,N~ dimethylformamide and dichloromethane and the combined filtrâtes were concentrated in vacuo. The residue was treated with 100 mL of brine and extracted with 4x50 mL of dichloromethane. The combined organic layers were washed with 3x50 mL of water, 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.0400.063 mm) as adsorbent (Merck) and hexanes:ethyl acetate = 4:1 as eluent to yield 0.71 g (48 %) of the title compound as a yellow amorphous solid. MS (El) 350.1 [M+Na]⁺.

c) 3-Chloro-l-r4-(hvdroxvimino-methvI)-phenvl]-lZ/-indole-2-carboxylic acid ethyl ester

X,

To a solution of 0.7 g (2.13 mmol) of 3-chloro-l-(4-formyl-phenyl)-l//-indole-

2- carboxylic acid ethyl ester in 10 mL of éthanol 0.72 g (8.54 mmol) of hydroxylamine hydrochloride and 1.5 mL (10.7 mmol) of triethylamine were added. The reaction mixture was stirred at room température for lh and evaporated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 2:l as eluent to yield 0.53 g (72 %) of the title compound as a white amorphous solid. MS (El) 343.1 (MH⁺).

d) l-(4-Aminomethyl-phenyl)-3-chloro-177-indole-2-carboxylic acid ethyl ester

A stirred mixture of 0.53 g (1.55 mmol) of 3-chloro-l-[4-(hydroxyiminomethyl)-phenyl]-l//-indole-2-carboxylic acid ethyl ester and 0.10 g of 10% Pd/C, 50 mL of éthanol and 10 mL of 2.44 M hydrogen chloride in ethyl acetate was hydrogenated at room température for 3 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to yield 0.56 g (100 %) of the title compound as a yellow solid. MS (El) 312.1 ([M-NH₂]⁺).

e) _______3-Chloro-l-f4-r((l-r(3-methoxy-isoxazole-5-carbonyl)-amino1-cvclopropane- carbonyn-amino)-methvll-phenylÎ-l/f-indole-2-carboxylic acid ethyl ester

To a solution of 0.28 g (0.77 mmol) of l-(4-aminomethyl-phenyl)-3-chloro-l/7indole-2-carboxylic acid ethyl ester in 5 mL of dichloromethane 0.17 g (0.85 mmol) of l-[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarboxylic acid (P. D. O’Shea et al. J. Org. Chem. 2009, 74, 4547-4553), 0.3 g (1.53 mmol) of EDC, 0.006 g (0.04 mmol) of hydroxybenzotriazole monohydrate and 0.86 mL (6.1 mmol) of triethylamine were added. The reaction mixture was stirred at room température ovemight. The mixture was diluted with 100 mL of dichloromethane and washed with 2x20 mL of saturated sodium hydrogencarbonate aqueous solution, 2x20 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chloroform:methanol = 95:5 as eluent to yield 0.38 g (92 %) of the title compound as an off-white foam. MS (El) 538.2 (MH⁺).

Example 35

3- Chloro-l-Î4-[(Îl-ÎÎ3-methoxv-isoxazole-5-carbonyl)-amino1-cyclopropanecarbonvll-amino)-methyll-phenylÎ-lZ7-indole-2-carboxylic acid dimethvlamide

a) _______3-Chloro-l--[4-[(( l-FO-methoxv-isoxazole-S-carbonvl'l-aminol-cvcloDropane- carbonyl } -am inoj-methyl] -phenyl} -1 /7-i ndolc-2-carboxylic acid

To a solution of 0.33 g (0.61 mmol) of 3-chloro-l-{4-[({l-[(3-methoxyisoxazole-5-carbonyl)-amino]-cyclopropanecarbonyl)-amino)-methyl]-phenyl}-l/7indole-2-carboxylic acid ethyl ester (Example 34e) in a mixture of 1 mL of methanol, 2 mL of tetrahydrofuran and 1 mL of water 0.128 g (0.3 mmol) of lithium hydroxide monohydrate was added. The reaction mixture was stirred at room température overnight. The reaction mixture was diluted with 2 mL of water and the pH was adjusted to 5 by the addition of IM aqueous hydrochloric acid solution and the so obtained mixture was extracted with 50 mL of chloroform. The organic layer was washed with 3x8 mL of water and 8 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and chloroform:methanol:acetic acid = 90:10:1 as eluent to yield 0.23 g (74 %) of the title compound as amorphous solid. MS (El) 509.1 (MH⁺).

b) _______3-Chloro- 1-f 4-Γ( {1 -r(3-methoxy-isoxazole-5-carbonyl)-amino1-cycïopropane- carbonvl }-amino)-methyl1-phenyl}-lff-indole-2-carboxvlic acid dimethylamide

To a solution of 0.15 g (0.29 mmol) of 3-chloro-l-{4-[({l-[(3-methoxyisoxazole-5-carbonyl)-amino]-cyclopropanecarbonyl} -amino)-methyl]-phenyl} -1Hindole-2-carboxylic acid in 5 mL of MN-dimethylformamide 0.13 g (0.33 mmol) of HBTU, 0.048 g (0.59 mmol) of dimethylamine hydrochloride and 0.17 mL (1.18 mmol) of triethylamine were added and the reaction mixture was stirred at room température for 1 h. The mixture was concentrated in vacuo. The oily residue was triturated with 50 mL of saturated sodium hydrogencarbonate solution, the precipitated solid was filtered off, washed with saturated sodium hydrogencarbonate solution and water to yield after drying 0.1 g (66 %) of the title compound as amorphous solid. MS (El) 536.2 (MH⁺).

Examplc 36 l-(2,2,2-Trifluoro-acctylamino)-cvclopropanecarboxylic acid 4-i2-(2-mcthyl-2/7tetrazol-S-vh-indol-l-yll-bcnzylamide

The title compound was prepared from 4-[2-(2-methyl-2/7-tetrazol-5-yl)-indolcyl]-benzylamine hydrochloride (Reference Example 5) according to the method described in Example 4. MS (El) 484.1 (MH*).

Exampie 37

3-Methoxy-isoxazole-5-carboxylic acid (l-Î4-l3-chloro-5-fluoro-2-(5-methyl|l,3,4loxadiazol-2-vl)-indol-l-vll-bcnzvlcarbamovB-cycloDroDvl)-amide

a) 3-ChIoro-5-fluoro-l//-indole-2-carboxvlic acid N'-acetvl-hvdrazide

To a solution of 2.62 g (12.27 mmol) of 3-chloro-5-fluoro-l/7-indole-2carboxylic acid (US2005/20645) in 30 mL of ΛζΝ-dimethylformamide 1.19 g (16 mmol) of acethydrazide, 5.82 g (15.3 mmol) of HBTU and 2.2 mL (15.3 mmol) of triethylamine were added and the pH of the mixture was adjusted to 8 by the addition of triethylamine. After stirring the reaction mixture for 4 h at room température an additional amount of HBTU (1.16 g, 3 mmol) was added and the mixture was stirred overnight at room température. The mixture was concentrated in vacuo, the residue was treated with 60 mL of saturated sodium hydrogencarbonate solution, the résultant suspension was stirred for 45 min, then filtered. The filter cake was washed consecutively with saturated sodium hydrogencarbonate solution and water and dried to yield 2.59 g (0.78 %) of the title compound as an orange amorphous solid. MS (El)

270.1 (MH*).

b) 3-Chloro-5-fluoro-2-(5-methyl-r 1.3,4]oxadiazol-2-yl)-l/f-indole

A stirred mixture of 2.55 g (9.45 mmol) of 3-chloro-5-fluoro-l/7-indole-2carboxylic acid N'-acetyl-hydrazide and 20 mL of phosphorous oxychloride was refluxed for 90 min. The cold reaction mixture was poured into 250 g of crushed ice, the precipitated solid was filtered off and thoroughly washed with water. The reddish brown solid was suspended in methanol (5 mL), stirred at room température for 30 min, filtered and washed with cold methanol to yield after drying 1.93 g (81 %) of the title compound as a beige solid. MS (El) 252.1 (MH*).

c) ________f 4-r3-Chloro-5-fluoro-2-(5-methvl-r 1,3,4]oxadiazol-2-yl)-indol-1 -ylj-benzyl ) - carbamic acid tert-butyl ester

To a solution of 1.9 g (7.55 mmol) of 3-chloro-5-fluoro-2-(5-methyl- [l,3,4]oxadiazol-2-yl)-l/7'indole in 40 mL of JV,ZV-dimethylformamide 2.85 g (11.33 mmol) of 4-(/er/-butoxycarbonylamino-methyl)-boronic acid, 2.75 g (I5.l mmol) of copper(II) acetate, 5.3 mL (30.2 mmol) of A,A-diisopropylethylamine and 4 g 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 96 h. The mixture was filtered through Celite. The filter cake was washed with A,A-dimethylfbrmarnidc and chloroform and the combined filtrâtes were concentrated in vacuo. The residue was treated with 300 mL of chloroform and extracted with 2x50 mL of 25% ammonium hydroxide solution and 2x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexanerethyl acetate = 3:l as eluent and rechromatographed in chloroform :acetone = 5:l to yield 1.99 g (57 %) of the title compound as a yellow foam. MS (El) 457.1 [M+Na]⁺.

d) 4-[3-Chloro-5-fluoro-2-(5-methyl-[l,3,4loxadiazol-2-vt)-indol-l-yll-benzylamine hydrochloride

To a solution of 1.54 g (3.37 mmol) of {4-[3-chloro-5-fluoro-2-(5-methyl- [1.3.4] oxadiazol-2-yl)-indoI-l-yl]-benzyl}-carbamic acid /erZ-butyl ester in 5 mL of ethyl acetate and 5 mL of anisole 30 mL of 2.44 M hydrogen chloride in ethyl acetate was added at 0 °C and the mixture was stirred at room température for 2h. The precipitated solid was filtered off, washed with ethyl acetate and ether and dried to yield 1.3 g (98 %) of the title compound as a beige amorphous solid. MS (El) 340.1 ([MNH₂]⁺).

e) 3-Methoxy-isoxazole-5-carboxvlic acid (l-{4-[3-chloro-5-fluoro-2-(5-methyl[l,3,4loxadiazol-2-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

To a solution of 0.24 g (0.61 mmol) of 4-[3-chIoro-5-fluoro-2-(5-methyl- [1.3.4] oxadiazol-2-yl)-indol-l-yl]-benzylamine in 3 mL of dichloromethane 0.145 g (0.64 mmol) of l-[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarboxylic acid (P.D. O’Shea et al. J. Org. Chem. 2009, 74, 4547-4553), 0.24 g (1.22 mmol) of EDC, 0.005 g (0.032 mmol) of hydroxybenzotriazole monohydrate and 0.68 mL (4.9 mmol) of triethylamine were added. The reaction mixture was stirred at room température ovemight. The mixture was diluted with 30 mL of dichloromethane and washed with 10 mL of saturated sodium hydrogencarbonate aqueous solution and 10 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

The residue was submitted to flash column chromatography using Kieselgel 60 (0.0400.063 mm) as adsorbent (Merck) and chloroform:acetone = 9: l as eluent to yield 0.13 g (38 %) of the title compound as amorphous solid. MS (El) 565.2 (MH⁺).

Example 38

3-Mcthoxy-isoxazolc-5-carboxvlic acid (l-(4-l3-chloro-2-(5-methyl-oxazol-2-vl)in dol-l-vll-bcnzvlcarbamoyl}-cyciopropvi)-amidc

a) 3-Chloro-2-(2-oxo-propylcarbamoyl)-indole

To a suspension of 0.3 g (1.53 mmol) of 3-chloro-l//-indole-2-carboxylic acid (Reference Example 4a) in 20 mL of dichloromethane and 0.05 mL of N.Ndimethylformamide 0.3 mL (3 mmol) of oxalyl chloride was added. The mixture was stirred at room température for l h, then refluxed for l h. The mixture was concentrated in vacuo and redissolved in 20 mL of dichloromethane. Under inert gas atmosphère, 0.33 g (3.3 mmol) of l-amino-propan-2-one hydrochloride and 0.9 mL (6.3 mmol) of triethylamine were added to the solution at 0°C. The suspension was stirred at room température for l h and diluted with 20 mL of dichloromethane and 10 mL of water. The solid product precipitated on standing was filtered off and dried to yield 0.19 g (50 %) of the title compound as a beige amorphous solid. MS (El) 251.1 (MH⁺).

b) 3 -Chloro-2-ί 5 -methyl -oxazol-2-yl)-indole

To a solution of 0.24 g (1 mmol) of Burgess-reagent in 6 mL of dry tetrahydrofuran 0.176 g (0.71 mmol) of 3-chloro-2-(2-oxo-propylcarbamoyl)-indole was added in argon athmosphere and the mixture was heated in a microwave oven (CEM) at 120 °C for 17 minutes. The mixture was diluted with 2 mL of methanol, the suspension was filtered and the filtrate was diluted with 40 mL of dichloromethane, extracted with 2x10 mL of water and 10 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 0.135 g (82 %) of the title compound as a yellow amorphous solid. MS (El) 233.1 (MH⁺).

c) {4-r3-Chloro-2-i5-methyl-oxazol-2-vl)-indol-l-vll-benzvl}-carbamic acid tert-butyl ester

-» r

To a solution of 0.1 g (0.42 mmol) of 3-chloro-2-(5-methyl-oxazol-2-yl)-indole in 4 mL of MV-dimethylformamide 0.16 g (0.63 mmol) of 4-(fô/7butoxycarbonylamino-methyl)-boronic acid, 0.16 g (0.84 mmol) of copper(II) acetate, 0.3 mL (1.68 mmol) of MV-diisopropylethylamine and 0.4 g of 3Â molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room température for 6 days. The mixture was filtered through Celite, the fïlter cake was washed with Λζ/V-dimethylformamide and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane.ethyl acetate = 4:1 as eluent to yield 0.16 g (89 %) of the title compound as a yellow foam. MS (El) 438.2 (MH⁺).

d) 4-[3-Chloro-2-(5-methyl-oxazol-2-vl)-indol-l-vl]-benzylamine

To a solution of 0.16 g (0.37 mmol) of {4-[3-chloro-2-(5-methyl-oxazol-2-yl)indol-l-yl]-benzyl}-carbamic acid tert-butyl ester in 1 mL of ethyl acetate and 1 mL of anisole 5 mL of 2.44 M hydrogen chloride in ethyl acetate was added at 0 °C and the mixture was stirred at room température for 90 min. The precipitated solid was filtered off, washed with ethyl acetate and ether, dried and submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chloroform:methanol:ammonium hydroxide solution (25%) = 9:1:0.1 as eluent to yield 0.097 g (78 %) of the title compound as a beige amorphous solid. MS (El) 338.2 (MH⁺).

e) 3-Methoxv-isoxazole-5-carboxylic acid (l-f4-f3-chloro-2-(5-methvl-oxazol-2-yl)indol-1 -Yll-benzylcarbamovn-cvclopropvD-amide

To a solution of 0.097 g (0.28 mmol) of 4-[3-chloro-2-(5-methyl-oxazol-2-yl)indol-l-yl]-benzylamine in 3 mL of dichloromethane 0.068 g (0.3 mmol) of l-[(3methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarboxylic acid (P. D. O’Shea et al. J. Org. Chem. 2009, 74, 4547-4553), (0.11 g (0.57 mmol) of EDC, 0.002 g (0.015 mmol) of hydroxybenzotriazole monohydrate and 0.24 mL (1.72 mmol) of triethylamine were added. The reaction mixture was stirred at room température for 48 h. The mixture was diluted with 20 mL of dichloromethane and washed with 2x5 mL of water and 10 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and chlorofomrmethanol =

V

98:2 as eluent to yield after trituration with water, filtration and drying 0.046 g (29 %) of the title compound as amorphous solid. MS (El) 546.2 (MH*).

