MXPA06009861A - (indol-3-yl)-heterocycle derivatives as agonists of the cannabinoid cb1 receptor - Google Patents

Abstract

The invention relates to (indol-3-yl)-heterocycle derivatives having general Formula (I) wherein A represents a 5-membered aromatic heterocyclic ring, wherein X1, X2 and X3 are independently selected from N, O, S and CR;R is H or (C1-4)alkyl;or R, when present in X2 or X3, may form together with R3 a 5-8 membered ring;R1 is a 5-8 mem-bered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S;R2 is H, CH3 or CH2-CH3;or R2 is joined together with R7 to form a 6-mem-bered ring, optionally containing a heteroatom selected from O and S, and which heteroatom is bonded to the 7-position of the indole ring;R3 and R4 are independent-ly H, (C1-6)alkyl or (C3-7)cycloalkyl, the alkyl groups being optionally substituted with OH, (C1-4)alkyloxy, (C1-4)alkylthio, (C1-4)alkylsulfonyl, CN or halogen;or R3 together with R4 and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O and S, and which is optionally sub-stituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy- (C1-4)alkyl, or halogen;or R3 together with R5 forms a 4-8 membered ring optionally containing a further hetero-atom selected from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy- (C1-4)alkyl, or halogen;or R3 together with R, when present in X2 or X3, forms a 5-8 membered ring;R5 is H or (C1-4)alkyl;or R5 together with R3 forms a 4-8 membered ring optionally containing a further heteroatom select-ed from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyl-oxy, (C1-4) alkyloxy- (C1-4)alkyl, orhalogen;R5'is H or (C1-4)alkyl;R6 represents 1-3 substituents independently selected from H, (C1-4 alkyl, (C1-4) alkyloxy, CN and halogen;R7 is H, (C1-4)alkyl, (C1-4)alkyloxy, CN or halogen;or R7 is joined together with R2 to form a 6-membered ring, optionally containing a further heteroatom selected from O and S, and which heteroatom is bonded to the 7-position of the indole ring;or a pharmaceutically acceptable salt thereof, as agonists of the cannabinoid CB1 receptor, which can be used in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

Description

DERIVATIVES OF (INDOL-3-I-HETEROCICLE AS AGNISTS OF THE CANABINOID RECEPTOR CB1 The present invention relates to (indol-3-yl) -heterocycle derivatives, to pharmaceutical compositions comprising the same and to the use of these (indol-3-yl) -heterocycle derivatives in therapy, especially in the treatment of pain . Pain management is often limited by the side effects of currently available medication. For moderate to severe pain, opioids are widely used. These agents are cheap and effective but suffer from serious and potentially life-threatening side effects, most notably respiratory depression and muscular rigidity. In addition, the doses of opioids that can be administered are limited by nausea, emesis, constipation, itching, and urinary retention, often resulting in patients choosing to receive sub-optimal pain control rather than suffering from these distressing side effects. In addition, these side effects often result in patients requiring extended hospitalization. Opioids are highly addictive and are drugs programmed in many territories. Therefore, there is a demand for new analgesics that have an improved side effect profile compared to currently used products, at equi-analgesic doses. The evidence is accumulating that cannabinoid agonists have potential as analgesics and anti-inflammatory agents. Two types of cannabinoid receptors are involved, the cannabinoid receptor CB1, which is located mainly in the central nervous system but is also expressed by peripheral neurons and to a lesser degree in other peripheral tissues, and the cannabinoid receptor CB2, which is located mostly in immune cells (Howlett, AC et al .: International Union of Pharmacology, XXVII, Classification of Cannabinoid Receptors, Pharmacol, Rev. 54. 161-202, 2002). Although the CB2 receptor has been implicated in the modulation of the immune and anti-inflammatory response of cannabinoids, cannabinoid receptor agonists, especially those acting on the CB1 receptor have been suggested as useful in the treatment of pain (see Iversen, L. and Chapman, V. Current Opinion in Pharmacology, 2, 50-55, 2002 30 and references therein). WIN 55,212-2, mesylate salt of (R) - (+) - [2,3-dihydro-5-methyl- [(morpholinyl) -methyl] pyrrolo [1, 2,3-de] -, 4-benzoxazinyl ] - (1 -naphthalenyl) methanone is described in U.S. Pat. U U. 4,939, 138 (Sterling Drug Inc.) as an analgesic agent. The compound is the prototype of aminoalquindoles as an analgesic agent. The compound is the prototype of aminoalkylindoles (Eissenstat, MA ef al., J. Med. Chem. 38, 3094-3105, 1995), which are potent CB1 cannabinoid receptor agonists that can produce antinociception with efficacy equivalent to morphine in animal models. of acute pain, persistent inflammatory pain and neuropathic pain.

The key structural features of aminoalkylindoles having canabimimetic properties (Adam, J. and Cowley, P. Expert Opin, Ther.Patents, .12., 1475-1489, 2002) are an aminoalkyl substituent in the 1-position of the indole portion. , and an additional bulky substituent at the 3-position of the indole ring, as exemplified by an aroyl group on the aminoalkylindoles described in U.S. Pat. 4,939, 138 (Sterling Drug Inc.) and in the most recent WO02060447 (University of Connecticut), or by a substituted amido group in the compounds described in WO0158869 (Bristol-Myers Squibb). Recently, 1 - (aminoalkyl) indole derivatives having a 3-oxadiazol-5-yl ring substituted at position 3 are described in WO0236590 (Amrad Operations PTY Ltd.) as cannabinoid receptor modulators and useful as analgesic agents. There remains a need for cannabinoid agonists with improved properties, such as increased water solubility, to be used as therapeutic agents. For this purpose the present invention provides (indol-3-yl) -heterocycle derivatives having the general Formula I Formula I wherein A represents a 5-membered aromatic heterocyclic ring, wherein X ^ X2 and X3 are independently selected from N, O, S and CR; R is H or (C1-) alkyl; or R, when present in X2 or X3, can together with R3 form a ring of 5-8 members; R-i is a 5-8 membered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S; R2 is H, CH3 or CH2-CH3; or R2 is ahed together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and such a heteroatom is ahed to the 7-position of the indole ring; R3 and R4 are independently H, (C1-6) alkyl or (C3-7) cycloalkyl, the alkyl groups being optionally substituted with OH, (d.4) alkyloxy, (C1.) Alkylthio, (C1-4) alkylsulfonyl, CN or halogen; or R3 together with R4 and the N to which they are ahed form a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C1-) alkyl, (C1-4) alkyloxy, (C 1-4) alkyloxy- (C 1-4) alkyl, or halogen; or R3 together with R5 forms a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C1-) alkyl, (C1-) alkyloxy, (C1-4) alkyloxy - (C1-4) alkyl, or halogen; or R3 together with R, when present in X2 or X3, forms a ring of 5-8 members; R5 is H or (C1-4) alkyl; or R5 together with R3 forms a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C1-4) alkylo, (C1-4) alkyloxy, (C1-) 4) Alkyloxy- (C 1-4) alkyl, or halogen; R5 'is H or (C1-4) alkyl; R6 represents 1 -3 substituents independently selected from H, (C 1-4) alkyl, (C 1 -) alkyloxy, CN and halogen; R7 is H, (C -4) a | cyl, (C? -) alkyloxy, CN or halogen; or R7 joins together with R2 to form a 6-membered ring, optionally containing an additional heteroatom selected from O and S, and such heteroatom is ahed to the 7-position of the indole ring; or a pharmaceutically acceptable salt thereof, such as CB 1 cannabinoid receptor agonists, which can be used in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with sclerosis multiple. The heterocycle A, as used in the definition of the Formula I, represents a 5-membered aromatic heterocyclic ring, containing 1 -3 heteroatoms selected from N, O and S. This means that at least one of X-, X2 and X3, used to define heterocycle A, can not be C R. Representative heterocycles A are those derived from thiophene, furan, triazole, thiazole, thiadiazole, oxazole, oxadiazole and its isomers including isothiazole, isothiadiazole, isoxazole and isoxadiazole. Preferred heterocycle A are 1, 2,4-oxadiazole (Xi is N, X2 is O, X3 is N), 1, 2,4-thiadiazole (Xi is N, X2 is S, X3 is N) and thiazole (Xi is S, X2 is CR, X3 is N). In the definition of the Formula IR, when present in X2 or X3, it can form together with R3 a ring of 5-8 members, to form together with a ring A a bicyclic ring system comprising a ring containing N of 5-8 members which is fused to the 5-membered aromatic heterocyclic A ring. Examples of such fused ring systems are those derived from 5,6-dihydro-4H-pyrrolo [3,4-d] isoxazole, 4,5,6,7-tetrahydro-oxazolo [5,4-c [pyridine, 4, 5,6,7-tetrahydro-thiazolo [5,4-c] pyridine, 5,6,7,8-tetrahydro-4H-isoxazolo [5,4-c] azepine, 5,6-dihydro-4H-pyrrolo [ 3,4-d] lthiazole and 5,6-dihydro-4H-pyrrolo [3,4-d] isothiazole. The term (C1-) alkyl as used in the definition of the Formula I means a branched or unbranched alkyl group having 1-4 carbon atoms, such as butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. In the term (C 1-4) alkyloxy, (C 1-4) alkyl has the meaning as defined above. The term halogen means F, Cl, Br or I. The term 5-8 membered saturated carbocyclic ring, as used in the definition of R-i of Formula 1, represents a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. Such rings may contain a heteroatom selected from O and S to form a saturated heterocyclic ring, such as tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl or tetrahydrothienyl. The preferred carbocyclic rings are cyclohexyl and tetrahydropyranyl. In the definition of Formula I R2 it may be joined together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, such an atom is attached to the 7-position of the indole ring. In these 5-membered heterocycles substituted by (indol-3-yl) of the invention, the indol-3-yl group is part of a tricyclic fused ring system, ie, a 2,3-dihydropyrrolo system [3 , 2, 1-yl] quinoline (R7 and R2 together represent -CH2-CH2-), a 2,3-dihydro-pyrrolo- [1, 2,3-de] -1,4-benzoxazine system (R7 and R2 together represent -O-CH2-), or a 2,3-dihydro-pyrrolo [1, 2,3-de] -1, 4-benzothiazine system (R7 and R2 together represent -S-CH2-). In the definition of Formula I R3 together with R4 and the N to which they are attached can form a ring of 4-8 members, optionally containing an additional heteroatom selected from O and S.

Examples of such a ring are pyrrolidin-1-yl, piperidin-1-yl, azepin-1-yl, morpholin-4-yl and thiomorpholin-4-yl. Pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl are preferred. In the definition of Formula I R3 together with R5 can form a ring of 4-8 members optionally containing an additional heteroatom selected from O and S. It is understood that the N to which R3 is attached and the carbon atom to which R5 is une are part of the 4-8 member ring. Examples of such rings are pyrrolidin-2-yl, piperidin-2-yl, azepin-2-yl, morpholin-3-yl and thiomorpholin-3-yl.

There is a preference for (indoI-3-yl) -heterocycle derivatives according to Formula I, wherein R2 is H or wherein R2 is attached together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and such an atom joins the 7-position of the indole ring. Also preferred are the (indol-3-yl) -heterocycle derivatives of the invention wherein R, R5, R5 'and Re are H. Also preferred are (indol-3-yl) -heterocycle derivatives according to formula I wherein R-i is cyclohexyl or tetrahydropyranyl. Especially preferred are the (indol-3-yl) -heterocycle derivatives according to Formula I wherein heterocycle A is 1, 2,4-oxadiazole (Xi is N, X2 is O, X3 is N), 1, 2,4-thiadiazole (Xi is N, X2 is S, X3 is N) or thiazole (Xi is S, X2 is CR, X3 is N). The specifically preferred (indol-3-yl) -heterocycle derivatives of the invention are: -7-Chloro-3- (5- { [N-ethyl-N- (2-methoxyethyl) amino] methyl.}. - [1, 2, 4] - thiadiazoI-3-yl) -1 - (tetrahydropyran-4-yl) methyl-1 H-indole; - 7-Chloro-3-. { 5 - [(pyrrolidin-1-yl) methyl] - [1, 2,4] -thiadiazol-3-yl} -1 - (tetrahydropyran-4-yl) methyl-1 H-indole; - 7-Chloro-3- (5-. {[[N-ethyl-N- (2-hydroxyethyl) amino] methyl] - [1, 2, 4] - thiadiazol-3-yl) -1 - ( tetrahydropyran-4-yl) methyl-1 H-indole; - 7-Chloro-3- (4- { [N- (2-hydroxyethyl) -N-isopropylamino] methyl.} - [1, 3] - thiazol-2-yl) -1 - (tetrahydrate) -4-yl) methyl-1 H-indole; - 7-Chloro-3- (4-. {[[N-ethyl-N- (2-hydroxyethyl) amino] methyl] - [1, 3] -thiazole-2-yl) -1 - (tetrahydropyran- 4-yl) methyl-1 H-indole; - 7-Chloro-3- (4- { [N- (2-methoxyethyl) -N-methylamino] methyl.} - [1, 3] -thiazol-2-yl) - 1 - (tetrahydrate) -4-yl) methyl-1 H-indole; - 7-Chloro-3-. { 5 - [(2,2-dimethyl-pyrrolidin-1-yl) methyI] - [1,4] oxadiazol-3-yl} -1 - (tetrahydropyran-4-yl) methyl-1 H-indole; or a pharmaceutically acceptable salt thereof. The (indol-3-yl) -heterocycle derivatives of the invention can be prepared by methods known in the art of organic chemistry in general. The (indol-3-yl) heterocycle derivatives of Formula I can for example be prepared from compounds of Formula II where Y is a leaving group, such as an alkylsulfonate or halogen group, by nucleophilic displacement of the leaving group with an amine of the formula NHR3R4. Compounds of Formula II wherein Y is an alkylsulfonate group can be prepared from compounds of Formula II wherein Y is hydroxy, by reaction with an alkylsulfonyl halide in the presence of a base such as triethylamine. (indol-3-yl) heterocycles of Formula I wherein R5 'is hydrogen can be prepared from compounds of Formula I11 by reductive amination, using an amine of the formula NHR3R4 in the presence of a reducing agent such as sodium triacetoxyborohydride. It is well known that the compounds of Formula II where Y is hydroxy and R5 'is hydrogen can be inter-converted with compounds of Formula III, by oxidation and reduction using suitable reducing and oxidizing agents, as described in Burke DS, Danheiser , RL Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing agents (Wiley: New York, 1999). Similarly, compounds of Formula II where Y is hydroxy and R5 and R5 'are both hydrogen, and compounds of Formula II wherein R5 is hydrogen, can be prepared from compounds of Formula IV wherein R8 is hydrogen or (C? -) alkyl, by reduction using suitable reducing agents. Compounds of Formula II where Y is hydroxy and R5 'is (C1-4) alkyl can be prepared from compounds of Formula I11 by nucleophilic addition, using a (1-4C) alkyl metal reagent such as an alkyl or alkyllithium Grignard reagent.

Formula II Formula II Formula IV Compounds of Formula I, Formula II, Formula 11 or Formula IV can be prepared from compounds of Formula V to Formula Xll inclusive, using methods well known in the art for building heterocyclic rings. Such methods are described in the general reference Katritzky, AR: Comprehensive heterocyclic chemistry (First Edition, Pergamon Press, 1984, see especially Volume 4, Part 3, Five-membered rings with one demand, sulfur or nitrogen atom and Volume 6, Part 4B , Five-membered rings with two or more oxygen, sulfur or nitrogen atoms).

Formula V Formula VI Formula Vi Formula VIII Formula IX Formula X Formula XI Formula XII Compounds of Formula V to Formula Xl inclusive, wherein Ri, R2, R6 and R7 have the meanings as previously defined and R8 is H or (C1-) alkyl, can be prepared by the literature procedures or modifications of the literature procedures known to those skilled in the art. For example, compounds of Formula VI can be prepared from compounds of Formula V, or activated derivatives thereof, by reaction with ammonia in a suitable solvent. Compounds of the Formula VI can be prepared from compounds of Formula VI using thionation reagents, such as phosphorus pentasulfide or Lawesson's reagent. Alternatively, compounds of Formula VII can be prepared from compounds of Formula VI I I by reaction with thioacetamide in a solvent such as dimethylformamide. Compounds of Formula VI II can be prepared from compounds of Formula VI by dehydration, for example using trifluoroacetic anhydride in the presence of a base such as triethylamine. Compounds of Formula X can be prepared from compounds of Formula IX by reaction with hydroxylamine in a suitable solvent. Compounds of Formula XI wherein Y is NH2 can be prepared from compounds of Formula V, or activated derivatives thereof, by reaction with cyanide anion to form an oxoacetonitrile, followed by reduction of the nitrile in a primary amine using a reducing agent, such as hydrogen gas in the presence of a catalyst such as palladium in charcoal. Compounds of the formula XI can be prepared from compounds of the formula VI I by reaction with hydroxylamine in a suitable solvent. Compounds of Formula V and compounds of Formula XI can be prepared by acylation of compounds of Formula X11. For example, compounds of Formula V where R8 is hydrogen can be prepared by acylation of compounds of Formula X11, using trifluoroacetic anhydride in a solvent such as dimethylformamide, followed by hydrolysis using aqueous sodium hydroxide at an elevated temperature. Compounds of Formula XI wherein Y is chloro can be prepared by acylation of compounds of Formula X11 using chloroacetyl chloride, in the presence of a base such as pyridine. Compounds of the formula IX can be prepared from compounds of the formula Xl l by formylation, for example using the Vilsmeier reaction (for a review see Jutz, Adv. Org Chem 9, pt.1, 225-342, 1976). Alternatively, compounds of Formula V can be prepared from compounds of Formula XIV using procedures described by Wijngaarden et al. (J. Med. Chem. 36, 3693-3699, 1993) or Hwu et al. (J. Org. Chem. 59, 1577-1582, 1994) or modifications of these procedures.

Formula Xlll Formula XIV Formula XV Compounds of Formula Xll can be prepared by literature procedures or modifications of literature procedures known to those skilled in the art. For example, compounds of Formula X11 can be prepared by alkylation of compounds of formula XV, by treatment with a base such as sodium hydride, followed by reaction with an alkylating agent Ri R2CHY, where Y is a leaving group, such as a halogen or alkylsulfonate group.

Compounds of Formula XV can be obtained from commercial sources, prepared by literature procedures or modifications of literature procedures known to those skilled in the art. Alternatively, compounds of Formula Xll I can be prepared from compounds of Formula XIV using Fischer indole synthesis or modifications thereof (Chem. Rev. 69, 227-250, 1969). Compounds of Formula XIV can be prepared by literature procedures or modifications of literature procedures known to those skilled in the art. For example compounds of Formula XIV where R2 is attached together with R7 to form a 6-membered carbocyclic ring, can be prepared from compounds of Formula XVI by reduction, using a reducing agent such as sodium borohydride in the presence of a catalyst such as nickel (II) chloride. Compounds of Formula XVI, for example, can be prepared by a coupling reaction, such as reaction of a 2-chloroquinoline with a Grignard reagent, in the presence of a nickel catalyst (I I). Compounds of Formula XIV where R2 is attached together with R7 to form a 6-membered ring containing oxygen or sulfur can be prepared by reaction of a compound of Formula XVII where Z is OH or SH, with a compound of Formula XVII I, where Y is a leaving group, to form an ether or thioether, followed by reduction of the nitro group to an amine and reductive cyclization. Reduction and cyclization, for example, can be carried out using hydrogen gas in the presence of a catalyst such as palladium in charcoal.

