RU2376302C2 - Derivatives (indole-3-yl) heterocyclic compounds as agonists of cannabinoid receptors cb1 - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1:

, where: A represents 5-member aromatic heterocyclic ring, where X₁, X₂ and X₃ are independently selected from N, O, S, CR; R means H, (C_1-4)alkyl; or R, when it is available in X₂ or X₃, may form 5-8-member ring together with R₃; R₁ means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R₂ means H; or R₂ is connected to R₇ with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R₃ and R₄ independently mean H, (C_1-6)alkyl, which is unnecessarily substituted with OH, (C_1-4)alkyloxy; or R₃ together with R₄ and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C_1-4)alkyl, (C_1-4)alkyloxy or (C_1-4)alkyloxy-(C_1-4)alkyl; or R₃ together with R₅ creates 4-8-member ring, unnecessarily substituted with OH, (C_1-4)alkyl, (C_1-4)alkyloxy; or R₃ together with R, when present in X₂ or X₃, creates 5-8-member ring; R₅ means H; or R₅ together with R₃ creates 4-8-member ring, unnecessarily substituted with OH, (C_1-4)alkyl, (C_1-4)alkyloxy; R_5' means H; R₆ means one substituent selected from H, (C_1-4)alkyl, (C_1-4)alkyloxy, halogen; R₇ means H, (C_1-4)alkyl, (C_1-4)alkyloxy, halogen; or R₇ is connected to R₂ with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

Description

The present invention relates to derivatives of (indol-3-yl) heterocyclic compounds, to pharmaceutical compositions containing them and to the use of these derivatives (indol-3-yl) heterocyclic compounds in therapy, especially in the treatment of pain.

Pain management is often limited by the side effects of currently available drugs. For moderate to severe pain, opioids are widely used. These drugs are inexpensive and effective, but have serious and potentially life-threatening side effects, especially respiratory depression and muscle stiffness. In addition, the doses of opioids that can be administered are limited to nausea, vomiting, constipation, pruritus, and urinary retention, which often result in patients choosing less optimal pain management than suffering these distressing side effects. Moreover, these side effects often lead to patients requiring prolonged hospitalization. Opioids are highly addictive drugs and are listed in many areas. Therefore, there is a need for new painkillers with an improved side effect profile compared to currently used products with equal painkillers.

Evidence is accumulating that cannabinoid agonists have potential as painkillers and anti-inflammatory drugs. Cannabinoid receptors include two types of receptors: CB1 cannabinoid receptors, which are mainly located in the central nervous system, but are also expressed by peripheral neurons and to a lesser extent in other peripheral tissues; and CB2 cannabinoid receptors, which are primarily located in cells of the immune system (Howlett, A.C. et al .: International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol. Rev. 54, 161-202, 2002). Although CB2 receptors are involved in modulating the immune and anti-inflammatory response of cannabinoids, cannabinoid receptor agonists, mainly those that interact with CB1 receptors, have been proposed as suitable for the treatment of pain (see Iversen, L. and Chapman, V. Current Opinion in Pharmacology, 2, 50-55, 2002 and references cited therein).

US Pat. No. 4,939,138 (Sterling Drug Inc.) describes WIN 55,212-2, the mesylate salt of (R) - (+) - [2,3-dihydro-5-methyl [(morpholinyl) methyl] pyrrolo [1, 2,3- de ] -1,4-benzoxazinyl] - (1-naphthalenyl) methanone. This compound is a prototype of aminoalkylindoles (Eissenstat, MA et al., J. Med. Chem. 38, 3094-3105, 1995), which are potent CB1 receptor agonists capable of eliciting antinociception with equal morphine efficacy in long-term acute pain animal models pain with inflammation and neuropathic pain.

The key structural features of aminoalkylindoles with cannabimimetic properties (Adam, J. and Cowley, P. Expert Opin. Ther. Patents, 12, 1475-1489, 2002) are the aminoalkyl substituent at position 1 of the indole group and, in addition, the bulky substituent at position 3 of the indole ring, an example of which is the aroyl group in the aminoalkyl indoles described in US Pat. No. 4,939,138 (Sterling Drug Inc.) or in the later application WO02060447 (University of Connecticut), or a substituted amido group in the compounds described in WO0158869 (Bristol-Myers Squibb ) Recently, WO0236590 (Amrad Operations PTY Ltd.) described 1- (aminoalkyl) indole derivatives having a substituted oxadiazol-5-yl ring in position 3 as cannabinoid receptor modulators and suitable as painkillers.

There remains a need for cannabinoid agonists with improved properties, such as increased solubility in water, for use as therapeutic agents.

In this regard, the present invention relates to derivatives of (indol-3-yl) heterocyclic compounds having the general formula I

where A represents a 5-membered aromatic heterocyclic ring, where X ₁ , X ₂ and X ₃ independently selected from N, O, S and CR;

R represents H or (C _1-4 ) alkyl; or

R, when present in X ₂ or X ₃ , may form a 5-8 membered ring together with R ₃ ;

R ₁ represents a 5-8 membered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S;

R ₂ represents H, CH ₃ or CH ₂ —CH ₃ ; or

R _{2 is} connected to R ₇ to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and wherein the heteroatom is bonded to position 7 of the indole ring;

R ₃ and R ₄ independently represent H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, wherein said alkyl groups are optionally substituted with OH, (C _1-4 ) alkyloxy, (C _1-4 ) alkylthio, (C _1-4 ) alkylsulfonyl, CN or halogen; or

R _3, together with R ₄ and N, to which they are attached, forms a 4-8 membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted with OH, (C _1-4 ) alkyl, (C _{1- 4} ) alkyloxy, (C _1-4 ) alkyloxy (C _1-4 ) alkyl or halogen; or

R ₃ together with R ₅ forms a 4-8 membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted with OH, (C _1-4 ) alkyl, (C _1-4 ) alkyloxy, (C _{1- 4} ) alkyloxy- (C _1-4 ) alkyl or halogen; or

R ₃ together with R, when present in X ₂ or X ₃ , forms a 5-8 membered ring;

R ₅ represents H, (C _1-4 ) alkyl; or

R ₅ together with R ₃ forms a 4-8 membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted with OH, (C _1-4 ) alkyl, (C _1-4 ) alkyloxy, (C _{1- 4} ) alkyloxy- (C _1-4 ) alkyl or halogen;

R ₅ 'represents H, (C _1-4 ) alkyl;

R ₆ represents 1-3 substituent groups independently selected from H, (C _1-4 ) alkyl, (C _1-4 ) alkyloxy, CN or halogen;

R ₇ represents H, (C _1-4 ) alkyl (C _1-4 ) alkyloxy, CN or halogen; or

R _{7 is} connected to R ₂ to form a 6-membered ring, optionally containing an additional heteroatom selected from O and S, and wherein the heteroatom is bonded to position 7 of the indole ring; or their pharmaceutically acceptable salts, as CB1 cannabinoid receptor agonists that can be used to treat pain, such as perioperative pain, chronic pain, neuropathic pain, cancer pain and pain and muscle spasticity for multiple sclerosis.

As used in the definition of formula I, heterocycle A is a 5-membered aromatic heterocyclic ring that contains 1-3 heteroatoms selected from N, O and S. This means that at least one of X ₁ , X ₂ and X ₃ used to determine the heterocycle A cannot be CR. Representative heterocycles A are heterocycles - derivatives of thiophene, furan, triazole, thiazole, thiadiazole, oxazole, oxadiazole and their isomers, including isothiazole, isothiadiazole, isoxazole and isoxadiazole. Preferred heterocycles A are 1,2,4-oxadiazole (X ₁ represents N, X ₂ represents O, X ₃ represents N), 1,2,4-thiadiazole (X ₁ represents N, X ₂ represents S, X ₃ represents N) and thiazole (X ₁ represents S, X ₂ represents CR, X ₃ represents N).

In the definition of formula IR, when it is present in X ₂ or X ₃ , it can form a 5–8 membered ring with R ₃ , thus forming together with ring A a bicyclic ring system containing a 5–8 membered N-containing ring, fused to a 5-membered aromatic heterocyclic ring A. Examples of such fused ring systems are fused ring systems derived from 5,6-dihydro-4 H -pyrrolo [3,4- d ] isoxazole, 4,5,6,7-tetrahydrooxazolo [ 5,4- c ] pyridine, 4,5,6,7-tetrahydrothiazolo [5,4- c ] pyridine, 5,6,7,8-tetrahydro-4 H -isoxazolo [5,4- c] azepine, 5,6-dihydro-4 H -pyrrolo [3,4- d] thiazole and 5,6-dihydro-4 H -pyrrolo [3,4- d] isothiazole.

As used in the definition of formula I, the term (C _1-4 ) alkyl means a branched or unbranched alkyl group with 1-4 carbon atoms, for example, butyl, isobutyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

In the term (C _1-4 ) alkyloxy, (C _1-4 ) alkyl has the meaning indicated above.

The term halogen means F, Cl, Br or I.

As used in the definition of R _{1 of} Formula I, the term 5-8 membered saturated carbocyclic ring is a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. Such rings may contain a heteroatom selected from O and S, forming a saturated heterocyclic ring, such as tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl or tetrahydrothienyl. Preferred carbocyclic rings are cyclohexyl and tetrahydropyranyl.

In the definition of the formula, IR ₂ may be coupled to R ₇ to form a 6 membered ring, optionally containing a heteroatom selected from O and S, which is bonded to position 7 of the indole ring. In such (indol-3-yl) substituted 5-membered heterocycles of the present invention, the indol-3-yl group is part of a tricyclic fused ring system, i.e. 2,3-dihydropyrrolo [3,2,1- ij ] quinoline systems (R ₇ and R ₂ are —CH ₂ —CH ₂ -), 2,3-dihydropyrrolo [1,2,3- de ] -1 systems , 4-benzoxazine (R ₇ and R ₂ are —O — CH ₂ -) or 2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzothiazine systems (R ₇ and R ₂ are - S-CH ₂ -).

In the definition of the formula, IR ₃ together with R ₄ and N to which they are attached forms a 4-8 membered ring, optionally containing an additional heteroatom selected from O and S. Examples of such rings are pyrrolidin-1-yl, piperidin-1- il, azepin-1-yl, morpholin-4-yl and thiomorpholin-4-yl. Preferred are pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl.

In the definition of the formula, IR ₃ together with R ₅ may form a 4-8 membered ring, optionally containing an additional heteroatom selected from O and S. It is understood that N with which R ₃ is attached and the carbon atom with which R ₅ is attached represent part of a 4-8 membered ring. Examples of such rings are pyrrolidin-2-yl, piperidin-2-yl, azepin-2-yl, morpholin-3-yl and thiomorpholin-3-yl.

In accordance with formula I, there is a preference for derivatives of (indol-3-yl) heterocyclic compounds, where R ₂ represents H or where R _{2 is} connected to R ₇ to form a 6-membered ring optionally containing a heteroatom selected from O and S, and where the heteroatom is attached to position 7 of the indole ring.

In addition, derivatives of the (indol-3-yl) heterocyclic compounds of the present invention are preferred, where R, R ₅ , R ₅ 'and R ₆ are H.

Also preferred are derivatives of (indol-3-yl) heterocyclic compounds according to formula I, wherein R ₁ is cyclohexyl or tetrahydropyranyl.

Particularly preferred are derivatives of (indol-3-yl) heterocyclic compounds according to formula I, wherein heterocycle A is 1,2,4-oxadiazole (X ₁ represents N, X ₂ represents O, X ₃ represents N) , 1,2,4-thiadiazole (X ₁ represents N, X ₂ represents S, X ₃ represents N) or thiazole (X ₁ represents S, X ₂ represents CR, X ₃ represents N).

Particularly preferred derivatives of the (indol-3-yl) heterocyclic compounds of the present invention are:

7-chloro-3- (5 - {[ N- ethyl- N - (2-methoxyethyl) amino] methyl} - [1,2,4] thiadiazol-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- (tetrahydropyran-4-yl) methyl-1 H is indole;

7-chloro-3- (4 - {[ N -ethyl- N - (2-hydroxyethyl) amino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl- 1 H is indole;

7-chloro-3- (4 - {[ N - (2-methoxyethyl) - N- methylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl-1 H is indole;

7-chloro-3- {5 - [(2,2-dimethylpyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl} -1- (tetrahydropyran-4-yl) methyl-1 H is the indole

or their pharmaceutically acceptable salts.