Example 39

3-Mcthoxv-isoxazole-5-carboxylic acid Îl-l4-(3-chloro-2-cvano-indoll-vl)-benzylcarbamovil-cvclopropyll-amide

The title compound was prepared from l-(4-aminornethyl-phcnyl)-3-chloro-l/7indole-2-carbonitrile hydrochloride (Reference Example 14) according to the method described in Example 2. MS (El) 490.1 (MH*).

Examplc 40 (J?)-l-(2.2_<2-Trifluoro-acetYlamino)-cvclopronanecarhoxvlic acid (l-i4-|3-chloro-2(5-mcthvl-Il,2,4loxadiazol-3-vi)-indol-Î-Yl|-phcnvl}-ethvl)-amidc

The title compound was prepared from (/î)-l-{4-[3-chloro-2-(5-methyl15 [l,2,4]oxadiazol-3-yl)-indol-l-yl]-phenyl}-ethylamine hydrochloride (Reference Example 15) according to the method described in Example 4. MS (El) 532.1 (MH*).

Example 41 (l?Î-3-MethoxY-isQxazole-5-carboxylic acid [l-il-I4-13-chloro-2-(5-methyl20 [l^^loxadiazol-S-yn-indol-l-vn-phenvlî-cthvlcarbamovll-cvclopropvll-amidc

The title compound was prepared from (Æ)-l-{4-[3-chloro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-phenyl} -ethylamine hydrochloride (Reference Example 15) according to the method described in Example 2. MS (El) 561.2 (MH*).

Example 42

3-Propvl-isoxazole-5-carboxyIic acid (l-Î4-i3-chloro-2-(5-mcthyl-H,2,4]oxadiazol3-yl)-indol-Î-vl]-benzYlcarbamoyll-cvclopropvl)-amidc

A mixture of 0.06 g (0.13 mmol) of 1-amino-cyclopropanecarboxylic acid 4-[3chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide hydrochloride (Reference Example 9), 0.022 g (0.142 mmol) of 3-propyl-isoxazole-5-carboxylic acid, 0.08 mL (0.575 mmol) of triethylamine, 0.054 g (0.142 mmol) of HBTU and 1.1 mL of M/V-dimethylformamide was stirred at room température for 2 h, then concentrated in ’î ^L vacuo. The residue was dissolved in dichloromethane and successively washed with saturated sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfate and concentrated, The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and toluene:acetone = 4:1 as eluent to yield 0.04 g (55%) of the title compound as white crystals. MS (El) 559.2 (MH*).

Example 43

3-Methoxv-îsoxazole-5-carboxylic acid {l-14-(5-chloro-2-cvano-indol-l-vDbenzylcarbamovll-cyclopropvH-amide

The title compound was prepared from l-(4-amînomethyl-phenyl)-5-chloro-l/findole-2-carbonitrile hydrochlorîde (Reference Example 16) according to the method described in Example 2. MS (El) 490.2 (MH*).

Example 44 7V-Îl-[4-(2-Cvano-5-methoxy-indol-l-vlÎ-benzvlcarbamovll-cvclopropvlÎ-5trifluoromethyl-nicotinamide

The title compound was prepared from 1-amino-cyclopropanecarboxylic acid 4(2-cyano-5-methoxy-indol-l-yl)-benzylamide hydrochlorîde (Reference Example 17) and 5-trifluoromethyl-nicotinic acid according to the method described in Example 42. MS (El) 534.2 (MH*).

Example 45 /V-n-14-(2-Cvano-5-fluoro-indol-l-vl)-benzvlcarbamovll-cyclopropyl}-5trifluoromcthyl-nicotinamide

The title compound was prepared from 1 -amino-cyclopropanecarboxylic acid 4(2-cyano-5-fluoro-indol-l-yl)-benzylamide hydrochlorîde (Reference Example 18) and 5-trifluoromethyl-nicotinic acid according to the method described in Example 42. MS (El) 522.2 (MH*).

Example 46 /V-(l-f4-l5-Fluoro-2-(5-methvl-m_t4loxadliazol-3-yl)-Îndol-l-yll-bcnzylcarbamovlÎcvclopropyl)-5-trifluoromethvl-nicotinamide

The title compound was prepared from l-amino-cyclopropanecarboxylic acid 4[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide hydrochloride 5 (Reference Example 19) and 5-trifluoromethyl-nicotinic acid according to the method described in Example 42. MS (El) 579.2 (MH⁺).

Example 47

3-Methoxy-isoxazole-5-carboxylic________acid________(l-l4-[5-fluoro-2-(5-methvl10 [1.2,41oxadiazol-3-ylÎ-indol-l-vl1-benzylcarbamovlÎ-cvclopropyO-amide

The title compound was prepared from l-amino-cyclopropanecarboxylic acid 4[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide hydrochloride (Reference Example 19) and 3-methoxy-isoxazole-5-carboxylic acid according to the method described in Example 42. MS (El) 531.2 (MH⁺).

Example 48

3-Methoxv-isoxazole-5-carboxylic acid ? l-|4-(2-cvano-5-mcthoxy-indol-l-yl)benzylcarbamoyll-cyclopropvB-amide

The title compound was prepared from l-amino-cyclopropanecarboxylic acid 420 (2-cyano-5-methoxy-indol-l-yl)-benzylamide hydrochloride (Reference Example 17) and 3-methoxy-isoxazole-5-carboxylic acid according to the method described in Example 42. MS (El) 486.2 (MH⁺),

Example 49

3-Methoxy-isoxazole-5-carboxvlic acid ll-14-(2-cyano-5-fluoro-indol-l-vl)benzylcarbamoyll-cvclopropyn-amidc

The title compound was prepared from l-amino-cyclopropanecarboxylic acid 4(2-cyano-5-fluoro-indol-l-yl)-benzylamide hydrochloride (Reference Example 18) and 3-methoxy-isoxazole-5-carboxylic acid according to the method described in Example 30 42. MS (El) 474.2 (MH⁺).

Example 50 jV-( 1 - (4- [3-Chloro-5-mcthoxv-2-(3-mcthyl-[ 1,2,4] oxadiazol-5-yl)-îndol- 1 -yll-bcnzy IcarbamoYlÎ-cvclopropyl)-5-trifluoromethyI-nicotinamide

The title compound was prepared from 1-amino-cyclopropanecarboxylic acid 4[3-chloro-5-methoxy-2-(3 -methy 1-[ 1,2,4] oxadiazol-5-yl) -indol-1 -y I] -benzy lam ide hydrochloride (Reference Example 20) and 5-trifluoromethyl-nicotinic acid according to the method described in Example 42. MS (El) 625.2 (MH⁺).

Example 51

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-5-methoxy-2-(3-methylfl.2,41oxadiazol-5-vl)-indol-l-yn-benzylcarbamoyn-cyclopropyl)-amide

The title compound was prepared from 1-amino-cyclopropanecarboxylic acid 4[3-chloro-5-methoxy-2-(3-methyl-[l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylamide hydrochloride (Reference Example 20) and 3-methoxy-isoxazole-5-carboxylic acid according to the method described in Example 42. MS (El) 577.2 (MH⁺).

Examplc 52

3-Methoxv-isoxazole-5-carboxylic acid fl-14-(3-chloro-2-cyano-5-methoxy~indol-lvl)-benzvlcarbamoyl|-cyclopropyl]-amide

The title compound was prepared from l-(4-aminomethyl-phenyl)-3-chloro-5methoxy-lH-indole-2-carbonitrile hydrochloride (Reference Example 21) according to the method described in Example 2. MS (El) 520.2 (MH⁺).

Examplc 53

3-Meth oxy-isoxazole-5-carb oxylic________acid________(l-f4-|5-chloro-2-(5-methylU.2,4|oxadiazoI-3-vl)-indol-l-vl]-benzylcarbamoylÎ-cyclopropyl)-amide

The title compound was prepared from 4-[5-chloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 22) according to the method described in Example 2. MS (El) 547.2 (MH⁺).

Example 54 3-Chloro-l-r3-fluoro-4-({ll-(2,2,2-trifluoro-acetylamino)-cvclopropanecarbonyllaininoÎ-methvl)-phenvl1-l/f-indolc-2-carboxylic acid methyl ester

The title compound was prepared from l-(4-aminomethyl-3-fluoro-phenyl)-3chloro-liZ-indole-2-carboxylic acid methyl ester hydrochloride (Reference Example 23) according to the method described in Example 4. MS (El) 512.1 (MH⁴).

Example 55

3-Chloro-l-(3-fluoro-4-i((l-|(3-methoxv-isoxazole-5-carbonvl)-amino]-cyclopropanecarbonvn-amÎnoÎ-methvll-phenylÎ-lH-indole-2-carboxylic acid methyl ester

The title compound was prepared from l-(4-aminomethyl-3-fluoro-phenyl)-310 chloro-l//-indole-2-carboxylic acid methyl ester hydrochloride (Reference Example 23) according to the method described in Example 2. MS (El) 541.1 (MH⁴).

Example 56

3-Methoxy-isoxazole-5-carboxvlic acid [l-(f5-f2-(3-mcthyl-H3«41oxadiazol-5-vn15 indol-l-vl|-nvridin-2-vlniethvH-carbamoyl)-cyclopropvll-amide

a) 2-f3-Methvl-r 1.2,41oxadiazoL5-yl)-1 H-indolc

The title compound was prepared from 1/7-indole-2-carboxy lie acid methyl ester according to the method described in Reference Example 20d. MS (El) 200.1 (MH⁴).

b) i 5-r2-f3-Methyl-[ 1,2,41oxadiazol-5-yl)-indol- l-vll-pyridin-2-vlmethyn-carbamic 20 acid tert-butyl ester

To a solution of 0.46 g (2.3 mmol) of 2-(3-methyl-[l,2,4]oxadiazol-5-yl)-l//indole in 10 mL of A'./V-dimethylformamide 0.58 g (2.3 mmol) of 6-(teributoxycarbonylamino-methyl)-3-pyridineboronic acid (Reference Example 3), 0.84 g (4.6 mmol) of copper(II) acetate, 1.6 mL (9.2 mmol) of MN-diisopropylethylaminc and 25 3 g 3Â molecular sieves were added. The reaction mixture was vigorously shaken and bubbled with a stream of dry air at room température for 6 days. The mixture was filtered and subsequently washed with ΛζΝ-dimethylformamide, concentrated ammonium hydroxide solution and Λζ/V-dimethylformamide and the filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography 30 using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane:ethyl acetate = 1:1 as eluent to yield 0.16 g (17%) of the title compound. MS (El) 406.2 (MH⁴) <u.

·* »

c) C-(5-[2-(3-Methyl-| l ,2.4loxadiazol-5-yl)-indol-l -vll-pyridin-2-ylÎ-methylamine dihydrochloride

To a solution of 0.16 g (0.395 mmol) of {5-[2-(3-methyi-[l,2,4]oxadiazol-5-yl)indol-l-yl]-pyridin-2-ylmethyl}-carbamic acid /eri-butyl ester in 2 mL of ethyl acetate and 0.8 mL of anisole 5 mL of 2.44 M hydrogen chloride in ethyl acetate was added at 0 °C and the mixture was stirred at room température for 3 h. The precipitated solid was filtered off, washed with ethyl acetate and ether and dried to yield 0.11 g (73%) of the title compound. MS (El) 306.2 (MH*)

d) 3-Methoxy-isoxazole-5-carboxvlic acid ri-({5-|2-(3-methvl-[1.2.41oxadiazol-5-vl')indol-l-vll-pvridin-2-vlmethYl}-carbamoyl)-cyciopropvl]-amide

To a solution of 0.378 g (1 mmol) of C-{5-[2-(3-methyl-[l,2,4]oxadiazol-5-yl)indol-l-yl]-pyridin-2-yl}-methylamine dihydrochloride in 14 mL of dichloromethane 0.237 g (1.05 mmol) of l-[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarboxylic acid (P.D. O’Shea et al. J. Org. Chem. 2009, 74, 4547-4553), 0.385 g (2 mmol) of EDC, 0.007 g (0.05 mmol) of hydroxybenzotriazole monohydrate and 1.25 mL (9 mmol) of triethylamine were added. The reaction mixture was stirred at room température overnight. The mixture was concentrated in vacuo and the residue was recrystallised from 2-propanol twice to yield 0.268 g (52%) of the title compound as a beige crystalline solid. MS (El) 514.2 (MH*)

Example 57

3-Mcthoxy-isoxazolc-5-carboxvlic acid H-(i5-f2-(5-methyl-H,2,41oxadiazol-3-yl)indol-l-vlî-pyridin-2-ylmethyB-carbamovh-cvclopropvl|-amide

a) 2-Î5-Methvl-n,2,41oxadiazol~3~vl)-17/-indole

The title compound was prepared from l//-indole-2-carbonitrile according to the methods described in Reference Example 9a and 9b. MS (El) 200.0 (MH*)

b) Î5-r2-(5-Methvl-[L2.41oxadiazol-3-vl)-indol-l-yll-pyridin-2-ylmethyU-carbamic acid terAbutyl ester

The title compound was prepared from 2-(5-methyl-[l,2,4]oxadiazol-3-yl)-l/7indole according to the method described in Example 56b. MS (El) 406.2 (MH*)

c) C- ( 5-r2-(5-Methvl-ll ,2,41oxadiazol-3-yl)-indol-l -vll-Dvridin-2-vn-methylamine dihydrochloride ·* .

The title compound was prepared from {5-[2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-l-yl]-pyridin-2-ylmethyl}-carbamic acid ZerZ-butyl ester according to the method described in Example 56c. MS (El) 306.2 (MH*)

d) 3-Methoxv-isoxazole-5-carboxvlic acid |T-((5-f2-C5-methvl-Fl,2,4]oxadiazol-3-vl)indol-1 -vll-nvridin-2-vlmethyl ) -carbamovD-cyclopropyl 1-amide

The title compound was prepared from C-{5-[2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-pyridin-2-yl}-methylamine dihydrochloride according to the method described in Example 56d. MS (El) 514.2 (MH*).

Example 58

3-Methoxy-isoxazole-5-carboxylic________acid________11 -( i5-[3-chloro-2-(3-methyII l,2_t41oxadiazol-5-vO-indol-l-yll-pvridin-2-vImethvIl-carbamovl)-cyclopropyllamide

a) 3-Chloro-2-(3-methvl-n.2.41oxadiazol-5-yD-l//-indole

The title compound was prepared from 3-chloro-l/7-indole-2-carboxylic acid methyl ester according to the method described in Reference Example 20d. MS (El)

234.1 (MH*).

b) {5-[3-Chloro-2-(3-methyl-n,2,41oxadiazol-5-yl)-indol-l-yl1-pyridin-2-vlmethyl)carbamic acid Zerf-butyl ester

The title compound was prepared from 3-chloro-2-(3-methyl-[l,2,4]oxadiazol-5yl)-l//-indole according to the method described in Example 56b. MS (El) 440.2 (MH*)

c) C- i 5-r3-Chloro-2-(3-methyl-r 1 J^loxadiazol^-vD-indol-1 -yll-pyridin-2-yl} -methylamine di hydrochloride

The title compound was prepared from {5-[3-chloro-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-pyridin-2-ylmethyl} -carbamic acid rerZ-butyl ester according to the method described in Example 56c. MS (El) 340.1 (MH*)

d) 3-Methoxy-isoxazole-5-carboxylic acid ri-(f5-r3-chloro-2-(3-methylΓ1,2,4]oxadiazol-5-yl)-indol-l-vn-pvridin-2-vlmethvl)-carbamovÎ)-cvclopropyll-amide

The title compound was prepared from C-{5-[3-chloro-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-pyridin-2-yl}-methylamine dihydrochioride according to the method described in Example 56d. MS (El) 548.2 (MH*).