Formula XVI Formula XVII Formula XVI I I Formula XIX Compounds of Formula XVII and Compounds of the Formula XVII I can be obtained from commercial sources, prepared by literature procedures or modifications of literature procedures known to those skilled in the art. For example, compounds of Formula XVI I wherein Y is bromine can be prepared from compounds of Formula XIX using a bromination agent such as bromine in a solvent such as methanol. Compounds of Formula I, Formula II, Formula 11 or Formula IV may alternatively be prepared from compounds of Formula XX using catalyzed coupling reactions of transition metal, as described in the general reference Hegedus, L.S. Transition Metals in the Synthesis of Complex Organic Molecules (Second Edition, University Science: Sausalito 1999). For example, compounds of Formula 11 I can be prepared by the reaction of compounds of Formula XX, where Yi is halogen, with compounds of Formula XXI, wherein Y 2 is a boronic acid or a boronic acid ester, using a Suzuki reaction. (Chem. Rev. 95, 2457-2483, 1995) or a modification thereof.

Formula XX Formula XXI Compounds of Formula XX and compounds of Formula XXI can be obtained from commercial sources, prepared by literature procedures or modifications of literature procedures known to those skilled in the art. For example, compounds of Formula XX where Yi is bromine can be prepared by bromination of a compound of Formula X11 using bromine in a solvent such as dimethylformamide. It will be appreciated by those skilled in the art that indole nitrogen can be temporarily protected during the transformations described above by using a protecting group, such as an arylsulfonyl group, to be deprotected and alkylated at a later stage in the synthesis. It will further be appreciated that such protecting groups can be used to modify the stability of intermediates and the reactivity of the indole ring towards electrophiles. Suitable protecting groups are described in Kocienski, P.J. : Protecting Groups, Thieme, Stuttgart; New York, 1994. The person skilled in the art will likewise appreciate that various (indol-3-yl) heterocycle derivatives of Formula I can be obtained by appropriate conversion reactions of functional groups corresponding to certain of the R3-R7 substituents. . For example, compounds of Formula I wherein R3 or R4 is a cyclic or branched alkyl group, linear C 1 to C6 optionally substituted with hydroxyl, (C? -4) alkyloxy, (C? -4) alkyllio, (C? -4 ) - alkylsulfonyl or cyano, can be prepared by the reaction of a compound of Formula I wherein R 3 or R 4 is hydrogen with a C 1 to C 6 alkyl halide or a functionalized C 1 to C 6 alkylalk, in the presence from a base such as potassium carbonate. The (indol-3-yl) -heterocycle derivatives of Formula I and their salts may contain at least one center of chirality, and therefore exist as stereoisomers, including enantiomers and diastereomers. The present invention includes the above-mentioned stereoisomers within its scope and each of the individual R and S enantiomers of the compounds of Formula I and their salts, substantially free, i.e., associated with less than 5%, preferably less than 2%. %, in particular less than 1% of the other enantiomer, and mixtures of such enantiomers in any ratio including the racemic mixtures containing substantially equal amounts of the two enantiomers. Methods for asymmetric synthesis or qiral separation by which pure stereoisomers are obtained as is well known in the art, for example, synthesis with chiral induction or initiation of commercially available chiral substrates, or separation of stereoisomers, for example, using chromatography in chiral media or by crystallization with a chiral counter-ion.

The pharmaceutically acceptable salts can be obtained by treating a free base of a compound of the Formula I with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, or an organic acid such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycoic acid, succinic acid, propionic acid, acetic acid and methane sulphonic acid. The compounds of the invention can exist in unsolvated forms as well as solvated with pharmaceutically acceptable solvents such as water, ethanol and the like.

In general, solvated forms are considered equivalent to unsolvated forms for the purpose of the invention. The present invention further provides pharmaceutical compositions comprising a (indol-3-yl) -heterocycle derivative according to general Formula I, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term "acceptable" means being compatible with the other ingredients of the composition and not harmful to the recipients thereof.

Compositions include, for example, those suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, pulmonary, local or rectal administration, and the like, all in unit dosage forms for administration. A preferred route of administration is the intravenous route.

For oral administration, the active ingredient can be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions and the like. For parenteral administration, the pharmaceutical composition of the invention can be presented in single-dose or multi-dose containers, for example, injection liquids in predetermined amounts, for example, in sealed vials and ampoules, and can also be stored in lyophilized condition requiring only the addition of sterile liquid vehicle, for example, water, before use. Mixed with such pharmaceutically acceptable auxiliaries, for example, as described in the standard reference, Gennaro, A.R. et al. , Remington: The Science and Practice of Pharmacy (20th Edition, Lippincott Williams &Wiikins, 2000, see especially Part 5: Pharmaceutical Manufacturing), the active agent can be compressed into dosage units, such as pills, tablets, or processed into capsules , suppositories or patches. By means of pharmaceutically acceptable liquids, the active agent can be applied as a fluid composition, for example, as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, for example, a nasal spray. To make solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions can be used, containing pharmaceutically acceptable dispersing agents and / or wetting agents, such as propylene glycol or butylene glycol. The invention further includes a pharmaceutical composition, as described above, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for use as described hereinabove. The (indol-3-yl) -heterocycle derivatives of the invention were found to be CB1 receptor agonists, as determined in a reporter assay of human CB1 using CHO cells. Methods for determining receptor binding as well as in vitro biological activity of cannabinoid receptor modulators are well known in the art. In general, the expressed receptor is contacted with the compound to be tested and the binding or stimulation or inhibition of a functional response is measured. To measure a functional response, the isolated DNA encoding the CB1 receptor gene, preferably the human receptor, is expressed in suitable host cells. Such a cell can be the Chinese Hamster Ovary cell, but other cells are also suitable. Preferably, the cells are of mammalian origin. Methods for constructing cell lines expressing recombinant CB 1 are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Springer Harbor, last edition). Expression of the receptor is achieved by the expression of the DNA encoding the desired protein. The techniques for ligation of additional sequences and construction of suitable expression systems are all, hitherto, well known in the art. The portions or all of the DNA encoding the desired protein can be constructed synthetically using standard solid phase techniques, preferably including restriction sites for ease of ligation. Suitable control elements for transcription and translation of the included coding sequence can be provided to the DNA coding sequences. As is well known, expression systems are now available which are compatible with a wide variety of hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, avian cells and the similar. The cells expressing the receptor are then contacted with the test compound to observe the binding, or stimulation or inhibition of a functional response. The alternatively isolated cell membranes containing the expressed CB1 receptor (or CB2) can be used to measure the binding of the compound. For the measurement of binding, radioactive or fluorescently labeled compounds can be used. The most widely used radiolabeled cannabinoid probe is [3H] CP55940, which has approximately equal affinity for CB1 and CB2 binding sites. Another test includes selecting the CB 1 receptor agonist compounds when determining the second messenger response, such as for example measurement of receptor-mediated changes in MAP or a cAMP trajectories. In this way, such a method includes the expression of the CB1 receptor on the cell surface of a host cell and exposing the cell to the test compound. The second messenger response is then measured. The level of the second messenger response will be reduced or increased, depending on the effect of the test compound on receptor binding. In addition to direct measurement of, for example, cAMP levels in the exposed cell, the cells can be used, which in addition to transfection with DNA encoding the receptor are also transfected with a second DNA encoding a reporter gene, the expression of which correlates with the activation of the receiver. In general, the expression of the reporter gene must be controlled by any response element reacting with changing levels of the second messenger. Suitable reporter genes are, for example, LacZ, alkaline phosphatase, firefly luicerase and green fluorescence protein. The principles of such transactivation assays are well known in the art and are described, for example, in Stratowa, Ch, Himmler, A. and Czernilofsky, A. P., Curr. Opin. Biotechnol. 6, 574 (1995). To select active agonist compounds in the CB1 receptor, the EC50 value should be <1. 10"5 M, preferably <10" 7 M. The compounds can be used as analgesic agents in the treatment of pain such as, for example, peri-operative pain chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis. The cannabinoid agonists of the invention would be potentially useful in the treatment of other disorders including multiple sclerosis, spasticity, inflammation, glaucoma, nausea and emesis, loss of appetite, sleep disturbances, respiratory disorders, allergies, epilepsy, migraine, cardiovascular disorders, neurodegenerative disorders, anxiety, traumatic brain injury and stroke. The compounds could also be used in conjunction with other drugs, for example, analgesic drugs such as opioids and nonsteroidal anti-inflammatory drugs (NSAIs Ds), including selective COX-2 inhibitors. The compounds of the invention can be administered to humans in a sufficient amount and for a sufficient amount of time to alleviate the symptoms. Illustratively, dosage levels for humans can be in the range of 0.001 -50 mg per kg body weight, preferably at a dosage of 0.01-20 mg per kg body weight. The invention is illustrated by the following Examples. General Methods Microwave reactions are performed using an Emrys Optimizer ™ (Personal Chemistry) unless otherwise stated. Flash column chromatography is performed on silica gel.

Semi-preparative high pressure liquid chromatography (HPLC semi-prep) is performed using the methods outlined below: Method (i): Agilent CombiHT (SB-C18, 5 μm) 12 mm I D x 100 mm; 5-95% acetonitrile-water over a gradient 9 minutes; 25 ml / min; 0.1% trifluoroacetic acid regulator; UV detection at 254 nm. Method (ii): Xterra Waters (RP18, 5 μm) 30 mm x 100 mm; 10-100% acetonitrile-water over a gradient of 25 minutes; 30 ml / min; 0.1% trifluoroacetic acid regulator; UV detection at 254 nm. 1H NMR coupling constants are given in Hz. Example 1 1 - (Cyclohexypmethyl-3-f5-r (dimethylamino) methyn-ri .2,41-oxadiazol-3-yl) -7-methoxy-1 H-indole, salt of hydrochloride A solution of 7-methoxyindole (45.0 g, 306 mmol) in dimethylformamide (360 ml) is cooled to 5 ° C under nitrogen and trifluoroacetic anhydride (60.5 ml, 433 mmol) is added over 20 minutes, keeping the temperature below of 10 ° C. The mixture is stirred at 5-10 ° C for 2 h, then poured into water (1600 ml). The resulting suspension is stirred for 15 minutes and the precipitate of 7- methoxy-3 - [(trifluoromethyl) carbonyl] -1H-indole is filtered, rinsing with water until neutral. The wet solid is suspended in 4 M aqueous sodium hydroxide (1700 ml) and heated to reflux with stirring for 2 h. The mixture is cooled and rinsed with diethyl ether (2 x 400 ml). The aqueous phase is then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate is filtered, rinsed with water until neutral and dried to give 7-methoxy-1 H-indole-3-carboxylic acid as a pink solid ( 42.7 g). To a solution of 7- methoxy-1H-indole-3-carboxylic acid (42.7 g, 224 mmol) in dimethylformamide (1250 ml) at 10 ° C under nitrogen is added sodium hydride (60% dispersion in mineral oil, 23.0 g, 575 mmol) per portion for 20 minutes, keeping the temperature below 15 ° C. The cold bath is removed and the suspension is stirred for 90 minutes. Cyclohexylmethyl bromide (64.7 ml, 464 mmol) is added. The mixture is heated to 60 ° C with stirring for 3 h. The mixture is cooled to 10 ° C and poured into water (3600 ml). The emulsion is rinsed with diethyl ether (3 x 500 ml). The aqueous phase is acidified to pH 1 using 5 M hydrochloric acid and the precipitate is filtered, rinsed with water until neutral and dried to provide 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3- acid. carboxylic acid (55 g) as a white solid. Oxalyl chloride (12.4 g, 97.4 mmol) is added dropwise to a mixture of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid (7.0 g, 24.4 mmol) and dichloromethane ( 150 ml) under cold water and the resulting mixture is stirred at room temperature for 18 h. Dichloromethane and excess oxalyl chloride are removed by evaporation and the residue obtained is mixed with dichloromethane (150 ml). Ammonia gas is bubbled into the resulting mixture for 30 min under cooling by cold water bath. The reaction mixture is concentrated in vacuo, then the solid obtained is triturated sequentially with 0.5 M hydrochloric acid, 5% aqueous sodium carbonate, and water, and dried under reduced pressure to provide 1 - (cyclohexyl) methyl acid amide. 7-methoxy-1 H-indole-3-carboxylic acid (5.1 g) as a brown solid. Trifluoroacetic anhydride (12.0 g, 57.1 mmol) is added dropwise to a mixture of 1- (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid amide (4.1 g, 14.3 mmol), triethylamine (11.6 g). g, 15 mmol), and 1,4-dioxane (250 ml) under cooling by cold water. The resulting mixture is stirred at room temperature for 12 h. Water (30 ml) is added and the resulting mixture is concentrated in vacuo. Water (300 ml) is added to the obtained residue, and the mixture is extracted with dichloromethane (4 x 300 ml). The organic layers are combined, rinsed with 5% aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue obtained is purified by column chromatography eluting with 10% (v / v) ethyl acetate in n-heptane to give 1- (cyclohexyl) methyl-7-methoxy-1H-indole-3-carbonitrile as a crystalline solid. (2.48 g). Hydroxylamine hydrochloride (966 mg, 13.9 mmol) is added to a mixture of 1- (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carbonitrile (2.48 g, 9.24 mmol), triethylamine (1.41 g, 13.9 mmol ), and ethanol (50 ml), then the resulting mixture is stirred at reflux for 20 h. After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue obtained is mixed with water (150 ml), adjusted to pH 10 by the addition of aqueous sodium hydroxide and extracted with di-chloromethane (4 x 100 ml). The organic layers are combined, rinsed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue obtained is purified by column chromatography eluting with 10% (v / v) acetone in dichloromethane to give 1- (cyclohexyl) methyl-N-hydroxy-7-methoxy-1 H-indole-3-carboxamidine (940 mg) . Molecular screens (4Á, powder, 200 mg) are added to a suspension of 1 - (cyclohexyl) methyl-N-hydroxy-7-methoxy-1 H -indole-3-carboxamidine (250 mg, 0.829 mmol) in tetrahydrofuran (6 ml) under nitrogen, and the mixture is stirred at room temperature for 30 min.

Sodium hydride (60% suspension in oil, 36 mg, 0.900 mmol) is added, then the resulting mixture is stirred at 60 ° C for 20 min. The reaction mixture is cooled to room temperature and N, N-dimethylglycine methyl ester (194 mg, 1.66 mmol) is added to the mixture. The resulting mixture is stirred at reflux temperature for 2 h and then concentrated in vacuo. The obtained residue is mixed with dichloromethane (200 ml), rinsed with 5% aqueous sodium carbonate, dried over magnesium sulfate and concentrated in vacuo. The oil obtained is purified by flash column chromatography eluting with 0.6% (v / v) methanol in dichloromethane to provide an oil. This oil is dissolved in isopropanol (3 ml), then hydrogen chloride (1 M solution in diethyl ether, 3 ml) is added to the solution. The resulting mixture is concentrated in vacuo to give the title compound (hydrochloride salt 1: 1) (66 mg). 1 H NMR (400MHz, CD3OD) d 0.96-1.30 (5H, m), 1 .52-1 .94 (6H, m), 3.13 (6H, s), 3.97 (3H, s), 4.30 (2H , d, J6.8), 4.83 (2H, s), 6.81 (1 H, d, J8.0), 7.13 (1 H, dd, J8.0, 8.0), 7.71 (1 H1 d, J 8.0) , 7.85 (1 H, s). EslMS: m / z 369.2 [M + H] +. Example 2 The method of Example 1 is further used to prepare the following compounds, using alternative commercially available or synthetic amino acid esters in place of N, N-dimethylglycine methyl ester. Methods for the synthesis of intermediate compounds of amino acid ester Method A Benzyl bromoacetate (500 mg, 2.18 mmol) is added to a mixture of pyrrolidine (171 mg, 2.40 mmol) and sodium carbonate (254 mg, 2.40 mmol) in tetrahydrofuran (7 ml). The mixture is stirred at room temperature for 18 h, then concentrated in vacuo. The residue is mixed with water (200 ml) and extracted with dichloromethane (3x100 ml). The organic layers are combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography eluting with 0-10% (v / v) methanol in dichloromethane provided pyrrolidin-1-yl acetic acid benzyl ester (230 mg, 1.05 mmol). Method B Methyl bromoacetate (199 μl, 2.10 mmol) is added to a mixture of (S) -2-methoxymethyl pyrrolidine (268 μl, 2.17 mmol), potassium carbonate (319 mg, 2.31 mmol) and sodium iodide (315 mg). mg, 2.10 mmol) in acetonitrile (3 ml). The mixture is subjected to microwave irradiation for 5 min at 160 ° C, then divided between dichloromethane and water. The aqueous layer is extracted with dichloromethane and the combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography eluting with 0-10% (v / v) methanol in dichloromethane gave methyl ester of (S) - (2-methoxymethyl-pyrrolidin-1-yl) acetic acid (133 mg, 0.71 mmol). Method C To a solution of sulfuric acid (3.5 ml, 65.3 mmol) in methanol (45 ml) is added D-proline (10.0 g, 86.9 mmol). The mixture is refluxed with stirring for 18 h. The solution is then cooled to 0 ° C and neutralized by the addition of aqueous potassium carbonate (2.5 M, 10 ml). Formaldehyde (37% solution in water; 1 ml, 136 mmol) is added and the mixture is stirred at 0 ° C for 15 minutes. Sodium borohydride (1.6 g, 42.3 mmol) is added at 0 ° C and the mixture is stirred at room temperature for 3 h. The precipitate is filtered and the filtrate divided between dichloromethane and water. The isolated aqueous layer is adjusted to pH 10 using solid sodium carbonate and extracted with dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated in vacuo to provide crude methyl (R) -1-methylpyrrolidine-2-carboxylic acid methyl ester (13.13 g). A portion of this crude product (5.0 g) is purified by flash column chromatography eluting with 0-2% (v / v) methanol in dichloromethane to provide methyl ester of (R) -1-methylpyridine-2-carboxylic acid (1.30). g). 2A: 1- (Cyclohexyl) methyl-7-methoxy-3- (5-r (pyrrolid! N-1-pmethyl-M, 2,4-oxadiazol-3-yl.) -1 H-indole, hydrochloride salt The title compound is prepared following the method of Example 1, using benzyl ester of pyrrolidin-1-yl acetic acid, prepared according to Method A. 1H NMR (400MHz, CD3OD) d 0.98-1.31 (5H, m), 1.54-1.94 (6H, m), 2.10-2.24 ( 4H, m), 3.46-3.74 (4H, m), 3.97 (3H, s), 4.30 (2H, d, J 7.2), 4.86 (2H, s), 6.81 (1H, d, J 8.0), 7.14 ( 1H, dd, J 8.0, 8.0), 7.70 (1H, d, J 8.0), 7.84 (1H, s). EslMS: m / z 395.2 [M + H] \ 2B: 1- (Cyclohexylmethyl-3-f5-r (N-ethyl-N-isopropylamino) methyn-r, 2,41-oxadiazole-3 -yl) -7-methoxy-1H-indole, hydrochloride salt The title compound is prepared using methyl ester of (N-ethyl-N-isopropylamino) acetic acid, which is prepared according to Method A, using methyl bromoacetate and N-ethyl isopropylamine. EslMS: m / z 411.1 [M + H] +. 2C: 1- (Cyclohexyl) methyl-7-methoxy-3- (5-frbis- (2-methoxyethyl) amino-1-methyl) -ri.2,41-oxadiazol-3-yl) -1H-indole, hydrochloride salt The title compound is prepared using [bis- (2-methoxyethyl) amino] acetic acid methyl ester, which is prepared according to Method A. using methyl bromoacetate and bis- (2-methoxyethyl) amine. It is MS: m / z 457.5 [M + H] +. 2D: 1 - (Cyclohexyl) methyl-3-. { 5-Ri- (dimethylarnino) etipri, 2,41-oxadiazol-3-yl) -7-methoxy-1 H-? Ndol, hydrochloride salt The title compound is prepared using 2-dimethylamino propionic acid methyl ester, which is prepared according to Method A. using methyl-2-bromopropionate and dimethylamine. EslMS: m / z 383.0 [M + H] +. 2E: (S - (Cyclohexy l) methyl-7-methoxy-3. {5-r (2-methoxymethyl pyrroidin-1-yl) me-t-ip-ri, 2, 41 oxadiazole-3 Fig. 1 H-indole hydrochloride salt The title compound is prepared using methyl ester of (S) - (2-methoxymethyl-pyrrolidin-1-yl) acetic acid, which is prepared according to Method B Esl MS: m / z 439.3 [M + H] +. 2F: (R) -1 - (Cyclohexylmethyl-7-methoxy-3-f5-r (2-methoxymethyl pi rrol) di n-1 - i I) metill-ri, 2, 41 oxadiazol-3-yl) -1 H-indole, hydrochloride salt The title compound is prepared using methyl ester of (R) - (2-methoxymethyl-pyrrolidin-1-yl) ) acetic, which is prepared according to Method B, using (R) -2-methoxy-methyl pyrrolidine Esl MS: m / z 439.1 [M + H] +; [a] D22 +21 .6 ° (c = 0.8 mg / ml in chloroform). 2G: (R) -1 - (Cyclohexyl) methi l-7-methoxy-3-r5- (1-methyl pyrrol id in-2-yl) -p, 2, 41-oxadiazol-3-p-1 H-indole . hydrochloride salt The title compound is prepared using (R) -1-methylpyrrolidine-2-carboxylic acid methyl ester, which is prepared according to Method C. EslMS: m / z 395.0 [M + H] +; [a] D22 +50.1 ° (c = 1.70 mg / ml in chloroform). 2H: (S) -1 - (Cyclohexyl) methyl-7-methoxy-3-r5- (1-methylpyrrolidin-2-yl) -ri .2.41-oxadiazol-3-yl-1 H-indole. hydrochloride salt The title compound is prepared using methyl ester of (S) -1-methylpyrrolidine-2-carboxylic acid, which is prepared according to Method C. using L-proline in place of D-proline. Esl MS: m / z 395.0 [M + H] +. [a] D22 -51.7 ° (c = 1.35 mg / ml in chloroform). 21: 1 - (Cid ohexyl) methyl-7-methoxy-3-r5- (1-methyl-piperidin-2-yl) -p, 2, 41-oxadiazol-3-y-1-H-indole, hydrochloride salt The title compound is prepared following the method of Example 1, using ethyl 1-methyl pipecolinate in place of N, N-dimethyiglycine methyl ester. EslMS: m / z 409.3 [M + H] +. EXAMPLE 3 1 - (Cyclohexyl) methyl-3-r (5-aminomet-p-ri, 2.41-oxadiazol-3-yn-7-methoxy-1 H-indole hydrochloride salt Molecular sieves (4Á, powder, 300 mg ) are added to a suspension of 1 - (cyclohexyl) methyl-N-hydroxy-7-methoxy-1 H-indole-3-carboxamidine (500 mg, 1.66 mmol) in tetrahydrofuran (10 ml), and the The resulting mixture is stirred at room temperature for 30 min.Sodium hydride (60% slurry in oil, 100 mg, 2.55 mmol) is added and the resulting mixture is stirred at 65 ° C for 20 min.The reaction mixture is cooled to Room temperature and N-Boc-glycine N-hydroxysuccinimide ester (871 mg, 3.32 mmol) is added to the mixture.