As a rule, derivatives of (indol-3-yl) heterocyclic compounds of the present invention can be obtained by methods known in the field of organic chemistry. For example, derivatives of (indol-3-yl) heterocyclic compounds of formula I can be prepared from compounds of formula II, wherein Y represents a leaving group, such as a halogen or alkyl sulfonate group, by nucleophilic substitution of the leaving group with an amine of the formula NHR ₃ R ₄ . Compounds of formula II where Y is an alkyl sulfonate group can be prepared from compounds of formula II where Y is a hydroxy group by reaction with an alkyl sulfonyl halide in the presence of a base such as triethylamine. Derivatives of (indol-3-yl) heterocyclic compounds of formula I, where R ₅ ′ is hydrogen, can be prepared from compounds of formula III by reductive amination using an amine of the formula NHR ₃ R ₄ in the presence of a reducing agent such as sodium triacetoxyborohydride. It is well known in the art that compounds of formula II, where Y is hydroxy and R ₅ ′ is hydrogen, can be interconverted with compounds of formula III by oxidation and reduction using suitable oxidizing agents or reducing agents, as described by Burke DS, Danheiser, RL in Handbook of Reagents for organic Synthesis: Oxidising and Reducing agents (Wiley: New York, 1999). Similarly, compounds of formula II where Y is hydroxy and R ₅ and R ₅ 'are hydrogen, and compounds of formula III where R ₅ is hydrogen can be prepared from compounds of formula IV, where R ₈ is hydrogen or ( C _1-4 ) alkyl, reduction using suitable reducing agents. Compounds of formula II, wherein Y is hydroxy and R ₅ 'is (C _1-4 ) alkyl, can be prepared from compounds of formula III by nucleophilic addition using a (C _1-4 ) alkyl metal reagent such as Grignard alkyl reagent or alkyl lithium.

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

Compounds of formula V-XII, inclusive, wherein R ₁ , R ₂ , R ₆ and R ₇ are as defined above and R ₈ is H or (C _1-4 ) alkyl, may be prepared by methods described in the literature or known to one skilled in the art areas of modifications of methods described in the literature.

For example, compounds of formula VI can be prepared from compounds of formula V or their activated derivatives by reaction with ammonia in an acceptable solvent.

Compounds of formula VII can be prepared from compounds of formula VI using thionic reagents such as phosphorus pentasulfide or Lawesson's reagent.

Alternatively, compounds of formula VII can be prepared from compounds of formula VIII by reaction with thioacetamide in a solvent such as dimethylformamide.

Compounds of formula VIII 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 may be prepared from compounds of formula IX by reaction with hydroxylamine in an acceptable solvent.

Compounds of formula XI where Y is NH ₂ can be prepared from compounds of formula V or their activated derivatives by reaction with a cyanide anion to form oxoacetonitrile followed by reduction of the nitrile to a primary amine using a reducing agent such as hydrogen gas in the presence of a catalyst such like palladium on activated carbon.

Compounds of formula XII can be prepared from compounds of formula VIII by reaction with hydroxylamine in an acceptable solvent.

Compounds of formula V and compounds of formula XI can be prepared by acylation of compounds of formula XIII. For example, compounds of formula V, where R ₈ is hydrogen, can be prepared by acylation of compounds of formula XIII using trifluoroacetic anhydride in a solvent such as dimethylformamide, followed by hydrolysis using aqueous sodium hydroxide at elevated temperature. Compounds of formula XI, where Y is chloro, can be prepared by acylating compounds of formula XIII using chloroacetyl chloride in the presence of a base such as pyridine.

Compounds of formula IX can be prepared from compounds of formula XIII 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 methods described by Wijngaarden et al. (J. Med. Chem. 36, 3693-3699, 1993) or Hwu et al. (J. Org. Chem. 59, 1577-1582, 1994), or using modifications of these methods.

Compounds of formula XIII may be prepared by methods described in the literature or modifications known to the person skilled in the art from methods described in the literature. For example, compounds of formula XIII 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 R ₁ R ₂ CHY, where Y is a leaving group such as a halogen or alkyl sulfonate group. Compounds of formula XV may be prepared from commercial sources, may be prepared by methods described in the literature, or modifications known to those skilled in the art that are described in the literature.

Alternatively, compounds of formula XIII 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 may be prepared by methods described in the literature or modifications known to the person skilled in the art from methods described in the literature. For example, compounds of formula XIV where R _{2 is} connected to R ₇ 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 can be prepared, for example, by a condensation reaction, such as the reaction of 2-chloroquinoline with a Grignard reagent in the presence of a nickel (II) catalyst.

Compounds of formula XIV where R _{2 is} combined with R ₇ to form a 6 membered ring containing oxygen or sulfur can be prepared by reaction with a compound of formula XVII, where Z is OH or SH, with a compound of formula XVIII, where Y is a leaving group , with the formation of an ester or thioether, followed by reduction of the nitro group to an amine and reductive cyclization. Reduction and cyclization can be carried out, for example, using hydrogen gas in the presence of a catalyst, such as palladium on activated carbon.

Compounds of formula XVII and compounds of formula XVIII can be obtained from commercial sources, can be obtained by methods described in the literature, or modifications known to a person skilled in the art, of methods described in the literature. For example, compounds of formula XVIII, where Y is bromo, can be prepared from compounds of formula XIX using a brominating agent such as bromine in a solvent such as methanol.

Alternatively, compounds of Formula I, Formula II, Formula III, or Formula IV can be prepared from compounds of Formula XX using a transition metal catalyzing coupling reactions as described in Hegedus, L.S. Transition Metals in the Synthesis of Complex Organic Molecules (Second Edition, University Science: Sausalito 1999).

For example, compounds of formula III can be prepared by reacting compounds of formula XX, where Y ₁ is halogen, with compounds of formula XXI, where Y ₂ is boronic acid or boronic acid ester, using the Suzuki reaction (Chem. Rev. 95, 2457- 2483, 1995) or its modifications.

Compounds of formula XX and compounds of formula XXI can be obtained from commercial sources, can be obtained by methods described in the literature, or modifications known to a person skilled in the art, of methods described in the literature. For example, compounds of formula XX, where Y ₁ is bromo, can be obtained by brominating compounds of formula XIII using bromine in a solvent such as dimethylformamide.

One skilled in the art will appreciate that indole nitrogen in the above transformations can be temporarily protected using a protecting group such as an arylsulfonyl group, followed by deprotection and alkylation in the later stages of the synthesis. In addition, it is understood that such protecting groups can be used to alter the stability of the intermediates and the reactivity of the indole ring against electrophiles. Suitable protecting groups are described by Kocienski, P.J .: in Protecting Groups, Thieme, Stuttgart; New York, 1994.

It will also be understood by one of ordinary skill in the art that various derivatives of (indol-3-yl) heterocyclic compounds of formula I can be prepared by suitable functional group conversion reactions corresponding to certain R ₃ -R ₇ substituents. For example, compounds of formula I, wherein R ₃ or R ₄ are linear, branched or cyclic C ₁ -C ₆ alkyl groups optionally substituted with hydroxyl, (C _1-4 ) alkyloxy, (C _1-4 ) alkylthio,

(C _1-4 ) alkylsulfonyl or cyano can be prepared by reacting a compound of formula I, wherein R ₃ or R ₄ is hydrogen, with a C ₁ -C ₆ alkyl halide or with a functionalized C ₁ -C ₆ alkyl halide in the presence of a base such as carbonate potassium.

Derivatives of (indol-3-yl) heterocyclic compounds of formula I and their salts may contain at least one chiral center and, therefore, be in the form of stereoisomers, including enantiomers and diastereoisomers. The present invention includes, in its scope, the above stereoisomers and each individual of the R and S enantiomers of the compounds of formula I and their salts, essentially pure, i.e. associated with less than 5%, preferably less than 2%, specifically, less than 1% of the other enantiomer, and mixtures of such enantiomers in any proportions, including racemic mixtures containing essentially equal amounts of two enantiomers.

The methods of asymmetric synthesis or chiral separation with which stereoisomers are obtained are well known in the art, for example, synthesis with chiral induction or from commercially available chiral substrates, or separation of stereoisomers, for example, using chromatography on a chiral medium, or crystallization with a chiral counterion.

Pharmaceutically acceptable salts can be obtained by treating the free base of the compound of formula I with an inorganic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, or an organic acid, such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid , malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid and methanesulfonic acid.

The compounds of the present invention may be in unsolvated form as well as in solvated form with a pharmaceutically acceptable solvent such as water, ethanol and the like. In general, for the purposes of the present invention, solvated forms are considered equivalent to unsolvated.

In addition, the present invention relates to pharmaceutical compositions containing a derivative (indol-3-yl) of a heterocyclic compound of the general formula I or a pharmaceutically acceptable salt thereof, in a mixture with pharmaceutically acceptable additives and, optionally, other therapeutic agents. The term "acceptable" means combined with other ingredients of the composition and harmless to its consumers. For example, compositions include compositions suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, pulmonary, local or rectal administration, etc. ., all in unit dosage forms for administration. The preferred route of administration is intravenous.

For oral administration, the active ingredient may be in the form of separate units, such as tablets, capsules, powders, granular forms, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical composition of the present invention can be in a container for a single dose or in multiple doses, for example, liquid for injection in predetermined quantities, for example, in sealed vials and ampoules, and can also be stored in a freeze-dried (lyophilized) state, in which only adding a sterile liquid carrier, such as water, before use.

Mixed with such pharmaceutically acceptable additives, for example, as described in Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Edition, Lippincott Williams & Wilkins, 2000, especially see Part 5: Pharmaceutical Manufacturing), the active agent can be compressed into solid unit doses, such as pills, tablets, or processed with capsules, suppositories or patches. By means of pharmaceutically acceptable liquids, the active agent can be used as a liquid composition, for example, as an injectable preparation in the form of a solution, suspension, emulsion or spray, for example a nasal spray.

To obtain solid dosage units, the use of conventional additives, such as fillers, dyes, polymeric binders, etc., is provided. In general, any pharmaceutically acceptable additives that do not interfere with the action of the active compounds can be used. Acceptable carriers with which the active substance of the present invention can be administered in the form of solid compositions include derivatives of lactose, starch, cellulose and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions containing pharmaceutically acceptable dispersing agents and / or moisturizing agents such as propylene glycol or butylene glycol can be used.

The invention further relates to the pharmaceutical composition described above in combination with packaging materials suitable for the composition, wherein said packaging materials include instructions for using the composition for the above use.

Derivatives of the (indol-3-yl) heterocyclic compounds of the present invention were found to be CB1 receptor agonists, as established in the analysis of human CB1 receptor reporter using CHO cells. Methods for determining in vitro receptor binding as well as the biological activity of cannabinoid receptor modulators in vitro are well known in the art. In general, an expressed receptor is contacted with a compound to be tested, and binding or stimulation or inhibition of a functional response is measured.

To measure the functional response, the isolated DNA encoding the CB1 receptor gene, preferably the human receptor, is expressed in suitable host cells. Such cells may be Chinese hamster ovary cells, but other cells are also suitable. Preferably, the cells are derived from mammals.

Methods for constructing recombinant CB1 expressing cell lines are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Receptor expression is achieved by expression of the DNA encoding the desired protein. All methods for ligating additional sequences and constructing suitable expression systems are currently well known in the art. Part or all of the DNA encoding the desired protein can be synthetically constructed using standard solid phase methods, preferably with the introduction of restriction sites to facilitate ligation. For DNA coding sequences, suitable control elements for transcription and translation of the introduced coding sequences can be provided. As is well known, expression systems are currently available that 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, bird cells, and the like.

The receptor-expressing cells are then contacted with a test compound to investigate binding or stimulation or inhibition of a functional response.