Example 59

3-Methoxv-isoxazole-5-carboxylic acid [l-({5-[3-chloro-5-fluoro-2-(2-methyl-2Aftetrazol-5-yl)-indol-l-vl]-pvridni-2-vlmethvlÎ-carbamoyl)-cvclopropyll-amide

a) 3-Chloro-5-fluoro-2-(2-methyl-2/7-tetrazol-5-vl)-l ff-indole

The title compound was prepared from 5-fluoro-l7ï-indole-2-carboxylic acid according to the methods described in Reference Example 4a-4d. MS (El) 252.1 (MH⁺).

b) ___________( 5-i 3-Chloro-5-fluoro-2-(2-methyl-2//-tetrazol-5-yl)-indol-1 -vll-pyridin-2- ylmethvH-carbamic acid fert-butyl ester

The title compound was prepared from 3-chloro-5-fluoro-2-(2-methyl-2/710 tetrazol-5-yl)-l#-indole according to the method described in Example 56b. MS (El)

458.2 (MH*)

c) C-i5-r3-Chloro-5-fluoro-2-(2-methvl-2H-tetrazol-5-vl)-indol-l-vll-pvridin-2-vl)methylamine trihvdrochloride

The title compound was prepared from {5-[3-chloro-5-fluoro-2-(2-methyl-2/715 tetrazol-5-yl)-indol-l-yl]-pyridin-2-ylmethyl}-carbamic acid /erf-butyl ester according to the method described in Example 56c. MS (El) 358.2 (MH*)

d) 3-Methoxy-isoxazole-5-carboxvlic acid [l-((5-r3-chloro-5-fluoro-2-i2-methyl-2fftetrazol-5-vl)-indol-1 -yll-pvridin-2-vlmethyl ) -carbamoyD-cyclopropyll-amide

The title compound was prepared from C-{5-[3-chloro-5-fluoro-2-(2-methyl-2Z/20 tetrazol-5-yl)-indol-l-yl]-pyridin-2-yl}-methylamine trihydrochloride according to the method described in Example 56d. MS (El) 566.2 (MH*).

Example 60

3-Methoxv-isoxazole-5-carboxylic acid 11-({5-f3-chloro-2-(2-mcthyl-2//-tetrazol-525 yl)-indol-l-yH-pyridin-2-ylmethylÎ-carbamQyl)-cyclopropyl|-amide

a) _________{5- r3-Chloro-2-(2-methvl-2tf-tetrazol- 5 -vl)-indol-1 -yll-pvridin-2-vlmethyl ) - carbamic acid Zer/-butyl ester

The title compound was prepared from 3-chloro-2-(2-methyl-2//-tctrazol-5-yl)1/7-indoIe (Example ld) according to the method described in Example 56b. MS (El) 30 440.2 (MH*)

b) C-15-f3-Chloro-2-(2-methyl-2H-tetrazol~5-y I )-indol-1 -vl]-pyridin-2-vl} -methylamine trihvdrochloride f*- »

The title compound was prepared from {5-[3-chloro-2-(2-methyl-2//-tetrazol-5yl)-indol-l-yl]-pyridin-2-ylmethyl}-carbamic acid tert-butyl ester according to the method described in Example 56c. MS (El) 340.2 (MH⁺)

c) 3-Methoxv-isoxazole-5-carboxylic acid |T-ii5-r3-chloro-2-(2-methvl-2//-tetrazol-5vl)-indol-1 -yll-pYridin-2-ylmethyl} -carbamoyD-cyclopropyll-amide

The title compound was prepared from C-{5-[3-chloro-2-(2-methyl-2//-tetrazol5-yl)-indol-l-yl]-pyridm-2-yl}-methylamine trihydrochloride according to the method described in Example 56d. MS (El) 548.2 (MH⁺).

Example 61

3-Mcthoxv-isoxazolc-5-carboxylic________acid________ll-(f5-15-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3-vl)-indol-l-vll-pyridiii-2-vImethyI}-cai'bamovl)-cyclopropynamide

a) 5-Fluoro-2-(5-methyl-[l ,2,41oxadiazol-3-yl)-l//-indoIe

The title compound was prepared from 5-fluoro-lrt-indole-2-carbomtrile (I. Borza at al. Bioorg. Med. Chem. Lett. 2005, 75, 5439-5441) according to the methods described in Reference Example 9a and 9b. MS (El) 218.1 (MH⁺).

b) f5-f5-Fluoro-2-i5-methyl-fl,2,41oxadiazol-3-Yl)-indol-l-yri-pyrïdm-2-ylmethYl)carbamic acid tert-butyl ester

The title compound was prepared from 5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-l//-indole according to the method described in Example 56b. MS (El) 424.2 (MH⁺)

c) C- {5-Γ5-Fluoro-2-ί5-methy 1-[ 1.2,41oxadiazol-3-vl)-indol-1 -vil-pyridin-2-yl 1 -methy 1amine dihydrochloride

The title compound was prepared from {5-[5-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester according to the method described in Example 56c. MS (El) 324.2 (MH⁺)

d) 3-Methoxy-isoxazole-5-carboxylic acid ri-(i5-r5-fluoro-2-(5-methvlΓ1.2,41oxadiazol-3-yl)-indol-1 -yl]-pyridin-2-ylmethyl} -carbamovD-cvclopropvll-amide

The title compound was prepared from C-(5-[5-fluoro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-pyridin-2-yl}-methylamine dihydrochloride according to the method described in Example 56d. MS (El) 532.2 (MH⁺).

U

Example 62

3-Methoxv-isoxazole-5-carboxylic acid [l-( {5-|3-chloro-5-fluoro-2-(5-methylll,2,4loxadiazol-3-yl)-indol-l-yl|-pyridin-2-ylmethyl}-carbamoyl)-cvclopropvllamide

a) 3-Chloro-5-fluoro-lH-indole-2-carbonitrile

The title compound was prepared from 5-fluoro-l/7-indole-2-carboxylic acid according to the methods described in Reference Example 4a-c.

b) 3-Chloro-5-fluoro-2-(5-methyl-[l ,2,41oxadiazol-3-yl)-177-indole

The title compound was prepared from 3-chloro-5-fluoro-l/f-indole-2carbonitrile according to the methods described in Reference Example 9a and 9b.

c) ______(5-r3-Chloro-5-fluoro-2-(5-methyl-rL2.4loxadiazol-3-yl)-indol-l-yll-pvridin-2- yl methyl)-carbamic acid tert-butyl ester

The title compound was prepared from 3-chloro-5-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-l/7-ïndole according to the method described in Example 56b. MS (El) 458.2 (MH⁴)

d) C- {5 - Γ3 -Chloro-5-fluoro-2-( 5 -methyl-l 1,2.4] oxadiazol-3 - vl)-i ndol-1 - vll-pyridin-2yl}-methylamine dihydrochloride

The title compound was prepared from {5-[3-chloro-5-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-pyridin-2-ylmethyl}-carbamic acid tert-butyl ester according to the method described in Example 56c. MS (El) 358.1 (MH⁺)

e) 3-Methoxy-isoxazole-5-carboxylic acid ri-(Î5-13-chloro-5-fluoro-2-(5-methylri.2.41oxadiazol-3-v0-indol-l-yl]-pyridin-2-ylmethvl}-carbamoyD-cyclopropyll-amide

The title compound was prepared from C-{5-[3-chloro-5-fluoro-2-(5-methyi- [1.2.4] oxadiazoI-3-yl)-indol-l -yl]-pyridin-2-yl}-methylamine dihydrochloride according to the method described in Example 56d. MS (El) 566.2 (MH⁴).

Example 63 l-(2,2.2-Trifluoro-acetvlaminoÎ-cvclopropanecarboxvlic acid 4-13-chloro-5methoxv-2-(5-methyl-H,2,4|oxadiazol-3-yh-indol-l-ylLbenzylamide

To a stirred and ice-cooled solution of 0.166 g (0.36 mmol) of 4-[3-chIoro-5methoxy-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamine (Reference

Example 24) in 2 mL of dichloromethane 0.093 g (0.47 mmol) of l-(2,2,2-trifluoro16404 acetylamino)-cyclopropanecarboxylic acid (M. R. Hickey et al. Synlett. 2005, 255-258) and 0.103 g (0.54 mmol) of EDC were added. The reaction mixture was allowed to warm to room température and stirred for 4 h. The reaction mixture was diluted with dichloromethane and subsequently extracted with O.IN hydrochloric acid solution, 5 water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane: ethyl acetate = 1:1 as eluent to yield 0.129 g (65%) of the title compound. MS (El) 548.1 (MH⁺).

Example 64

3-Methoxv-isoxazole-5-carboxvlic acid (l-f4-f3-chloro-5-methoxv-2-(5-methvlil,2,4|oxadiazol-3-vl)-indol-l-vl|-benzvlcarbamovl}-cvclonropyl)-aniide

To a stirred and ice-cooled solution of 0.166 g (0.36 mmol) of 4-[3-chloro-515 methoxy-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylamine (Reference

Example 24) in 2 mL of dichloromethane 0.107 g (0.47 mmol) of l-[3-methoxyisoxazole-5-carbonyl)-amino]-cyclopropanecarboxylic acid (P.D. O’Shea et al. J. Org. Chem. 2009, 74, 4547-4553) and 0.103 g (0.54 mmol) of EDC were added. The reaction mixture was allowed to warm to room température and stirred for 4 h. The 20 reaction mixture was diluted with dichloromethane and subsequently extracted with

0.1N hydrochloric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnésium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane: ethyl acetate = 1:1 as eluent to 25 yield 0.132 g (64%) of the title compound. MS (El) 577.1 (MH⁺).

Example 65 l-(2J^-Trifluoro-acetvlaminoÎ-cyclopropanecarboxvlic acid 4-i3,5-dichloro-2-(5methvl-[l,2,4|oxadiazol-3-vl)-indol-l-vl]-benzylamide

The title compound was prepared from 4-[3,5-dichloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamine (Reference Example 27a) according to the method described in Example 63. MS (El) 552.1 (MH⁺).

1&L

Example 66

3-Methoxy-isoxazole-5- ca rboxylic______acid______(l-Î4-|3,5-dichloro-2-(5-methvlfl,2,4loxadiazol-3-Yl)-indol-l-vl|-benzylcarbainovlÎ-cvcl<>propyl)-amide

The title compound was prepared from 4-[3,5-dichloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamine (Reference Example 27a) according to the method described in Example 64. MS (El) 581.1 (MH*).

Example 67

3-Methoxv-isoxazole-5-carboxvIic acid (l-{4-l3-chloro-5-fluoro-2-(5-mcthylH,2,4loxadiazol-3-yl)-indol-l-vl|-benzvlcarbamoyl}-cvclonronvl)-amidc

The title compound was prepared from 5-fluoro-177-indole-2-carboxylic acid (Reference Example 28a) according to the method described in Example 64. MS (El)

565.1 (MH⁺).

Example 68 3-Chloro-4-fluoro-l-f4-Kfl-f(3-methoxy-isoxazole-5-carbonyl)-amino|-cyclopropanecarbonvl}-amino)-methYl]-phenvlÎ-ljff-indole-2-carboxylic acid methyl ester

The title compound was prepared from l-(4-aminomethyl-phenyl)-3-chloro-4~ fluoro-177-indole-2-carboxylic acid methyl ester (Reference Example 25) according to the method described in Exampie 64. MS (El) 541 (MH⁺).

Example 69 3-Chloro-4-fluoro-l-i4-(ni-(2,2_t2-trifluoro-acetvlamino)-cvclopropanecarbonvl|aminoÎ-methvl)-phcnvll-lf/-indole-2-carboxylic acid methyl ester

The title compound was prepared from l-(4-aminomethyl-phenyl)-3-chloro-4fluoro-l//-indole-2-carboxylic acid methyl ester (Reference Example 25) according to the method described in Example 63. MS (El) 512 (MH⁺).

Example 70

2-Chloro-JV-(l-Î4-(3,5-dichIoro-2-(5-methvl-ri,2,4loxadiazol3-vl)-indol-l-vl[benzylcarbamovB-cvcloprQPvb-nicotinamide

To a solution of 31.51 mg (0.2 mmol) of 2-chloro-nicotinic acid in 2 mL of dichloromethane and 0.2 mL of TVJV-dimethylformamîde 45.63 mg (0.1 mmol) of 15 amino-cyclopropanecarboxylic acid 4-[3,5-dichloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-l-yl]-benzylamide (Référencé Example 27), 76 mg (0.2 mmol) of HATU and 104.6 pL (0.6 mmol) of TV, JV-diisopropylethy lamine (DIPEA) were added. The mixture was shaken for 8 h at room température, then purified by column chromatography using n-hexane and ethyl acetate as eluent to yield 26 mg (43.6%) of the title compound. MS 10 (El) 597.1 (MH*).

Compounds of Table 2 were prepared according to the method described in Example 70.