The resulting mixture is heated to reflux with stirring for 2 h, then cooled to room temperature. Aqueous sodium hydroxide (4M, 5 ml) is added and the resulting mixture is stirred for 14 h. The reaction mixture is concentrated in vacuo, then the obtained residue is mixed with water (200 ml). The resulting mixture is extracted with dichloromethane (4 x 200 ml). The organic layers are combined, rinsed with brine, dried over magnesium sulfate and concentrated in vacuo. The oil obtained is purified by column chromatography eluting with 0.4% (v / v) methanol in dichloromethane to give tert-butyl ester of. (3- {1 - (cyclohexyl) -methyl-7-methoxy-1 H -indol-3-yl] [1, 2,4-oxadiazol-5-yl] methyl) carbamic acid (125 mg). A mixture of (. {3- [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] [1,2,4] oxadiazoi-5-yl acid tert-butyl ester. meti I), carbamic (10 mg, 0.25 mmol) and trifluoroacetic acid (4 ml) are stirred at room temperature for 1.5 h. The reaction mixture is carefully poured into 5% aqueous sodium carbonate (200 ml) and the resulting mixture is extracted with dichloromethane (4 x 200 ml). The organic layers are combined, then rinsed with brine, dried over magnesium sulfate, and concentrated in vacuo. The oil obtained is purified by column chromatography eluting with 1.5% (v / v) methanol in dichloromethane to provide the free base of the title compound as a yellow oil. This oil is dissolved in diethyl ether, and then hydrogen chloride (1 M solution in diethyl ether, 3 ml) is added to the solution. The resulting mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt (71 mg). 1H NMR (400MHz, CD3OD) d 0.98-1.29 (5H, m), 1.52-1.78 (5H, m), 1.79-1.94 (1H, m), 3.98 (3H, s), 4.31 (2H, d, J 7.2 ), 4.55 (2H, s), 6.81 (1H, d, J 7.6), 7.14 (1H, dd, J7.6, 8.0), 7.72 (1H, d, J 8.0), 7.83 (1H, s). EslMS: m / z 341.1 [M + H] +. Example 4 1- (Cyclohexyl) methyl-3-. { 5-R (dimethylamino) metin-ri, 2,41-oxadiazol-3-yl) -7-fluoro-1H-indole, hydrochloride salt The title compound is prepared following the method of Example 1, using 7-fluoroindole instead of 7-methoxyindole. EslMS: m / z 357.3 [M + H] +, 247.4. Example 5 7-Chloro-1- (cyclohexyl) methyl-3- (5-r (dimethylamino) rnetip-ri, 2,41-oxadiazol-3-yl) -1H-indole, hydrochloride salt The title compound is prepared following the method of Example 1, using 7-chloroindole in place of 7-methoxyindole. EslMS: m / z 375.1, 373.1 [M + H] +. Example 6 1- (Cyclohexyl) methyl-3- (5- { RN-isopropyl-N- (2-methoxyethyl) amino-methyl) -ri.2,41-triazol-3-yl) -7-methoxy- 1 H-indole, hydrochloride salt Hydrochloride gas is bubbled, for 30 mins, through a cold (0 ° C) solution of 1- (cyclohexyl) methylo-7-methoxy-1H-indole-3-carbonitrile (prepared as described in Example 1, 3.15 g, 11.0 mmol) in methanol (200 ml). The resulting mixture is allowed to remain for 72 h before being concentrated, by two thirds, in vacuo. Crystallization of the product is achieved in addition of diethyl ether, and the resulting solid is collected through filtration to give methyl ester of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxymethyl acid as the salt of hydrochloride (3.82 g). Salt of methyl ester hydrochloride of 1- (Cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboximide acid (0.10 g, 0.297 mmol), hydrazine hydrate (0.289 mL, 5.94 mmol), aluminum chloride ( 39.6 mg, 0.297 mmol) and toluene (18 ml) are combined and the mixture is irradiated by microwave for 60 min at 120 ° C. The resulting mixture is concentrated in vacuo, re-dissolved in toluene and concentrated in vacuo two more times. The residue obtained is suspended in a mixture of toluene / acetonitrile (12/1) (19.5 ml) and chloroacetyl chloride (0.1 18 ml, 1.49 mmol) is added, before the mixture is subjected to microwave irradiation for 12 min at 120 ° C. The resulting mixture is concentrated in vacuo and re-dissolved in acetonitrile (3 ml). N- (2-methoxyethyl) isopropylamine (0.068 ml, 0.446 mmol), potassium carbonate (45.2 mg, 0.327 mmol) and sodium iodide (44 mg, 0.297 mmol) is added and the mixture is subjected to microwave irradiation for 5 min at 160 ° C before allowing to stand for 72 hours and then concentrated in vacuo. The obtained residue is purified by column chromatography eluting with 2.5% -5% (v / v) methanol in dichloromethane to provide the title compound as a 1: 1 hydrochloride salt (46 mg). 1H NMR (400 MHz, CD3OD): 0.95-1.12 (2H, m), 1.13-1.24 (3H, m), 1.50 (6H, s (br)), 1.55-1.73 (5H, m ), 1.79-1.93 (1H, m), 3.34-3.50 (5H, m), 3.70-3.99 (6H, m), 4.24 (2H, d, J 6.4), 4.67 (2H, s (br)), 6.70 (1H, d, J 7.7), 7.16 (1H, t, J7.7), 7.95 (1H, d, J7.7), 8.02 (1H, s (br)); EslMS: m / z 440.3 [M + H] +. Example 7 1- (Cyclohexyl) methyl-3- (5-rrdethylamino) metin-p, 2,41-thiadiazol-3-yl > 7-methoxy-1H-indole, hydrochloride salt To a suspension of 1- (cyclohexyl) methyl-7-methoxy-1H-indole-3-carboxylic acid amide (prepared from 7-methoxyindole as described in the Example 1; 4.0 g, 14 mmol) in tetrahydrofuran (120 ml) is added chlorocarbonylsulfenyl chloride (2.4 ml, 28.4 mmol) and the reaction mixture is refluxed for 15 minutes and allowed to cool. The excess solvent and reagent are then removed in vacuo to leave 5- (1-cyclohexylmethyl-7-methoxy-1 H-indole) - [1,4] -oxathiazol-2-one (5.2 g, 14.4 mmol ) as a pink solid. A suspension of 5- (1-cyclohexylmethyl-7-methoxy-1 H-indole) - [1,3,4] -oxathiazol-2-one (1.0 g, 2.77 mmol) in m-xylene (15 ml) was add ethyl cyanoformate (2.74 ml, 27.7 mmol) and the reaction is subjected to microwave irradiation at 160 ° C for 10 min using an Emrys ™ Optimizer EXP. The reaction is repeated three times on the same scale, combined and purified by flash column chromatography eluting with 0-50% (v / v) dichloromethane in heptane to give 3- (1-cyclohexylmethyl-7-methoxy) ethyl ester. 1H-indol-3-yl) - [1, 2,4] thiadiazole-5-carboxylic acid (4.38 g, 11 mmol) as a white solid. To a cold (ice / methanol bath) solution of ethyl 3- (1! -cyclohexylmethyl-7-methoxy-1H-indol-3-yl) - [1,4] thiadiazole-5-carboxylic acid ethyl ester (4.0 g, 10 mmol) in tetrahydrofuran (80 ml) and methanol (80 ml) is added sodium borohydride in portions. The reaction is stirred for a further 20 minutes and then quenched with 1 M hydrochloric acid (20 ml). The methanol and tetrahydrofuran are removed in vacuo and dichloromethane (200 ml) and 2M hydrochloric acid (50 ml) are added. The organics are separated and rinsed with brine (50 ml), dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue is purified by flash column chromatography eluting with 50% (v / v) diethyl ether in heptane to give [3- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) - [1, 2,4] thiadiazol-5-yl] -methanol (3.15 g, 8.8 mmol) as a light pink solid. To a cold solution (ice / methanol bath) of [3- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) - [1,4] thiadiazol-5-yl] -methane I ( 2.3 g, 6.4 mmol) in dichloromethane (150 ml) is added methanesulfonyl chloride (0.595 ml, 7.68 mmol) and triethylamine (1.16 ml, 8.32 mmol) sequentially. The reaction is allowed to stir for 10 min and then poured into a separate funnel. The organics are rinsed with 5% aqueous sodium carbonate solution (2 x 100 ml), brine (100 ml), dried over magnesium sulfate and the solvent is removed in vacuo to provide 3- (1-cyclohexylmet-7-methoxy). -1 H-indol-3-yl) - [1, 2,4] thiadiazol-5-ylmethyl methanesulfonic acid ester (2.9 g, 6.7 mmol) which was used without further purification. To a solution of methanesulfonic acid 3- (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl) - [1, 2,4] thiadiazol-5-ylmethyl ester (93 mg, 0.2 mmol) in tetrahydrofuran (1 ml) is added diethylamine (0.22 ml, 2. 13 mmol) and the reaction is subjected to microwave irradiation to 150 ° C for 15 minutes. The reaction is poured into a separate funnel and diluted with dichloromethane (40 ml). The combined organics are rinsed with 5% aqueous sodium carbonate solution (2 x 20 ml), brine (2 x 20 ml), dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue is purified by flash column chromatography to provide the title compound (54 mg, 0.13 mmol) as the free base. The free base is dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether, 1.0 ml, 2.0 mmol) is added. The mixture is concentrated in vacuo to give the title compound as a 1: 1 hydrochloride salt. H NMR (400 MHz, CD3OD): 0.95-1.12 (2H, m), 1 .16-1 .27 (3H, m), 1 .45 (6H, t, J7), 1 .55-1 .63 (2H, m), 1 .63-1 .8 (3H, m), 1.8-1.95 (1 H, m), 3.28-3.32 (4H, m), 3.97 (3H, s), 4.3 (2H, d, J7), 4.96 (2H, s), 6.79 (1H, d) , J8), 7.13 (1 H, t, J8), 7.95 (1 H, s), 8.04 (1 H, d, J8); Esl MS: m / z 413.1 [M + H] +. EXAMPLE 8 The method of Example 7 is further used to prepare the following compounds: 8A: 1- (Cyclohexyl) methyl-7-methoxy-3- (5-frbis- (2-methoxyethyl) amino-methyl> -f1, 2.41 -thiadiazol-3-yl) -1 H-indole, hydrochloride salt The title compound is prepared using bis- (2-methoxyethyl) amine instead of diethylamine. EslMS: m / z 473.1 [M + H] +. 8B: 1 - (Cyclohexyl) methyl-7-methoxy-3- (5-r (pyrrolidin-1-inmetpyr, 2,3-thiadiazol-3-yl) -1 H-indole, hydrochloride salt The compound of the title is prepared using pyrrolidine in place of diethylamine EslMS: m / z 41 1 .1 [M + H] +, 342.0. 8C: 1 - (Cyclohexyl) methyl-7-methoxy-3-f5-r 2- methylpiperidin-1-l) metip-ri, 2,41-thiadiazol-3-yl-11-1 H-indole, trifluoroacetic acid sapon The title compound is prepared using 2-methylpiperidine in place of diethylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 439.3 [M + H] +. 8D: 1 - (Cyclohexyl) methyl-3- (5-frN- (2-hydroxyethyn-N-methylamino-rnethyl) -ri, 2,41-thiadiazol-3-yl) -7-methoxy-1 H- »ndol, salt of hydrochloride The title compound is prepared using (2-hydroxyethyl) methylamine in place of diethylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 415.3 [M + H] +, 328.3. 8Ej 1 - (Cyclohexylmethyl-7-methoxy-3- (5-fNN- (2-methoxyethylN-methyl-1-ylmethyl) -ri, 2,41-thiadiazol-3-yl) -1H-indole, hydrochloride sax The title compound is prepared using N- (2-methoxyethyl) -N-methylamine in place of diethylamine EslMS: m / z 429.4 [M + H] + Example 9 1- (Cyclohexyl) methyl- 3-f5-ri - (diethylamine) etin-p, 2,4-diazazol-3-yl-7-methoxy-1 H-indole hydrochloride salt To a cold solution (dry ice acetone bath) of ethyl ester of acid 3- (1-Cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) - [1,4-] thiadiazole-5-carboxylic acid (500 mg, 1.3 mmol) in diethyl ether (50 mL) was add methyl magnesium bromide solution (0.52 ml, 3M in diethyl ether, 1.56 mmol) and the reaction is stirred for 15 minutes, an additional portion of methyl magnesium bromide solution (0.25 ml, 3M in ether) diethyl, 0.75 mmol) is then added and the reaction mixture is stirred for 5 minutes, then the reaction is quenched with saturated aqueous ammonium chloride (5 ml) and the The heating is allowed to warm to room temperature. The reaction mixture is poured into a separate funnel and the organics are rinsed with water (20 ml). The aqueous layer is rinsed again with diethyl ether (20 ml). The combined organic layers are dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The resulting residue is purified by flash column chromatography to give 1 - [3- (1-cyclohexyl-methyl-7-methoxy-1 H-indol-3-yl) - [1,2,4] thiadiazole-5- il] -ethanone (1 70 mg, 0.46 mmol) as a yellow solid. To a solution of 1 - [3- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) - [1, 2,4] thiadiazol-5-yl] -ethanone (90 mg, * 0.24 mmol) in acetonitrile (3 ml) is added diethylamine (0.248 ml, 2.4 mmol) and acetic acid (0.1 37 ml, 2.4 mmol) and the The reaction mixture is stirred for 30 minutes. To the reaction is added cyano-borohydride supported by polymer (204 mg, charge 2.35 mmlog "1, 0.48 mmol) and the reaction mixture is subjected to microwave irradiation at 150 ° C for 10 minutes. through a 5 g Strata ™ SCX giga tube.The tube is rinsed with methanol and then eluted with 2M ammonia in methanol.The metabolic ammonia solution is evaporated and the resulting residue is purified by flash column chromatography to give the compound The title (62 mg, 0.145 mmol) as the free base The free base is dissolved in dichloromethane (1 ml) and 2M HCl in diethyl ether (1 ml, 2 mmol) is added, the excess reagent and the solvent are removed in vacuo to provide the title compound as a 1: 1 H NMR hydrochloride salt (400 MHz, CD3OD): 1.0-1.2 (2H, m), 1.16-1.26 (3H, m), 1 .38-1.5 (6H, m), 1.55-1.78 (5H, m), 1.82-1.94 (4H, m), 3.32-3.68 (4H, m), 3.97 (3H, s), 4.3 (2H, d, J 7.5), 5.36-5.48 (1 H, m), 6.8 (1 H, d , J8), 7.14 (1 H, t, J 7.5), 7.94 (1 H, s), 8.02 (1 H, d, J8); EslMS: m / z 427.4 [M + H] +, 328.4. EXAMPLE 10 1- (Cyclohexyl) methyl-3-f5-rf-diethylaminolmetin-p .2,41-thiadiazol-3-yl-7-fluoro-1 H-indole, trifluoroacetic acid salt The title compound is prepared following the method of Example 7, using 1- (cyclohexyl) methyl-7-fluoro-1 H-indoI-3-carboxylic acid amide (prepared from 7-fluoroindole) and using diethylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 401 .3 [M + H] +. EXAMPLE 11 7-Chloro-1 - (cyclohexyl) methyl-3-f5-rfpyrrolidin-1-yl) rnetip-p, 2.4-thiadiazol-3-yl) -1 H-indole, trifluoroacetic acid salt The title compound is prepared following the method of Example 7, using 7-chloro-1 - (cyclohexyl) methyl-1 H-indole-3-carboxylic acid amide (prepared from 7-chloroindole) and using pyrrolidine in place of diethylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 417.3, 415.3 [M + H] +. EXAMPLE 12 1 - (Cyclohexinmethyl-7-ethyl-3-f5-r (pyrrolidin-1 -nmet-p-p. 2, 4-thiadiazol-3-yl) -1 H-indole, trifluoroacetic acid salt The title compound is prepared using the method of Example 7, using 1- (cyclohexyl) methyl-7-ethyl-1 H-indole-3-carboxylic acid amide (prepared from 7-ethyl-indole) and using pyrrolidine in place of diethylamine. The free base is purified by semi-prep HPLC [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 409.3 [M + H] + Example 13 ÍR) -3-Cyclohexyl-6- (5-r (diethylamino) metnp, 2.41-thiadiazol-3-yl> -2,3-dihydro-pyrrolori, 2,3-de1-1, 4-benzoxazine, salt of hydrochloride To a mixture of (R) -N-Boc-2-cyclohexylethanolamine (prepared as described for the (S) enantiomer, Lu ly et al., J. Org. Chem. 52, 1487-1492, 1987; 29.4 g, 94.5 mmol) and triphenylphosphine (37.2 g, 141.8 mmol) in toluene (150 ml) at 0 ° C is added diisopropyl azodicarboxylate (19.5 ml, 99.2 mmol). After stirring for 1 h, 2-bromo-phenol (12.1 ml, 1 04.0 mmol) was added to the mixture at 0 ° C. The reaction mixture is stirred for 2 h at 0 ° C and for 20 h at room temperature. The resulting mixture is divided between dichloromethane and water. The aqueous layer is extracted with dichloromethane and the combined organic layers are rinsed with 2N sodium hydroxide solution and brine, dried over sodium sulfate and concentrated. The residue is purified by flash column chromatography eluting with 0-1 0% (v / v) ethyl acetate in heptane to provide (R) -2- (2-tert-butoxycarbonylamino-2-cyclohexyl-ethoxy) bromobenzene (12.80 g, 32.1 mmol). A mixture of (R) -2- (2-tert-butoxycarbonylamino-2-cyclohexyioethoxy) bromobenzene (500 mg, 1.26 mmol), titanium ester (triphenylphosphine) palladium (0) (146 mg, 0.126 mmol) and tert sodium-butoxide (1 81 mg 1.88 mmol) in toluene (4.0 ml) is exposed to microwave irradiation for 1 0 min at 120 ° C. The resulting mixture is divided between dichloromethane and water. The aqueous layer is extracted with dichloromethane and combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated. The residue is purified by flash column chromatography eluting with 0-1 7% (v / v) ethyl acetate in heptane to provide (R) -4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2H- 1,4-benzoxazine (270 mg, 0.85 mmol). This reaction is repeated 1 3 times on the same scale to provide the same intermediate compound (a total of 3.98 g, 12.5 mmol). A mixture of (R) -4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (3.98 g 12.5 mmol), 5N hydrochloric acid (10 ml) and ethanol (10 ml) stir at 70 ° C for 50 min. Ethanol is removed in vacuo and the residue is partitioned between dichloromethane and 2N sodium hydroxide solution. The aqueous layer is extracted with dichloromethane and the combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated to provide (R) -3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (2.72 g). 12.5 mmol). (R) -3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (2.72 g, 12.5 mmol) is dissolved in N, N-dimethylformamide (20 ml) and a solution of sodium nitrite (949 mg , 13.8 mmol) in water (3.0 ml) is added at 0 ° C. Then, 5N hydrochloric acid (6.0 ml) is added at 0 ° C. The reaction mixture is stirred at 0 ° C for 1 h, then divided between ethyl acetate and water. The aqueous layer is extracted with ethyl acetate and the combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated. The residue obtained is dissolved in diethyl ether (50 ml), and lithium aluminum hydride in tetrahydrofuran (1.0 M, 9.51 ml, 9.51 mmol) is added at 0 ° C. The reaction mixture is stirred at 0 ° C for 1 h, then quenched with cold water. Ethyl acetate is added to the mixture and the mixture is filtered through a plug of Celite, and the filter cake is rinsed with ethyl acetate. The filtrate is divided and the aqueous layer is extracted with ethyl acetate. The combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated. The residue is purified by flash column chromatography eluting with 0-17% (v / v) ethyl acetate in heptane to provide (R) -4-amino-3-cyclohexyl-3,4-dihydro-2H-1, 4 -benzoxazine (1.47g, 6.33 mmol). Ethyl pyruvate (882 mg, 7.59 mmol) is added to a solution of (R) -4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6. 33 mmol) in ethanol (40 ml). The reaction mixture is stirred at room temperature for 15 min. To the reaction mixture, sulfuric acid (10% v / v in ethanol; 8.0 ml) is added. The reaction mixture is refluxed for 2 h. The mixture is cooled to room temperature and partitioned between ethyl acetate and sodium carbonate solution. The aqueous layer is extracted with ethyl acetate and the combined organic layers are rinsed with brine, dry over sodium sulfate and concentrate. The residue is purified by flash column chromatography with 0-10% (v / v) ethyl acetate in heptane to provide ethyl (R) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3-de] -1,4-benzoxazine-5-carboxylate (1.49 g, 4.76 mmol). To a solution of ethyl (R) -3-cyclohexyl-2,3-dihydropyrrolo [1, 2,3-de] -benzoxazine-5-carboxylate (1.49 g, 4.76 mmol) in ethanol (50 ml) is added 4N sodium hydroxide (5.94 ml, 23.8 mmol). The mixture is stirred at 70 ° C for 40 min. Ethanol is removed in vacuo, and the residue is neutralized with 2N hydrochloric acid, and partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane and the ined organic layers are rinsed with brine, dried over sodium sulfate and concentrated. The residue is dissolved in quinoline (20 ml), then copper powder (453 mg, 7.13 mmol) is added. The mixture is stirred at 210 ° C for 1 h. Ethyl acetate and water are added to the mixture at room temperature, and the mixture is filtered through a plug of Celite, and the filter cake is quenched with ethyl acetate. The filtrate is acidified with 5N hydrochloric acid and divided. The aqueous layer is extracted with ethyl acetate and the ined organic layers are rinsed with 1 N hydrochloric acid and brine, dried over sodium sulfate and concentrated. The residue is purified by flash column chromatography eluting with 0-1 0% (v / v) ethyl acetate in heptane to provide (R) -3-cyclohexyl-2,3-dihydropyrrolo [1, 2,3-de ] -benzoxazine (984 mg, 4.08 mmol). To a solution of (R) -cyclohexyl-2,3-dihydropyrrolo-1, 4-benzoxazine (600 mg, 2.49 mmol) in N, N-dimethylformamide (5.0 ml) at 0 ° C is added trifluoroacetic anhydride (0.31 ml) 2.73 mmol). The mixture is stirred at room temperature for 5 h, then divided between dichloromethane and water. The aqueous layer is extracted with dichloromethane, and the ined organic layers are rinsed with brine, dried over Na 2 SO 4 and concentrated. The residue is purified by flash chromatography eluting with 0-25% (v / v) ethyl acetate in heptane to provide (R) -3-cyclohexyl-6-trifluoromethylcarbonyl-2,3-dihydropyrrolo [1, 2,3-de ] -1,4-benzoxazine (628 mg, 1.86 mmol). To a solution of (R) -3-cyclohexyl-6-trifluoromethylcarbonyl-2,3-dihydropyrrolo [1, 2,3-de] -1,4-benzoxazine (628 mg, 1.86 mmol) in 1, 4- dioxane (20 ml) is added 4N NaOH (5.0 ml). The mixture is refluxed for 42 h, then acidified to pH 1 using 5N hydrochloric acid and partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane, and the ined organic layers are rinsed with brine, dried over Na2SO4 and concentrated to give (R) -3-cyclohexyl-2,3-dihydropyrrolo acid amide [1, 2.3- of] benzoxazine-6-carboxylic acid (572 mg). The title ound is prepared following the method of Example 7, using (R) -3-cyclohexyl-2,3-dihydropyrrolo [1, 2,3-de] -1,4-benzoxazine-6-carboxylic acid amide ( prepared from (R) -3-cyclohexyl-2,3-dihydropyrrolo [1, 2,3-de] -1,4-benzoxazine-6-carboxylic acid) in place of 1 - (cyclohexyl) methyl-7 acid amide -methoxy-1H-indole-3-carboxylic acid. EslMS: m / z 41 1 .0 [M + H] +; [a] 22-30.7 ° (c = 1.50 mg / ml in chloroform) Example 14 The following compounds are prepared following the method of Example 7, using 7-fluoro-1- (tetrahydropyran-4-yl) acid amide. ) methyl-1 H-indole-3-carboxylic acid in place of 1- (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid amide. Amide of 7-fluoro-1- (tetrahydropyran-4-yl) methyl-1 H-indole-3-carboxylic acid is prepared following the method of Example 1, using 7-fluoroindole in place of 7-methoxyindole and toluene-4 -sulfonic tetrahydropyran-4-ylmethyl ester in place of cyclohexylmethyl bromide. Method for synthesis of the intermediate compound of toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester p-Toluenesulfonyl chloride (29.8 g, 157 mmol) is added per portion to a mixture of tetrahydro-2H-pyran-4-yl-methanol ( 20.0 g, 172 mmol) and pyridine (25.2 L, 313 mmol) in dichloromethane (200 ml). The mixture is stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M, 100 ml). The layers are separated and the aqueous layer is extracted with dichloromethane (2 x 100 ml). The organic layers are combined and concentrated in vacuo. Recrystallization of di-chloromethane: heptane (5: 1) afforded toluene-4-suphonic acid tetrahydro-pyran-4-methyl-methyl ester. The stock solutions are further purified by silica gel column chromatography eluting with 50% dichloromethane in n-heptane to yield an additional amount of toluene-4-sulfonic acid tetrahydro-pyran-4-methyl-methyl ester (total production 41.6 g. 154 mmol). 14A: 3-f5-r (diethylamino) metin-ri .2.41-thiadiazol-3-yl) -7-fluoro-1 - (tetrahydropyran-4-yl) methyl-1 H-indole, hydrochloride salt The title compound is prepared using diethylamine. Esl MS: m / z 403.1 [M + H] +. 14B: 7-fluoro-3-f5-r (pyrrolidin-1-mmetip-ri .2,41-thiadiazol-3-yl.} -1- (tetrahydropyran-4-yl) methyl-1 H- indole, hydrochloride salt The title compound is prepared using pyrrolidine in place of diethylamine Esl MS: m / z 401.0 [MH-H] +. 14C: 3-f5-r (dimethylamino) metip-ri .2.41- thiadiazol-3-yl) -7-fluoro-1 - (tetrahydropyran-4-yl) methyl-1 H-indole, hydrochloride salt The title compound is prepared using dimethylamine in place of diethylamine. EslMS: m / z 375.0 [M + H] +. Example 15 The following compounds are prepared following the method of Example 7, using 7-chloro-1- (tetrahydropyran-4-yl) methyl-1 H-indole-3-carboxylic acid amide in place of 1 - ( cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid. 7-Chloro-1- (tetrahydropyran-4-yl) methyl-1 H-indole-3-carboxylic acid amide is prepared following the method of Example 1, using 7-chloroindole in place of 7-methoxyindole and toluene-4 -sulfonic tetrahydropyran-4-ylmethyl ester in place of cyclohexylmethyl bromide. 15A: 7-chloro-3- (5-frN-ethyl-N- (2-methoxyethylamino-methyl> -ri .2.41-thiadiazol-3-yl) -1 - (tetrahydropyran-4-yl) methi 1-1 H- indole, hydrochloride salt The title compound is prepared using N-ethyl-N- (2-methoxyethyl) amine instead of diethylamine EslMS: m / z 451.0, 449.0 [M + H] +. 15B: 7-chloro- 3- (5-r (Pyrrolidin-1-yl) met.p-ri .2.41-thiadiazol-3-yl-1 - (tetrahydropyran-4-yl) methyl-1 H-indol, hydrochloride salt The compound of the title is prepared using pyrrolidine in place of diethylamine Esl MS: m / z 419.3, 417.3 [M + H] +. 15C: 7-chloro-3- (5-frN-ethyl-N- (2-hydroxyethinamino-methyl-methyl) ri .2,41-thiadiazol-3-yl) -1 - (tetrahydropyran-4-yl) methy1-H-indole The title compound is prepared using N-ethyl-N- (2-hydroxyethyl) amine in EslMS: m / z437.1, 435.1 [M + H] + Example 16 1 - (Cyclohexyl) methyl-7-methoxy-3- 4 -fN- (2-methoxyethy-N-methylamino-methyl) -ri , 31-thiazol-2-yl) -1 H-indole, hydrochloride salt A mixture of 1 - (cyclohexyl) methyl-7-m acid amide ethoxy-1 H-indole-3-carboxylic acid (prepared from 7-methoxyindole as described in Example 1; 5.10 g, 17.8 mmol), Lawesson's reagent (7.92 g, 19.6 mmol), and toluene (150 mL) is stirred at room temperature for 4 days. The reaction mixture is concentrated in vacuo and the residue obtained is purified by column chromatography eluting with dichloromethane to give 1- (cyclohexyl) methyl-7-methoxy-1H-indo-3-carbothioic acid amide (3.58 g). A mixture of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carbothioic acid amide (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0.99 mmol), and ethanol (2.0 mL) is stirred at 60 ° C for 1 h. The reaction mixture is concentrated in vacuo, and the obtained residue is mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture is extracted with dichloromethane (4 x 100 ml). The organic layers are combined, rinsed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue is purified by column chromatography eluting with 25% (v / v) ethyl acetate in n-heptane to give 3- [4- (chloromethyl) thiazol-2-yl] -1 - (cyclohexyl) methyl-7 -methoxy-1 H-indole (200 mg). A mixture of 3- [4- (chloromethyl) thiazol-2-yl] -1 - (cyclohexyl) methyl-7-methoxy-1 H-indole (100 mg, 0.27 mmol), (2-methoxyethyl) methylamine ( 1 19 mg, 1.33 mmol), 1,4-dioxane (2 ml), and acetonitrile (1 ml) is subjected to microwave irradiation for 10 min at 160 ° C. The reaction mixture is concentrated in vacuo and the obtained residue is mixed with aqueous sodium hydroxide (1 M; 50 ml) and extracted with dichloromethane (4 x 50 ml). The combined organic layers are rinsed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue is purified by column chromatography eluting with ethyl acetate to give the free base of the title compound as an oil. Formation of the hydrochloride salt is achieved by the addition of hydrogen chloride (1 M solution in diethyl ether, 3 ml) to a solution of the free base in diethyl ether (15 ml). The mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt (95.1 mg). 1H NMR (400MHz, CD3OD) d 1.00-1.30 (5H, m), 1.55-1.94 (6H, m), 3.00 (3H, s), 3.32- 3.66 (5H, m), 3.80 (2H, t, J 5.0 ), 3.97 (3H, s), 4.29 (2H, d, J 7.2), 4.52 (2H, s), 6.81 (1H, d, J78.0), 7.16 (1H, dd, J 8.0, 8.0), 7.62 (1H, s), 7.80 (1H, d, J 8.0), 7.85 (1H, s). EslMS: m / z 428.1 [M + H] +, 339.0. Example 17 The method of Example 16 is further used to prepare the following compounds using alternative amines in place of (2-methoxyethyl) methylamine. 17A: 1- (Cyclohexyl) methyl-7-methoxy-3-f4-r (morpholin-4-yl) metin-ri.31-thiazol-2-yl > -1H-indole, hydrochloride salt The title compound is prepared using morpholine in place of (2-methoxyethyl) -methylamine. EslMS: m / z 426.3 [M + H] +, 339.1. 17B: 1- (Cyclohexyl) methyl-3-f4-r (4-hydroxypiperidin-J1-yl) metin-ri.31-thiazol-2-yl} -7-methoxy-1 H-indole. hydrochloride salt The title compound is prepared using 4-hydroxypiperidine in place of (2-methoxy-ethyl) methylamine. EslMS: m / z 440.1 [M + H] +, 399.0. 17C: 1- (Cíclohexinmet¡l-3- (4-FRN-¡sopropil-N- (2-methoxyethyl) amJno1metil > -ri.31-thiazol-2-yl) -7-methoxy-1H-8ndol salt. hydrochloride the title compound is prepared using N-isopropyl-N- (2- methoxyethyl) amine instead of (2-methoxyethyl) methylamine EslMS. m / z 456.4 [m + H] +, 339.1 17D. fS) -1- (Cyclohexyl) methyl-3- (4-r (2-hydroxymethylpyrrolidin-1-immethyl-RI-31-thiazol-2-yl-7-methoxy-1 H-indole The title compound is prepared using (S) - (+) - prolinoI in place of (2-methoxyethyl) methylamine and isolate as the free base Esl MS: m / z 440.1 [M + H] +, 339.1; [a] D22-10.0 ° (c = 0.65 mg / ml in chloroform) 17E: 1 - Cyclohexyl) methyl-7-methoxy-3-f4-r (thiomorpholin-4-yl) metin- p, 31-thiazol-2-yl) -1 H. -indole, hydrochloride salt The title compound is prepared using thiomorpholine in place of (2-methoxyethyl) methylamine. Esl MS: m / z 442.0 [M + H] +, 339.0. Example 18 1 - (Cyclohexyl) methyl-7-methoxy-3-f4-ri - (-inetin pirrolid¡n-1-p, 31-thiazol-2-yl) -1 H-indole, hydrochloride salt A solution of 1-chloro-2,3-butanedione (0.717 g, 5.95 mmol) in ethanol (3 ml) is added dropwise to a solution of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3 acid amide -carbothioic acid (prepared as in Example 16; 1.20 g, 3.97 mmol) in ethanol (12 ml) at room temperature, and then the resulting mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated in vacuo and the obtained residue is mixed with dichloromethane (50 ml) and rinsed sequentially with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue is purified by column chromatography eluting with 33% (v / v) ethyl acetate in n-heptane to give 1 -. { 2- [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] thiazoI-4-yl} ethanone as a brown solid (1.1 g). A mixture of 1 - [2- [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] thiazol-4-yl} Ethanone (100 mg, 0.27 mmol), pyrrolidine (193 mg, 2.71 mmol), acetic acid (163 mg, 2.71 mmol) and acetonitrile (3 mL) are stirred at room temperature for 2 h. Methylpolystyrene cyanoborohydride triethylammonium macroporous (MP-cyanoborohydride, loading: 2.35 mmol / g, 231 mg, 0.543 mmol) is added and the resulting mixture was subjected to microwave irradiation at 130 ° C for 10 min. The resin is removed by filtration, rinsing with dichloromethane and the filtrate concentrated in vacuo. The obtained residue is mixed with aqueous sodium hydroxide (1 M, 100 ml) and extracted with dichloromethane (4 x 100 ml). The organic layers are combined, then rinsed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue obtained is purified by column chromatography eluting with 5% methanol in ethyl acetate. The oil obtained is dissolved in diethyl ether (10 ml), then hydrochloric acid (1 M solution in diethyl ether).; 3 ml) is added to the solution. The resulting mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt (30.1 mg). 1 H N M R (400MHz, CD3O D) d; 0.98-1.32 (5H, m), 1 .54-2.22 (13H, m), 3.22-3.44 (3H, m), 3.66-3.84 (1H, m), 3.97 (3H, s), 4.29 (2H, d, J 7.2), 4.60-4.72 (1 H, m), 6.81 (1 H, d, J7.6), 7.15 (1 H, dd, J7.6, 8.0), 7.51 (1H, s > 7.79-7.90 (2H, m) EslMS: m / z 424.1 [M + H] +, 353.1 Example 19 1- (Cyclohexyl) methyl-7-fluoro-3- (4-frN-isopropylN- (2 - methoxyethanol) aminomethyl) -ri, 31-thiazole-2-yl) -1 H-indole, trifluoroacetic acid salt The title compound is prepared following the method of Example 16, using acid amide 1- (cyclohexyl) methyl-7-fluoro-1H-indole-3-carboxylic acid (prepared from 7-fluoroindole) and N-isopropyl-N- (2-methoxyethyl) amine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 444.3 [M + H] +, 327.3. Example 19A 1- (Cyclohexyl) methyl-6-fluoro-3-r4-diethylamino) methyn-ri, 31-thiazol-2-yl) -1 H-indole, trifluoroacetic acid salt The title compound is prepare by following the method of Example 16, using 1- (cyclohexyl) methyl-6-fluoro-1H-indole-3-carboxylic acid amide (prepared from 6-fIuoroindole) and diethylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 400.1 [M + H] +, 327.1. Example 20 7-Chloro-1- (cyclohexyl) methyl-3- (4-ITN-isopropyl-N- (2-methoxyethyl) to ino-methyl) -ri, 31-thiazol-2-yl) -1H-indole, sakh . hydrochloride The title compound is prepared following the method of Example 16, using 7-chloro-1 - (cyclohexyl) methyl-1 H-indole-3-carboxylic acid amide (prepared from 7-chloroindole) and N-isopropyl-N - (2-methoxyethyl) amine. EslMS: m / z 462.3, 460.3 [M + H] +, 343.1. Example 21 1 - (Cyclohexyl) methyl-7-ethyl-3- (4-gN-isopropyl-N- (2-methoxyethyl) amino-1-methyl) -ri, 31-thiazol-2-yl) -1 H-indole, salt of trifluoroacetic acid The title compound is prepared following the method of Example 16, using 1- (cyclohexyl) methyl-7-ethyl-1 H-indole-3-carboxylic acid amide (prepared from 7-ethylindole) and N-isopropyl- N- (2-methoxyethyl) amine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 454.5 [M + H] +, 337.3. EXAMPLE 22 The following compounds are prepared following the method of Example 16 using (R) -3-cyclohexyl-2,3-dihydropyrrolo [1, 2,3-de] -1,4-benzoxazine-6-carboxylic acid amide ( prepared from (R) -3-cyclohexyl-2,3-dihydropyrrolo [1, 2,3-de] -1,4-benzoxazine-6-carboxylic acid, described in Example 13) in place of 1 - ( cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid. 22A: R) -3-Cyclohexyl-6- (4-r (diethylamino) metin-ri, 31-thiazol-2-yl) -2,3-dihydropyrrolo-p .2,3-de1-1, 4-benzoxazine , hydrochloride salt The title compound is prepared using diethylamine in place of (2-methoxyethyl) methylamine. EslMS: m / z 410.3 [M + H] +, 337.3; [a] D22-37.50 (c = 1.30 mg / ml in chloroform). 22B: (R) -3-Cyclohexyl-β-f4-r (N-ethyl-N-isopropylamino) metip-M, 31-thiazol-2-yl > -2.3-dihydropyrrolo-ri, 2,3-de1-1, 4-benzoxazine, trifluoroacetic acid salt The title compound is prepared using N-ethyl-N-isopropylamine in place of (2-methoxyethyl) methylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 424.3 [M + H] +, 337.3; [a] D22-27.4 ° (c = 1.25 mg / ml in chloroform) 22C: fR) -3-Cyclohexyl-6-f4-r (pyrrolidin-1-yl) methyl p.31-thiazol-2-yl) -2,3-dihydropyrrolo-ri, 2,3-de1-1, 4-benzoxazine, trifluoroacetic acid salt The title compound is prepared using pyrrolidine in place of (2) -methoxyethyl) -methylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. Esl MS: m / z 408.3 [M + H] +, 337.3; [a] D22-32.6 ° (c = 2.15 mg / ml in chloroform). 22D: (R) -3-Cyclohexyl-6- (4-frN-isopropyl-N-t2-methoxyethyl) amino-1-methyl} > -ri. 31-thiazol-2-yl) -2,3-dihydropyrrolo-p, 2,3-del-1,4-benzoxazine, trifluoroacetic acid salt The title compound is prepared using N-isopropyl-N- ( 2-methoxyethyl) amine instead of (2-methoxyethyl) methylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1.