Alternatively, isolated cell membranes containing the expressed CB1 receptor (or CB2) can be used to measure the binding of the compound.

To measure binding, radioactive or fluorescently labeled compounds can be used. The most widely used radioactive cannabinoid probe is [ ³ H] CP55940, which has approximately equal affinity for the CB1 and CB2 binding sites.

Another study involves screening cannabinoid CB1 agonist compounds by determining the response of secondary messengers, such as for example measuring receptor-mediated changes in cAMP or MAP kinase pathways. Thus, such a method involves expressing the CB1 receptor on the cell surface of the host cell and exposing the cell to the test compound. Then measure the response of the secondary messengers. The level of secondary messengers will be reduced or increased depending on the action of the test compound upon binding to the receptor.

In addition to directly measuring, for example, cAMP levels in the exposed cell, you can use cells that, in addition to transfecting the DNA encoding the receptor, are transfected with a second DNA encoding the reporter gene, the expression of which correlates with the activation of the receptor. Basically, the expression of the reporter gene can be controlled by any responding element that responds to altered levels of the secondary messenger. Suitable reporter genes are, for example, LacZ, alkaline phosphatase, firefly luciferase and green fluorescent protein. The principles of such transactivation assays are well known in the art, for example, in Stratowa, Ch, Himmler, A. and Czernilofsky, AP, Curr. Opin. Biotechnol. 6, 574 (1995). To select active agonist compounds for the CB1 receptor, the EC ₅₀ should be <10 ^-5 M, preferably <10 ^-7 M.

The compounds can be used as painkillers for treating pain, for example, such as perioperative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

Also, the cannabinoid agonists of this invention may be potentially useful in the treatment of other disorders, including multiple sclerosis, spasticity, inflammation, glaucoma, nausea and vomiting, loss of appetite, sleep disturbance, respiratory failure, allergies, epilepsy, migraine, cardiovascular disorders, neurodegenerative disturbances, anxiety, traumatic brain damage and stroke.

The compounds can also be used in combination with other drugs, for example, painkillers, such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors.

The compounds of this invention can be administered to humans in a sufficient amount and for a sufficient period of time to alleviate the symptoms. By way of illustration, dosage levels for humans may be in the range of 0.001-50 mg per kg of body weight, preferably at a dose of 0.01-20 mg per kg of body weight.

The invention is illustrated by the following examples.

General methods

Unless otherwise indicated, microwave reactions were performed using Emrys ™ Optimizer (Personal Chemistry). Flash column chromatography was performed on silica gel. Semi-preparative high-performance liquid chromatography (semi-preparative HPLC) was performed using the following methods:

Method (i): Agilent CombiHT (SB-C18, 5 μm) 12 mm ID × 100 mm; 5-95% acetonitrile-water with a 9 minute gradient; 25 ml / min; 0.1% trifluoroacetate acid buffer; UV detection at 254 nm.

Method (ii): Waters Xterra (RP18, 5 μm) 30 mm × 100 mm; 10-100% acetonitrile-water with a 25 minute gradient; 30 ml / min; 0.1% trifluoroacetate acid buffer; UV detection at 254 nm.

¹ H NMR interaction constants are given in hertz.

Example 1

1- (Cyclohexyl) methyl-3- {5 - [(dimethylamino) methyl] - [1,2,4] oxadiazol-3-yl-7-methoxy-1 H -indole, hydrochloride salt

A solution of 7-methoxyindole (45.0 g, 306 mmol) in dimethylformamide (360 ml) was cooled to 5 ° C under nitrogen for 20 minutes and trifluoroacetic anhydride (60.5 ml, 433 mmol) was added, keeping the temperature below 10 ° C. The mixture was stirred at 5-10 ° C for 2 hours, then poured into water (1600 ml). The resulting suspension was stirred for 15 minutes and the precipitate of 7-methoxy-3 - [(trifluoromethyl) carbonyl] -1 H -indole was filtered off, washing with water until neutral.

The wet solid was suspended in 4M aqueous sodium hydroxide (1700 ml) and heated to reflux with stirring for 2 hours. The mixture was cooled and washed with diethyl ether (2 × 400 ml). Then, the aqueous phase was acidified to pH 1 using 5 M hydrochloric acid, and the resulting pure precipitate was filtered off, washed with water until neutral and dried to obtain 7-methoxy-1 H- indole-3-carboxylic acid as a pink solid (42.7 g )

To a solution of 7-methoxy-1 H- indole-3-carboxylic acid (42.7 g, 224 mmol) in dimethylformamide (1250 ml) at 10 ° C in nitrogen atmosphere in portions for 20 minutes, maintaining the temperature below 15 ° C, sodium hydride (60% dispersion in mineral oil, 23.0 g, 575 mmol) was added. The cooling bath was removed and the suspension was stirred for 90 minutes. Cyclohexylmethyl bromide (64.7 ml, 464 mmol) was added. The mixture was heated at 60 ° C with stirring for 3 hours. The mixture was cooled to 10 ° C and poured into water (3600 ml). The emulsion was washed with diethyl ether (3 × 500 ml). The aqueous phase was acidified to pH 1 using 5M hydrochloric acid, and the precipitate was filtered off, washed with water until neutral and dried to obtain 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-carboxylic acid (55 g) as white solid.

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) was added dropwise oxalyl chloride (12, 4 g, 97.4 mmol) and the resulting mixture was stirred at room temperature for 18 hours. Dichloromethane and excess oxalyl chloride were removed by evaporation and the resulting precipitate was mixed with dichloromethane (150 ml). Ammonia gas was bubbled into the resulting mixture for 30 minutes while cooling in an ice-water bath. The reaction mixture was concentrated in vacuo, then the resulting solid was triturated successively with 0.5 M hydrochloric acid, 5% aqueous sodium carbonate and water and dried under reduced pressure to obtain 1- (cyclohexyl) methyl-7-methoxy-1 H -indole- amide 3-carboxylic acid (5.1 g) as a brown solid.

To a mixture of 1- (cyclohexyl) methyl-7-methoxy- 1H- indole-3-carboxylic acid amide (4.1 g, 14.3 mmol), triethylamine (11.6 g, 115 mmol) and 1.4- dioxane (250 ml), while cooling in ice water, trifluoroacetic anhydride (12.0 g, 57.1 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 12 hours. Water (30 ml) was added and the resulting mixture was concentrated in vacuo. Water (300 ml) was added to the resulting precipitate, and the mixture was extracted with dichloromethane (4 × 300 ml). The organic layers were combined, washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was purified by column chromatography, eluting with 10% (v / v) ethyl acetate in n-heptane to give 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-carbonitrile as a crystalline solid (2, 48 g).

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 ) hydroxylamine hydrochloride (966 mg, 13.9 mmol) was added, then the resulting mixture was stirred at reflux for 20 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting precipitate was mixed with water (150 ml), adjusted to pH 10 by the addition of aqueous sodium hydroxide and extracted with dichloromethane (4 × 100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was 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).

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) in a nitrogen atmosphere were added molecular sieves (4 Å, as powder, 200 mg) and the mixture was stirred at room temperature for 30 minutes. Sodium hydride (60% suspension in oil, 36 mg, 0.900 mmol) was added, then the resulting mixture was stirred at 60 ° C for 20 minutes. The reaction mixture was cooled to room temperature and N , N- dimethylglycine methyl ether (194 mg, 1.66 mmol) was added to the mixture. The resulting mixture was stirred at reflux for 2 hours and then concentrated in vacuo. The resulting precipitate was mixed with dichloromethane (200 ml), washed with 5% aqueous sodium carbonate, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was purified by flash column chromatography, eluting with 0.6% (v / v) methanol in dichloromethane to give an oil. The resulting oil was dissolved in isopropanol (3 ml), hydrogen chloride (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to give the title compound (1: 1 hydrochloride salt) (66 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 0.96-1.30 (5H, m), 1.52-1.94 (6H, m), 3.13 (6H, s), 3.97 (3H, s), 4.30 (2H, d, J = 6.8), 4.83 (2H, s), 6.81 (1H, d, J = 8.0), 7.13 (1H dd, J = 8.0, 8.0), 7.71 (1H, d, J = 8.0), 7.85 (1H, s). EsIMS: m / z 369.2 [M + H] ⁺ .

Example 2

Further, the method of Example 1 was used to prepare the following compounds using alternative synthetic or commercially available amino acid esters instead of N , N- dimethyl glycine methyl ether.

Methods for the synthesis of amino acid intermediate esters

Method A

To a mixture of pyrrolidine (171 mg, 2.40 mmol) and sodium carbonate (254 mg, 2.40 mmol) in tetrahydrofuran (7 ml) was added benzyl bromoacetate (500 mg, 2.18 mmol). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The precipitate was mixed with water (200 ml) and extracted with dichloromethane (3 × 100 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with 0-10% (v / v) methanol in dichloromethane, afforded pyrrolidin-1-yl-acetic acid benzyl ester (230 mg, 1.05 mmol).

Method B

To a mixture of ( S ) -2-methoxymethylpyrrolidine (268 μl, 2.17 mmol), potassium carbonate (319 mg, 2.31 mmol) and sodium iodide (315 mg, 2.10 mmol) in acetonitrile (3 ml) was added methyl bromoacetate (199 μl, 2.10 mmol). The mixture was microwaved for 5 minutes at 160 ° C, then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the mixed organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with 0-10% (v / v) methanol in dichloromethane, gave ( S ) - (2-methoxymethylpyrrolidin-1-yl) acetic acid methyl ester (133 mg, 0.71 mmol).

Method C

To a solution of sulfuric acid (3.5 ml, 65.3 mmol) in methanol (45 ml) was added D-proline (10.0 g, 86.9 mmol). The mixture was refluxed with stirring for 18 hours. Then the solution was cooled to 0 ° C and neutralized by the addition of aqueous potassium carbonate (2.5 M; 10 ml). Formaldehyde (37% solution in water; 11 ml, 136 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Sodium borohydride (1.6 g, 42.3 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 3 hours. The precipitate was filtered off and the filtrate was partitioned between dichloromethane and water. The separated aqueous layer was adjusted to pH 10 using solid sodium carbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude methyl ester of ( R ) -1-methylpyrrolidine-2-carboxylic acid (13.13 g).

A portion of the obtained crude product (5.0 g) was purified by flash column chromatography, eluting with 0-2% (v / v) methanol in dichloromethane to give ( R ) -1-methylpyrrolidine-2-carboxylic acid methyl ester (1, 30 g).

2A : 1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl} -1 H -indole, hydrochloride salt

The title compound was prepared following the method of Example 1 using pyrrolidin-1-yl-acetic acid benzyl ester obtained by the method A.

¹ H NMR (400 MHz, CD ₃ OD) δ 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). EsIMS: m / z 395.2 [M + H] ⁺ .

2B: 1- (Cyclohexyl) methyl-3- {5 - [( N- ethyl- N- isopropylamino) methyl] - [1,2,4] oxadiazol-3-yl} -7-methoxy-1 H -indole, hydrochloride salt

The title compound was prepared using ( N- ethyl- N- isopropylamino) acetic acid methyl ester, which was prepared by Method A using methyl bromoacetate and N- ethylisopropylamine. EsIMS: m / z 411.1 [M + H] ⁺ .

2C: 1- (Cyclohexyl) methyl-7-methoxy-3- (5 - {[bis- (2-methoxyethyl) amino] methyl} - [1,2,4] oxadiazol-3-yl} -1 H- indole, hydrochloride salt

The title compound was prepared using [bis- (2-methoxyethyl) amino] acetic acid methyl ester, which was obtained by Method A using methyl bromoacetate and bis- (2-methoxyethyl) amine. EsIMS: m / z 457.5 [M + H] ⁺ .

2D: 1- (Cyclohexyl) methyl-3- {5- [1- (dimethylamino) ethyl] - [1,2,4] oxadiazol-3-yl} -7-methyl-1 H- indole, hydrochloride salt.

The title compound was prepared using 2-dimethylaminopropionic acid methyl ester, which was obtained by Method A using methyl 2-bromopropionate and dimethylamine. EsIMS: m / z 383.0 [M + H] ⁺ .