Table 2

Example	Name	Starting Material	MS (El) (MH*)
71	TV-( 1 - {4- [3,5-Dichloro-2-(5 -methyl- [1,2,4]oxadiazol-3-yl)-indol-l -y 1]benzy lcarbamoy 1} -cyclopropy l)-3 -fluorobenzamîde	Reference Example 27	579.2
72	5-Methyl-pyrazine-2-carboxylie acid (1-(4-(3,5dichloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-1 -y 1 ]-benzy lcarbamoy 1} -cyclopropy l)-amide	Reference Example 27	577.1
73	5-Methyl-isoxazole-3-carboxylic acid (1 -(4-(3,5dichIoro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)indol-1 -yl]-benzylcarbamoyl}-cyclopropy l)-amide	Reference Example 27	566.1
74	TV-(l-(4-[3,5-Dichloro-2-(5-methyl- [ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyl} -cyclopropyl)-2-fl uoroisonicotinamide	Reference Example 27	580.1

Example	Name	Starting Material	MS (El) (MH+)
75	5-Cyclopropyl-isoxazole-3-carboxylic acid (1 -{4[3,5-dichloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide	Reference Example 27	592.1
76	7V-(l-{4-[3,5-Dichloro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1 -y 1]benzylcarbamoy 1} -cyclopropy l)-5trifluoromethyl-nicotinamide	Reference Example 27	630.1
77	2-MethylsulfanyI-pyrimidine-5-carboxylic acid (l-{4-[3-chioro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l -yl]-benzylcarbamoyl}-cyclopropy 1)amide	Reference Example 9	575.2
78	l-(3,3,3-Trifluoro-propionylamino)cyclopropanecarboxylic acid 4-[5-methoxy-2-(3methyl-[ 1,2,4]oxadiazol-5-yl)-indol-l -yl]benzylamide	Reference Example 30	528.2
79	jV-( 1 - {4 - [5 -Methoxy-2-(3 -methy 1[ 1,2,4]oxadiazol-5-yl)-indoI- 1-ylJbenzylcarbamoyl} -cyclopropy l)-5tri fluoromethyl-nicotinamide	Reference Example 30	591.2
80	3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5methoxy-2-(3-methyl-[l,2,4]oxadiazol-5-yl)indol-1 -yl] -benzylcarbamoy 1} -cyclopropy l)-amide	Reference Example 30	543.2
81	1-(3,3,3 -Trifluoro-propiony lamino)cyclopropanecarboxylic acid 4-[2-(5-methyl[ 1,2,4] ox adiazol-3 -y l)-i ndol-1 -yl ]-benzy lamide	Reference Example 36	498.2
82	JV-(l-{4-[2-(5-Methyl-[l,2,4]oxadiazol-3-yl)indol-1 -y 1] -benzy lcarbamoy 1} -cyclopropy l)-5 -	Reference Example 36	561.2

Example	Name	Starting Material	MS (El) (MH4)
	trifluoromethyl-nicotinamide
83	Ar-(l-{4-[2-(3-Methyl-[l,2,4]oxadiazol-5-yl)indol~l-yl]-benzylcarbamoyl}-cyclopropyl)-5trifluoromethyl-nicotinamide	Reference Example 37	561.2
84	/V-{ 1 -[4-(2-Cyano-indol-l -yl)-benzylcarbamoyl]cyclopropy i} -5 -trifluoromethyl-nicotinamide	Reference Example 38	504.2
85	2-Chloro-Ar-(l-{4-[3-chloro-5-fluoro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]- benzyl car bamoy 1} -cyclopropy l)-nicoti namide	Reference Example 28	580.1
86	JV-( 1 - {4-[3-Ch loro-5-fluoro-2-(5-methy 1 [ 1,2,4]oxadiazol-3-yl)-indol-1 -y 1]benzy lcarbamoy 1} -cyclopropy l)-3-fluorobenzamide	Reference Example 28	563.1
87	5-Methyl-pyrazine-2-carboxylic acid (l-{4-[3chloro-5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3y l ) - i ndo 1 -1 -y 1] -benzy lcarbamoy 1} -cyclopro py 1 )amide	Reference Example 28	560.2
88	5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3chloro-5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)amide	Reference Example 28	549.2
89	A/-(l-{4-[3-Chloro-5-fluoro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyl}-cyclopropy l)-2-fluoroisonicotinamide	Reference Example 28	564.2
90	5-Cyclopropyl-isoxazole-3-carboxylic acid (l-{4- [3-chloro-5-fluoro-2-(5-methyl-[ 1,2,4]oxadiazol-	Reference Example 28	576.2

4.1

Example	Namc	Starting Material	MS (El) (MH*)
	3-y 1) -i ndol-1 -y l]-benzylcarbamoy 1} -cyc lopropy 1 )amide
91	7V-(l-{4-[3-Chloro-5-fluoro-2-(5-methyl[ 1,2,4]oxadiazol-3-y l)-indol-1 -yl]benzy lcarbamoy 1} -cycl opropy 1 )-5trifluoromethy 1-nicotinamide	Reference Example 28	614.1
92	JV-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3 -y l)-indo 1-1 -yl] -benzyl carbamoy 1} -cyclopropy 1)- 2-fluoro-3-trifluoromethyl-benzamide	Reference Example 9	613.2
93	N-( 1 -{4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol3-yl)-i ndol-1 -y 1] -benzy lcarbamoy 1} -cyclopropy 1)3-fluoro-4-trifluoromethyl-benzamide	Reference Example 9	613.2
94	7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3-y 1 ) -i ndol-1 -yl]-benzy lcarbamoy 1} -cyclopropy 1 )- 3 -fluoro-5-tri fluoromethy 1 -benzamide	Reference Example 9	613.2
95	7V-( 1 - (4-[3-Chloro-2-(5-methy l-[ 1,2,4] ox ad iazol- 3-yl)-indol-1 -yl]-benzylcarbamoy 1} -cyc lopropy 1)- 2-fluoro-nîcotmamide	Reference Example 9	546.2
96	/V-(l-{4-[3-Chloro-2-(5-mcthyl-[l,2,4]oxadiazol- 3-yl)-indol-l-yl]-benzyicarbamoyl}-cyclopropyl)- 2-fl uoro-5 -tri fluoromethy 1-benzamide	Reference Example 9	613.2
97	À/-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3 -y 1 )-i ndol-1 -yl]-benzy le arbamoy 1} -cyclopropyl)- 3-fluoro-isonicotinamide	Reference Example 9	546.2
98	Ύ-( 1 - {4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol3-yl)-indol-1 -yl]-benzy lcarbamoy 1} -cyclopropyl)- 4-fluoro-3-trifluoromethyl-benzamide	Reference Example 9	613.2

Example	Name	Starting Material	MS (El) (MH*)
99	JV-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3 -y l)-indo H -y 1] -benzy lcarbamoyl} -cycl opropyl)- 6-fluoro-nicoti namide	Reference Example 9	545.2
100	N- {1 -[4-(5-Chloro-2-cyano-indol-1 -yl)benzy lcarbamoy I] -cyclopropy 1} -5 tri fluoromethy 1 -nicotinamide	Reference Example 16	538.2
101	l-(3,3,3-Trifluoro-propionylamino)cyclopropanecarboxylic acid 4-[5-fluoro-2-(3methyl-[ 1,2,4]oxadiazol-5-yl)-indol- 1-yl]benzylamide	Reference Example 26	516.2
102	N-( 1 -{4-[5-Fluoro-2-(3-methyl-[ 1,2,4]oxadiazol5-yl)-indol-1 -y l]-benzylcarbamoyl} -cyclopropyl)5-trifluoromethyl-nicotinamide	Reference Example 26	579.2
103	3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5fluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)-indol- 1 -yl]-benzy lcarbamoyl} -cyclopropy l)-ami de	Reference Example 26	531.2
104	2-Chloro-7V-(l-{4-[3-chloro-2-(5-methyl[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluorobenzylcarbamoyl} -cyclopropyl)-nicotînamide	Reference Example 9	579.1
105	y-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3 -yl)-indol-1 -y 1]-2-fl uoro -benzylcarbamoy 1} cyclopropyl)-3-fluoro-benzamide	Reference Example 9	562.2
106	5-Methyl-pyrazine-2-carboxylic acid (l-{4-[3chloro-2-(5 -methy 1- ( 1,2,4] oxad iazol-3 -y l)-i ndoll-yl]-2-fluoro-benzylcarbamoyl}-cyclopropyl)amide	Reference Example 9	560.2

ύι

Example	Name	Sterling Material	MS (El) (MH4)
107	5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3chloro-2-(5-methyl- [ 1,2,4] oxadi azol-3-y l)-îndol- 1 -yl]-2-fluoro-benzylcarbamoyl }-cyclopropyl)amide	Reference Exemple 9	549.2
108	1 -(3,3,3 -T rifluoro-propiony lami no)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2fluoro-benzylamide	Reference Example 9	550.1
109	y-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3 -y 1 )-ind ol-1 -y 1 ] -2-fluoro-benzy lcarbamoy 1} cyclopropyl)-2-fluoro-isonicotinamide	Reference Example 9	563.2
110	5-Cycïopropyl-isoxazole-3-carboxylic acid (1-{4- [3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)- i ndol-1 -yl]-2-fluoro-benzy lcarbamoy 1} cyclopropyl)-amide	Reference Example 9	575.2
111	7V-( 1 - {4- [3 -Ch loro-2-(5-methy 1- [ 1,2,4]oxadiazol3-yl)-indol-1 -yl]-2-fluoro-benzylcarbamoyl }cyclopropyl)-5-trifluoromethyl-nicotinamide	Reference Example 9	613.1
112	l-(3,3,3-Trifluoro-propionylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(3methyl-[l ,2,4]oxadiazol-5-yl)-indol-l -yl]benzylamide	Reference Example 35	532.2
113	JV-(l-{4-[3-Chloro-2-(3-methyl-[l,2,4]oxadiazol- 5 -y l)-indol-1 -yl] -benzy lcarbamoy 1} -cyclopropy ))- 2-fluoro-isonicotinamide	Reference Example 35	545.1
114	5-Cyclopropyl-isoxazole-3-carboxylic acid (1 -{4- [3-chloro-2-(3-methyl-[ 1,2,4]oxadiazol-5-yl)-	Reference Example 35	557.2

ιοο

Example	Name	Starting Material	MS (El) (MH*)
	indol-1 -y l]-benzy Icarbamoy 1} -cyclopropy l)-amide
115	Ύ-( 1 - {4-[3-Chloro-2-(3-methy l-[ 1,2,4]oxadiazo 15-y l)-indol-1 -yl] -benzylcarbamoyl} -cyclopropy 1 )5-trifluoromethyl-nicotinamide	Reference Example 35	596.2
116	2-Fluoro-V-(l-{4-[5-methoxy-2-(3-methyl- [ 1,2,4]oxadiazol-5-yl)-indol-l -yl]benzy Icarbamoy I} -cyclopropyl)-nicotinamide	Reference Example 30	541.2
117	7V-( 1 - { 4- [3 -Chloro-5 -fluoro-2-(5-methy 1[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyl} -cyclopropy l)-2-fluoronicotinamide	Reference Example 28	564.2
118	JV-( 1 - {4- [3-Chloro-5-methoxy-2-(3 -methy 1[ 1,2,4]oxadiazoI-5-yl)-indol-1 -y 1] benzylcarbamoyl} -cyclopropy l)-2-fluoronicotinamide	Reference Example 20	576.2
119	7V-( 1 - { 4- [3 -Chloro-2-(2-methy l-2//-tctrazol-5-y 1 ) indol-1 -yl] -benzyl carbamoy I} -cyclopropyl)-2fluoro-nicotinamide	Reference Example 4	546.2
120	2-Fluoro-V-(l-{4-[5-fluoro-2-(5-methyl- [1,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyl}-cyclopropy 1 )-nicotinamide	Reference Example 19	529.2
121	1 -Methyl-1//-pyrazole-4-carboxylie acid (l-{4-[3chloro-2-(5-methyl - [ 1,2,4] oxadiazol-3-yl )-indo 1- 1 -y 1] -benzylcarbamoyl} -cyclopropy l)-amide	Reference Example 9	531.2
122	2-Oxo-imidazolidine-4-carboxylic acid (1 -{4-[3chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol- 1 -yl] -benzyl carbamoy 1} -cyclopropy l)-amide	Reference Example 9	535.2

ΙΟΙ

Example	Name	Starting Material	MS (El) (MH4)
123	3-Ethyl-isoxazole-5-carboxylic acid (l-{4-[3chloro-2-(5-methyl-( 1,2,4]oxadiazol-3-yl)-indol- 1 -yl]-benzylcarbamoyl }-cyclopropyl)-amide	Référencé Example 9	546.2
124	l-(3,3,3-Trifluoro-propîonylamino)cyclopropanecarboxylic acid 4-[5-methoxy-2-(5methyl-[ 1,3,4]oxadiazol-2-yl)-indol-1 -y 1] benzylamide	Référencé Example 29	528.2
125	N-( 1 -{4-[5-Methoxy-2-(5-methyl[ 1,3,4]oxadiazol-2-yl)-îndol-l -yl]benzylcarbamoyl }-cyclopropyl)-5trifluoromethyl-nicotinamide	Reference Example 29	591.2
126	3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5methoxy-2-(5-methy 1- [ 1,3,4] oxad iazo 1-2-y 1)indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide	Reference Example 29	543.2
127	l-(3,3,3-Trifluoro-propionylamino)cyclopropanecarboxylic acid 4-[5-chloro-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylamide	Reference Example 22	532.2
128	7V-(l-{4-[5-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3-yl)-indol-l-yl]-benzylcarbamoyl]-cyclopropyl)- 5-trifluoromethyl-nicotinamide	Reference Example 22	596.2
129	5-Methyl-pyrazine-2-carboxylic acid ( 1 ~{4-[3chIoro-5-methoxy-2-(5-methyl-[l ,2,4]oxadiazol3-yl)-indol-l-yl]-benzylcarbamoyl)-cyclopropyl)amide	Reference Example 24	572.2
130	Λ-( 1 -{4-[3-Chloro-5-methoxy-2-(5-methyl- [1,2,4]oxadiazol-3-yl)-indol-1 -yl]-	Reference Example 24	625.2

102

Example	Name	Starting Material	MS (El) (MH*)
	benzy lcarbamoy l} -cyclopropy l)-5 tri fl uoromethy 1-n i cotinamide
131	5-Methyl-pyrazine-2-carboxylic acid (1 -{2fluoro-4-[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol3-yl)-indol-l-y 1 ]-benzy lcarbamoy 1} -cy c lopropy 1)amide	Reference Example 19	544.2
132	JV-( l-{2-Fluoro-4-[5-fluoro-2-(5-methyi[1,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyl) -cyclopropyl)-5trifluoromethyl-nicotinamide	Reference Example 19	597.2
133	3-Methoxy-isoxazole-5-carboxylic acid (l-{2fluoro-4-[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol3-yl)-îndol-1 -y 1]-benzy lcarbamoy 1} -cyclopropy 1)amide	Reference Example 19	549.2

Example 134 lsoxazole-5-carboxvlic acid il-{4-13-chloro-2-(5-methyl-il,2,4]oxadiazol-3-vl)indol-l-vll-benzvlcarbamovn-cyclopropylÎ-amide

To a solution of 12.0 mg (0.106 mmol) of isoxazole-5-carboxylic acid in 2 mL of dichloromethane and 0.2 mL of MN-dimethylfbrmamide 15 mg (0.036 mmol) of 1amino-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)indol-l-yl]-benzylamide (Reference Example 9), 40.5 mg (0.106 mmol) of HBTU and 28.8 pL (0.43 mmol) of triethylamine were added. The mixture was shaken at room 10 température for 18 h, then purified by column chromatography using n-hexane and ethylacetate as eluent to yield 17 mg (91%) of the title compound. MS (El) 517.1 (MH⁺).

Compounds of Table 3 were prepared according to the method described in Example 134.