EslMS: m / z 454.3 [M + H] +, 337.3; [] D22-58.4 ° (c = 2.09 mg / ml in methanol). 22E: (R) -3-Cyclohexyl-6- (4-frbis- (2-methoxyethyl) amino-1-methyl-1, 3-thiazol-2-yl) -2,3-dihydropyrrolo-ri, 2, 3-de1-1, 4-benzoxazine, trifluoroacetic acid salt The title compound is prepared using bis- (2-methoxyethyl) amine instead of (2-methoxyethyl) methylamine. The free base is purified by semi-prep HPLC. [method (i)] to provide the title compound as a trifluoroacetic acid salt 1: 1. EslMS: m / z 470.3 [M + H] +, 337.3; [] D22-28.5 ° (c = 1.20 mg / ml in chloroform). EXAMPLE 23 The following compounds are prepared following the method of Example 16, using 7-chloro-1- (tetrahydropyran-4-yl) methyl-1 H-indole-3-carboxylic acid amide in place of 1 - ( cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid. Amide of 7-chloro-1 - (tetrahydropyran-4-yl) methyl-1 H-indole-3-carboxylic acid is prepared following the method of Example 1, using 7-chloroindole instead of 7-methoxyindole and toluene-4 sulfonic tetrahydropyran-4-ymethyl ester (prepared as described in Example 14) in place of cyclohexylmethyl bromide. 23A: 7-chloro-3-f4-r (diethylamino) metin-p.31-thiazol-2-yl) -1 - (tetrahydropyran-4-yl) methyl-1 H-indole, hydrochloride salt The title compound is prepared using diethylamine. EIMS: m / z 420.0, 418.4 [M + H] +, 347.0, 345.0. 23B: 7-Chloro-3- (4-frN-2-hydroxyethyl) -N-isopropylamino-methyl> > -p .31-thiazor-2-yl) -1 - (tetrahydropyran-4-yl) methy1H-indole The title compound is prepared using N- (2-hydroxyethyl) -N-isopropylamine. EI-MS: m / z 448.4 [M + H] +, 347.1, 345.1. 23C: 7-Chloro-3- (4-frN-ethyl-N- (2-hydroxyethyl) amino-1-methyl} -ri, 31-thiazole-2-i) -1 - (tetrahydropyran-4-yl) methyl 1 -1 H-indole The title compound is prepared using N-ethyl-N- (2-hydroxyethyl) amine. EIMS: m / z 436.3, 434.4 [M + H] +, 347.0, 345.0. 23D: 7-Chloro-3- (4-qN- (2-methoxyethyl-8-N-methylamino-1-methyl, 31-thiazole -2-i I) -1 - (tetrahydric-4-yl) methi 1-1 H -indole, hydrochloride sax The title compound is prepared using N- (2-methoxyethyl) -N-methylamine MS: m / z 436.1, 434.1 [M + H] +, 347.0, 345.0 Example 24 1 - ( Cyclohexylmethyl-3- (4-r (dimethylamino) methan-5-et.lp.33-t-azole-2'-l) -7-methoxy-1H-indole, hydrochloride Sodium ethoxide (0.68 g, 9.94 mmol) is added per portion to a mixture of ethyldichloroacetate (1.22 ml, 9.94 mmol) and diethyl ether (10 ml) under cooling by cold water and the resulting mixture is stirred at 0 °. C for 30 minutes Propionaldehyde (0.79 ml, 10.93 mmol) is then added and the reaction mixture is allowed to warm to room temperature slowly and stirring is continued for 72 hours.The reaction mixture is then poured into water (10 ml) and extracted with diethyl ether (2 x 15 ml) The organic layers are combined, dried over magnesium sulfate, and concentrated in vacuo. to produce ethyl ester of crude 3-chloro-2-oxo-pentanoic acid (1.8 g) which was used in the next step without further purification.