2E: ( S ) -1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(2-methoxymethylpyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl-1 H -indole hydrochloride salt

The title compound was prepared using ( S ) - (2-methoxymethylpyrrolidin-1-yl) acetic acid methyl ester, which was prepared according to B. EsIMS: m / z 439.3 [M + H] ⁺ .

2F : ( R ) -1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(2-methoxymethylpyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl} -1 H- indole, hydrochloride salt

The title compound was prepared using ( R ) - (2-methoxymethylpyrrolidin-1-yl) acetic acid methyl ester, which was obtained by Method B using (R) -2-methoxymethylpyrrolidine.

EsIMS: m / z 439.1 [M + H] ⁺ ; [α] _D ²² + 21.6 ° (c = 0.8 mg / ml in chloroform).

2G : ( R ) -1- (Cyclohexyl) methyl-7-methoxy-3- [5- (1-methylpyrrolidin-2-yl) - [1,2,4] oxadiazol-3-yl] -1 H- indole, hydrochloride salt

The title compound was prepared using ( R ) -1-methylpyrrolidine-2-carboxylic acid methyl ester, which was prepared by Method C.

EsIMS: m / z 395.0 [M + H] ⁺ [α] _D ²² + 50.1 ° (c = 1.70 mg / ml in chloroform).

2H : ( S ) -1- (Cyclohexyl) methyl-7-methoxy-3- [5- (1-methylpyrrolidin-2-yl) - [1,2,4] oxadiazol-3-yl] -1 H- indole hydrochloride salt

The title compound was prepared using ( S ) -1-methylpyrrolidine-2-carboxylic acid methyl ester, which was prepared by Method C, using L-Proline instead of D-Proline. EsIMS: m / z 395,0 [M + H] + [α] D ²² -51,7 (c = 1,35 mg / ml in chloroform).

2I: 1- (Cyclohexyl) methyl-7-methoxy-3- [5- (1-methylpiperidin-2-yl) - [1,2,4] oxadiazol-3-yl] -1 H- indole, hydrochloride salt

The title compound was prepared following the method of Example 1 using ethyl 1-methylpipecolinate instead of N , N- dimethylglycine methyl ester.

EsIMS: m / z 409.3 [M + H] ⁺ .

Example 3

1- (Cyclohexyl) methyl-3 - [(5-aminomethyl) - [1,2,4] oxadiazol-3-yl] -7-methoxy-1 H -indole, hydrochloride salt

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) were added molecular sieves (4 Å, in powder form) , 300 mg) and the resulting mixture was stirred at room temperature for 30 minutes. Sodium hydride (60% suspension in oil, 100 mg, 2.55 mmol) was added and the resulting mixture was stirred at 65 ° C for 20 minutes. The reaction mixture was cooled to room temperature and thereto was added N -gidroksisuktsinimidny ester N -Boc-glycine (871 mg, 3.32 mmol). The resulting mixture was heated to reflux with stirring for 2 hours, then cooled to room temperature. Aqueous sodium hydroxide (4M; 5 ml) was added and the resulting mixture was stirred for 14 hours. The reaction mixture was concentrated in vacuo, then the resulting precipitate was mixed with water (200 ml). The resulting mixture was extracted with dichloromethane (4 × 200 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was purified by column chromatography, eluting with 0.4% (v / v) methanol in dichloromethane to give tert-butyl ether ({3- [1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3 -yl] - [1,2,4] oxadiazol-5-yl} methyl) carbamic acid (125 mg).

A mixture of tert-butyl ether ({3- [1- (cyclohexyl) methyl-7-methoxy-1 H- indol-3-yl] - [1,2,4] oxadiazol-5-yl} methyl) carbamic acid (110 mg, 0.25 mmol) and trifluoroacetic acid (4 ml) were stirred at room temperature for 1.5 hours. The reaction mixture was carefully poured into 5% aqueous sodium carbonate (200 ml) and the resulting mixture was extracted with dichloromethane (4 × 200 ml). The organic layers were combined, then washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was purified by column chromatography eluting with 1.5% (v / v) methanol in dichloromethane to give the free base of the title compound as a yellow oil. The resulting oil was dissolved in diethyl ether and then hydrogen chloride (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to give the title compound as the hydrochloride salt, 1: 1 (71 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 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, J = 7.6, 8.0), 7.72 (1H, d, J = 8.0), 7.83 (1H, s). EsIMS: m / z 341.1 [M + H] ⁺ .

Example 4

1- (Cyclohexyl) methyl-3- {5 - [(dimethylamino) methyl] - [1,2,4] oxadiazol-3-yl} -7-fluoro-1 H -indole, hydrochloride salt

The title compound was prepared following the method of Example 1 using 7-fluorindole instead of 7-methoxyindole. EsIMS: m / z 357.3 [M + H] ⁺ , 247.4.

Example 5

7-Chloro-1- (cyclohexyl) methyl-3- {5 - [(dimethylamino) methyl] - [1,2,4] oxadiazol-3-yl} -1 H- indole, hydrochloride salt.

The title compound was prepared following the method of Example 1 using 7-chloroindole instead of 7-methoxyindole EsIMS: m / z 375.1, 373.1 [M + H] ⁺ .

Example 6

1- (Cyclohexyl) methyl-3- (5 - {[N-isopropyl -N- (2-methoxyethyl) amino] methyl} - [1,2,4] triazol-3-yl) -7-methoxy-1 H- indole, hydrochloride salt

Hydrogen chloride gas was bubbled through for 30 minutes through a cooled (0 ° C) solution of 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-carbonitrile (prepared as described in Example 1; 3.15 g, 11 , 0 mmol) in methanol (200 ml). Before concentration, the resulting mixture was allowed to stand for two-thirds for 72 hours in vacuum. Crystallization of the product was carried out by adding diethyl ether, the solid product was collected by filtration to obtain 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-carboxylic acid methyl ester as the hydrochloride salt (3.82 g).

1- (Cyclohexyl) methyl ester methyl 7-methoxy-1 H- indole-3-carboxylic acid, hydrochloride salt (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) were mixed and the mixture was microwaved for 60 minutes at 120 ° C. The resulting mixture was concentrated in vacuo, redissolved in toluene, and concentrated in vacuo two more times. The resulting precipitate was suspended in toluene / acetonitrile (12/1) (19.5 ml) and chloroacetyl chloride (0.118 ml, 1.49 mmol) was added, then the mixture was microwaved for 12 minutes at 120 ° C. The resulting mixture was concentrated in vacuo and redissolved in acetonitrile (3 ml). The mixture was left to stand for 72 hours, 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) were added, then microwaved for 5 min at 160 ° C. and then concentrated in vacuo The resulting precipitate was purified by column chromatography, eluting with 2.5% -5% (v / v) methanol in dichloromethane to give the title compound as a hydrochloride salt, 1 : 1 (46 mg).

¹ H NMR (400 MHz, CD ₃ OD): 0.95-1.12 (2H, m), 1.13-1.24 (3H, m), 1.50 (6H, s (broad)) 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 (broad)), 6.70 (1H, d, J = 7.7), 7.16 ( 1H, t, J = 7.7), 7.95 (1H, d, J = 7.7), 8.02 (1H, s (broad)); EsIMS: m / z 440.3 [M + H] ⁺ .

Example 7

1- (Cyclohexyl) methyl-3- {5 - [(diethylamino) methyl] - [1,2,4] thiadiazol-3-yl} -7-methoxy-1 H -indole, hydrochloride salt

To a suspension of 1- (cyclohexyl) methyl-7-methoxy-1 H -indole-3-carboxylic acid amide (obtained from 7-methoxyindole as described in Example 1; 4.0 g, 14 mmol) in tetrahydrofuran (120 ml) chlorocarbonylsulphenyl chloride (2.4 ml, 28.4 mmol) was added and the reaction mixture was refluxed for 15 minutes and allowed to cool. The solution and excess reagent were then removed in vacuo to give 5- (1-cyclohexylmethyl-7-methoxy-1 H -indole) - [1,3,4] oxathiazol-2-one (5.2 g, 14.4 mmol) in the form of a solid pink substance.

To 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) ethyl cyanoformate (2.74 ml, 27.7 mmol) was added and the reaction mixture was microwaved at 160 ° C. for 10 min using Emrys ™ Optimizer EXP. The reaction was repeated three times at the same amounts, combining and purifying by flash chromatography, eluting with 0-50% (v / v) dichloromethane in heptane to give 3- (1-cyclohexylmethyl-7-methoxy-1 H- ethyl ester) indol-3-yl) - [1,2,4] thiadiazole-5-carboxylic acid (4.38 g, 11 mmol) as a white solid.

To a cooled solution (ice / methanol bath) of 3- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) - [1,2,4] thiadiazole-5-carboxylic acid ethyl ester (4.0 g , 10 mmol) in tetrahydrofuran (80 ml) and methanol (80 ml) sodium borohydride was added in successive portions. The reaction mixture was stirred for the next 20 minutes and quenched with 1M hydrochloric acid (20 ml). Methanol and tetrahydrofuran were removed in vacuo and dichloromethane (200 ml) and 2M hydrochloric acid (50 ml) were added. The organics were separated and washed with brine (50 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The resulting precipitate was 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 the cooled solution (ice / methanol bath) [3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) - [1,2,4] thiadiazol-5-yl] methanol (2.3 g , 6.4 mmol) in dichloromethane (150 ml), methanesulfonyl chloride (0.595 ml, 7.68 mmol) and triethylamine (1.16 ml, 8.32 mmol) were successively added. The reaction mixture was stirred for 10 minutes and then poured into a separatory funnel. The organics were washed with 5% aqueous sodium carbonate (2 × 100 ml), brine (100 ml), dried over magnesium sulfate and the solvent was removed in vacuo to give 3- (1-cyclohexylmethyl-7-methoxy-1 H -indole -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 3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) - [1,2,4] thiadiazol-5-ylmethyl methanesulfonic acid ester (93 mg, 0.2 mmol) in tetrahydrofuran ( 1 ml) diethylamine (0.22 ml, 2.13 mmol) was added and the reaction mixture was microwaved at 150 ° C. for 15 minutes. The reaction mixture was poured into a separatory funnel and diluted with dichloromethane (40 ml). The combined organic phase was washed with 5% aqueous sodium carbonate solution (2 × 20 ml), brine (2 × 20 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The resulting precipitate was purified by flash column chromatography to give the title compound (54 mg, 0.13 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1.0 ml, 2.0 mmol) was added. The mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt, 1: 1.

¹ H NMR (400 MHz, CD ₃ OD): 0.95-1.12 (2H, m), 1.16-1.27 (3H, m), 1.45 (6H, t, J = 7) 1.55-1.63 (2H, m), 1.63-1.8 (3H, m), 1.8-1.95 (1H, m), 3.28-3.32 (4H, m), 3.97 (3H, s), 4.3 (2H, d, J = 7), 4.96 (2H, s), 6.79 (1H, d, J = 8), 7.13 (1H, t, J = 8), 7.95 (1H, s), 8.04 (1H, d, J = 8); EsIMS: m / z 413.1 [M + H] ⁺ .

Example 8

Further, the method of example 7 was used to obtain the following compounds:

8A : 1- (Cyclohexyl) methyl-7-methoxy-3- (5 - {[bis- (2-methoxyethyl) amino] methyl} - [1,2,4] thiadiazol-3-yl) -1 H -indole hydrochloride salt

The title compound was prepared using bis- (2-methoxyethyl) amine instead of diethylamine. EsIMS: m / z 473.1 [M + H] ⁺ .

8B : 1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl-1 H -indole, hydrochloride salt

The title compound was prepared using pyrrolidine instead of diethylamine. EsIMS: m / z 411.1 [M + H] ⁺ , 342.0.

8C : 1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(2-methylpiperidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1 H- indole, trifluoroacetic acid salt

The title compound was prepared using 2-methylpiperidine instead of diethylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 439.3 [M + H] ⁺ .