¹⁵

103

Table 3

Example	Name	Starting Material	MS (El) (MH*)
135	5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol- 1 -y 1 J-benzy 1 car bamoyl} -cyclopropy l)-am ide	Reference Example 9	531.2
136	Tetrahydro-furan-2-carboxylic acid (1 -{4-[3chloro-2-(5 -methyl -[1,2,4] oxad iazo 1 -3 -y l)-i ndol- 1 -yl]-benzylcarbamoyl} -cyclopropyl)-amîde	Reference Example 9	520.2
137	Furan-3-carboxylic acid (l-{4-[3-chloro-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yljbenzylcarbamoyl}-cyclopropy l)-am ide	Reference Example 9	516.2
138	2-Methyl-cyclopropanecarboxylic acid (l-{4-[3chloro-2-(5-methy 1- [ 1,2,4] oxadi azol-3-yl )-indol- 1 -y 1] -benzylcarbamoyl} -cyclopropy 1 )-amide	Reference Example 9	504.2
139	l-Pent-4-ynoylamino-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3yl)-indol-l-yl]-benzylamide	Reference Example 9	502.2
140	1 -(4-Methyl-pentanoylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -y 1 ] benzylamide	Reference Example 9	521.2
141	177-Pyrazole-4-carboxylic acid (l-{4-[3-chloro-2(5-methyl-[l,2,4]oxadiazol-3-yi)-indol-l-yl]benzylcarbamoyl} -cyclopropy l)-amide	Reference Example 9	516.1
142	1-Cyano-cyclopropanecarboxylic acid (l-{4-[3chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol- 1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide	Reference Example 9	515.2

104

Examplc	Name	Starting Material	MS (El) (MH*)
143	Cyclobutanecarboxylic acid (l-{4-[3-chloro-2-(5methyl-[l ,2,4]oxadiazol-3-yl)-indol-l -yl]benzylcarbamoyl}-cyclopropyl)-amide	Reference Example 9	504.2
144	Cyclopentanecarboxylic acid (l-{4-[3-chloro-2(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -y 1 ]benzylcarbamoyl}-cyclopropyl)-am ide	Reference Example 9	519.2
145	Furan-2-carboxylic acid (l-{4-[3-chloro-2-(5methyl-[l ,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyl}-cyclopropyl)-amide	Reference Example 9	516.1
146	7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3-yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropy 1)- 3-cyano-benzamide	Reference Example 9	551.2
147	1 -(2-Thiophen-3-yl-acetylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methy 1- [1,2,4] oxadiazol-3 -y l)-i ndol-1 -y 1]benzylamide	Reference Example 9	547.1
148	l,5-Dimethyl-17/-pyrazole-3-carboxylic acid (1- (4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)indol-1 -y i]-benzylcarbamoyl }-cyclopropyl)-amide	Reference Example 9	544.2
149	4-Methyl-thiazole-5-carboxylic acid (l-{4-[3chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol- 1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide	Reference Example 9	548.1
150	2,4-Dimethyl-thiazole-5-carboxylic acid (l-{4-[3chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol- 1 -y l]-benzy lcarbamoyl} -cyclopropy l)-amide	Reference Example 9	562.1
151	l-(2-Acetylamino-3-hydroxy-propionylamino)~	Reference Example 9	551.2

105

Exemple	Name	Starting Material	MS (El) (MH*)
	cyclopropanecarboxyiic acid 4-[3-chloro-2-(5methyl-[l ,2,4]oxadiazol-3-yl)-indol-l -yl]benzylamide
152	5-Methyl-lH-pyrazole-3-carboxylic acid (1-(4-(3chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol- 1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide	Reference Example 9	530.2
153	2-Chloro-Ar-(l-{4-|3-chloro-2-(5-methyl- [ 1,2,4]oxadiazol-3-yl)-indol-l -yl] benzylcarbamoyl} -cyciopropyl)-nicotinamide	Reference Example 9	562.1
154	7V-( 1 - (4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol3 -y l)-indol-1 -y 1] -benzylcarbamoyl} -cyclopropy 1)6-methy 1 -nicoti nami de	Reference Example 9	542.2
155	7V-( 1 - {4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol3-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)2-methyl-nicotinamide	Reference Example 9	542.2
156	2-Chloro-7V-(l-{4-[3-chioro-2-(5-methyl[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzy lcarbamoyl} -cyclopropy l)-6-methy 1nicot inami de	Reference Example 9	576.1
157	6-Bromo-pyridine-2-carboxylic acid (1-(4-(3chloro-2-(5-methyl-[ 1,2,4] oxadi azol-3-yl )-indo 1- 1 -y 1]-benzylcarbamoyl (-cyclopropy l)-amide	Reference Example 9	606.1
158	N-(l-(4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)- nicotinamide	Reference Example 9	527.1
159	Quinoline-3-carboxylic acid (l-(4-[3-chloro-2-(5- methyl-(l,2,4]oxadiazol-3-yl)-indol-l-yl]-	Reference Example 9	578.1

Vil16404

106

Example	Name	Starting Material	MS (El) (MH*)
	benzylcarbamoyl} -cyclopropyl)-amide
160	6-Oxo-l,6-dihydro-pyridine-3-carboxylic acid (1(4- [3 -ch loro-2-(5 -methyl -[1,2,4] oxadiazol-3-yl)indol -1 -y l]-benzy 1 carbamoy 1} -cyclopropyl)-amide	Reference Example 9	543.2
161	5-Methyl-pyrazine-2-carboxylic acid (l-{4-[3chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indoI- 1 -y] ]-benzy Icarbamoy 1} -cyclopropyl)-amide	Reference Example 9	542.1
162	6-Oxo-l,6-dihydro-pyridine-2-carboxylic acid (1(4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol-3-yl)indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide	Reference Example 9	543.1
163	l-(3,3,3-Trifluoro-propionylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methy 1- [1,2,4] oxadiazol-3 -y l)-indol -1 -y 1] benzylamide	Reference Example 9	532.1
164	N-( 1 - {4-[3-Chloro-2-(5-methyl-[ l ,2,4]oxadiazol- 3-yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropy 1)- 2-fluoro-isonicotinamide	Reference Example 9	545.1
165	5-Cyclopropyl-isoxazoIe-3-carboxylic acid (l-{4- [3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)indo 1-1 -y 1]-benzy Icarbamoy 1} -cyclopropyl )-amide	Reference Example 9	557.2
166	Pyrimidine-5-carboxylic acid (l-{4-[3-chioro-2(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-l-yl]benzy Icarbamoy 1} -cycl opropy l)-amide	Reference Example 9	528.2
167	Thiophene-3-carboxylic acid (l-{4-[3-chloro-2(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-amide	Reference Example 9	532.7

107

Example	Name	Starting Material	MS (El) (MH+)
168	5-Oxo-pyrroiidine-2-carboxylic acid (l-{4-[3chloro-2-(5 -methy l-[ 1,2,4] oxad iazo 1-3-y 1 )-ind ο 1 - 1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide	Reference Example 9	533,7
169	1 -(3-Furan-3-yl-acryloylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -y 1 ]benzylamide	Reference Example 9	543.0
170	N-( 1 - {4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol3-yl)-îndol-1 -yl]-benzylcarbamoyl} -cyclopropyl)4-cyano-benzamide	Reference Example 9	551.7
171	1 -(3-Furan-2-yl-acryloylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methyl-[l ,2,4]oxadiazol-3-yl)-indol-l -yl]benzylamide	Reference Example 9	542.7
172	Thiophene-2-carboxylic acid (l-{4-[3-chloro-2(5-methyl-[ 1,2,4]oxadiazol-3-y l)-i ndol-1 -y 1]benzy lcarbamoyl} -cyclopropy l)-amide	Reference Example 9	532.6
173	5-Methylsulfanyl-thiophene-2-carboxylie acid (1{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide	Reference Example 9	578.7
174	[l,2,3]Thiadiazole-4-carboxylic acid (l-{4-[3chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol- 1 -yl]-benzy lcarbamoyl} -cyclopropy l)-amide	Reference Example 9	534.6
175	7V-(l-{4-[3-Chloro-2-(5-methyI-[l,2,4]oxadiazol- 3-yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)- 3 -methoxy-benzamide	Reference Example 9	557.0

108

Example	Name	Starting Material	MS (El) (MH4)
176	N-( 1 - {4-[3-Chloro-2-(5 -methy 1- [ 1,2,4] oxad iazol- 3 -y l)-indol-1 -y 1] -benzy Icarbamoyl} -cycl opropy 1)- 3 -iodo-benzamide	Reference Example 9	652.2
177	JV-( 1 -{4- [3 -Chloro-2-(5-methyl- [ 1,2,4]oxadi azol- 3-yl)-indol-l-yl]-benzyIcarbamoyl}-cyclopropyl)- 3-trifluoromethyl-benzamide	Reference Example 9	594.2
178	Ύ-( 1 - {4- [3 -Chloro-2-(5-methy 1- [1,2,4]oxadiazol- 3-y 1 ) -indol-1 -yl] -benzy Icarbamoyl} -cyclopropy 1)- 3 -fl uoro-benzamide	Reference Example 9	544.2
179	7V-(l-{4-[3-Chloro-2-(5-methyi-[ 1,2,4]oxadiazol- 3-yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)3-methyl-benzamide	Reference Example 9	541.0
180	7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol- 3-yl)-indol-1-yl]-benzylcarbamoyl}-cyclopropyl)- 5-trifluoromethyl-nicotinamide	Reference Example 9	596.0
181	3-Methyl-isoxazole-4-carboxylic acid (l-{4-[3chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol- 1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide	Reference Example 9	531.2
182	Quinoline-3-carboxylic acid (l-{4-[3-chloro-2-(5methyl-[ 1,3,4] oxadiazol-2-y l)-indol-1-y 1]benzylcarbamoy 1} -cyclopropy 1 ) -amide	Reference Example 7	578.2
183	l-(3,3,3-Trifluoro-propionylamino)cyclopropanecarboxylic acid 4-[3-chloro-2-(5methyl-[ 1,3,4]oxadiazol-2-yl)-indol-1 -y 1]benzyl amide	Reference Example 7	532.2
184	Pyrimidine-5-carboxylic acid (l-{4-[3-ch!oro-2-	Reference Example 7	528.2

109

Example	Name	Starting Material	MS (El) (MH4)
	(5-methy 1- [ 1,3,4] oxadi azol-2-y 1 )-indol-1 -y 1] benzylcarbamoyl }-cyclopropyl)-amide
185	2-Methyl-pyrimidine-5-carboxylic acid (1-(4-(3chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol- 1-y 1]-benzylcarbamoyl }-cyclopropyl)-amide	Reference Example 9	543.2

Examplc 186 S-Amino-TV-il-M-lS-chloro-l-ÎS-méthyl-U^^loxadiazol-S-vD-indol-l-vllbenzylcarbamovB-cvclonronvD-bcnzamidc hydrochloride

a) ___________[3-il-{4-I3-Chloro-2-(5-methyl-IT.2.4]oxadiazol-3-Yl)-indoLl-v]l-benzvl- carbamovn-cyclopropylcarbamovD-phenyll-carbamic acid tert-butyl ester

The title compound was prepared from 1-ammo-cyclopropanecarboxylic acid 4[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide (Reference Example 9) and 3-/ert-butoxycarbonylamino-benzoic acid according to the method described in Example 134.

b) __________3-Amino-7V-(l-f4-r3-chloro-2-i5-methvl-n.2,41oxadiazol-3-yl)-indol-l-vll- benzylcarbamoyl }-cvclopropvl)-benzamide hydrochloride

The title compound was prepared from [3-(l-{4-[3-chloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzyl-carbamoyl}-cyclopropylcarbamoyl)-phenyl]carbamîc acîd tert-butyl ester according to the method described in Reference Example 14 b. MS (El) 542.0 (MH⁺).

Examplc 187 3-Chloro-l-14-(fH-(2,2,2-trifluoro-acetvlamino)-cvclopropanecarbonyll-amino}mcthyl)-phcnvll-l//-indolc-2-carboxvlic acid amide

The title compound was prepared from l-(4-aminomethyl-phenyl)-3-chloro-177indole-2-carboxylic acid amide (Reference Examplc 32) according to the method described in Example 4. MS (El) 479.1 (MH⁺).

?» L

ΙΟ

Example 188

3-ChIorô-l-{4-iïil-ii3-methoxyisoxazole-5-carbonyh-amino|-cyclopropanecarbQnvl}-ammoÎ-iMtethyll-phcnvl}-l/7-indole-2-carboxYlic acid amide

The title compound was prepared from l-(4-aminomethyl-phenyl)-3-chloro-177indole-2-carboxylic acid amide hydrochloride (Reference Example 32) according to the method described in Example 2. MS (El) 508.2 (MH⁺).

Example 189

1- (2J,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-f3-chloro-5-fluoro-

2- (5-methyI-[l_t2,41oxadiazol-3-yD-indol-l-vll-benzvlamide

The title compound was prepared from 4-[3-chloro-5-fluoro-2-(5-methyl- [1,2.4]oxadiazol-3-yl)-indol-l-yl]-benzylamine (Reference Example 28a) according to the method described in Example 4. MS (El) 536.1 (MH⁺).

Example 190 l-(2J,2-Trifluoro-acetylamino')-cyclopropanccarboxylic acid (i/?l-l-i4-[3-chloro-2(5-inethvl-H,2,4]oxadiazol-3-yD-indol-l-yI1-2-fluoro-phenyIÎ-ethvl)-amide

The title compound was prepared from (17f)-l-{4-[3-chloro-2-(5-methyl-l,2,4oxadiazol-3-yl)-l/7-indol-l-yl]-2-fluorophenyl}ethanamine hydrochloride (Reference Example 33) according to the method described in Example 4. MS (El) 550.0 (MH⁺).

Example 191

3- Methoxv-isoxazole-5-carboxvlic acid ll-((R)-l-{4-13-chloro-2-(5-methvl- |l,2,4|oxadiazol-3-vl)-indol-l-vl|-2-fluor()-phenvi}-ethvlcarbamovl)-cyclopropvl|amide

The title compound was prepared from ( l/f)-l-{4-[3-chloro-2-(5-methyl-1,2,4oxadiazol-3-yl)-l//-indol-1 -yl]-2-fluorophenyl)ethanamine hydrochloride (Reference Example 33) according to the method described in Example 2. MS (El) 579.2 (MH⁺).

Example 192

3-Mcthoxv-isoxazo le-S-car boxvlic________acid________(l-Î4-I3-chloro-2-(5-methyl[l_t2,41oxadiazol-3-vü-indol-l-vll-2-fluoro-benzvlcarbamoyl|-cyclopropvl)-amide

U ni

The title compound was prepared from 4-[3-chloro-2-(5-methyl[ l .2.4]oxadiazol-3-yl)-indol- ] -yl]-2-fluoro-benzylamine hydrochloride (Reference Example 34) according to the method described ïn Example 2. MS (El) 565.0 (MH*).

Example 193

3-Methoxy-isoxazole-5-ca rboxy lie________acid________(l-i4-[3-chlorO“2-(3-mcthyl|l_t2_t4]oxadiazol-5-yl)-indol-l-vIl-benzykarbaniovn-cyclopropylÎ-amide

The title compound was prepared from 4-[3-chioro-2-(3-methyl- [l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 35b) according to the method described in Example 2. MS (El) 547.3 (MH⁺).

Example 194 l-(2,2_<2-Trifluoro-acetvIamino)-cvclopropanccarboxylic acid 4-f3-chloro-2-(3methyl-l 1,2,4] oxadiazol~5-yl)-indol-l-yll-benzylamide

The title compound was prepared from 4-[3-chloro-2-(3-methyl- [l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 35b) according to the method described in Example 4. MS (El) 518.2 (MH⁺).

Examplc 195

3-Methoxy-isoxazole-5-carboxvlic acid (l-Î4-|2-(5-methyI-[l,2,41oxadiazol-3-vi)indol-l-vll-benzylcarbamoyll-cyclopropvb-amide

The title compound was prepared from l-amino-cyclopropanecarboxylic acid 4[2-(5-methyl- [ 1,2.4] oxadîazol-3 -yl)-indol-1 -yl] -benzylamîde hydrochloride (Reference Example 36b) according to the method described in Example 2. MS (El) 513.2 (MH*).

Examplc 196

3-Mcthoxv-isoxazolc~5-carboxylic acid (l-{4-|2-(3-mcthyl-il,2,41oxadiazol-5-vnindol-l-vll-benzvlcarbamovH-cvclopropyB-ainide

The title compound was prepared from 4-[2-(3-methyl-[l,2,4]oxadiazol-5-yl)indol-l-yl]-benzylamine hydrochloride (Reference Example 37b) according to the method described in Reference Example 2. MS (El) 513.2 (MH*).