A mixture of 1- (cyclohexyl) methyl-7-methoxy-1H-indole-3-carbothioic acid amide (0.227 g, 0.754 mmol) and crude ethyl 3-chloro-2-oxo-pentanoic acid ester (1.34 g) , 7.52 mmol) in dimethylformamide (4 ml) is subjected to microwave irradiation for 25 min at 140 ° C. The reaction mixture is concentrated in vacuo and the obtained residue is purified by silica gel column chromatography eluting with 25% acetone in heptane to give ethyl 2- (1-cyclohexylmethyl-7-methoxy-1H-indole) ethyl ester. -3-yl) -5-ethyl-thiazole-4-carboxylic acid (0.490 g). This material is used in the next step without further purification. Lithium borohydride (200 mg, 9.09 mmol) is added per portion to a mixture of 2- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) -5-ethyl-thiazole-4-ethyl ester. carboxylic (490 mg, 1.15 mmol) and tetrahydrofuran (5 ml) under cooling by cold water and the resulting mixture is stirred at 0 ° C for 2 h. The reaction mixture is quenched with aqueous hydrochloric acid (2M, 2 ml), and the aqueous layer is extracted with dichloromethane (2 x 100 ml). The organic layers are combined, dried over magnesium sulfate, and concentrated in vacuo to yield the crude product. Column chromatography on silica gel eluting with 66% ethyl acetate in heptane dio [2- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -5-ethyl-thiazol-4-yl] - methanol (210 mg). This material is used in the next step without further purification. Methanesulfonylchloride (90 μL, 1.16 mmol) is added to a mixture of [2- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -5-ethyl-thiazol-4-yl] -methanol (210 mg, 0.547 mmol), diisopropylethylamine (150 μl, 0.91 mmol) and dichloromethane (5 ml) under cooling by cold water and the resulting mixture is allowed to warm to room temperature slowly. Stirring is continued for 22 hours. The reaction mixture is quenched with 5% aqueous sodium carbonate (2 ml), and the aqueous layer is extracted with dichloromethane (2 x 10 ml). The organic layers are combined, dried over magnesium sulfate, and concentrated in vacuo to yield the crude product. Flash column chromatography eluting with 10% acetone in n-heptane gave 3- (4-chloromethyl-l-5-ethyl-thiazol-2-yl) -1-cyclohexy-1-methyl-7-methoxy-1H-indole (109 mg). Dimethylamine (2.2M solution in tetrahydrofuran, 0.50 ml) is added to a mixture of 3- (4-chloromethyl-5-ethyl-thiazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1 H-indole (38 mg , 0.095 mmol), potassium carbonate (16 mg, 0.1 13 mmol) and sodium iodide (14 mg, 0.095 mmol) in acetonitrile (2 mL). The mixture is subjected to microwave irradiation for 5 min at 160 ° C, then divided between dichloromethane (20 ml) and 5% aqueous sodium carbonate (5 ml). The aqueous layer is extracted with dichloromethane (10 ml) and the combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The resulting oil is dissolved in diethyl ether, then hydrogen chloride (1 M solution in diethyl ether, 3 ml) is added to the solution. The resulting mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt (40 mg, 0.089 mmol). 1H NMR (400MHz, CD3OD) d 1 .04-1 .15 (2H, m), 1 .16-1.30 (3H, m), 1.43 (3H, t, J7.0), 1 .55-1 .78 (5H, m), 1 .82-1 .92 (1 H, m), 3.05 (8H, m), 3.99 (3H, s), 4.33 (2H, d, J 7), 4.62 (2H, s) , 6.91 (1 H, d, J 8.0), 7.29 (1 H, t, J8.0), 7.62 (1 H, d, J 8), 8.30 (1 H, s). EIMS: m / z 412.3 [M + H] +, 367.0. Example 25 1 - (Cyclohexinmethyl-3-f5-r (diethylamino) metin-4-methyl-p, 31-thiazol-2-yl-7-methoxy-1 H-indole, hydrochloride salt A amide solution of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carbothioic acid (604 mg, 2.00 mmol) in EtOH (5.0 ml) is added ethyl 2-chloro-3-oxobutanoate (0.332 ml, 2.40 mmol) The mixture is refluxed for 1 h After cooling to 0 ° C, the precipitate is collected by filtration to give 1-cyclohexylmethyl-3- (5-ethoxycarbonyl-4-methylthiazol-2-yl) - 7-methoxy-1 H-indole (505 mg, 1.22 mmol) To a solution of 1-cyclohexylmethyl-3- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -7-methoxy-1 H-indole (680 mg, 1.65 mmol) in THF (20 ml) is added lithium aluminum hydride (125 mg, 3.30 mmol) at 0 ° C.