8D : 1- (Cyclohexyl) methyl-3- (5 - {[ N - (2-hydroxyethyl) -N- methylamino] methyl} - [1,2,4] thiadiazol-3-yl) -7-methoxy-1 H- indole, hydrochloride salt

The title compound was prepared using (2-hydroxyethyl) methylamine instead of diethylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 415.3 [M + H] ⁺ , 328.3.

8E : 1- (Cyclohexyl) methyl-7-methoxy-3- (5 - {[ N - (2-methoxyethyl) -N- methylamino] methyl [1,2,4] thiadiazol-3-yl) -1 H - indole hydrochloride salt

The title compound was prepared using N- (2-methoxyethyl) -N- methylamine instead of diethylamine. EsIMS: m / z 429.4 [M + H] ⁺ .

Example 9

1- (Cyclohexyl) methyl-3- {5- [1- (diethylamino) ethyl] - [1,2,4] thiadiazol-3-yl} -7-methoxy-1 H -indole, hydrochloride salt

To a cooled solution (dry ice / acetone bath) of ethyl 3- (1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) - [1,2,4] thiadiazole-5-carboxylic acid (500 mg, 1.3 mmol) in diethyl ether (50 ml) was added a solution of methyl magnesium bromide (0.52 ml, 3M in diethyl ether, 1.56 mmol) and the reaction mixture was stirred for 15 minutes, then another part of a solution of methyl magnesium bromide (0.25) was added. ml, 3M in diethyl ether, 0.75 mmol) and the reaction mixture was stirred for 5 minutes. Then the reaction was quenched with saturated aqueous ammonium chloride (5 ml) and the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into a separatory funnel and the organic phase was washed with water (20 ml). Then the aqueous layer was washed with diethyl ether (20 ml). The combined organic layers were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting precipitate was purified by flash column chromatography to give 1- [3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) - [1,2,4] thiadiazol-5-yl] ethanone (170 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 diethylamine (0.248 ml, 2.4 mmol) and acetic acid (0.137 ml, 2.4 mmol) were added to acetonitrile (3 ml) and the reaction mixture was stirred for 30 minutes. Polymer-coated cyanoborohydride (204 mg, loading 2.35 mmol ^-1 , 0.48 mmol) was added to the reaction mixture, and the reaction mixture was microwaved at 150 ° C. for 10 minutes. The reaction mixture was filtered through a 5 g column of Strata ™ SCX giga. The column was washed with methanol and then eluted with 2M ammonia in methanol. A solution of ammonia in methanol was evaporated and the resulting residue was purified by flash column chromatography to give the title compound (62 mg, 0.145 mmol) as a free base. The free base was dissolved in dichloromethane (1 ml) and 2M HCl in diethyl ether (1 ml, 2 mmol) was added, the excess reagent and the solvent were removed in vacuo to give the title compound as the hydrochloride salt, 1: 1.

¹ H NMR (400 MHz, CD ₃ OD): 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 (1H, m), 6.8 (1H, d, J = 8), 7.14 (1H, t, J = 7.5), 7.94 (1H, s), 8.02 (1H, d, J = 8); EsIMS: m / z 427.4 [M + H] ⁺ , 328.4.

Example 10

1- (Cyclohexyl) methyl-3- {5 - [(diethylamino) methyl] - [1,2,4] thiadiazol-3-yl} -7-fluoro-1 H -indole, trifluoroacetic acid salt

The title compound was prepared following the method of Example 7 using 1- (cyclohexyl) methyl-7-fluoro-1 H -indole-3-carboxylic acid amide (obtained from 7-fluorindole) and diethylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 401.3 [M + H] ⁺ .

Example 11

7-Chloro-1- (cyclohexyl) methyl-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1 H- indole, trifluoroacetic acid salt

The title compound was prepared following the method of Example 7 using 7-chloro-1- (cyclohexyl) methyl-1 H -indole-3-carboxylic acid amide (obtained from 7-chloroindole) and using pyrrolidine instead of diethylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 417.3, 415.3 [M + H] ⁺ .

Example 12

1- (Cyclohexyl) methyl-7-ethyl-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1 H- indole, trifluoroacetic acid salt

The title compound was prepared using the method of Example 7 using 1- (cyclohexyl) methyl-7-ethyl-1 H -indole-3-carboxylic acid amide (obtained from 7-ethylindole) and using pyrrolidine instead of diethylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 409.3 [M + H] ⁺ .

Example 13

( R ) -3-cyclohexyl-6- {5 - [(diethylamino) methyl] - [1,2,4] thiadiazol-3-yl-2,3-dihydropyrrolo [1,2,3- de ] -1, 4-benzoxazine hydrochloride salt

To a mixture of ( R ) -N- Boc-2-cyclohexylethanolamine (prepared as described for the ( S ) enantiomer, Luly 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, diisopropylazodicarboxylate (19.5 ml, 99.2 mmol) was added. After stirring for 1 hour, 2-bromophenol (12.1 ml, 104.0 mmol) was added to the mixture at 0 ° C. The reaction mixture was stirred for 2 hours at 0 ° C and for 20 hours at room temperature. The resulting mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with 2n. sodium hydroxide solution and brine, dried over sodium sulfate and concentrated. The precipitate was purified by flash column chromatography, eluting with 0-10% (v / v) ethyl acetate in heptane to give ( R ) -2- (2-tert-butoxycarbonylamino-2-cyclohexylethoxy) bromobenzene (12.80 g, 32 , 1 mmol).

A mixture of ( R ) -2- (2-tert-butoxycarbonylamino-2-cyclohexylethoxy) bromobenzene (500 mg, 1.26 mmol), tetrakis (triphenylphosphine) palladium (0) (146 mg, 0.126 mmol) and sodium tert-butoxide ( 181 mg of 1.88 mmol) in toluene (4.0 ml) was microwaved for 10 min at 120 ° C. The resulting mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The precipitate was purified by flash column chromatography, eluting with 0-17% (v / v) ethyl acetate in heptane to give ( R ) -4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2 H -1, 4-benzoxazine (270 mg, 0.85 mmol). This reaction was repeated 13 times at the same amounts to give the above intermediate compound (a total of 3.98 g, 12.5 mmol).

A mixture of ( R ) -4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2 H -1,4-benzoxazine (3.98 g, 12.5 mmol), 5N. hydrochloric acid (10 ml) and ethanol (10 ml) were stirred at 70 ° C for 50 minutes. Ethanol was removed in vacuo and the residue was partitioned between dichloromethane and 2N. sodium hydroxide solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give ( R ) -3-cyclohexyl-3,4-dihydro-2 H -1,4-benzoxazine (2.72 g, 12 5 mmol).

( R ) -3-cyclohexyl-3,4-dihydro-2 H -1,4-benzoxazine (2.72 g, 12.5 mmol) was dissolved in N , N- dimethylformamide (20 ml) and sodium nitrite solution ( 949 mg, 13.8 mmol) in water (3.0 ml) at 0 ° C. Then added 5N. hydrochloric acid (6.0 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting precipitate was dissolved in diethyl ether (50 ml) and lithium aluminum hydride was added in tetrahydrofuran (1.0 M; 9.51 ml, 9.51 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, then quenched with ice water. Ethyl acetate was added to the mixture, the mixture was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The precipitate was purified by flash column chromatography, eluting with 0-17% (v / v) ethyl acetate in heptane to give ( R ) -4-amino-3-cyclohexyl-3,4-dihydro-2 H -1,4- benzoxazine (1.47 g, 6.33 mmol).

Ethyl pyruvate (882 mg, 7.59 mmol) was added to a solution of ( R ) -4-amino-3-cyclohexyl-3,4-dihydro-2 H -1,4-benzoxazine (1.47 g, 6.33 mmol) in ethanol (40 ml). The reaction mixture was stirred at room temperature for 15 minutes. Sulfuric acid (10% v / v in ethanol; 8.0 ml) was added to the reaction mixture. The reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and sodium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The precipitate was purified by flash column chromatography, eluting with 0-10% (v / v) ethyl acetate in heptane to give 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 ] -1,4-benzoxazine-5-carboxylate (1.49 g, 4.76 mmol) in ethanol ( 50 ml) was added 4N. sodium hydroxide (5.94 ml, 23.8 mmol). The mixture was stirred at 70 ° C for 40 minutes. Ethanol was removed in vacuo, the precipitate was neutralized with 2n. hydrochloric acid and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The precipitate was dissolved in quinoline (20 ml), then copper powder (453 mg, 7.13 mmol) was added. The mixture was stirred at 210 ° C for 1 hour. Ethyl acetate and water were added to the mixture at room temperature, the mixture was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was acidified with 5N. hydrochloric acid and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with 1N. hydrochloric acid and brine, dried over sodium sulfate and concentrated. The precipitate was purified by flash column chromatography, eluting with 0-10% (v / v) ethyl acetate in heptane to give ( R ) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3- de ] -1, 4-benzoxazine (984 mg, 4.08 mmol).

To a solution of ( R ) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzoxazine (600 mg, 2.49 mmol) in N , N- dimethylformamide (5.0 ml ) trifluoroacetic anhydride (0.311 ml, 2.73 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 5 hours, then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The precipitate was purified by flash chromatography, eluting with 0-25% (v / v) ethyl acetate in heptane to give ( 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) was added 4N. NaOH (5.0 ml). The mixture was refluxed for 42 hours, then acidified to pH 1 using 5N. hydrochloric acid, and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give ( R ) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3- de ] -1,4- benzoxazine-6-carboxylic acid (572 mg).

The title compound following the method of Example 7 using the amide ( R ) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid (obtained from ( R ) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid) instead of 1- (cyclohexyl) methyl-7-methoxy-1 H -indole amide -3-carboxylic acid. EsIMS: m / z 411.0 [M + H] ⁺ ; [α] _D ²² -30.7 ° (c = 1.50 mg / ml in chloroform).

Example 14

The following compounds were prepared following the method of Example 7 using 7-fluoro-1- (tetrahydropyran-4-yl) methyl-1 H -indole-3-carboxylic acid amide instead of 1- (cyclohexyl) methyl-7-methoxy-1 amide H- indole-3-carboxylic acid.

The 7-fluoro-1- (tetrahydropyran-4-yl) methyl-1 H -indole-3-carboxylic acid amide was obtained following the procedure of Example 1 using 7-fluorindole instead of 7-methoxyindole and tetrahydropyran-4-ylmethyl ether toluene- 4-sulfonic acid instead of cyclohexylmethyl bromide.

Method for the synthesis of toluene-4-sulfonic acid intermediate tetrahydropyran-4-ylmethyl ester

To a mixture of tetrahydro-2 H- pyran-4-ylmethanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml), p-toluenesulfonyl chloride (29.8 g, 157) was added portionwise. mmol). The mixture was stirred at room temperature for 17 hours, then quenched with an aqueous solution of hydrochloric acid (2M; 100 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 100 ml). The organic layers were combined and concentrated in vacuo. Recrystallization from dichloromethane: heptane (5: 1) gave tetrahydropyran-4-ylmethyl ether toluene-4-sulfonic acid. The mother liquors were then purified by silica gel column chromatography, eluting with 50% dichloromethane in n-heptane, to give an additional amount of toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol).

14A: 3- {5 - [(Diethylamino) methyl] - [1,2,4] thiadiazol-3-yl} -7-fluoro-1- (tetrahydropyran-4-yl) methyl-1 H -indole, hydrochloride salt

The title compound was prepared using diethylamine. EsIMS: m / z 403.1 [M + H] ⁺ .

14B: 7-Fluoro-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1- (tetrahydropyran-4-yl) methyl-1 H- indole, hydrochloride salt

The title compound was prepared using pyrrolidine instead of diethylamine. EsIMS: m / z 401.0 [M + H] ⁺ .

14C: 3- {5 - [(Dimethylamino) methyl} - [1,2,4] thiadiazol-3-yl} -7-fluoro-1- (tetrahydropyran-4-yl) methyl-1 H -indole, hydrochloride salt

The title compound was prepared using dimethylamine instead of diethylamine. EsIMS: m / z 375.0 [M + H] ⁺ .