Il2

Example 197

3-Methoxv-isoxazole-5-carboxylic acid (l-f4-[3-chloro-5-fluoro-2-(5-methylH,2,4|oxadiazol-3-yl)-indol-l-vl1-2-fluoro-benzylcarbamoylï-cyclopropvl)-amide

a) ________4- r3-Chloro-5-fluoro-2-( 5 -methy 1-Γ 1,2,41 oxadiazol-3-y l)-indo 1-1 -vil -2-fluoro- benzylamine hydrochloride

The title compound was prepared from 3-fluoro-4-(/ert-butoxycarbonylamÎnomethyl)-phenylboronïc acid (Reference Example 1) and 3-chloro-5-fluoro-2-(5methyl-l,2,4-oxadiazol-3-yl)-l H-indole (Example 62 b) according to the methods described in Reference Example 9c. MS (El) 358.1 [(M-NH2)]*.

b) 3-Methoxy-isoxazole-5-carboxvlic acid (l-i4-[3-chloro-5-fluoro-2-(5-methvln,2,4Îoxadiazol-3-vl)-indol-l-yl1-2-fluoro-benzylcarbamoylÎ-cycloDropvl)-amide

The title compound was prepared from 4-[3-chloro-5-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-2-fluoro-benzylamine hydrochloride according to the method described in Example 2. MS (El) 583.2 (MH⁺).

Example 198

3-Mcthoxy-isoxazolc-5-carboxylic______acid______(l-{4-[3,5-difluoro-2-(5-methvl[l,2,41oxadiazol-3-vl)-indoI-l-Yl|-benzvkarbamovl)-cyclopropvl)-amide

The title compound was prepared from 4-[3,5-difluoro-2-(5-methyl- [1.2.4] oxadiazol-3~yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 39) according to the method described in Example 2. MS (El) 549.2 (MH*).

Examplc 199

1-(2^ J-Trifluoro-acetylaminol-cyclopropanecarboxylic acid 4-|3,5-difluoro-2-(5methyl-il,2,41oxadiazol-3-vl)-indol-l-yH-bcnzylamide

The title compound was prepared from 4-[3,5-difluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylamine hydrochloride (Reference Example 39) according to the method described in Example 4. MS (El) 520.2 (MH*).

Example 200

3-Methoxy-isoxazole-5-carboxylic acid (l-i4-15“fluoro-3-methyl-2-(5-methvlîl,2,41oxadiazol-3-vl)-indol-l-vll-benzvlcarbamovlï-cvclopropyl)-amide

Ά L ll3

a) 5-FIuoro-3-methyl-lH-indole-2-carboxylic acid amide

The title compound was prepared from 5-fluoro-3-methyl-l/7-indole-2carboxylic acid (US2005/222148) according to the methods described in Reference Example 4b. MS (El) 193.2 (MH*).

b) 5-Fluoro-3-methyl-l H-indole-2-carbonitrile

The title compound was prepared from 5-fluoro-3-methyl-17/-indole-2carboxylic acid amide according to the method described in Reference Example 4c. MS (El) 175.2 (MH*).

c) 5-Fluoro-7V-hydroxy-3-methyl-1//-indole-2-carboxamidine

The title compound was prepared from 5-fluoro-3-methyl-l/f-indole-2carbonîtrile according to the method described in Reference Example 9a. MS (El) 208.1 (MH⁺).

d) 5-Fluoro-3-methyl-2-(5-methyl-[ 1,2,41oxadiazol-3-vl)-l/f-indole

The title compound was prepared from 5-fluoro-A^/-hydroxy-3-methyl-l/7-indok-

2-carboxamidine according to the method described in Reference Example 9b. MS (El) 232.1 (MH*).

e) _______i 4-r5-Fluoro-3-methyl-2-(5-methyl-[ 1,2,41oxadiazol-3-vl)-indol-l -vll-benzvl ΐ - carbamic acid tert-butyl ester

The title compound was prepared from 5-fluoro-3-methyl-2-(5-methyl- [1.2.4] oxadiazol-3-y 1)-1//-indole according to the method described in Reference Example 24f. MS (El) 459.2 [M+Na]*.

f) 4-f5-Fluoro-3-methyl-2-(5-methyl-r 1.2,41oxadiazol-3-vl)-indol-l -yll-benzylamine

The title compound was prepared from {4-[5-fluoro-3-methyl-2-(5-methyl- [1.2.4] oxadiazol-3-yI)-indol-l-yl]-benzyl}-carbamic acid tert-butyl ester according to the method described in Example 37d. MS (El) 320.2 [(M-NH2)]*.

g) 3-Methoxy-isoxazole-5-carboxvlic acid (l-i4-r5-fluoro-3-methyl-2-(5-methylri.2.41oxadiazol-3-yI)-indol-l-vl1-benzvlcarbamoyH-cycloDropvl)-amide

The title compound was prepared from 4-[5-fluoro-3-methyl-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylamine according to the method described in Example 34e. MS (El) 545.2 (MH*).

Example 201

ÎvL ll4

3-Mcthoxy-isoxazole-5-carboxvlic acid (l-l4-|3-chloro-2-(4-niethvl-5-oxo-4,5dîhvdro-il^.4loxadiazol-3-yl)-indol-l-vll-benzylcarbamoyll-cvclonropyl)-amide

a) 3-i3-Chloro-l//-indol-2~yl)-4/7-l 1 ,2.41oxadiazol-5-one

A mixture of 4.91 g (23.4 mmol) of 3-chloro-A^l'-hydroxy-l/7-indoie-2carboxamidine (Reference Example 9a) and 4.91 g (30.28 mmol) of 1,1’carbonyldiimidazole in 49.1 mL of tetrahydrofuran was refluxed for 1.5 h. The reaction mixture was cooled, concentrated in vacuo and the residue was stirred with 50 mL of water. The precipitated product was filtered off, washed with water and dried to yield 4.0 g (72.5 %) of the title compound. Mp: 240-241 °C.

b) 3-(3-Chloro-l/Z-indol-2-yl)-4-methyl-4/7-n ,2.41oxadiazol-5-one

A mixture of 3.69 g (15.6 mmol) of 3-(3-chloro-l//-indol-2-yl)-4Zf- [1.2.4] oxadiazol-5-one, 3.69 mL (59.2 mmol) of iodomethan in 240 mL of acetone was refluxed for 1 h. The reaction mixture was cooled to 20 °C, filtered and the filtrate was concentrated. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane : ethyl acetate = 2:1 as eluent to yield 0.4 g (10.2 %) of the title compound. MS (El) 250.1 (MH*).

c) 3 -Γ1 -(4-Aminomethy l-phenyl ]-3-chloro-177-i ndol-2-yll -4-meth yl -4 /7- [ 1,2,41oxadiazol-5-one hydrochloride

The title compound was prepared from 3-(3-chloro-l/f-indol-2-yl)-4-methyl-4/7- [1.2.4] oxadiazol-5-one and of 4-(teri-butoxycarbonylamino-methyl)phenylboronic acid (Reference Example 1) according to the method described in Reference Example 9c. MS (El) 355.1 (MH*).

d) 3-Methoxy-isoxazole-5-carboxylic acid (l-(4-[3-chloro-2-(4-methyl-5-oxo-4,5dihydro-Γ 1.2„41oxadiazol-3-yl)-indol-1 -yli-benzylcarbamoyl ) -cyclopropvD-amide

The title compound was prepared from 3-[l-(4-aminomethyl-phenyl)-3-chloro177-indol-2-yl]-4-methyl-4/7-[l,2,4]oxadiazol-5-one hydrochloride and l-[(3-methoxyisoxazole-5-carbonyl)-amino]-cyclopropanecarboxylic acid (P. D. O’Shea et al. J. Org. Chem. 2009, 74, 4547-4553) according to the method described in Example 34e. MS (El) 563.2 (MH*).

Préparation of pharmaceutical compositions lis

The following formulation examples illustrate représentative pharmaceutical compositions of this invention. The présent invention however not limited to the following pharmaceutical compositions. The concentration of mixtures are expressed in weight percent.

Préparation Examplc 1

Préparation of pharmaceutical compositions:

a) Tablets:

0.01-50 % of active ingrédient of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of polyvinyl pyrrolîdone, 1-5 % of talc, 0.01-3 % of magnésium stéarate, 1-3 % of colloid silicon dioxide and 2-7 % of ultraamylopectin were mixed, then granulated by wet granulation and pressed to tablets.

b) Dragées, filmcoatcd tablets:

The tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragées were polished by a mixture of beeswax and camuba wax.

c) Capsules:

0.01-50 % of active ingrédient of formula (I), 1-5 % of sodium lauryl sulfate, 1550 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of 20 magnésium stéarate were thoroughly mixed, the mixture was passed through a sieve and filled in hard gelatin capsules.

d) Suspensions:

Ingrédients: 0.01-15 % of active ingrédient of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 425 hydroxybenzoate), 0.005-0.02 % of nîpasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % éthanol, 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.

To solution of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions under vigorous stirring, and the solution was left to stand for 30 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally the éthanolic raspberry flavor were added with stirring. To this carrier the active ingrédient was added in small portions and suspended with an «

116 immersing homogenizator. Finally the suspension was filled up to the desired final volume with distilled water and the suspension syrup was passed through a colloid milling equipment.

e) Suppositories:

For each supposîtory 0.01-15% of active ingrédient of formula (1) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro supposîtory (for example Witepsol 4) was melted, cooled to 35 °C and the mixture of active ingrédient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms,

f) Lyophilizcd powder ampoule compositions:

A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to hâve stérile solution. A 0.01-5 % solution of the active ingrédient of formula (I) was also made with bidistilled water for injection use, and this solution was filtered so as to hâve stérile solution. These two solutions were mixed under aseptie conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in stérile water or 0.9 % (physiological) stérile aqueous sodium chloride solution before administration.

The invention described and claimed herein is not to be limited in scope by the spécifie embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any équivalent embodiments are intended to be withîn the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoîng description. Such modifications are also intended to fall within the scope of the appended daims.

8 MAR. 2013

Claims (10)

l. Indole dérivatives of formula (I) wherein R1 R2 R3 is hydrogen atom, halogen atom or Ci-C^-alkoxy group; is hydrogen atom, halogen atom, C]-C4-alkyl group or cyano group; is selected from (1) -COOR; (2) -CN; (3) -CONRaRb; is hydrogen atom or halogen atom; is hydrogen atom or CpC.i-alkyl group; is selected from R4 R5 R6 (1) Cs-Ce-cycioalkyl;

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3,5-difluoro-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-benzylamide

1 -(2,2,2~Trifluoro-acetylamino)-cyclopropanecarboxylic acid ((Æ)-l-{4-[3-chloro-2-(5methyl-[l ,2,4]oxadiazol-3-yl)-indol- l-yl]-2-fluoro-phenyl }-ethyl)-amide fA

H. _t

I3l

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-5-fluoro-2-(5methyl-[l ,2,4]oxadiazol-3-yI)-indol-l -yl]-benzy 1 amide

1 -(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(5methy 1- [1,3,4] oxadiazol-2-y l)-indol-1 -y 1] -benzy lami de

Pyrimidine-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l ,3,4]oxadiazol-2-yl)-indol1 -y 1]-benzylcarbamoyl} -cyclopropyl)-amide

1- yl]-benzylcarbamoyl}-cyclopropyl)-amide

1 -(3-Furan-2-yl-acryloylamino)-cyclopropanecarboxylîc acid 4-[3-chloro-2-(5-methyl- [1,2,4] oxadiazol-3-y l)-indol-l -y l]-benzyl amide

Thiophene-2-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol-3-yl)-indol1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

1 -(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[3-chIoro-2-(5methyl- [1,2,4] oxadiazol-3 -yl)-indo 1-1 -yl] -benzy I am ide

7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-2-fluoro-isonicotinamide

1- (2-Acetylamino-3-hydroxy-propionylamino)-cyclopropanecarboxylic acid 4-[3- chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzyIamide

1,5-Dimethyl-l H-pyrazole-3-carboxylic acid (1 - {4-[3-chloro-2-(5-methyl[ 1,2,4]oxad i azol-3 -y l)-indol-1 -y 1] -benzy Icarbamoyl} -cyclopropy l)-amide

1 -Cyano-cyclopropanecarboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

128

Cyclobutanecarboxylîc acid (l -{4-[3-chloro-2-(5-methyl-[ l ,2,4]oxadiazol-3-yl)-indol- l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

Cyclopentanecarboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indoll -yl] -benzy Icarbamoyl} -cyclopropyl)-amide

Furan-2-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzy Icarbamoyl }-cyclopropyl)-amide

A-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-3-cyano~benzamide l -(2-Thiophen-3-yl-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methyl- [1,2,4] oxadiazol-3 -yl)-indo 1-1 -y 1] -benzy lamide

1 -(4-Methyl-pentanoylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylamide lH-Pyrazole-4-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

1 -Pent-4-ynoylamîno-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methyl[ 1,2,4] oxadiazol-3-y l)-i ndol-1-y l]-benzylamide

1 -(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[5-methoxy-2-(5methy 1- [1,3,4] oxadiazol-2-yl)-indo 1-1 -y 1] -benzy lamide ,V-(1 -{4-[5-Methoxy-2-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-indol-l -yl]-benzylcarbamoyl}cyc lopropy l)-5 -tri fluoromethy 1- nicotinamide

1 -Methyl- lH-pyrazole-4-carboxylic acid ( 1-{4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol3 -y l)-indol-1 -yl] -benzylcarbamoyl} -cycl opropy 1 )-ami de

1 -(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(3methyl-[l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylamide /V-( 1 - {4-[3-Chloro-2-(3-methy l-[ 1,2,4 ] oxadiazol-5-y 1)-indol-1-y I ]-benzy le arbamoy 1} cyclopropyl)-2-fluoro-isonicotinamide

1 -(S^S-Trifluoro-propionylaminoj-cyclopropanecarboxylic acid 4-[5-fIuoro-2-(3methyl-[ 1,2,4]oxadiazol-5-yl)-indol-1 -yl]-benzylamide

N-( 1 - {4-[5-Fluoro-2-(3-methyl-[ 1,2,4]oxadiazol-5-yl)-indol-1 -yl] -benzylcarbamoyl} cyclopropyl)-5-trifluoromethyl-nicotinamide

1 - { 4- [3 -Chloro-2-(5 -methyl- [1,2,4] oxadiazol-3-y 1) -i ndol-1 -y 1 ]-benzylcarbamoy 1} cyclopropyl)-3-fluoro-4-trifluoromethyl-benzamide 7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-3-fluoro-5-trifluoromethyl-benzamide

125 /V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropy l )-2-fluoro-nicotinamide jV-( i -{4-[3-Chloro-2-(5-methyl-[ l ,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylcarbamoyl} cyclopropyl)-2-fluoro-5-trifluoromethyl-benzamide

JV-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-3-fluoro-isonicotinamide

7V-(1 -{4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylcarbamoyl} cyclopropyl)-4-fluoro-3-trifluoromethyl-benzamide

7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-6-fluoro-nicotinamide

N- {l-[4-(5-Chloro-2-cyano-indol-l -yl)-benzylcarbamoyl]-cyclopropyl} -5trifluoromethyl-nicotinamide

1- (3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylamide jV-( 1 - {4- [ 2-( 5 -Methyl - [ 1,2,4] oxad iazol-3 -y l)-indol-1 -yl ]-benzy lcarbamoy 1} cyclopropyl)-5-trifluoromethyl-nicotinamide