The mixture is stirred at 0 ° C for 1 h, then quenched with cold water and extracted with dichloromethane. The combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with 25-50% (v / v) ethyl acetate in heptane then 10% (v / v) methanol in dichloromethane to give 1-cyclohexylmethyl-3- (5-hydroxymethyl-4-methylthiazol-2-yl) -7-methoxy-1 H- indole (532 mg, 1.44 mmol). To a solution of 1-cyclohexylmethyl-3- (5-hydroxymethyl-4-methylthiazol-2-yl) -7-methoxy-1 H-indole (74 mg, 0.20 mmol) and triethylamine (26 mg, 0.26 mmol) in dichloromethane (1.0 ml), methanesulfonyl chloride (28 mg, 0.24 mmol) is added. The mixture is stirred at room temperature for 40 min. and it is partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate. The aqueous layer is extracted with dichloromethane, then the combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated to give 1-cyclohexylmethyl-3- (5-methanesulfonyloxymethyl-4-methylthiazol-2-yl) -7-methoxy. -1 H crude indole (65 mg, 0.15 mmol). A mixture of crude 1-cyclohexy lomethyl-3- (5-methanesulfonyl) yl-methyl-4-methylthiazol-2-yl) -7-methoxy-1H-indole (64 mg, 0.14 mmol), potassium carbonate (29 mg) , 0.21 mmol), sodium iodide (31 mg, 0.21 mmol) and diethylamine (21 mg, 0.28 mmol) in THF (1.5 mL) and acetonitrile (1.5 mL) is subjected to microwave irradiation for 5 min at 160 ° C. The resulting mixture is divided between dichloromethane and water. The aqueous layer is extracted with dichloromethane and the combined organic layers are rinsed with brine, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with 50-100% (v / v) ethyl acetate in heptane to give 1-cyclohexylmethyl-3- (5-diethyl-aminomethyl-4-methylthiazol-2-yl) -7-methoxy. -1 f / -indole (27 mg, 0.064 mmol). Formation of the hydrochloride salt is achieved by the addition of hydrogen chloride (1 M solution in diethyl ether, 1 ml) to a solution of the free base in diethyl ether (1 ml) and ethanol (2 ml). The solvent is removed in vacuo and the precipitate is dried to provide the title compound as a 1: 1 hydrochloride salt (26 mg, 0.056 mmol). 1 H NMR (400MHz, DMSO-d6) d 0.95-1 .25 (5H, m), 1.29 (6H, t, J 7.2), 1 .40-1.52 (2H, m), 1 .55-1 .70 (3H, m), 1 .72- 1.84 (1 H, m), 3.10-3.25 (4H, m), 3.93 (3H, s), 4.27 (2H, d, J 7.0), 4.56 (2H, d, J 5.0), 6.82 (1 H, d, J 7.6), 7.14 (1 H, t, J 7.6), 7.72 (1 H, d, J 7.6), 8.00 (1 H, s), 9.90 (1 H, br s); Esl MS: m / z 426.3 [M + H] +, 353.1. EXAMPLE 26 1 - (Cyclohexinmethyl-3-f2-r (diethylamino) methnp.31-thiazol-4-yl> -7- methoxy-1 H-indole, hydrochloride salt To a solution of 7-methoxyindole ( 5.00 g, 34.0 mmol) in dimethylformamide (50 ml) under nitrogen is added sodium hydride (60% dispersion in mineral oil, 1.50 g, 37.4 mmol) The mixture is stirred at room temperature for 10 minutes before the addition of bromomethylcyclohexane (5.20 ml, 37.4 mmol) The resulting mixture is stirred at room temperature for 42 hours and then divided between ethyl acetate (150 ml) and water (150 ml) The aqueous layer is extracted with ethyl acetate (150 ml). ) and the combined organic layers are rinsed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo.The crude intermediate compound is purified by flash column chromatography eluting with 0-10% (v / v) ethyl acetate in n-heptane to give 1- (cyclohexyl) methyl-7-methoxy-1 H-indole (7.48 g, 30.7 mmol). Chloroacetyl chloride (8.66 ml, 109 mmol) is added dropwise over a period of 1.5 hours, to a stirred solution of pyridine (2.20 ml, 27.2 mmol) and 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole (6.60 g, 27.2 mmol) in toluene (50 ml) at 55 ° C. The resulting mixture is heated at 55 ° C for 0.5 h more then allowed to cool to room temperature. Water (60 ml) and methanol (10 ml) are added. The organic layer is separated and concentrated under reduced pressure to provide a dark brown residue. The residue is purified by column chromatography eluting with 5% (v / v) ethyl acetate in n-heptane. The solid obtained is repeated and recrystallized from ether to give 2-cyoro-1 - [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] ethanone as a white solid (1.40 g). 2-Chloro-1 - [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] ethanone (0.73 g, 2.30 mmol) and 2- (tert-butylcarbonyloxy) thioacetamide (1.21 g, 6.89 mmol) are suspended in ethanol (10 ml) and the resulting mixture is subjected to microwave irradiation at 150 ° C for 10 min using an Emrys ™ Optimizer EXP. The reaction mixture is concentrated in vacuo and the residue obtained is purified by flash column chromatography eluting with 5% (v / v) ethyl acetate in n-heptane to provide 1- (cyclohexyl) methyl-7-methoxy-3- . { 2- [(tert-butylcarbonyloxy) methyl] thiazol-4-yl} -1 H-indole as a yellow oil (1.0 g). 1 - (cyclohexy I) methy1-7-methoxy-3-. { 2 - [(tert-butylcarbonyloxy) methyl] thiazol-4-yl} -1H-indole (0.92 g, 2.10 mmol) is dissolved in methanol (20 ml) and 4N sodium hydroxide (5 ml) is added. The solution is stirred at room temperature for 2 h. The reaction mixture is concentrated in vacuo and the residue is taken up in dichloromethane. Water (10 ml) is added and the organic layer is separated. The aqueous layer is extracted with dichloromethane and the combined organic layers concentrated in vacuo to yield 1- (cyclohexyl) methyl-3- [2- (hydroxymethyl) thiazol-4-yl] -7-methoxy-1 H-indole as a foam. pale orange (0.55 g). Methanesulfonyl chloride (174 μL, 2.25 mmol) is added to a solution of 1- (cyclohexy I) methyl-3- [2- (hydroxymethyl) thiazol-4-yl] -7-methoxy-1H- indole (0.40 g, 1.12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture is stirred at room temperature overnight. Additional methanesulfonyl chloride (87 μL, 1.12 mmol) is added and stirring is continued for 0.5 h. The mixture is concentrated in vacuo and the resulting orange residue is purified by flash column chromatography eluting with dichloromethane to provide 3- [2- (chloromethyl) thiazol-4-yl] -1 - (cyclohexyl) methyl-7-methoxy-1 H-indole as a yellow oil (0.415 g). 3- [2- (Chloromethyl) thiazol-4-yl] -1 - (cyclohexyl) methyl-7-methoxy-1 H-indole (0.08 g, 0.214 mmol) and diethylamine (221 μl, 2.14 mmol) are dissolved in acetonitrile (2 ml). The resulting mixture is exposed to microwave irradiation at 100 ° C for 5 min. The mixture is concentrated in vacuo and the resulting residue is purified by column chromatography eluting with 33% (v / v) ethyl acetate in n-heptane. The resulting product is taken in diethyl ether and hydrogen chloride (1 M solution in diethyl ether; 1 ml) is added. The solution is concentrated in vacuo and the resulting solid is triturated with ether, then dried to provide the title compound as a 1: 1 hydrochloride salt (0.034 g). 1 H NMR (400MHz, CD3OD) d 0.99-1.25 (5H, m), 1 .43 (6H, t, J 7.5), 1 .56-1.90 (6H, m), 3.35-3.42 (4H, m), 3.96 (3H, s), 4.27 (2H, d, J 7.5), 4.75-4.80 (2H, s, hidden by maximum H2O), 6.75 (1 H, d, J 8.0), 7.08 (1 H, dd, J8 .0, 8.0), 7.64-7.68 (3H, m). EslMS: m / z 412.1 [M + H] +, 339.0. Example 27 1 - (CyclohexSl) methyl-7-methoxy-3-. { 2-r (pyrrolidin-1-yl) metH-ri, 31-thiazol-4-yl) -1 H-indole, hydrochloride salt The title compound is prepared following the method of Example 26, using pyrrolidine instead of diethylamine. EslMS: m / z 410.3 [M + H] +, 339.1. Example 28 1 - (Cyclohexyl) methyl-3- (2-r (dimethylamino) metin-p, 31-thiazol-5-yl> -7- methoxy-1 H-indole, hydrochloride salt A suspension of acid 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (5 g, 17.4 mmol) in dichloromethane (100 ml) is added oxalyl chloride (3.04 ml, 34.8 mmol) and the resulting solution is stirred overnight Excess solvent and reagent are then removed by evaporation, to the resulting residue copper (I) cyanide (6.2 g, 69.6 mmol), toluene (200 ml) and acetonitrile (10 ml) are added and the resulting reaction mixture the mixture is refluxed for 7 hours, an additional portion of copper (I) cyanide (1.6 g, 17.9 mmol) is added and the reaction mixture is heated to reflux overnight, the reaction mixture is cooled and filtered. through a dicalite bearing, the dicalite is rinsed with acetonitrile and the combined filtrate is evaporated to leave a red solid.The solid is purified by flash column chromatography eluting with 50% (v / v) dichloromethane in heptane to provide (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) -oxoacetonitrile (4.7 g, 14.7 mmol). To a solution of (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) -oxoacetonitrile (975 mg, 3.29 mmol) in acetic acid (40 ml) under nitrogen is added 10% palladium on charcoal (90 mg). The reaction is placed under a hydrogen atmosphere and stirred for 14 h. The reaction mixture is then filtered through a dicalite bearing. The dicalite is rinsed with acetic acid and the combined filtrate is evaporated to leave a red oil. The red oil is taken up in dichloromethane (50 ml) and to this is added methylchloroxoacetate (0.393 ml, 4.28 mmol) followed by N-ethyldiisopropylamine (1.7 ml, 9.87 mmol) per drops. The reaction is stirred for 1 h and poured into a separate funnel. The organics are sequentially rinsed with 2M aqueous hydrochloric acid (50 ml), 5% aqueous sodium carbonate (50 ml) and brine (50 ml). The organics are dried over sodium sulfate, filtered and the solvent is removed in vacuo to leave a brown oil. The oil is purified by flash chromatography using dichloromethane followed by 66% (v / v) diethyl ether in heptane to provide methyl ester of N - [(1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) - 2-oxo-ethyl] oxalamic acid (573 mg, 1.48 mmol) as a yellow / brown solid. To a solution of N - [(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl) -2-oxo-ethyl] -oxalmic acid methyl ester (429 mg, 1.1 mmol) in chloroform ml) phosphorus pentasulfide (538 mg, 1.21 mmol) is added and the reaction mixture is heated at reflux for 3.5 h. The reaction mixture is cooled, poured into a separate funnel and rinsed with water and then brine. The organic layers are then dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The resulting solid was purified by flash column chromatography eluting with dichloromethane to give 5- (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl) thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol ) as a brown solid. To a solution of 5- (1-cyclohexylmethyl-7-methoxy-1H-indo! -3-yl) thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) is added sodium borohydride (83 mg, 2.18 mmol) per portion for 2 minutes. The reaction is stirred for a further 1 h and then quenched with aqueous hydrochloric acid (1 M; 10 ml). The mixture is poured into a separate funnel, diluted with dichloromethane (50 ml) and rinsed with water (20 ml). The combined organic layers are dried, filtered and the solvent is removed in vacuo to leave a yellow oil. The oil is purified by flash column chromatography using 50-100% (v / v) diethyl ether in heptane to give [5- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) thiazole-2- i!] - methanol (308 mg, 0.86 mmol) as a white foam. To a solution of [5- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) thiazol-2-yl] -methanol (308 mg, 0.86 mmol) in dichloromethane (20 ml) is added methanesulfonyl (80 μl, 1.03 mmol) followed by triethylamine (0.156 ml, 1.12 mmol). The reaction is stirred for 30 minutes, then poured into a separate funnel, rinsed with 5% aqueous sodium carbonate, then with brine and dried over magnesium sulfate. The solvent is removed in vacuo to provide 5- (1-cyclohexyl-methyl-7-methoxy-1H-indol-3-yl) -thiazol-2-yl-methanesulfonic acid methyl ester (41.1 mg, 0.94 mmol). To a solution of 5- (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl) -thiazole-2-methanesulfonic acid methyl ester (93 mg, 0.215 mmol) in tetrahydrofuran (2 ml) is added dimethylamine (2 M in tetrahydrofuran; 1 ml, 2 mmol) and the reaction mixture is exposed to microwave irradiation at 150 ° C for 15 minutes. The reaction mixture is diluted with dichloromethane (40 ml) and rinsed with a 1: 1 (v / v) mixture of brine and saturated sodium bicarbonate, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting oil is purified by flash column chromatography to provide the title compound (70 mg, 0.18 mmol) as the free base. The free base is dissolved in dichloromethane (5 ml), hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) is added and the solvent is removed in vacuo to give the title compound as a hydrochloride 1 salt: 1 . 1 H NMR (400 MHz, CD3OD): 0.96-1.12 (2H, m), 1.13-1.26 (3H, m), 1.5-5.62 (2H, m), 1.662-1 .78 (3H, m), 1 .78-1 .92 (1 H, m), 3.01 (6H, s), 3.96 (3H, s), 4.26 (2H, d, J 5.5), 4.71 (2H, s), 6.78 (1 H, d, J 8.0), 7.1 1 (1 H, t, J 8.0), 7.41 (1 H, d, J 8.0), 7.52 (1 H, s), 8.08 (1 H, s); EslMS: m / z 384.0 [M + H] +, 339.0, 243.1. EXAMPLE 29 1-r Cyclohexinmethyl-3-f4-r (diethylamino) metin-p.31-oxazole-2-yl > -7- methoxy-1 H-indole, hydrochloride salt To a solution of 1-cyclohexylmethyl-7-methoxy-1 H-indole-3-carboxylic acid amide (500 mg, 1.75 mmol) in toluene ( 4 ml) is added 1,3-dichloroacetone (333 mg, 2.62 mmol) and the reaction mixture is subjected to microwave irradiation at 150 ° C for 30 minutes. The resulting black solution is diluted with dichloromethane (50 ml) and rinse with 5% aqueous sodium carbonate solution (5 x ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown oil is purified by flash column chromatography using 5% (v / v) acetone in petroleum ether 40-60 to give 3- (4-chloromethyl-oxazol-2-yl) -1-cyclohexylmethyl-7-methoxy. -1 H-indole (510 mg, 1.42 mmol) as a white solid. To a solution of 3- (4-chloromethyl-oxazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1H-5 indole (100 mg, 0.28 mmol) in tetrahydrofuran (1 ml) is added diethylamine (0.29 ml). , 2.8 mmol) and the reaction mixture is subjected to microwave irradiation at 150 ° C for 15 minutes. The reaction mixture is poured into a separate funnel, diluted with dichloromethane (40 ml) and rinsed with 5% aqueous sodium carbonate solution (2 x 25 ml), brine (20 ml), dried over magnesium sulfate and the solvent evaporate in vacuo to leave an orange oil. The oil is purified by flash column chromatography using 10% (v / v) methanol in dichloromethane to give the title compound (92 mg, 0.23 mmol) as the free base. The free base is dissolved in dichloromethane and hydrogen chloride (1 M solution in diethyl ether, 2 ml, 2 mmol) is added. The mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt. 1 H NMR (400 MHz, CD3OD): 0.97-1.28 (5H, m), 1.44 (6H, t, J 7.0), 1.5-1.8 (5H, m), 1.8-1.95 (1H, m), 3.3-3.5 ( 4H, m), 3.97 (3H, s), 4.29 (2H, d, J 7.0), 4.38 (2H, s), 6.8 (1H, d, J 8.0), 7.2 (1H, t, J 8.0), 7.8 (1H, s), 7.82 (1H, s), 8.2 (1H, s); EslMS: m / z 396.0 [M + H] +, 323.4, 295.4, 268.3. EXAMPLE 30 1- (Cyclohexyl) methyl-7-methoxy-3- (5-r (pyrrolidin-1-inmetin-ri.31-oxazol-2-yl) -1 H-indole trifluoroacetic acid salt A mixture of amide of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (563 mg, 1.97 mmol), 2-chloro-3-oxo-propionic acid methyl ester (Gangjee et al., J. Med. Chem. 44, 1993-2003, 2001; 1.48 g, 9.85 mmol) and dimethylacetamide (10 ml) is subjected to microwave irradiation at 90 ° C for 2 x 5 minutes using a Emrys ™ Optimizer EXP. The reaction mixture is diluted with dichloromethane (150 ml), then rinsed with 5% aqueous magnesium sulfate (2 x 100 ml) and brine (150 ml). The organic extracts are dried over magnesium sulfate and concentrated in vacuo. The resulting residue is purified by flash column chromatography eluting with 25% (v / v) ethyl acetate in heptane to provide an inseparable mixture of 2- (1-cyclohexylmethyl-7-methoxy-1H-indole) methyl ester. 3-yl) -oxazole-5-carboxylic acid and 1-cyclohexyl-methyl-7-methoxy-3-oxazol-2-yl-1 H-indole (87:13 ratio by HPLC, 0.613 g). Lithium aluminum hydride solution (1M solution in diethyl ether, 2.88 ml, 2.88 mmol) is added dropwise to a mixture of methyl ester of 2- (1-cyclohexylmethyl-7-methoxy-1H-indole-3- il) -oxazole-5-carboxylic acid and 1-cyclohexy I methyl-7-methoxy-3-oxazole-2-yl-1 H-indole (557 mg) dissolved in tetrahydrofuran (10 ml) under cooling with cold methanol. The resulting mixture is stirred for 30 minutes at 0 ° C, then diluted with diethyl ether (40 ml). Excess sodium sulfate dehydrochloride is then added and the resulting mixture is stirred at room temperature for 18 h. The mixture is filtered through a dicalite bearing and rinsed with diethyl ether (100 ml); the filtrate is then concentrated in vacuo. The resulting residue is purified by column chromatography eluting with 50% ethyl acetate in n-heptane to provide [2- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -oxazol-5-yl] -metanoi as a yellow solid (242 mg, 0.71 mmol). Methanesulfonyl chloride (98 mg, 0.85 mmol) is added dropwise to a solution of [2- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -oxazol-5-yl] -methanol (242) mg, 0.71 mmol) dissolved in dichloromethane (15 ml) under cooling of cold methanol, then triethylamine (93 mg, 0.92 mmol) is added dropwise, the cooling is then removed and the mixture is stirred for 16 h. The mixture is then diluted with dichloromethane (30 ml), rinse with saturated sodium carbonate solution (30 ml) in a hydrophobic fried tube. The organic extracts are dried over magnesium sulfate, then concentrated in vacuo. A mixture of the resulting residue (10 mg, 0.26 mmol), pyrrolidine (185 mg, 2.60 mmol) and tetrahydrofuran (2.5 ml) is subjected to microwave irradiation at 150 ° C for 15 minutes. The resulting mixture is concentrated in vacuo and purified by flash column chromatography (2% (v / v) ammonia in methanol / dichloromethane in a 1:49 ratio as eluent) to give a brown gum. The gum is further purified by semi-prep HPLC. [method (i)] to provide 1-cyclohexylmethyl-7- methoxy-3- (5-pyrrolidin-1-ylmethyl-oxazol-2-yl) -1 H-indole as a trifluoroacetic acid salt (14 mg). 1 HN MR (400MHz, CD3OD) d 0.99-1.27 (5H, m), 1 .54-1 .78 (5H, m), 1.86 (1 H, m), 2.00-2.24 (4H, m), 3.25- 3.44 (2H, m), 3.53-3.74 (2H, m), 3.97 (3H, s), 4.29 (2H, d, J 7.0), 4.64 (2H, s), 6.81 (1 H, s, J7.0 ), 7.15 (1 H, t, J8.0), 7.41 (1 H, s), 7.79 (1 H, d, .77.5), 7.82 (1 H, s). EslMS: m / z 394.1 [M + H] +, 323.1. Example 31 1 - (Cyclohexyl) methyl-3-f5-r diethylamino) metin-4-methyl-p. 31-oxazol-2-yl) -7-methoxy-1 H-indole, hydrochloride salt A mixture of amide of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carboxylic acid (500 mg, 1.75 mmol), ethyl-2-chloroacetoacetate (2.88 g, 17.6 mmol) and dimethylformamide (10 ml) is subjected to microwave irradiation at 185 ° C for 15 minutes using a Emrys ™ Optimizer EXP. The reaction mixture is diluted with dichloromethane (100 ml), then rinsed with 5% aqueous magnesium sulfate (2 x 50 ml), water (50 ml) and brine (50 ml). The organic extracts are dried over magnesium sulfate and concentrated in vacuo. The resulting residue is purified by column chromatography eluting with 33% (v / v) dichloromethane in n-heptane to provide an inseparable mixture of 2- (1-cyclohexylmethyl-7-methoxy-1H-indoic acid ethyl ester. -yl) -4-methyl-oxazole-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3- (4-methyl-oxazol-2-yl) -1H-indole (78:22 ratio by HPLC; 0.586 g ). This reaction is repeated on the same scale. Lithium aluminum hydride (1 M solution in diethyl ether, 5.8 ml, . 8 mmol) is added dropwise to a mixture of 2- (1-cyclohexymethyl-7-methoxy-1 H-indol-3-yl) -4-methyl-oxazole-5-carboxylic acid ethyl ester and 1-cyclohexylmethyl -7-methoxy-3- (4-methyl-oxazol-2-yl) -1H-indole (1 171 mg) dissolved in tetrahydrofuran (20 ml) under cooling of cold methanol. The resulting mixture is stirred for 20 minutes at 0 ° C, then diluted with diethyl ether (40 ml). Excess sodium sulfate decahydrate is added and the resulting mixture is stirred at room temperature for 18 h. The mixture is filtered through a dicalite bearing, rinsing with diethyl ether (100 ml) and the filtrate concentrated in vacuo. The residue is purified by flash column chromatography eluting with 50% (v / v) ethyl acetate in n-heptane to provide [2- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) -4 -methyl-oxazol-5-yl] -methanol as a white solid (774 mg). Sulfonyl methanol chloride (281 mg, 2.45 mmol) is added dropwise to a solution of [2- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -4-methyl-oxazole-5-yl. ] -methanol (724 mg, 2.04 mmol) dissolved in dichloromethane (40 ml) at -78 ° C under nitrogen. Triethylamine (269 mg, 2.66 mmol) is added dropwise and the mixture is allowed to warm to room temperature with stirring for 2 h. The mixture is then diluted with dichloromethane (100 ml), rinsed with saturated sodium carbonate solution (2 x 100 ml) and brine (100 ml). The organic extracts are dried over magnesium sulfate, then concentrated in vacuo. A mixture of the resulting residue (100 mg, 0.23 mmol), diethylamine (169 mg, 2.30 mmol) and tetrahydrofuran (2 ml) is subjected to microwave irradiation at 150 ° C for 15 minutes. The resulting mixture is concentrated in vacuo and purified by flash column chromatography, eluting with 2% ammonia in methanol / dichloromethane in a 1:49 ratio, to give a brown gum. The gum is dissolved in dichloromethane (0.5 ml), then hydrogen chloride (1 M solution in diethyl ether, 0.5 ml) is added and the mixture is concentrated in vacuo to give the title compound as a 1: 1 hydrochloride salt ( 32 mg). 1 H NMR (400MHz, CD3OD) d 0.85-1.38 (6H, m), 1.46 (6H, t, J 7.5), 1 .55-1.78 (4H, m), 1.88 (1H, m), 2.39 (3H, s), 3.34 (4H, q, J 7.6), 3.98 (3H, s), 4.34 (2H, d, J 6.9), 4.65 (2H, s), 6.88 (1 H, d , J 8.2), 7.23 (1 H, t, J 8.0), 7.74 (1 H, d, J 8.0), 8.00 (1 H, s). EslMS: m / z 410.3 [M + Hf, 337.1. EXAMPLE 32 1- (Cyclohexinmethyl-3- (2-rd-diethylamino) met.p-ri, 3-oxazol-5-yl) -7-methoxy-1 H-indole, hydrochloride salt A solution of (1 -cyclohexylmethyl-7-methoxy-1H-indol-3-yl) -oxoacetonitrile (prepared as described in Example 28; 2.39 g, 8.06 mmol) in acetic acid (50 ml) under nitrogen was added 10% palladium in charcoal (240 mg). The reaction is placed under a hydrogen atmosphere and stirred overnight. The reaction mixture is then filtered through a dicalite bearing. The dicalite is rinsed with acetic acid and the combined filtrate is evaporated to leave a red oil. The red oil is taken up in dichloromethane (50 ml) and to this is added chloroacetyl chloride (0.77 ml, 9.67 mmol) followed by triethylamine (3.4 ml)., 24.2 mmol) per drops. The reaction is stirred for 30 minutes and poured into a separate funnel. The organics are sequentially rinsed with 5% aqueous sodium carbonate (2 x 30 ml) and brine (30 ml). The organics are dried over magnesium sulfate, filtered and the solvent is removed in vacuo to leave a red / brown oil. The oil is purified by flash chromatography using 20-100% (v / v) dichloromethane in heptane followed by 25-50% (v / v) diethyl ether in heptane to provide 2-chloro-N- [2- (1-cyclohexylmethyl -7-methoxy-1 H-indol-3-yl) -2-oxoethyl] -acetamide (2.32 g, 6.1 mmol). To a solution of 2-chloro-N- [2- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -2-oxoethyl] -acetamide (200 mg, 0.53 mmol) in tetrahydrofuran (2 ml Diethylamine (0.55 ml, 5.3 mmol) is added and the reaction mixture is subjected to microwave irradiation at 150 ° C for 15 minutes. The reaction mixture is poured into a separate funnel and dichloromethane (30 ml) is added. The organics are sequentially rinsed with 5% aqueous sodium carbonate and brine. The organics are dried over magnesium sulfate, filtered and the solvent is removed in vacuo to give a brown solid. The brown solid is dissolved in tetrahydrofuran (2 ml) and hydroxide (methoxycarbonyl-sulfamoyl) triethylammonium, inner salt (505 mg, 2.12 mmol) is added. The resulting reaction mixture is subjected to microwave irradiation at 150 ° C for 15 minutes and quenched with methanol (20 ml). The solvent is removed in vacuo and the residue purified by flash chromatography using 50% (v / v) ethyl acetate in heptane, followed by semi-prep HPLC. [Method (ii)] to provide a white solid. The solid is dissolved in dichloromethane (~5 ml) and hydrogen chloride (1 M solution in diethyl ether: 1 ml) is added. The mixture is concentrated in vacuo to give the title compound as a 1: 1 hydrochloride salt (77 mg, 0.2 mmol). 1 H NMR (400 MHz, CD3OD) dH 0.97-1.12 (2H, m), 1.15-1.25 (3H, m), 1.44 (6H, t, J 6.9), 1.52-1.62 (2H, m) , 1 .62-1.77 (3H, m), 1 .7-7-1 .9 (1 H, m), 3.36 (4H, q, J 6.7), 3.95 (3H, s), 4.26 (2H, d , J7), 4.64 (2H, s), 6.77 (1 H, d, J8), 7.1 1 (1 H, t, J 8), 7.38 (1 H, s), 7.41 (1 H, d, J 8 ), 7.56 (1 H, s); Esl MS: m / z 396.1 [M + H] +, 323.4, 268.4. EXAMPLE 33 1- (Cyclohexinmethyl-3- (5-etiU5,6-dihydro-4H-pyrrolor-3,4-disothiazol-3-yl) -7-methoxy-1 H-indole, hydrochloride salt A suspension of 5- ( 1-Cyclohexylmethyl-7-methoxy-1 H-indoI) - [1, 3,4] -oxatjazol-2-o? A (prepared as described in Example 7; 100 mg, 0.25 mmol) in m- xylene (0.5 ml) is added diethylacetylene dicarboxylate (0.2 ml, 1.25 mmol) and the reaction is subjected to microwave irradiation at 200 ° C for 5 minutes.The reaction mixture is then directly purified by flash column chromatography using 0- 100% (v / v) dichloromethane in heptane to provide diethyl ester of 3- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -iso-thiazole-4,5-dicarboxylic acid ester (141 mg, 0.3 mmol) This reaction is repeated on a scale of 1.255 mmol and the whole is combined and purified by flash column chromatography using 50-60% (v / v) dichloromethane in heptane to give the same intermediate compound (882 mg 1.87 mmol) to a cold solution (water bath). ice / methanol) of 3- (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl) -isothiazole-4,5-dicarboxylic acid diethyl ester (400 mg, 0.85 mmol) in tetrahydrofuran (20 ml) lithium aluminum hydride (1 M solution in THF; 1.91 mL, 1.91 mmol) and the reaction mixture is stirred for 20 minutes. Sodium sulfate decahydrate in excess is added to the reaction mixture and the reaction is stirred vigorously for 1.5 hours. The resulting mixture is filtered through a dicalite bearing, rinsing with diethyl ether. The filtrate is concentrated in vacuo and the resulting oil is purified by flash column chromatography to provide 3- (1-cyclohexylmethyl-7-methoxy-1 H-indol-3-yl) -4-hydroxymethyl-isothiazol-5-yl] -methanol (141 mg, 0.3 mmol). To a solution of 3- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -4-hydroxymethyl-isothiazol-5-yl] -methanol (194 mg, 0.5 mmol) in dichloromethane (10 ml) Methanesulfonyl chloride (0.182 mL, 1.16 mmol) is added followed by triethylamine (0.175 mL, 1.26 mmol) and the reaction mixture is stirred for 45 minutes. An additional portion of methanesulfonyl chloride (0.07 ml, 0.44 mmol) and triethylamine (0.15 ml, 1 mmol) is added and the reaction is stirred for a further 2 hours. The reaction mixture is poured into a separate funnel, rinsed with 5% aqueous sodium carbonate solution, then with brine, dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting residue is purified by flash column chromatography using 33% -100% (v / v) dichloromethane in heptane and then diethyl ether to provide methyl ester of acid. { 4-Cromomethyl-3- [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] -isothiazol-5-yl} methanesulfonic acid (13 mg, 0.23 mmol). To a solution of methyl acid ester. { 4-chloromethyl-3- [1 - (cyclohexyl) methyl-7-methoxy-1 H-indol-3-yl] -isothiazol-5-yl} methanesulfonic acid (90 mg, 0.19 mmol) in tetrahydrofuran (1 ml) is added ethylamine (0.186 ml, 0.37 mmol) and triethylamine (0.05 ml, 0.37 mmol) and the reaction mixture is subjected to microwave irradiation at 150 ° C for 15 minutes. minutes The reaction mixture is poured into a separate funnelDilute with dichloromethane (30 ml) and rinse with 5% aqueous sodium carbonate solution (2 x 10 ml), brine (10 ml), dry over magnesium sulfate and remove the solvent in vacuo. The reaction is repeated on a scale of 0.166 mmol to give the same intermediate compound. The crude products are combined and purified by flash column chromatography using ethyl acetate to give the title compound (36 mg, 0.09 mmol) as the free base. The free base is dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) is added. The mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt. 1H NMR (400 MHz, CD3OD): 0.97-1.15 (2H, m), 1.15-1.27 (3H, m), 1.47 (3H, t, J7), 1.52-1.61 (2H, m) , 1 .62-1 .77 (3H, m), 1 .81 -1 .95 (1 H, m), 3.63 (2H, q, J7), 3.95 (3H, s), 4.28 (2H, d, J7), 4.62-4.75 (2H, m), 4.95-5.12 (2H, m), 6.77 (1 H, d, J 8), 7.09 (1 H, t, J8), 7.43 (1 H, s), 8.01 (1 H, d, J 8); EslMS: m / z 396.0 [M + H] +, 353.4, 351.3, 320.3. EXAMPLE 34 1 - (Cyclohexyl) methyl-7-methoxy-3- (5-r (pyrrolidin-1-yl) methan-isoxazol-3-yl) -1 H-indole, trifluoroacetic acid salt Phosphorous oxychloride (12 ml, 0.13 mol) is added slowly for 30 minutes to dimethylformamide (30 ml) at -10 ° C. The solution is allowed to warm to 0 ° C for 1 h, then 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole (prepared as in Example 26; 3.2 g, 13 mmol) is added per portion and the solution Stir at room temperature for 16 h. The solution is cooled in a cold bath and diluted with water, then carefully neutralized with sodium bicarbonate and extracted with ethyl acetate (3 x 50 ml), the organic extracts are combined and the solvent is removed in vacuo. The residue (3.5 g) is dissolved in aqueous sodium hydroxide solution (5 M, 100 ml) and the mixture is refluxed at 100 ° C for a further 16 h. The solution is cooled and extracted with ethyl acetate (3 x 50 ml), the organic extracts are combined and the solvent is removed in vacuo to give 1- (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carbaldehyde (2.2 g, 8.12 mmol) as a white solid. To a solution of 1 - (cyclohexyl) methyl-7-methoxy-1 H-indole-3-carbaldehyde (780 mg, 2.9 mmol) in a mixture of ethanol (8 ml) and water (2 ml) is added hydroxylamine hydrochloride (403 mg, 5.8 mmol) and sodium acetate (713 mg, 8.7 mmol) and the solution is stirred for 64 h at room temperature. The mixture is concentrated in vacuo and the residue is diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The product is recrystallized from diethyl ether / hexane to produce 1-cyclohexyl-methyl-7-methoxy-1 H-indole-3-carbaldehyde oxime (380 mg, 1.3 mmol) as a yellow powder. To a solution of 1-cyclohexylmethyl-7-methoxy-1 H-indole-3-carbaldehyde oxime (170 mg, 0.59 mmol) in dichloromethane (5 ml) cooled to 0 ° C, add N-chlorosuccinimide (1 ml). mg, 0.89 mmol) and the mixture is allowed to warm to room temperature with stirring for 1 h. Propargyl bromide (8 μl, 0.65 mmol) and triethylamine (9 μl, 0.65 mmol) are added and the mixture is stirred at room temperature for 16 h. The solvent is removed in vacuo and the residue is purified by flash column chromatography eluting with 60-80% (v / v) dichloromethane in n-heptane to provide 3- (5-bromomethyl-isoxazol-3-yl) -1 - Cyclohexylmethyl-7-methoxy-1 H-indole (150 mg, 0.37 mmol) as a yellow solid. To a solution of 3- (5-bromomethyl-isoxazol-3-yl) -1-cyclohexylmethyl-7-methoxy-1 H-indole (120 mg, 0.31 mmol) in acetonitrile (3 mL), diethylamine (0.024 mL, 0.34) mmol) is added. The mixture is stirred at room temperature for 16 h. The mixture is filtered and the solvent is removed in vacuo. The residue is purified using semi-prep HPLC. [Method (ii)] to provide the title compound as a trifluoroacetic acid salt (20 mg). 1 H NMR (400 MHz, CD3OD) d 1 .03-1 .09 (2H, m), 1.21 (3H, m), 1 .57-1 .74 (5H, m), 1.83-1.89 (1 H, m), 2.14 (4H, m), 3.38-3.60 (4H, m), 3.96 (3H, s), 4.27-4.29 (2H, d, J 6.9), 4.69 (2H, s), 6.78 (1 H, d, J 7.5), 7.02 (1 H, s), 7.08-7.12 (1 H, m), 7.67 (1 H, s), 7.67-7.69 (1 H, d, J8.1). EslMS: m / z 394.1 [M + H] +, 323.4. Example 35 1-Cyclohexyl) methyl-7-methoxy-3- (5-frib- (2-hydroxyethyl) amino-1-methyl-isoxazol-3-yl) -1H-indole, trifluoroacetic acid salt The title compound is prepared following the method of Example 34 using diethanolamine in place of pyrrolidine. EslMS: m / z 428.4 [M + H] +, 323.4. Example 36 1 - (Cyclohexyl) methyl-7-fluoro-3-f5-r (pyrrolidin-1-inmethyl-thiophene-2-n-1 H-indole, hydrochloride salt A cold solution of 7-fluoroindole (2.0 g, 14.8 mmol) in dimethylformamide (50 ml) is added sodium hydride (60% dispersion in mineral oil; 0.88 g, 22.2 mmol) and the mixture is stirred for 15 min before the addition by drops of benzenesulfonyl chloride (2.26 ml, 17. 8 mmol). The mixture is then stirred at room temperature for 18 h. The suspension is then diluted with water (200 ml), extracted with methyl tert-butyl ether (3 x 100 ml) and the combined organic layers are rinsed with water (3 x 100 ml), dried with sodium sulfate and concentrated in vacuo. . The residue is purified by flash column chromatography eluting with 20% (v / v) ethyl acetate in isohexane to give 1-benzenesulfonyl-7-fluoroindole as an uncoloured solid (3.96 g, 14.4 mmol). To a solution of 1-benzenesulfonyl-7-fluoroindole (2.0 g, 7.27 mmol) in dimethylformamide (10 ml) is added a solution of bromine (0.75 ml, 14.55 mmol) in di-methylformamide (25 ml) per drops for 3 min. . The mixture is then stirred at room temperature for 10 min and poured into a mixture of sodium metabisulfite (2 g), ammonium hydroxide solution (3 ml), water (100 ml) and crushed ice (100 g). The resulting suspension is stirred until all the color has been discharged and extracted into methyl-tert-butyl ether (2 x 100 ml). The combined organic layers are rinsed with water (2 x 100 ml), dried with sodium sulfate and the solvent removed in vacuo to give 1-benzenesulfonyl-3-bromo-7-fluoroindole as a salmon colored solid (2.35 g, 6.64 g. mmol). A solution of 1-benzenesulfonyl-3-bromo-7-fluoroindole (0.5 g, 1.41 mmol), 5-formyl-2-tyne-boronic acid (0.24 g, 1.55 mmol), bis (triphenylphosphine) palladium (II ) dichloride (0.06 g, 0.08 mmol) and triethylamine (0.39 ml, 2.82 mmol) in ethanol (4 ml) is subjected to microwave irradiation at 150 ° C for 420 s. The resulting suspension is concentrated under reduced pressure and the residue is passed through a silica pad eluting with dichloromethane to give crude 5- (1-benzenesulfonyl-7-fluoroindol-3-yl) -thiophene-2-carboxaldehyde as a brown solid (0.42 g) which was used in the next step without further purification. To the crude 5- (1-benzenesulfonyl-7-fluoroindol-3-yl) -thiophene-2-carboxaldehyde were added sequentially 4 A molecular sieves (1 g), pyrrolidine (0.44 ml, 5.36 mmol), sodium cyanoborohydride (0.034 g) , 0.54 mmol) and glacial acetic acid (1 drop). The resulting mixture is then stirred at room temperature for 18 h, filtered and the filter cake is rinsed with methanol (2 x 30 ml) and dichloromethane (2 x 30 ml). The combined filtrate is concentrated in vacuo, dissolved in dichloromethane (20 ml), rinsed with aqueous sodium hydroxide (2 M, 15 ml), dried with sodium sulfate and concentrated in vacuo. The residue is then purified by flash column chromatography eluting with 0-10% (v / v) methanol in dichloromethane to provide 1-benzenesulfonyl-7-fluoro-3- (5-pyrrolidin-1-methylmethyl-thiophen-2). -il) -indole as a yellow oil (0.22 g, 0.46 mmol). 1-Benzenesulfonyl-7-fluoro-3- (5-pyrrolidin-1-ylmethyl-thiophen-2-yl) -indole (0.20 g, 0.46 mmol) and potassium carbonate (0.25 g, 1.82 mmol) are treated with a mixture of methanol and water (3: 1 v / v; 4 ml) and subjected to microwave irradiation at 100 ° C for 600 s. The resulting suspension is then concentrated under reduced pressure and partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase is separated and the aqueous phase is rinsed with dichloromethane (10 ml). The combined organic layers are dried with sodium sulfate and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 0-10% (v / v) methanol in dichloromethane to provide 7-fluoro-3- (5-pyrrolidin-1-ylmethyl-thiophen-2-yl) -indole as a solid without color (0.10 g, 0.35 mmol). To a solution of 7-fluoro-3- (5-pyrrolidin-1-ylmethyl-thiophen-2-yl) -indole (0.10 g, 0.35 mmol) in dimethylformamide (3 ml) is added sodium hydride (60% dispersion in mineral oil, 0.03 g, 0.71 mmol) and the mixture is stirred at room temperature for 15 minutes.