Example 15

The following compounds were prepared following the method of Example 7 using 7-chloro-1- (tetrahydropyran-4-yl) methyl-1 H -indole-3-carboxylic acid amide instead of 1- (cyclohexyl) methyl-7-methoxy-1 amide H- indole-3-carboxylic acid.

Amide 7-chloro-1- (tetrahydropyran-4-yl) methyl- 1H- indole-3-carboxylic acid was obtained following the method of example 1, using 7-chloroindole instead of 7-methoxyindole and tetrahydropyran-4-ylmethyl ether toluene- 4-sulfonic acid instead of cyclohexylmethyl bromide.

15A: 7-Chloro-3- (5 - {[N -ethyl -N- (2-methoxyethyl) amino] methyl} - [1,2,4] thiadiazol-3-yl) -1- (tetrahydropyran-4-yl) methyl 1 H -indole, hydrochloride salt

The title compound was prepared using N- ethyl- N - (2-methoxyethyl) amine instead of diethylamine. EsIMS: m / z 451.0, 449.0 [M + H] ⁺ .

15B: 7-Chloro-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1- (tetrahydropyran-4-yl) methyl-1 H- indole, hydrochloride salt

The title compound was prepared using pyrrolidine instead of diethylamine. EsIMS: m / z 419.3, 417.3 [M + H] ⁺ .

15C: 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

The title compound was prepared using N -ethyl -N- (2-hydroxyethyl) amine instead of diethylamine. EsIMS: m / z 437.1, 435.1 [M + H] ⁺ .

Example 16

1- (Cyclohexyl) methyl-7-methoxy-3- (4 - {[ N - (2-methoxyethyl) - N- methylamino] methyl} - [1,3] thiazol-2-yl) -1 H- indole, hydrochloride salt

A mixture of 1- (cyclohexyl) methyl-7-methoxy- 1H- indole-3-carboxylic acid amide (obtained 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) were stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography, eluting with dichloromethane, to give 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-thiocarboxylic acid amide (3.58 g).

A mixture of 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-thiocarboxylic acid amide (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0.99 mmol) and ethanol (2 , 0 ml) was stirred at 60 ° C for 1 hour. The reaction mixture was concentrated in vacuo and the resulting precipitate was mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture was extracted with dichloromethane (4 × 100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was 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).

Mixture of 3- [4- (chloromethyl) thiazol-2-yl] -1- (cyclohexyl) methyl-7-methoxy-1 H -indole (100 mg, 0.27 mmol), (2-methoxyethyl) methylamine (119 mg , 1.33 mmol), 1,4-dioxane (2 ml) and acetonitrile (1 ml) were microwaved for 10 min at 160 ° C. The reaction mixture was concentrated in vacuo and the resulting residue was mixed with aqueous sodium hydroxide (1M; 50 ml) and extracted with dichloromethane (4 × 50 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was purified by column chromatography eluting with ethyl acetate to give the free base of the title compound as an oil. Hydrochloride salt formation was achieved by adding hydrogen chloride (1M solution in diethyl ether; 3 ml) to a solution of the free base in diethyl ether (15 ml). The mixture was concentrated in vacuo to give the title compound as the hydrochloride salt, 1: 1 (95.1 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 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, J = 8.0), 7.16 (1H, dd, J = 8.0, 8.0), 7.62 (1H, s) 7.80 (1H, d, J = 8.0); 7.85 (1H, s). EsIMS: m / z 428.1 [M + H] ⁺ , 339.0.

Example 17

Further, the method of Example 16 was used to prepare the following compounds using alternative amines instead of (2-methoxyethyl) methylamine.

17A: 1- (Cyclohexyl) methyl-7-methoxy-3- {4 - [(morpholin-4-yl) methyl] - [1,3] thiazol-2-yl} -1 H- indole, hydrochloride salt

The title compound was prepared using morpholine instead of (2-methoxyethyl) methylamine. EsIMS: m / z 426.3 [M + H] ⁺ , 339.1.

17B: 1- (Cyclohexyl) methyl-3- {4 - [(4-hydroxypiperidin-1-yl) methyl] - [1,3] thiazol-2-yl} -7-methoxy-1 H -indole, hydrochloride salt

The title compound was prepared using 4-hydroxypiperidine instead of (2-methoxyethyl) methylamine. EsIMS: m / z 440.1 [M + H] ⁺ , 399.0.

17C:  1- (Cyclohexyl) methyl-3- (4 - {[ N isopropyl- N- (2-methoxyethyl) amino] methyl} - [1,3] thiazol-2-yl) -7-methoxy-1 H -indole, hydrochloride salt

The title compound was prepared using N- isopropyl- N - (2-methoxyethyl) amine instead of (2-methoxyethyl) methylamine. EsIMS: m / z 456.4 [M + H] ⁺ , 339.1.

17D: ( S ) -1- (Cyclohexyl) methyl-3- {4 - [(2-hydroxymethylpyrrolidin-1-yl) methyl] - [1,3] thiazol-2-yl-7-methoxy-1 H -indole

The title compound was prepared using ( S ) - (+) - prolinol instead of (2-methoxyethyl) methylamine and isolated as the free base. EsIMS: m / z 440.1 [M + H] ⁺ , 339.1; [a] _D ²² -10.0 ° (c = 0.65 mg / ml in chloroform).

17E: 1- (Cyclohexyl) methyl-7-methoxy-3- {4 - [(thiomorpholin-4-yl) methyl] - [1,3] thiazol-2-yl} -1 H- indole, hydrochloride salt

The title compound was prepared using thiomorpholine instead of (2-methoxyethyl) methylamine. EsIMS: m / z 442.0 [M + H] ⁺ , 339.0.

Example 18

1- (Cyclohexyl) methyl-7-methoxy-3- {4- [1- (pyrrolidin-1-yl) ethyl] - [1,3] 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) was added dropwise to a solution of 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-thiocarbonyl amide acid (obtained as in example 16; 1.20 g, 3.97 mmol) in ethanol (12 ml) at room temperature and then the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo, the resulting precipitate was mixed with dichloromethane (50 ml) and washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was 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] thiazol-4-yl} ethanone as a brown solid (1.11 g).

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) were stirred at room temperature for 2 hours. Macroporous triethylammonium methyl polystyrene cyanoborohydride (MP-cyanoborohydride, loading: 2.35 mmol / g, 231 mg, 0.543 mmol) was added and the resulting mixture was microwaved at 130 ° C for 10 min. The resin was removed by filtration, washing with dichloromethane, and the filtrate was concentrated in vacuo. The resulting precipitate was mixed with aqueous sodium hydroxide (1M; 100 ml) and extracted with dichloromethane (4 × 100 ml). The organic layers were combined, then washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was purified by column chromatography, eluting with 5% methanol in ethyl acetate. The resulting oil was dissolved in diethyl ether (10 ml), then HCl (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt, 1: 1 (30.1 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 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 (1H, m) 6.81 (1H, d, J = 7.6), 7.15 (1H, dd, J = 7.6, 8.0), 7.51 (1H, s), 7.79-7, 90 (2H, m). EsIMS: m / z 424.1 [M + H] ⁺ , 353.1.

Example 19

1- (Cyclohexyl) methyl-7-fluoro-3- (4 - {[N-isopropyl -N- (2-methoxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -1 H -indole trifluoroacetic acid salt

The title compound was prepared following the method of Example 16 using 1- (cyclohexyl) methyl-7-fluoro-1 H -indole-3-carboxylic acid amide (obtained from 7-fluorindole) and N- isopropyl- N- (2 -methoxyethyl) amine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 444.3 [M + H] ⁺ , 327.3.

Example 19A

1- (Cyclohexyl) methyl-6-fluoro-3- [4- (diethylamino) methyl] - [1,3] thiazol-2-yl) -1 H -indole, trifluoroacetic acid salt

The title compound was prepared following the method of Example 16 using 1- (cyclohexyl) methyl-6-fluoro-1 H -indole-3-carboxylic acid amide (derived from 6-fluorindole) and diethylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 400.1 [M + H] ⁺ , 327.1.

Example 20

7-Chloro-1- (cyclohexyl) methyl-3- (4 - {[N-isopropyl -N- (2-methoxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -1 H -indole hydrochloride salt

The title compound was prepared following the method of Example 16 using 7-chloro-1- (cyclohexyl) methyl-1 H -indole-3-carboxylic acid amide (obtained from 7-chloroindole) and N -isopropyl- N- (2 -methoxyethyl) amine. EsIMS: m / z 462.3, 460.3 [M + H] ⁺ , 343.1.

Example 21

1- (Cyclohexyl) methyl-7-ethyl-3- (4 - {[N-isopropyl -N- (2-methoxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -1 H -indole trifluoroacetic acid salt

The title compound was prepared following the method of Example 16 using 1- (cyclohexyl) methyl-7-ethyl-1 H -indole-3-carboxylic acid amide (obtained from 7-ethylindole) and N- isopropyl- N - (2 -methoxyethyl) amine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 454.5 [M + H] ⁺ , 337.3.

Example 22

The following compounds were 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 (obtained from ( R ) -3-cyclohexyl-2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid described in example 13) instead of 1- (cyclohexyl) methyl-7-methoxy- amide 1 H- indole-3-carboxylic acid.

22A: ( R ) -3-cyclohexyl-6- {4 - [(diethylamino) methyl] - [1,3] thiazol-2-yl} -2,3-dihydropyrrolo [1,2,3- de ] -1,4 -benzoxazine, hydrochloride salt

The title compound was prepared using diethylamine instead of (2-methoxyethyl) methylamine. EsIMS: m / z 410.3 [M + H] ⁺ , 337.3; [α] _D ²² -37.5 ° (c = 1.30 mg / ml in chloroform).

22B: ( R ) -3-cyclohexyl-6- {4 - [( N- ethyl- N- isopropylamino) methyl] - [1,3] thiazol-2-yl} -2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzoxazine, trifluoroacetic acid salt

The title compound was prepared using N- ethyl- N- isopropylamine instead of (2-methoxyethyl) methylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 424.3 [M + H] ⁺ , 337.3; [α] _D ²² -27.4 ° (c = 1.25 mg / ml in chloroform).

22C: ( R ) -3-cyclohexyl-6- {4 - [(pyrrolidin-1-yl) methyl] - [1,3] thiazol-2-yl} -2,3-dihydropyrrolo [1,2,3- de ] -1,4-benzoxazine, trifluoroacetic acid salt

The title compound was prepared using pyrrolidine instead of (2-methoxyethyl) methylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1.

EsIMS: m / z 408.3 [M + H] ⁺ , 337.3; [a] _D ²² -32.6 ° (c = 2.15 mg / ml in chloroform).

22D: (R) -3-cyclohexyl-6- (4 - {[N-isopropyl -N- (2-methoxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -2,3-dihydro-pyrrolo [1 , 2,3- de ] -1,4-benzoxazine, trifluoroacetic acid salt

The title compound was prepared using N-isopropyl -N- (2-methoxyethyl) amine instead of (2-methoxyethyl) methylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 454.3 [M + H] ⁺ , 337.3; [α] _D ²² -58.4 ° (c = 2.09 mg / ml in methanol).

22E: ( R ) -3-cyclohexyl-6- (4 - {[bis- (2-methoxyethyl) amino] methyl} - [1,3] thiazol-2-yl) -2,3-dihydropyrrolo [1,2,3 - de ] -1,4-benzoxazine, trifluoroacetic acid salt

The title compound was prepared using bis- (2-methoxyethyl) amine instead of (2-methoxyethyl) methylamine. The free base was purified by semi-preparative HPLC [method (i)] to give the title compound as a trifluoroacetic acid salt, 1: 1. EsIMS: m / z 470.3 [M + H] ⁺ , 337.3; [α] _D ²² -28.5 ° (c = 1.20 mg / ml in chloroform).

Example 23

The following compounds were prepared following the method of Example 16 using 7-chloro-1- (tetrahydropyran-4-yl) methyl-1 H -indole-3-carboxylic acid amide instead of 1- (cyclohexyl) methyl-7-methoxy-1 amide H- indole-3-carboxylic acid.