JV-(l-{4-[2-(3-Methyl-[l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-5-trifluoromethyl-nicotinamide ;V-{ 1 -[4-(2-Cyano-indol-1 -y l)-benzy lcarbamoy l]-cyclopropyl} -5-trifluoromethylnicotinamide

1 -(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[5-methoxy-2-(3methyl-[l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylamide îvL·

124

7V-(1 - (4-[5-Methoxy-2-(3-methyl-[ l ,2,4]oxadiazol-5-yl)-indol-1 -yl |-benzylcarbamoyl} cyclopropyl)-5-trifluoromethyl-nicotinamide

1 -(2,2,2-T rifluoro-acetyl amino)-cyclopropanecarboxylic acid 4- [3,5-d ichloro-2-(5 methyl- [1,2,4] oxadiazol-3 -y l)-indol-1 -y 1] -benzylamide

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-5-methoxy-2(5-methyl-[l,2,4]oxadiazoI-3-yl)-indol-l-yl]-benzylamide

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid (l-{4-[3-chloro-2(pyrrolidine-l-carbonyl)-indol-l-yl]-phenyl}-ethyl)-amide

1-(3,3,3,-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(2- methyl-2J7-tetrazol-5-yl)-indol-1 -y l]-benzylamide

N-( 1 - {4- [3 -chloro-2-(2-methy l-2/7-tctrazol-5-y I )-i ndol-1 -y 1] -benzy lcarbamoy 1} cyclopropyl)-5-trifluoromethyl-nicotinamide

I2l

V-( 1 - {4 - [3 -chloro-2-(2-methy l-2/7-tctrazol-5-y l)-i ndol-1 -yl] -benzylcarbamoyl} cyclopropyl)-3-fluoro-benzamide

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methy I- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide

1 -(2,2,2-Trifluoro-acety lam ino)-cyclopropanecarboxy 1 ic acid 4- [3,5 -d ichioro-2-(2methyl-27/-tetrazol-5-yl)-indol-l-yl]-2-fluoro-benzylamide

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3,5-dichloro-2-(2methyl-2//-tetrazol-5-yl)-indol-l-yl]-benzylamide

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-( 1 -methyl1 H-tetrazol-5-yl)-indol-1-yl]-benzylamide

20 3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol3-yl) -indol-1 -yl] -benzy lcarbamoy 1} -cyclopropy 1 )-ami de

1 -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4- [3-chloro-2-(5-methy 115 [ 1,3,4] ox ad iazo 1-2-y 1)- indol-1 -y 1] -benzylamide

2- Methyl-pyrimidine-5-carboxylic acid (1 -{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

2-ChIoro-A/-(l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-6-methyl-nicotinamide

2- Chloro-A/-(l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl} -cyclopropyl)-nicotinamide

A-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-6-methyl-nicotinamide

A-( 1-{4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1-yl]-benzylcarbamoyl}cyclopropyl)-2-methyl-nicotinamide

2,4-Dimethyl-thiazole-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol3-yI)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

2-Methyl-cyclopropanecarboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

2- Oxo-imidazolidine-4-carboxylic acid (l-(4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3- yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

2-Fluoro-7V-(l-{4-[5-fluoro-2-(5-niethyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-nicotinamide

2-Fluoro-JV-(l -{4-[5-methoxy-2-(3-methyl-[l ,2,4]oxadiazol-5-yl)-indol-l -yl]benzylcarbamoyl} -cyclopropy 1) -nicotinamide

A^r-(l-{4-[3-Chloro-5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-2-fluoro-nicotinamide #-( 1 - {4-[3-Chloro-5-methoxy-2-(3-methyl-[ 1,2,4] oxad iazo 1-5-yl)-i ndol-1-y 1] benzylcarbamoyl}-cyclopropy l)-2-fluoro-nicotinamide

JV-(l-{4-[3-Chloro-2-(2-methyl-2/7-tetrazol-5-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-2-fluoro-nicotinamide

2-Chloro-7V-(l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluorobenzylcarbamoyl} -cyclopropyl)-nicotinamide

JV-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluorobenzylcarbamoyl}-cyclopropyl)-3-fluoro-benzamide

2- Chloro-7V-(l-{4-[3-chloro-5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-nicotinamide

7V-(l-{4-[3-Chloro-5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-3-fluoro-benzamide

2-MethyIsulfanyl-pyrimidine-5-carboxyIic acid (1 -{4-[3-chloro-2-(5-methyl- [1,2,4] oxadiazol-3 -y 1 )-indol-1 -yl ] -benzylcarbamoy 1} -cyc lopropy 1 )-amide

2- Chloro-A-( 1 ~{4-[3,5-dichloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoy 1}-cyclopropyl)-nicotinamide A-(l-{4-[3,5-Dichloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-ylJbenzylcarbamoyl}-cyclopropyl)-3-fluoro-benzamide 5-Methyl-pyrazîne-2-carboxylic acid (l-{4-[3,5-dichloro-2-(5-methyI-[l,2,4]oxadiazol-

2-Chloro-/V-(l-(4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)-indol-l-yl]benzylcarbamoyl} -cyclopropyl)-nicotinamide

JV-(l-{4-[3-chloro-2-(2-methyl-2/7-tetrazol-5-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-2-fluoro-isonicotinamide

2. A compound of Claim l selected from the group of l-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(2-methyl-

(2) optionally substituted five- or six-membered aromatic ring with two nitrogen atoms;

3. Process for preparing the compounds of formula (I) as claimed in Claim 1 characterized by

a) reacting an indole dérivative of formula (II) (kl »- «

- wherein the meaning of R¹, R² and R³ is as described for the formula (I) in Claim 1 with a boronic acid of formula (III)

- wherein the meaning of R⁴ and R⁵ is as described for the formula (I) in Claim 1 - then the so obtained indole dérivative of formula (IV)

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described for the formula (I) in

Claim 1 - is deprotected to yield an amine dérivative of formula (V)

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described for the formula (I) in

Claim 1 - finally the latter is reacted with an acid dérivative of formula (VI) (VI)

- wherein the meaning of R⁶ is as described for the formula (I) in Claim 1 ; or b) reacting an indole dérivative of formula (II)

- wherein the meaning of R¹, R² and R³ is as described for the formula (I) in Claim 1 with a boronic acid of formula (VII) \XV°^H \

OH (VII)

15 then the so obtained indole dérivative of formula (VIII)

- wherein the meaning of R¹, R² and R³ is as described for the formula (I) in Claim 1 is reacted with hydroxylamine hydrochloride to yield the indole dérivative of formula 5 (IX)

- wherein the meaning of R¹, R² and R³ is as described for the formula (I) in Claim 1 the latter is hydrogenated to fumish an amine dérivative of formula (X)

- wherein the meaning of R¹, R² and R³ is as described for the formula (I) in Claim 1 finally the latter is reacted with an acid dérivative of formula (VI)

135 (VI)

- wherein the meaning of R⁶ is as described for the formula (I) in Claim 1; or

c) reacting the amine dérivatives of formula (V) or formula (X) - obtained according to

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5-fluoro-3-methyl-2-(5-methyl[ 1,2,4]oxadiazol-3 -yl)-indol-1 -yl] -benzylcarbamoyl} -cyclopropyl)-amide and 3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-2-(4-methyl-5-oxo-4,5dîhydro-[l ,2,4]oxadîazol-3-yl)-indol-l -yl]-benzylcarbamoyl}-cyclopropyl)-amide and optical antipodes or racemates and/or salts thereof.

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3,5-difluoro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzyIcarbamoyl}-cyciopropyl)-amide

3-Methoxy-isoxazole-5-carboxyIic acid (1 - {4-[3-chloro-5-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3 -y l)-indo I-1 -y 1 ] -2-fl uoro-benzy lcarbamoyl} -cycl opropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[2-(3-methyl-[ 1,2,4]oxadiazol-5-yl)indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[2-(5-methyl-[l ,2,4]oxadiazoi-3-yl)indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (1 - {4-[3-chloro-2-(3-methyl-[ 1,2,4]oxadiazol5-yl)-indo!-l-yl]-benzylcarbamoyl}-cyciopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol3 -y l)-indol-1 -y 1] -2-fl uoro-benzy le arbamoy 1} -cyclopropy l)-am ide

3-Methoxy-isoxazole-5-carboxylic acid [ l-((R)- l-{4-[3-chloro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-2-fluoro-phenyl}-ethylcarbamoyl)-cyclopropyl]amide

3 -Chloro-1 - {4-[( {1 - [(3-methoxy-ïsoxazole-5 -car bony l)-amino] -cyclopropanecarbonyl}-amino)-methyl]-phenyl}-l//-indole-2-carboxylic acid amide

3-Chloro-1 - [4-( {[ 1 -(2,2,2-tri fluoro-acety lamino)-cyc lopropanecarbonyl] -amino} methyl)-phenyl]-l//-indole-2-carboxylic acid amide

3- Amino-N-(l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazoi-3-yl)-indol-l-yl]benzylcarbamoyl}-cycl opropy l)-benzamide hydrochloride

3-Methyl-isoxazole-4-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol-3yl )-indol-1 -y I ] -benzylcarbamoyl} -cycl opropy l)-amide

Quinoline-3-carboxylic acid ( 1 -{4-[3-chloro-2-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-indol-

3 -y l)-i ndol-1 -y 1] -benzylcarbamoy 1} -cyclopropy l)-am ide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5-methoxy-2-(5-methyl- [ 1,3,4]oxadiazol-2-yl)-indol-l -yl]-benzylcarbamoyl} -cyclopropyl)-amide

I27 l -(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[5-chloro-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylamide

H-(l-{4-[5-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-5-trifluoromethyl-nicotinamide

3- Ethyl-isoxazole-5-carboxylic acid (l-(4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5-methoxy-2-(3-methyl- [1.2.4] oxadiazol-5-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

3- y 1) - indol-1 -yl ] -benzy Icarbamoyl} -cyclopropy l)-amîde

3-Methoxy-isoxazole-5 -car boxyl ic acid ( 1 - {4- [3 -chloro-5 - fluoro-2-(5-methy I- [1.2.4] oxadiazol-3 -yl)-indol-1 -yl ]-benzylc arbamoyl} -cyclopropy 1 )-amide 3-Chloro-4-fluoro-l -{4-[({ 1 -[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-phenyl}-l//-indole-2-carboxylic acid methyl ester 3-Chloro-4-fluoro-l -[4-( {[ 1 -(2,2,2-trifluoro-acetylamîno)-cyclopropanecarbonyl]amino]-methyl)-phenyl]-l//-indole-2-carboxylic acid methyl ester

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[3,5-dichloro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl]-cyclopropyl)-amide

3 -Methoxy-isoxazole-5-carboxy 1 i c aci d ( 1 - {4- [3 -chl oro-5 -methoxy-2-( 5 -methyl [ 1,2,4] oxadiazol-3-y l)-indol-l -yl]-benzylcarbamoyl}-cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid [ 1 -({5-[3-chloro-5-fluoro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-pyridin-2-ylmethyl}-carbamoyl)-cyclopropyl]-amide fit

123

3-Methoxy-isoxazole-5-carboxylic acid [ 1 -( {5- [ 3-chloro-2-(3-methyI-[ 1,2,4]oxadiazol5-yl)-indol-l-yl]-pyridin-2-ylmethyl}-carbamoyl)-cyclopropyl]-amide 3-Methoxy-isoxazole-5-carboxylic acid [1 -({5-[3-chloro-5-fluoro-2-(2-methyl-2Htetrazol-5-y l)-i ndol-1 -y 1] -pyridin-2-ylmethy 1} -carbamoy 1) -cyclopropyl] -amide 3-Methoxy-isoxazole-5-carboxylic acid [ 1 -( {5-[3-chIoro-2-(2-methyl-2//-tetrazol-5-yl)indol-1 -yl]-pyridin-2-ylmethyl} -carbamoyl)-cyclopropyl]-amide 3-Methoxy-isoxazole-5-carboxylic acid [l-({5-[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol3-yl)-indol-l-yl]-pyridin-2-ylmethyl}-carbamoyl)-cyclopropyl]-amide

3-Chloro-l-[3-fluoro-4-({[l-(2,2,2-trifluoro-acetylamino)-cyclopropanecarbonyl]amino}-methyl)-phenyl]-l/7-indole-2-carboxylic acid methyl ester 3-Chloro-l-{3-fluoro-4-[({l - [(3-methoxy-i soxazole-5 -carbony l)-ami no] -cyc lopropanecarbonyl}-amino)-methyl]-phenyl}-lZ7-indole-2-carboxylic acid methyl ester 3-Methoxy-isoxazole-5-carboxylic acid [ 1 -( {5-[2-(3-methyl-[ 1,2,4]oxadiazol-5-yl)indol- l-yl]-pyridin-2-ylmethyl} -carbamoyl)-cyclopropyl]-amide 3-Methoxy-isoxazole-5-carboxylic acid [ 1 -({5-[2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)indol-l-yl]-pyridm-2-ylmethyl}-carbamoyl)-cyclopropyl]-amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5-chloro-2-(5-methyl-[l,2,4]oxadiazol3-yl)-indol-1 -yl]-benzylcarbamoyi} -cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid ( 1 - {4- [3 -ch I oro-5 -methoxy-2-(3 -methyl[ 1,2,4] oxadiazol-5-y l)-indo 1-1-y 1] - benzy 1 carbamoyl}-cyclopropy l)-amide 3-Methoxy-isoxazole-5-carboxylic acid {l-[4-(3-chloro-2-cyano-5-methoxy-indol-lyl)-benzylcarbamoyl]-cyclopropyl}-amide

3-Methoxy-isoxazole-5-carboxylic acid {l-[4-(2-cyano-5-fluoro-indol-l-yl)benzylcarbamoy l]-cyclopropy 1} -amide 7V-(l-{4-[3-Chloro-5-methoxy-2-(3-methyl-[l,2,4]oxadiazol-5-yl)-indol-l-yl]-benzylcarbamoy 1} -cyclopropy l)- 5 -trifluoromethy 1-nicoti nam ide

3-Methoxy-isoxazole-5-carboxylic acid {l-[4-(2-cyano-5-methoxy-indol-l-yl)benzy lcarbamoyl ]-cyclopropyl} -amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid {l-[4-(5-chloro-2-cyano-indol-l-yl)benzy Icarbamoy 1] -cyclopropy 1} -amide

N- {1 - [4-(2-Cyano-5 -methoxy-indol -1 -y l)-benzy 1 carbamoy 1] -cyclopropy 1} -5 trifluoromethyl-nicotinamide

2V- {1 -[4-(2-Cyano-5-fluoro-indol-1 -yl)-benzylcarbamoyl]-cyclopropyl }-5trifl uoromethyl-nicoti nam ide

N-(l-{4-[5-Fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropy l)-5-tri fl uoromethyl -nicotinamide

122

3-Methoxy-isoxazole-5-carboxylic acid {l-[4-(3-chloro-2-cyano-indol-l-yl)-benzylcarbamoylj-cyclopropyl }-amide (7f)-l-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid (l-{4-[3-chloro-2-(5methyl-[ 1,2,4]oxadiazol-3-yl)-indol-l -yl]-phenyl} -ethyl)-amide (7î)-3-Methoxy-isoxazole-5-carboxylic acid [1 -(1 -{4-[3-chloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-phenyl}-ethylcarbamoyl)-cyclopropyl]-amide 3-Propyl-isoxazole-5-carboxylic acid (1 - {4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-oxazol-2-yl)-indol1 -y l] -benzylcarbamoyl} -cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-5-fluoro-2-(5-methyl[ 1,3,4]oxadi azol-2-y 1) -indol -1 -y l]-benzy Icarbamoy 1} -cyclopropy l)-amide