Bromomethylcyclohexane (0.05 ml, 0.39 mmol) is added and the mixture is stirred at 60 ° C for 18 h. The suspension is then diluted with water (30 ml), extracted in methyl tert-butyl ether (2 x 30 ml), the combined organic layers are rinsed with water (2 x 20 ml), they are dried with sodium sulphate and evaporated under reduced pressure. The residue is purified by flash chromatography eluting with 5% (v / v) dichloromethane in methanol to give the title compound (free base) as an uncoloured solid (0.05 g, 0.13 mmol). This is dissolved in diethyl ether (3 ml) and treated with hydrogen chloride (1M solution in diethyl ether) to evaporate the title compound (hydrochloride salt 1: 1) as an uncoloured solid. 1 H NMR (400 MHz, CD3OD) dH 1.02-1.34 (5H, m), 1.57-1.93 (6H, m), 2.11-2.19 (4H, m), 3.38-3.57 (4H, m), 4.19 (2H, d, J 7.4), 4.65 (2H, s), 6.91-7.36 (4H, m), 7.58 (1H, s), 7.71 (1H, d, J 8.1); EslMS: m / z 396.9 [M + H] +, 326.0 Example 37 1- (Cyclohexyl) methyl-3- (5-r (diethylamino) metin-ri, 3,41-oxadiazol-2-yl> - 7-methoxy-1H-indole, hydrochloride salt To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (1.0 g, 3.48 mmol) in dichloromethane (20 ml) is added oxalyl chloride (0.6 ml, 6.96 mmol) and the reaction is stirred for 3.5 h The solvent is evaporated under reduced pressure and the resulting residue is redissolved in dichloromethane (20 ml) To the solution is added chloroacetic acid hydrazide (1.3 g, 8.97 mmol. ) and triethylamine (2.9 ml, 20.9 mmol) and the reaction mixture is stirred for 4 h and then left to stand overnight.The solvent is evaporated under reduced pressure and the resulting residue is purified by flash column chromatography eluting with 50 ml. -1.00% (v / v) ethyl acetate in. Heptane to give 1-cyclohexylmethyl-7-methoxy-1H-indoi-3-carboxylic acid N '- (2-chloroacetyl) hydrazide (397 mg, 1.05) mmol) to a solution of ac 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N- (2-chloroacetyl) hydrazide (250 mg, 0.662 mmol) in tetrahydrofuran (3 ml) is added (methoxycarbonylsulfamoyl) triethylammonium hydroxide, inner salt ( 31 mg, 1.32 mmol) and the resulting reaction mixture is subjected to microwave irradiation at 150 ° C for 15 minutes. The reaction mixture is quenched with methanol and the solvent is evaporated. The resulting residue is purified by flash chromatography using 33-50% (v / v) ethyl acetate in heptane to give 3- (5-chloromethyl- [1, 3,4] oxadiazol-2-yl) -1-cyclohexylmethyl- 7-methoxy-1 H-indole (169 mg, 0.47 mmol) as a yellow solid. This reaction is repeated on a 0.53 mmol scale to provide the same intermediate compound (a total of 276 mg, 0.77 mmol). To a solution of 3- (5-chloromethyl- [1, 3,4] oxadiazol-2-yl) -1-cyclohexy! Methy! -7-methoxy-1 H-indole (92 mg, 0.26 mmol) in tetrahydrofuran ( 1 ml) is added diethylamine (0.134 ml, 1.28 mmol) and the reaction mixture is subjected to microwave irradiation at 50 ° C for 15 minutes. The resulting mixture is purified by flash column chromatography to provide the title compound (87 mg, 0.22 mmol) as the free base. The free base is dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1 mL, 2 mmol) is added. The excess reagent and solvent are removed by evaporation to leave the title compound (hydrochloride salt 1: 1) as a white solid. 1 H NMR (400 MHz, CD3OD): 0.97-1.12 (2H, m), 1 .15-1 .26 (3H, m), 1.46 (6H, t, J 7), 1.53-1. 63 (2H, m), 1 .63-1 .78 (3H, m), 1 .8-1 .95 (1 H, m), 3.44 (4H, q, Jl), 3.98 (3H, s), 4.33 (2H, d, J7), 4.84 (2H, s), 6.85 (1H, d, J7), 7.19 (1H, t, J7.9), 7.73 (1H, d, J 8), 7.94 (1 H, s) j EslMS: m / z 397.1 [M + H] +, 324.4, 270.5. Example 38 1 - (Cyclohexinmethyl-7-methoxy-3-f5-r (pyrrolidin-1-yl) metin-ri, 3,41-thiadiazol-2-yl.} -1 H-indole, hydrochloride salt A solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N '- (2-chloroacetyl) hydrazide (prepared as described in Example 37; 50 mg, 0.139 mmol) in tetrahydrofuran (0.5 ml) was add phosphorus pentasulfide (62 mg, 0.139 mmol) and the reaction mixture is subjected to microwave irradiation at 150 ° C for 5 minutes.The reaction is repeated twice on a scale of 0.7 mmol.The combined reaction mixture is poured in a separate funnel and dilute with dicyoromethane (60 ml) The organics are rinsed with 5% aqueous sodium carbonate (2 x 30 ml), brine (30 ml), dry over sodium sulfate and the solvent is removed in vacuo. The resulting residue is purified by flash column chromatography to provide 3- (5-chloromethyl- [1, 3,4] thiadiazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1 H-indole (186 mg, 0.49 mmol). To a solution of 3- (5-chloromethyl [1, 3,4] thiadiazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1 H-indole (93 mg, 0.25 mmol) in tetrahydrofuran is added pyrrolidine ( 0.101 ml, 1235 mmol) and the mixture is subjected to microwave irradiation at 150 ° C for 5 minutes. The resulting reaction mixture is purified by flash column chromatography to give the title compound (42 mg, 0.1 mmol) as the free base. The free base is dissolved in dichloromethane and hydrogen chloride (1 M solution in diethyl ether; 1 ml, 1 mmol) is added. The excess reagent and solvent are removed in vacuo to provide the title compound as a 1: 1 hydrochloride salt. 1 H NMR (400 MHz, CDCl 3): 0.94-1.1 (2H, m), 1.13-1.23 (3H, m), 1.5-1.75 (8H, m), 1.8-1.9 (5H, m), 2.66-2.73 (4H , m), 3.95 (3H, s), 4.12 (2H, s), 4.23 (2H, d, JT), 6.73 (1H, d, J 7.8), 7.17 (1H, t, J 8), 7.66 (1H , s), 7.77 (1H, d, J8); EslMS: m / z411.1 [M + H] +, 340.0, 324.4, 286.1, 270.5. Example 39 7-Chloro-3-. { 5-r (2.2-dimethyl-pyrrolidin-1-inmetip-ri.2.41oxadiazol-3-yl.}. -1- (tetrahydropyran-4-yl) methyl-1H-indole, hydrochloride salt Method for the synthesis of 2, 2-dimethyl-pyrrolidinone. sodium borohydride (3.36 g, 89 mmol) is added by portion to a stirred and cooled (0 ° C) of NiCI2.6H2O in methanol (200 ml) The reaction mixture is stirred for 30 min before the addition of methyl-4-methyl-4-nitropentanoate as solution in methanol (100 ml) The reaction temperature is maintained at 0 ° C before the addition of sodium borohydride (7.86 g, 208 mmol) by portion. the reaction was then allowed to stir for 72 hours, before filtration through a celite bearing .. the resulting cake was rinsed with methanol (150 ml) and the filtrate evaporated to dryness. the resulting solid was triturated with dichloromethane (400 ml) and filtered through a celite pad.After rinsing the cake with dichloromethane (200 ml) the filtrate is evaporated to give the product, 2,2-dimethyl-p Irrolidinone, as pale green gum (6.8 g). Method for Synthesis of 2,2-dimethyl-pyrrolidine: Lithium aluminum hydride (1 M solution in tetrohidrofuran; 120 ml, 120 mmol) to a stirred solution of 2,2-dimethyl-pyrrolidinone (6 slowly added g, 53 mmol) in tetrahydrofuran (150 ml). In the complete addition, the reaction is heated to reflux, and stirred under reflux under argon for 16 hours. After this time, the reaction is allowed to cool to 0 ° C before the addition of water (2.2 ml), 10% sodium hydroxide solution (2.2 ml) and water (6.6 ml) at 45 minute intervals. The resulting paste is diluted with diethyl ether (150 ml) and filtered through a celite pad. The cake is rinsed with diethyl ether (250 ml) and the filtrate is acidified with hydrochloric acid (1 M solution in diethyl ether, 63 ml). The resulting yellow solid is filtered to provide 2,2-dimethyl-pyrrolidine hydrochloride (4.8 g). Method for the synthesis of acid ethyl ether (2,2-dimethyl-pyrrolidin-1 -yl) -acetic acid: ethylchloroacetate (0.15 mL, 1 .37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2.2 dimethyl-pyrrolidine (0.280 mg, 2.06 mmol) are suspended in ethanol (3 ml) and subjected to microwave irradiation at 120 ° C for 45 min. The resulting mixture is suspended in diethyl ether (30 ml), extracted with 2M hydrochloric acid (30 ml) and the organic layer is discarded. The aqueous layer is treated with a slight excess of 4N sodium hydroxide solution and extracted with diethyl ether (3 x 30 ml). The organic layers are combined, dried over sodium sulfate, filtered and the solvent is removed under reduced pressure to provide ethyl ester of (2,2-dimethyl-pyrrolidin-1-yl) -acetic acid (156 mg). The title compound is prepared following the method of Example 1 using 7-chloroindole instead of 7-methoxyindole; toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester (prepared as described in Example 14) in place of cyclohexylmethyl bromide and ethyl ester of (2,2-dimethyl-pyrrolidin-1-yl) -acetic acid instead of Methyl N, N-dimethylglycine ester. 1H NMR (400 MHz, CD3OD) d 1.45 (10H, m), 2.22 (5H, m), 3.35 (2H, m), 3.59 (1H, br s), 3.91 (2H, d, J 11.1), 4.12 ( 1H, br s), 4.52 (2H, d, J 7.1), 4.71 (1H, br s), 4.95 (1H, br s); 7.23 (1H, t, J 7.6), 7.32 (1H, d, J 7.6), 8.08 (1H, s), 8.13 (1H, d, 'J 7.6). EslMS: m / z429.5 [M + H] +. Example 40 1-rCyclohexyl) methyl-3-f5-r (pyrrolidin-1-yl) metin-ri.2,41-thiadiazol-3-yl > -1H-Indole-7-carbonitrile, hydrochloride salt A suspension of [3- (7-bromo-1-cyclohexylmethyl-1 H-indol-3-yl) - [1,4] thiadiazol-5-yl] -methanol (prepared from 7-bromoindole as described in Example 7; 2 x 250 mg, 0.16 mmol), zinc (II) cyanide (2 x 72 mg, 0.61 mmol) and titanium ester (triphenylphosphine) -palladium (0) ) (2 x 21 mg, 1 8.3 μmol) in DM F (2 x 4 ml) is subjected to microwave irradiation at 200 ° C for 5 min using an Emrys ™ Optimizer EXP. The reactions are combined and poured into a separate funnel, to which dichloromethane (~ 50 ml) is added. The organics are rinsed successively with water (2 x 20 ml), 1 M aqueous HCl (20 ml) and brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The resulting oil is purified by flash column chromatography eluting with 50-100% (v / v) dichloromethane in heptane and then diethyl ether to give 1-cyclohexylmethyl-3- (5-hydroxymethyl- [1,4,4] thiadiazole- 3-yl) -1 H -indole-7-carbonitrile (416 mg, 1.118 mmol) as a light yellow oil which crystallizes permanently. To a solution of 1-cyclohexylmethyl-3- (5-hydroxymethyl- [1, 2,4] thiadiazol-3-yl) -1 H -indole-7-carbonitrile (416 mg, 1.118 mmol) in dichloromethane (40 mg). ml) methanesulfonyl chloride (0.1 ml, 1.42 mmol) and triethylamine (0.214 mL, 1.53 mmol) sequentially. The reaction is allowed to stir for 1 h and then poured into a separate funnel. The organics are rinsed with 2M aqueous sodium carbonate solution (20 ml), brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo to provide 3- (7-cyano) acid ester. 1-cyclohexylmethyl-1 H-indol-3-yl) - [1, 2,4] thiadiazol-5-ylmethyl methanesulfonic acid (503 mg, 1.1 mmol) which was used without further purification. To a solution of 3- (7-cyano-1-cyclohexylmethyl-1H-indol-3-yl) - [1, 2,4] thiadiazol-5-ylmethyl methanesulfonic acid ester (120 mg, 0.28 mmol) in dichloromethane (3 ml) pyrrolidine (0.12 ml, 1.4 mmol) is added and the reaction is subjected to microwave irradiation at 100 ° C for 5 minutes. The reaction is purified directly by flash column chromatography eluting with dichloromethane then 25-50% (v / v) ethyl acetate in heptane to give the title compound (71 mg, 0.175 mmol) as the free base. The free base (35 mg, 0.086 mmol) is dissolved in dichloromethane (2 ml) and hydrogen chloride (1 M solution in diethyl ether) is added. The mixture is concentrated in vacuo to provide the title compound as a 1: 1 hydrochloride salt. 1 H NMR (400 MHz, CD3OD): 1.06-1.36 (7H, m), 1.62-1.80 (5H, m), 1.91 -2.07 (1 H, m), 2.09-2.34 (2H, br m), 3.35-4.20 (4H, br m), 4.42 (2H, d, J 7), 5.07 (2H, s), 7.37 (1 H, t, J 8), 7.69 (1 H, dd, J7 , 1), 8.23 (1 H, s); 8.84 (1 H, dd, J8, 1) EslMS: m / z406.4 [M + H] +. EXAMPLE 41 In Vitro Determination of Efficacy and Potency in the Human CB1 Receptor Expressed in CHO Cells The Chinese Hamster Ovarian (CHO) cells expressing the human CB1 receptor and a luciferase reporter gene are suspended in the red phenol / DMEM free mixture. serum / F-12 nut containing penicillin / streptomycin (50U / 50 μg / ml) and fungizone (1 μg / ml) and seeded in 96-well plates at a density of 3 × 10 4 cells per well (final volume 100 μl). Cells are incubated overnight (approximately 18 h at 37 ° C, 5% CO2 / 95% air) before testing. The test compound (10 mM solution in dimethylsulfoxide) is diluted in F12 Nut Mixture to give a range of stock solutions from 0.1 1 mM to 0.1 1 nM. The reserve solutions (10 μl) are added directly to the relevant cavities. The plates are incubated at 37 ° C for 5 h to allow expression induced by the luciferase enzyme agonist. Under low light, LucLite substrate (Packard; reconstituted as per the manufacturer's instructions; 100 μl) is added to each cavity. The plates are covered with Superior Seal and then incubated at room temperature for 5 minutes before counting in the Packard TopCount (single photon count, counting time 0.01 minutes, countdown delay of 5 minutes). A 'best fit' curve is adjusted by a minimum sum of squared method for the count per second (CPS) versus compound concentration (M) chart to obtain an EC50 value. Table 1 shows the PEC50 values obtained for some representative compounds of the invention Table 1 Example 42 Fast Tail Motion Latency in Mice Mice are trained to sit still on a fast tail movement device (Ugo Basile, Italy) while the latency of fast tail movement is measured. The tail is exposed to a focused beam of radiant heat at a point about 2.5 cm from the tip. The latency of fast movement of the tail is defined as the interval between the application of the thermal stimulus and extraction of the tail. A cut of 12 seconds is used to prevent tissue damage. Four groups of eight mice are treated with vehicle or one of three doses of the test compound, administered intravenously (vehicle: 10% Tween-80 in saline, injection volume 10 ml / kg). The latency of rapid tail movement is measured before administration of the test compound and at regular intervals (typically 20, 40 and 60 minutes) after administration of the compound. The ED50 are calculated in Tmax. Compounds of examples 2G, 13, 14B, 15A, 15B, 15C, 20, 23B, 23C, 23D and 39 significantly increased the latency of fast tail movement with an ED50 < 5 μmol / kg.