Amide 7-chloro-1- (tetrahydropyran-4-yl) methyl- 1H- indole-3-carboxylic acid was obtained following the method of example 1, using 7-chloroindole instead of 7-methoxyindole and tetrahydropyran-4-ylmethyl ether toluene- 4-sulfonic acid (prepared as described in Example 14) instead of cyclohexylmethyl bromide.

23A: 7-Chloro-3- {4 - [(diethylamino) methyl] - [1,3] thiazol-2-yl} -1- (tetrahydropyran-4-yl) methyl-1 H- indole, hydrochloride salt

The title compound was prepared using diethylamine. EIMS: m / z 420.0, 418.4 [M + H] ⁺ , 347.0, 345.0.

23B: 7-Chloro-3- {4 - {{ N - (2-hydroxyethyl) -N- isopropylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl-1 H is indole

The title compound was prepared using N - (2-hydroxyethyl) -N- isopropylamine. EIMS: m / z 448.4 [M + H] ⁺ , 347.1, 345.1.

23C: 7-Chloro-3- (4 - {[N -ethyl -N- (2-hydroxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -1- (tetrahydropyranyl-4-yl) methyl- 1 H -indole

The title compound was 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 - {[ N - (2-methoxyethyl) -N- methylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl- 1 H- indole, hydrochloride salt

The title compound was prepared using N - (2-methoxyethyl) -N- methylamine. EIMS: m / z 436.1, 434.1 [M + H] ⁺ , 347.0, 345.0.

Example 24

1- (Cyclohexyl) methyl-3- {4 - [(dimethylamino) methyl] -5-ethyl- [1,3] thiazol-2-yl} -7-methoxy-1 H -indole, hydrochloride salt

Sodium ethoxide (0.68 g, 9.94 mmol) was added portionwise to a mixture of ethyl dichloroacetate (1.22 ml, 9.94 mmol) and diethyl ether (10 ml) under cooling in ice water, and the resulting mixture was stirred at 0 ° C in within 30 minutes. Then propionic aldehyde (0.79 ml, 10.93 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature, stirring continuously for 72 hours. Then the reaction mixture was poured into water (10 ml) and was extracted with diethyl ether (2 × 15 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give crude 3-chloro-2-oxopentanoic acid ethyl ester (1.8 g), which was used in the next step without further purification.

A mixture of 1- (cyclohexyl) methyl-7-methoxy-1 H- indole-3-thiocarboxylic acid amide (0.227 g, 0.754 mmol) and crude 3-chloro-2-oxopentanoic acid ethyl ester (1.34 g, 7.52 mmol) in dimethylformamide (4 ml) was microwaved for 25 min at 140 ° C. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography eluting with 25% acetone in heptane to give crude 2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -5-ethylthiazole ethyl ester -4-carboxylic acid (0.490 g). The resulting material was used in the next step without further purification.

To a mixture of 2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -5-ethylthiazole-4-carboxylic acid ethyl ester (490 mg, 1.15 mmol) and tetrahydrofuran (5 ml) was added in portions lithium borohydride (200 mg, 9.09 mmol) was cooled in ice water and the resulting mixture was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with an aqueous solution of hydrochloric acid (2M; 2 ml) and the aqueous layer was extracted with dichloromethane (2 × 100 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a crude product. Column chromatography on silica gel afforded crude [2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -5-ethylthiazol-4-yl] methanol (210 mg), eluting with 66% ethyl acetate in heptane. The resulting material was used in the next step without further purification.

To a mixture of [2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -5-ethylthiazol-4-yl] methanol (210 mg, 0.547 mmol), diisopropylethylamine (150 μl, 0.91 mmol ) and dichloromethane (5 ml) were added with cooling in ice water methanesulfonyl chloride (90 μl, 1.16 mmol) and the resulting mixture was allowed to slowly warm to room temperature. Stirring was continued for 22 hours. The reaction mixture was quenched with 5% aqueous sodium carbonate (2 ml) and the aqueous layer was extracted with dichloromethane (2 × 10 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a crude product. Flash column chromatography, eluting with 10% acetone in n-heptane, afforded 3- (4-chloromethyl-5-ethylthiazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1 H -indole (109 mg).

To a mixture of 3- (4-chloromethyl-5-ethylthiazol-2-yl) -1-cyclohexylmethyl-7-methoxy- 1H- indole (38 mg, 0.095 mmol), potassium carbonate (16 mg, 0.113 mmol) and sodium iodide (14 mg, 0.095 mmol) in acetonitrile (2 ml) was added dimethylamine (2.2 M solution in tetrahydrofuran; 0.50 ml). The mixture was microwaved for 5 minutes at 160 ° C, then partitioned between dichloromethane (20 ml) and 5% aqueous sodium carbonate (5 ml). The aqueous layer was extracted with dichloromethane (10 ml) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting oil was dissolved in diethyl ether, then hydrogen chloride (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt, 1: 1 (40 mg, 0.089 mmol).

¹ H NMR (400 MHz, CD ₃ OD) δ 1.04-1.15 (2H, m), 1.16-1.30 (3H, m), 1.43 (3H, t, J = 7, 0), 1.55-1.78 (5H, m), 1.82-1.92 (1H, m), 3.05 (8H, m), 3.99 (3H, s), 4.33 (2H, d, J = 7), 4.62 (2H, s), 6.91 (1H, d, J = 8.0), 7.29 (1H, t, J = 8.0), 7 62 (1H, d, J = 8), 8.30 (1H, s). EsIMS: m / z 412.3 [M + H] ⁺ , 367.0.

Example 25

1- (Cyclohexyl) methyl-3- {5 - [(diethylamino) methyl] -4-methyl [1,3] thiazol-2-yl} -7-methoxy-1 H -indole, hydrochloride salt

To a solution of 1- (cyclohexyl) methyl-7-methoxy- 1H- indole-3-thiocarboxylic acid amide (604 mg, 2.00 mmol) in EtOH (5.0 ml) was added ethyl 2-chloro-3-oxobutanoate (0.332 ml, 2.40 mmol). The mixture was refluxed for 1 hour. After cooling to 0 ° C, the precipitate was collected by filtration to obtain 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) was added lithium aluminum hydride (125 mg , 3.30 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour, then quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The precipitate was 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- 1H- 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) was added methanesulfonyl chloride (28 mg, 0.24 mmol). The mixture was stirred at room temperature for 40 minutes and partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, then the combined organic layers were washed with brine, dried over sodium sulfate and concentrated to obtain crude 1-cyclohexylmethyl-3- (5-methanesulfonyloxymethyl-4-methylthiazol-2-yl) -7-methoxy-1 H - indole (65 mg, 0.15 mmol). A mixture of crude 1-cyclohexylmethyl-3- (5-methanesulfonyloxymethyl-4-methylthiazol-2-yl) -7-methoxy-1 H -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) were microwaved for 5 min at 160 ° C. The resulting mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The precipitate was purified by flash chromatography, eluting with 50-100% (v / v) ethyl acetate in heptane to give 1-cyclohexylmethyl-3- (5-diethylaminoethyl-4-methylthiazol-2-yl) -7-methoxy-1 H -indole (27 mg, 0.064 mmol). Hydrochloride salt formation was achieved by adding hydrogen chloride (1M solution in diethyl ether; 1 ml) to a solution of the free base in diethyl ether (1 ml) and ethanol (2 ml). The solvent was removed in vacuo and the precipitate was dried to obtain the title compound as the hydrochloride salt, 1: 1 (26 mg, 0.056 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 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 (1H, 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 (1H, d, J = 7.6), 7.14 (1H, t, J = 7.6), 7.72 (1H, d, J = 7.6), 8.00 (1H, s), 9.90 (1H, br s); EsIMS: m / z 426.3 [M + H] ⁺ , 353.1.

Example 26

1- (Cyclohexyl) methyl-3- {2 - [(diethylamino) methyl] - [1,3] 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) in a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil; 1.50 g, 37.4 mmol). Before adding bromomethylcyclohexane (5.20 ml, 37.4 mmol), the mixture was stirred at room temperature for 10 minutes. The resulting mixture was stirred at room temperature for 42 hours and then partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic layers were washed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo. The crude intermediate was 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).

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, chloroacetyl chloride (8.66 ml, 109 mmol) was added dropwise over 1.5 hours. The resulting mixture was heated to 55 ° C for the next 0.5 hours, then allowed to cool to room temperature. Water (60 ml) and methanol (10 ml) were added. The organic layer was separated and concentrated under reduced pressure to obtain a dark brown precipitate. The precipitate was purified by column chromatography eluting with 5% (v / v) ethyl acetate in n-heptane. The resulting solid was recrystallized from ether to give 2-chloro-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) were suspended in ethanol (10 ml) and the resulting mixture was microwaved at 150 ° C. for 10 minutes using Emrys ™ Optimizer EXP. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography eluting with 5% (v / v) ethyl acetate in n-heptane to give 1- (cyclohexyl) methyl-7-methoxy-3- {2 - [( tert-butylcarbonyloxy) methyl] thiazol-4-yl} -1 H- indole as a yellow oil (1.01 g).

1- (Cyclohexyl) methyl-7-methoxy-3- {2 - [(tert-butylcarbonyloxy) methyl] thiazol-4-yl} -1 H- indole (0.92 g, 2.10 mmol) was dissolved in methanol (20 ml ) and 4n was added. sodium hydroxide (5 ml). The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in dichloromethane. Water was added and the organic layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were concentrated in vacuo to give 1- (cyclohexyl) methyl-3- [2- (hydroxymethyl) thiazol-4-yl] -7-methoxy-1 H -indole as a pale orange foam ( 0.55 g).

Methanesulfonyl chloride (174 μl, 2.25 mmol) was added to a solution of 1- (cyclohexyl) methyl-3- [2- (hydroxymethyl) thiazol-4-yl] -7-methoxy-1 H -indole (0.40 g, 1 , 12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at room temperature overnight. Then methanesulfonyl chloride (87 μl, 1.12 mmol) was added and stirred continuously for 0.5 hours. The mixture was concentrated in vacuo and the resulting orange precipitate was purified by flash column chromatography eluting with dichloromethane to give 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) dissolved in acetonitrile (2 ml). The resulting mixture was microwaved at 100 ° C for 5 minutes. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography, eluting with 33% (v / v) ethyl acetate in n-heptane. The resulting product was transferred into diethyl ether and hydrogen chloride (1M solution in diethyl ether; 1 ml) was added. The solution was concentrated in vacuo and the resulting solid was triturated with ether, then dried to give the title compound as the hydrochloride salt, 1: 1 (0.034 g).

¹ H NMR (400 MHz, CD ₃ OD) δ 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, masked by H ₂ O peak), 6.75 (1H, d, J = 8.0), 7.08 (1H, dd, J = 8.0, 8.0), 7.64-7.68 (3H, m). EsIMS:

m / z 412.1 [M + H] ⁺ , 339.0.

Example 27

1- (Cyclohexyl) methyl-7-methoxy-3- {2 - [(pyrrolidin-1-yl) methyl] - [1,3] thiazol-4-yl} -1 H- indole, hydrochloride salt

The title compound was prepared by the method of Example 26 using pyrrolidine instead of diethylamine. EsIMS: m / z 410.3 [M + H] ⁺ , 339.1.