3-Chloro-l-{4-[([l-[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarbony!}-amino)-methyl]-phenyl}-177-indole-2-carboxylic acid dimethylamide l-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[2-(2-methyl-277tetrazol-5-yl)-indol-l-yl]-benzylamide

3-Chloro-l-{4-[({l-[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-phenyl}-l//-indole-2-carboxylic acid ethyl ester

3-Chloro-1-[4-( 1 - {[ 1-(2,2,2-tri fluoro-acety 1 ami no)-cyclopropanecarbonyl ]-ami no} ethyl)-phenyl]-l//-indole-2-carboxylîc acid methylamide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-cyano-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-5fluoro-2-(2-methyl-2//tetrazol-5-yl)-indol-l-yl]-2-fluoro-benzylcarbamoyl]-cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[3,5-dichloro-2-(2-methyl-2/7-tetrazol-5yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide l -(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-5-fluoro-2-(2methy l-2//-tetrazol-5 -y l)-indol-1 -yl ] -2-fluoro-benzy lam ide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-2-(l,3- oxazol-5-yl)-indol-ly 1] -benzylcarbamoy I} -cyclopropy 1 )-ami de

3-Methoxy-isoxazole-5-carboxylic acid ( 1 -{4-[3-chloro-2-(2-methyl-2//-tetrazol-5-yl)indol-1 -yl]-2-fluorobenzylcarbamoyl} -cyclopropyl)-amide

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[3-chloro-5-fluoro-2-(2-methyl-2/Ztetrazol-5-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

30 1 - {4- [( {1 - [(3 -Methoxy-isoxazole-5-carbony i)-amino] -cy cl opropanecarbony 1} -amino) methyl]-phenyl}-l//-indole-2-carboxylic acid methyl ester

U

120

3-Chloro-1 - {4- [( {1 -[(3-methoxy-isoxazole-5-carbonyl)-amino]-cyclopropane25 carbonyl}-amino)-methyl]-phenyl}-l R-indole-2-carboxylic acid methyl ester l-(2,2,2-TrifIuoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-5-fluoro-2-(2methyl-2Jï-tetrazol-5-yl)-indol-l-yi]-benzylamide

3-Chloro-l-[4-({[l-(2,2,2-trifluoro-acetylamino)-cyc lopropanecarbony 1] -amino} methyl)-phenyl]-l//-indole-2-carboxylic acid methyl ester

3-Methoxy-isoxazole-5-carboxylic acid (1 -{4-[3-chloro-2-( 1 -methyl-177-tetrazol-5-yl)i ndol-1 -y 1] -benzy lcarbamoy 1} -cyclopropy 1) -amide

3 -Methoxy-/V- [ 1 -( {4- [3 -chloro-2-(5-methy 1-1,3,4-oxad iazol-2-yl )-1 H- indo 1 -1 y 1] benzy 1} carbamoy l)cyclopropy I ] isoxazole-5-carboxamide

3 -Methoxy-isoxazole-5 -carboxylic acid ( 1 - {4-[2-(2-methy l-2//-tetrazol-5-y 1 )-indo 1-1 y 1] -benzy lcarbamoy 1} -cyclopropy 1 )-amide

10 l-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(2-methyl2/7-tetrazol-5-yl)-indoI-1 -yl]-2-fluorobenzylamide

3-Methoxy-isoxazole-5-carboxylic acid (l-{4-[3-chloro-2-(2-methyl-2/7-tetrazoI-5-yl)indol-1 -y l] -benzy lcarbamoy!} -cyclopropy l)-amide

(3) optionally substituted pyridyl;

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in Claim 1 and optical antipodes or racemates and/or salts thereof as active ingrédients and pharmaceutically acceptable auxiliary material s.

4- Methyl-thiazole-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[i,2,4]oxadiazol-3yl)-indol-1 -yl]-benzy Icarbamoyl} -cyclopropyl)-amide

(4) optionally substituted five-membered aromatic ring with one heteroatom selected from O or S;

5. Process for manufacturing pharmaceutical composition having sélective bradykinin Bl receptor antagonist effect characterized by mixing a therapeutically effective amount of a compound of formula (I) as claimed in Claim 1 and optical antipodes or racemates and/or salts thereof as active ingrédients and auxiliary materials.

5 the method described in method a) and method b) - with the amino acid dérivative of formula (XI) (Xi) and the so obtained indole dérivative of formula (XII)

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described for the formula (I) in

Claim 1 - is deprotected to yield an amine dérivative of formula (XIII) *?

136 (XIII)

- wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as described for the formula (I) in

Claim 1 - fînally the latter is reacted with an acid dérivative of formula (XIV)

O (XIV)

- wherein the meaning of R⁶ is as described for the formula (I) in Claim 1; and optionally an indole dérivative of formula (1) obtained in process a) or b) or c) and optical antipodes or racemates and/or salts thereof can be transformed into an other compound of formula (I) and optical antipodes or racemates and/or salts thereof by introducing new substituents and/or modifying or removing the existing ones.

5-Methylsulfanyl-thiophene-2-carboxylic acid (1 - (4-[3-chloro-2-(5-methyl[ 1,2,4] oxadiazol-3 -yl)-indol-1 -yl]-benzy 1 carbamoy 1} -cyclopropy l)-amide [l,2,3]Thiadiazole-4-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

130 ?/-( 1 - {4-[3-Chloro-2-(5-methy I-[ 1,2,4] oxadiazol-3-y I )-indol-1 -y 1] -benzy lcarbamoy 1} cyclopropy l)-3 -methoxy-benzamide

N-( 1 - {4-[3 -Chloro-2-(5-methyl- [ 1,2,4]oxadiazol-3-yl)-îndol-1 -yl] -benzylcarbamoyl} cyclopropy l)-3 -îodo -benzami de

7V-(]-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yI]-benzylcarbamoyl}cyclopropyl)-3-trifluoromethyl-benzamide

N-( 1 - {4-[3 -Chloro-2-(5-methyl- [ 1,2,4]oxadiazol-3 -yl)-indol-1 -yl] -benzylcarbamoyl} cyclopropyl)-3-fluoro-benzamide

7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-3-methyl-benzamide /V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyc lopropy l)-5 -tri fluoro methyl-nicotinamide

5-Oxo-pyrrolidine-2-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-îndol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide l-(3-Furan-3-yl-acryioylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(5-methyl- [1.2.4] oxadiazol-3 -y I)-indol-1 -y 1] -benzyl amide

A-(l -{4-[3-Chloro-2-(5-methyl-[l ,2,4]oxadiazol-3-yl)-indol-l -yl]-benzylcarbamoyl}cyclopropyl)-4-cyano-benzamide

5-Cyclopropyl-isoxazole-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

Pyrimidine-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadîazol-3-yl)-indol1 -yl]-benzy lcarbamoyl} -cyclopropyl )-amide

Thiophene-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

5- Methyl-pyrazine-2-carboxylic acid (l - [4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

5- Methyl-l//-pyrazole-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-

5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l ,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

Tetrahydro-furan-2-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)indol-1 -y 1]-benzylcarbamoyl} -cyclopropyl)-amide

Furan-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzy lcarbamoy l} -cyclopropy 1 )-amide

5-Methyl-pyrazine-2-carboxylic acid (l-{2-fluoro-4-[5-fluoro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

JV-(l-{2-Fluoro-4-[5-fluoro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide 3-Methoxy-isoxazole-5-carboxylic acid ( 1 -{2-fluoro-4-[5-fluoro-2-(5-methyI[ 1,2,4]oxadiazol-3-y l)-i ndol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

Isoxazole-5-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-l yl]-benzylcarbamoyl}-cyclopropyl)-amide

5-Methyl-pyrazine-2-carboxylic acid (l-(4-[3-chloro-5-methoxy-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide jV~(l-{4-[3“ChIoro-5-methoxy-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]benzylcarbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide

5-Cyclopropyl-isoxazole-3-carboxylic acid (l-{4-[3-chloro-2-(3-methyl[ 1,2,4]oxadiazol-5-yl)-indol-1 -y 1] -benzylcarbamoyl} -cyclopropy l)-amide //-(1- {4-[3-Chloro-2-(3-methy l-[ 1,2,4]oxadiazol-5-yl)-indoi-1 -yl]-benzylcarbamoyl} cyclopropyl)-5-trifIuoromethyl-nicotinamide

5-Cyclopropyl-isoxazole-3 -carboxyl ic acid ( 1 - {4-[3 -chloro-2-(5-methyl- [l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluoro-benzylcarbamoyl}-cyclopropyl)-amide

126 jV-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluorobenzy lcarbamoy 1} -cyclopropy 1 )-5-trifl uoromethyl -nicotinamide

5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indo!-l-yl]-2-fluoro-benzylcarbamoyl}-cyclopropyl)-amide l-(3,3,3-Trifluoro-propionylamino)-cyclopropanecarboxylic acid 4-[3-chloro-2-(5methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluoro-benzylamide

7V-(l-{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-2-fluorO“ benzylcarbamoyl} -cyclopropyl)-2-fluoro-isonicotinamide

5-Methyl-pyrazine-2-carboxylic acid (1 -{4-[3-chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3y I )-i ndol-1 -yl] -2-fl uoro -benzylcarbamoyl} -cyclopropy l)-am ide

5-Methyl-isoxazole-3-carboxylic acid (1 -{4-[3-chloro-5-fluoro-2-(5-methyl- [1.2.4] oxadiazol-3 -y l)-i ndol-1 -y 1] -benzy 1 carbamoy 1} -cyc lopropy l)-amide

Ύ-( 1 - {4-[3-Chloro-5-fluoro-2-(5-methyl-[ 1,2,4]oxadiazol-3-y l)-indol-1 -y 1 ]benzylcarbamoyl}-cyclopropyl)-2-fluoro-isonicotinamide 5-Cyclopropyl-isoxazole-3-carboxylic acid (1 -{4-[3-chloro-5-fluoro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylcarbamoyl }-cyclopropyl)-amide /V-( 1 - {4-[3-Chloro-5-fluoro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]benzylcarbamoyI}-cyclopropyl)-5-trifluoromethyl-nicotinamide

N-(l~{4-[3-Chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}cyclopropyl)-2-fluoro-3-trifluoromethyl-benzamide

5-Methyl-pyrazine-2-carboxylic acid (1 - {4-[3-chloro-5-fluoro-2-(5-methyl[ 1,2,4]oxadiazol-3-yl)-indol-1-yl]-benzylcarbamoyl}-cyclopropyl)-amide

5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3,5-dichloro-2-(5-methyl- [1.2.4] oxadiazol-3-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide JV-( 1 -{4-[3,5-Dichloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -y 1]benzylcarbamoyl}-cyclopropyl)-2-fluoro-isonicotinamide 5-Cyclopropyl-isoxazole-3-carboxylic acid (1 -{4-[3,5-dîchloro-2-(5-methyl- [1.2.4] oxadiazol-3 -y l)-indo 1-1 -yl] -benzylcarbamoy 1} -cyclopropyl)-amide W-( 1 - {4- [3,5-Dichloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl] benzylcarbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide

5-Methyl-isoxazole-3-carboxylic acid (l-{4-[3-chloro-2-(2-methyl-22/-tetrazol-5-yl)indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

5-Methyl-pyrazine-2-carboxylic acid (l-(4-[3-chloro-2-(2-methyl-2/7-tetrazol-5-yl)i ndo 1-1 -y 1] -benzy Icarbamoyl} -cyclopropy l)-amide

5-Cyclopropyl-isoxazoIe-3-carboxylic acid (1 -{4-[3-chloro-2-(2-methyl-2Z/-tetrazol-5yl)-indol-1 -yl]-benzylcarbamoyl} -cyclopropyl)-amide

5 2/7-tetrazol-5-yl)-indol-l -yl]-benzylamide

(5) -CF₃; (6) -CH2-CF3; (7) -CH₂-CH₂-C=CH; (8) -CH₂-CH2-CH(CH₃)₂ ;

'ü L

XI (27) NC^Z is -CH- or nitrogen atom;

is C|-C₄ alkyl group;

R

R^a and R^b are independently from each other hydrogen atom; Ci-C₄ alkyl group or pyrrolidin-l-yl group;

R^c is hydrogen atom; Ci-C₄ alkyl or C|-C₄ alkoxy group;

R^d is hydrogen atom; C|-C₄ alkyl or C3-C6 cycloalkyl group;

R^c and R^f are independently from each other hydrogen atom; halogen atom; C]-C₄ alkoxy; -CF3; -CN or -NH₂ group;

U ·* « ll9 and optical antipodes or racemates and/or salts thereof.

6. A compound of formula (I) as claimed in Claim 1 and optical antipodes or racemates and/or sait thereof for use as sélective bradykinin Bl receptor antagonist.

6- Oxo-1,6-dihydro-pyridine-2-carboxylic acid ( 1 - {4-[3 -chloro-2-(5-methyl- [1.2.4] oxadiazoi-3 -y l)-indo 1-1 -y 1] -benzy 1 carbamoy 1} -cyclopropy l)-amîde

6- Bromo-pyridine-2-carboxylic acid (1 -{4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide jV-( 1 - {4-[3-Chloro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-indol-1 -yl]-benzylcarbamoyl} cyclopropyl)-nicotinamide

Ή

129

Quinoline-3-carboxylic acid (l-(4-[3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-indoll -yl]-benzylcarbamoyl} -cyclopropyl)-amide 6-Oxo-l,6-dihydro-pyridine-3-carboxylic acid (l-{4-[3-chloro-2-(5-methyl- [1.2.4] oxadîazol-3-yl)-indol-l-yl]-benzylcarbamoyl}-cyclopropyl)-amide

7. A compound of formula (I) as claimed in Claim 1 and optical antipodes or racemates and/or salts thereof for use in the treatment or prévention of disorders associated with bradykinin Bl receptor activity.

8. A compound In accordance with claim 7 wherein disorder is selected from the group of pain and inflammation, including somatic musculo-skeletal pain, low-back

I37 pain, répétitive motion disorders, myofascial pain syndrome, arthritis - including osteoarthritis, rheumatoid arthritis and goût - fibromyalgia, viscéral pain, inflammatory skin disorders and skin injuries, complications associated with diabètes such as neuropathy, nephropathy, vasculopathy, retinopathy, cancer pain and inflammatory bowel disease.

9. Method of treatment and/or prévention of a disorder which requires inhibition of a bradykinin 1 receptor characterized by administering an effective amount of a compound of formula (I) as claimed in Claim 1 and optical antipodes or racemates and/or salts thereof as such or combined with pharmaceutically acceptable auxîliary materials and the like usuaily applied in pharmaceuticals to the mammal to be treated.

10. Method in accordance with claim 9 wherein disorder is selected from the group of pain and inflammation, including somatic musculo-skeletal pain, low-back pain, répétitive motion disorders, myofascial pain syndrome, arthritis - including osteoarthritis, rheumatoid arthritis and goût - fibromyalgia, viscéral pain, inflammatory skin disorders and skin injuries, complications associated with diabètes such as neuropathy, nephropathy, vasculopathy, retinopathy, cancer pain and inflammatory bowel disease.