Claims (10)

1. CLAIMS 1. A (indol-3-yl) -heterocycle derivative having the general Formula I
2. Formula I wherein A represents a 5-membered aromatic heterocyclic ring, wherein Xi, X2 and X3 are independently selected from N, O, S and
3. CR; R is H or (C? -) alkyl; or R, when present in X2 or X3, can form a ring of 5-8 members with R3; R1 is a 5-8 membered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S; R2 is H, CH3 or CH2-CH3; or R2 is attached together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and such a heteroatom is attached to the 7-position of the indole ring; R3 and R4 are independently H, (C6-6) alkyl or (C3-7) cycloalkyl, the alkyl groups being optionally substituted with OH, (Ci.4) alkyloxy, (C1.) Alkaline, (C1-4) alkylsulfonyl, CN or halogen; or R3 together with R4 and the N to which they are attached form a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C? -4) alkyl, (C1- 4) alkyloxy, (C? -) alkyloxy- (C? -4) alkyl, or halogen; or R3 together with R5 forms a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C? -4) alkyl, (C? -4) alkyloxy, (C -4) alkyloxy- (C? _4) alkyl, or halogen; or R3 together with R, when present in X2 or X3, forms a ring of 5-8 members; R5 is H or (C1-4) alkyl; or R6 together with R3 forms a 4-8 membered ring optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C? -4) alkyl, (C? -4) alkyloxy, (C -4) alkyloxy- (C1-) alkyl, or halogen; R5 'is H or (C1-4) alkyl; R6 represents 1 -3 substituents independently selected from H, (C? -) alkyl, (C? -4) alkyloxy, CN and halogen; R 7 is H, (C 4 -4) alkyl, (C 1-4) alkyloxy, CN or halogen; or R7 is joined together with R2 to form a 6-membered ring, optionally containing an additional heteroatom selected from O and S, and such heteroatom is attached to the 7-position of the indole ring; or a pharmaceutically acceptable salt thereof. 2. The (indoi-3-yl) -heterocycle derivative according to claim 1, characterized in that R2 is H or is joined together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and such atom is attached to position 7 of the indole ring. 3. The (indol-3-yl) -heterocyclic derivative according to claim 1 or 2, characterized in that R, R5, R5 'and R6 are H.
4. 4. The (ndol-3-yl) -heterocycle derivative according to any of claims 1 -3, characterized in that Ri is cyclohexyl or tetrahydropyranyl.
5. 5. The (indol-3-yl) -heterocycle derivative according to any of claims 1 -4, characterized in that the heterocycle A is 1, 2,4-oxadiazole (Xi is N, X2 is O, X3 is N), 1, 2,4-thiadiazoI (Xi is N, X2 is S, X3 is N) or thiazole (Xi is S, X2 is CR, X3 is N).
6. 6. The (indol-3-yl) -heterocycle derivative according to claim 1 which is selected from: - 7-Chloro-3- (5- { [N-ethyl-N- (2-methoxyethyl) amino] methyl.}. - [1, 2,4] -thiazol-3-yl) -1- (tetrahypiper-4-yl) methyl-1 H-indole; - 7-Chloro-3-. { 5 - [(pyrrolidin-1-yl) methyl] - [1, 2,4] -thiadiazol-3-yl} -1 - (tetrah id ropiran-4-yl) methyl-1 H-indole; - 7-Chloro-3- (5- { [N-ethyl-N- (2-hydroxyethyl) amino] methyl.} - - [1,4] - thiadiazol-3-yl) -1 - ( tetrah id ropyran-4-yl) methyl-1 H-indole; - 7-Chloro-3- (4- { [N- (2-hydroxyethyl) -N-isopropylamino] methyl.} - [1, 3] - thiazol-2-yl) -1 - (tetrahydrate) -4-yl) methyl-1 H-indole; - 7-Chloro-3- (4-. {[[N-ethyl-N- (2-hydroxyethyl) amino] methyl] - [1, 3] -thiazole-2-yl) -1 - (tetrahydropyran -4-yl) methyl-1 H-indole; - 7-Chloro-3- (4- { [N- (2-methoxyethyl) -N-methylamino] methyl.} - - [1, 3] -thiazol-2-yl) -1- (tetrahydropyran-4) -yl) methyl-1 H-indole; - 7-Chloro-3-. { 5 - [(2,2-dimethyl-pyrrolidin-1-yl) methyl] - [1, 2,4] oxadiazol-3-i I.}. - 1 - (tetrah id ropiran-4-il) methyl-1 H-in do I; or a pharmaceutically acceptable salt thereof.
7. 7. The (indol-3-yl) -heterocycle derivative according to any of claims 1-6 for use in therapy.
8. 8. A pharmaceutical composition comprising a (indol-3-yl) -heterocycle derivative according to any of claims 1-6 in admixture with pharmaceutically acceptable auxiliaries.
9. 9. Use of a (indol-3-yl) heterocycle derivative of Formula I according to claim 1, in the preparation of a medicament for the treatment of pain.
10. 10. A method of treating pain such as perioperative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis, when administering a derivative of (indole-3-yl) to a patient in need thereof. -heterocycle according to any of claims 1-6. SUMMARY The invention relates to (indol-3-yl) -heterocycle derivatives having the general Formula (I) wherein A represents a 5-membered aromatic heterocyclic ring, wherein X ^ X2 and X3 are independently selected from N, O , S and CR; R is H or (Ci 4) alkyl; or R, when present in X2 or X3, can together with R3 form a ring of 5-8 members; R1 is a 5-8 membered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S; R2 is H, CH3 or CH2-CH3; or R2 is attached together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and such a heteroatom is attached to the 7-position of the indole ring; R3 and R4 are independently H, (C? .6) alkyl or (C3-7) cycloalkyl, the alkyl groups being optionally substituted with OH, (C? -) alkyloxy, (C? 4) alkylthio, (C? ) alkylsulfonyl, CN or halogen; or R3 together with R and the N to which they are attached form a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C? -) alkyl, (C? - 4) alkyloxy, (C? -4) alkyloxy- (C -4) alkyl, or halogen; or R3 together with R5 forms a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C? -4) alkyl, (C? -) alkyloxy, (C? -4) alkyloxy- (C? -) alkyl, or halogen; or R3 together with R, when present in X2 or X3, forms a ring of 5-8 members; R5 is H or (C? -4) alkyl; or R5 together with R3 forms a ring of 4-8 members optionally containing an additional heteroatom selected from O and S, and which is optionally substituted with OH, (C? _) alkyl, (C 1-4) alkyloxy, (C? 4) Alkyloxy- (C 1-4) alkyl, or halogen; R5 'is H or (C? _4) alkyl; R6 represents 1 -3 substituents independently selected from H, (C? -) alkyl, (C? -) alkyloxy, CN and halogen; R7 is H, (C? -) alkyl, (C? -4) alkyloxy, CN or halogen; or R7 is joined together with R2 to form a 6-membered ring, optionally containing an additional heteroatom selected from O and S, and such heteroatom is attached to the 7-position of the indole ring; or a pharmaceutically acceptable salt thereof, such as cannabinoid CB1 receptor agonists, which can be used in the treatment of pain such as, for example, peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.