Example 28

1- (Cyclohexyl) methyl-3- {2 - [(dimethylamino) methyl] - [1,3] thiazol-5-yl} -7-methoxy-1 H -indole, hydrochloride salt

To a suspension of 1-cyclohexylmethyl-7-methoxy-1 H- indole-3-carboxylic acid (5 g, 17.4 mmol) in dichloromethane (100 ml) was added oxalyl chloride (3.04 ml, 34.8 mmol) and the resulting solution stirred overnight. Then, excess solvent and reagent were removed by evaporation. Copper (I) cyanide (6.2 g, 69.6 mmol), toluene (200 ml) and acetonitrile (10 ml) were added to the resulting precipitate, and the resulting reaction mixture was refluxed for 7 hours. Then, another portion of copper (I) cyanide (1.6 g, 17.9 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was cooled and filtered through a pad of dicalite, washed with acetonitrile and the combined filtrate was evaporated to give a red solid. The solid was purified by flash column chromatography, eluting with 50% (v / v) dichloromethane in heptane to give (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) in a nitrogen atmosphere was added 10% palladium on activated carbon (90 mg ) The reaction mixture was placed in a hydrogen atmosphere and stirred for 14 hours. Then the reaction mixture was filtered through a layer of dicalite. Dicalit was washed with acetic acid and the combined filtrate was evaporated to give a red oil. Red oil was transferred to dichloromethane (50 ml) and methyl chloroacetoacetate (0.393 ml, 4.28 mmol) was added thereto, followed by dropwise addition of N- ethyldiisopropylamine (1.7 ml, 9.87 mmol). The reaction mixture was stirred for 1 hour and poured into a separatory funnel. The organic layers were washed successively with 2M aqueous hydrochloric acid (50 ml), 5% aqueous sodium carbonate (50 ml) and brine (50 ml). The organics were dried over sodium sulfate, filtered and the solvent was removed in vacuo to give a brown oil. The oil was purified by flash column chromatography using dichloromethane and then 66% (v / v) diethyl ether in heptane to give N - [(1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) - methyl ester 2-oxoethyl] oxalamic acid (573 mg, 1.48 mmol) as a yellow / brown solid.

To a solution of N - [(1-cyclohexylmethyl-7-methoxy-1 H -indol-3-yl) -2-oxoethyl] oxalamic acid methyl ester (429 mg, 1.11 mmol) in chloroform (20 ml) was added phosphorus pentasulfide (538 mg, 1.21 mmol) and the reaction mixture was heated for 3.5 hours. The reaction mixture was cooled, poured into a separatory funnel, washed with water and then brine. Then the organic layers were dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The resulting solid was purified by flash column chromatography eluting with dichloromethane to give 5- (1-cyclohexylmethyl-7-methoxy-1 H -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-1 H -indol-3-yl) thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml ) sodium borohydride (83 mg, 2.18 mmol) was added in portions over 2 minutes. Then the reaction mixture was stirred for 1 hour and then quenched with an aqueous solution of hydrochloric acid (1M; 10 ml). The mixture was poured into a separatory funnel, diluted with dichloromethane (50 ml) and washed with water (20 ml). The combined organic layers were dried, filtered and the solvent was removed in vacuo to give a yellow oil. The oil was 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) thiazol-2- silt] methanol (308 mg, 0.86 mmol) as an off-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) was added methanesulfonyl chloride (80 μl, 1.03 mmol) and then triethylamine (0.156 ml, 1.12 mmol). The reaction mixture was stirred for 30 minutes, then poured into a separatory funnel, washed with 5% aqueous sodium carbonate, then brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give 5- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) thiazol-2-ylmethanesulfonic acid methyl ester (411 mg, 0.94 mmol). To a solution of 5- (1-cyclohexylmethyl-7-methoxy- 1H- indol-3-yl) thiazol-2-ylmethanesulfonic acid methyl ester (93 mg, 0.215 mmol) in tetrahydrofuran (2 ml) was added dimethylamine (2M in tetrahydrofuran; 1 ml, 2 mmol) and the reaction mixture was microwaved at 150 ° C for 15 minutes. The reaction mixture was diluted with dichloromethane (40 ml) and washed with a mixture of brine and saturated sodium bicarbonate at a ratio of 1: 1 (v / v), dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The resulting oil was purified by flash column chromatography to give the title compound (70 mg, 0.18 mmol) as the free base. The free base was dissolved in dichloromethane (5 ml), hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) was added and the solvent was removed in vacuo to give the title compound as the hydrochloride salt, 1: 1.

¹ H NMR (400 MHz, CD ₃ OD): 0.96-1.12 (2H, m), 1.13-1.26 (3H, m), 1.5-1.62 (2H, m) 1.62-1.78 (3H, m), 1.78-1.92 (1H, m), 3.01 (6H, s), 3.96 (3H, s), 4.26 (2H d, J = 5.5), 4.71 (2H, s), 6.78 (1H, d, J = 8.0), 7.11 (1H, t, J = 8.0), 7 41 (1H, d, J = 8.0), 7.52 (1H, s), 8.08 (1H, s); EsIMS: m / z 384.0 [M + H] ⁺ , 339.0, 243.1.

Example 29

1- (Cyclohexyl) methyl-3- {4 - [(diethylamino) methyl] - [1,3] oxazol-2-yl-7-methoxy-1 H -indole, hydrochloride salt

To a solution of 1-cyclohexylmethyl-7-methoxy- 1H- indole-3-carboxylic acid amide (500 mg, 1.75 mmol) in toluene (4 ml) was added 1,3-dichloroacetone (333 mg, 2.62 mmol) and the reaction mixture was microwaved at 150 ° C. for 30 minutes. The resulting black solution was diluted with dichloromethane (50 ml) and washed with 5% aqueous sodium carbonate (5 × 20 ml), dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The resulting brown oil was purified by flash column chromatography using 5% (v / v) acetone in 40-60 ml petroleum ether to give 3- (4-chloromethyloxazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1 H- indole (510 mg, 1.42 mmol) as a white solid.

To a solution of 3- (4-chloromethyloxazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1-indole (100 mg, 0.28 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0.29 ml, 2, 8 mmol) and the reaction mixture was microwaved at 150 ° C for 15 minutes. The reaction mixture was added to a separatory funnel, diluted with dichloromethane (40 ml) and washed with 5% aqueous sodium carbonate solution (2 × 25 ml), brine (20 ml), dried over magnesium sulfate and the solvent was evaporated in vacuo to give an orange oil. The oil was 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 was dissolved in dichloromethane and hydrogen chloride (1M solution in diethyl ether; 2 ml, 2 mmol) was added. The mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt, 1: 1.

¹ H NMR (400 MHz, CD ₃ OD): 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); EsIMS: m / z 396.0 [M + H] ⁺ , 323.4, 295.4, 268.3.

Example 30

1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,3] oxazol-2-yl} -1 H- indole, trifluoroacetic acid salt

Mixture of 1-cyclohexylmethyl-7-methoxy- 1H- indole-3-carboxylic acid amide (563 mg, 1.97 mmol), 2-chloro-3-oxopropionic acid methyl ester (Gangjee et al., J. Med. Chem 44, 1993-2003, 2001; 1.48 g, 9.85 mmol) and dimethylacetamide (10 ml) were microwaved at 90 ° C. for 2 × 5 minutes using Emrys ™ Optimizer EXP. The reaction mixture was diluted with dichloromethane (150 ml), then washed with 5% aqueous magnesium sulfate (2 × 100 ml) and brine (150 ml). The organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was purified by flash column chromatography, eluting with 25% (v / v) ethyl acetate in heptane to give an inseparable mixture of 2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -oxazole methyl ester -5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3-oxazol-2-yl-1 H -indole (HPLC ratio 87:13; 0.613 g).

To a mixture of 2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) oxazole-5-carboxylic acid methyl ester and 1-cyclohexylmethyl-7-methoxy-3-oxazol-2-yl-1 H - of indole (557 mg) dissolved in tetrahydrofuran (10 ml), while cooling in an ice-methanol system, a solution of lithium aluminum hydride (1 M solution in diethyl ether; 2.88 ml, 2.88 mmol) was added dropwise. The resulting mixture was stirred for 30 minutes at 0 ° C, then diluted with diethyl ether (40 ml). Then an excess of sodium sulfate decahydrate was added and the resulting mixture was stirred at room temperature for 18 hours. The mixture was filtered through a layer of dicalite and washed with diethyl ether (100 ml); then the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with 50% ethyl acetate in n-heptane, to give [2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -oxazol-5-yl] methanol as a solid yellow substances (242 mg, 0.71 mmol).

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), at while cooling in the ice-methanol system, methanesulfonyl chloride (98 mg, 0.85 mmol) was added dropwise, then triethylamine (93 mg, 0.92 mmol) was added dropwise, then the cooling was stopped and the mixture was stirred for 16 hours. Then the mixture was diluted with dichloromethane (30 ml), washed with a saturated solution of sodium carbonate (30 ml) in a hydrophobic tube with frit. The organic extracts were dried over magnesium sulfate and then concentrated in vacuo. A mixture of the resulting precipitate (110 mg, 0.26 mmol), pyrrolidine (185 mg, 2.60 mmol) and tetrahydrofuran (2.5 ml) was microwaved at 150 ° C for 15 minutes. The resulting mixture was concentrated in vacuo and purified by flash column chromatography (2% (v / v) ammonia in methanol / dichloromethane at a ratio of 1:49 as eluent) to give a brown gum. The resin was then purified by semi-preparative HPLC [method (i)] to give 1-cyclohexylmethyl-7-methoxy-3- (5-pyrrolidin-1-ylmethyloxazol-2-yl) -1 H -indole as trifluoroacetic acid salt (14 mg) .

¹ H NMR (400 MHz, CD ₃ OD) δ 0.99-1.27 (5H, m), 1.54-1.78 (5H, m), 1.86 (1H, 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 (1H, s, J = 7.0), 7.15 (1H, t, J = 8.0), 7 41 (1H, s); 7.79 (1H, d, J = 7.5); 7.82 (1H, s). EsIMS: m / z 394.1 [M + H] ⁺ , 323.1.

Example 31

1- (Cyclohexyl) methyl-3- {5 - [(diethylamino) methyl] -4-methyl [1,3] oxazol-2-yl} -7-methoxy-1 H -indole, hydrochloride salt

A mixture of 1- (cyclohexyl) methyl-7-methoxy- 1H- indole-3-carboxylic acid amide (500 mg, 1.75 mmol), ethyl 2-chloroacetoacetate (2.88 g, 17.6 mmol) and dimethylformamide (10 ml) was microwaved at 185 ° C for 15 minutes using the Emrys ™ Optimizer EXP. The reaction mixture was diluted with dichloromethane (100 ml), then washed with 5% aqueous magnesium sulfate (2 × 50 ml), water (50 ml) and brine (50 ml). The organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting precipitate was purified by column chromatography, eluting with 33% (v / v) dichloromethane in n-heptane to give an indivisible mixture of ethyl 2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -4 -methyloxazole-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3- (4-methyloxazol-2-yl) -1 H -indole (78:22 ratio by HPLC; 0.586 g). This reaction was repeated with the same amounts.

To a mixture of ethyl 2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -4-methyloxazole-5-carboxylic acid and 1-cyclohexylmethyl-7-methoxy-3- (4-methyloxazole-2 -yl) -1 H -indole (1171 mg) dissolved in tetrahydrofuran (20 ml), while cooling in the ice-methanol system, lithium aluminum hydride (1M solution in diethyl ether; 5.8 ml, 5.8 mmol) was added dropwise. The resulting mixture was stirred for 20 minutes at 0 ° C, then diluted with diethyl ether (40 ml). An excess of sodium sulfate decahydrate was added and the resulting mixture was stirred at room temperature for 18 hours. The mixture was filtered through a layer of dicalite, washing with diethyl ether (100 ml) and the filtrate was concentrated in vacuo. The precipitate was purified by flash column chromatography, eluting with 50% (v / v) ethyl acetate in n-heptane to give [2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -4-methyloxazole -5-yl] methanol as a white solid (774 mg). To a solution of [2- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -4-methyloxazol-5-yl] methanol (724 mg, 2.04 mmol) in dichloromethane (40 ml) at - 78 ° C. under nitrogen atmosphere, methanesulfonyl chloride (281 mg, 2.45 mmol) was added dropwise. Triethylamine (269 mg, 2.66 mmol) was added dropwise and the mixture was allowed to warm to room temperature with stirring for 2 hours. Then the mixture was diluted with dichloromethane (100 ml), washed with saturated sodium carbonate solution (2 × 100 ml) and brine (100 ml). The organic extracts were dried over magnesium sulfate and then concentrated in vacuo. A mixture of the resulting precipitate (100 mg, 0.23 mmol), diethylamine (169 mg, 2.30 mmol) and tetrahydrofuran (2 ml) was microwaved at 150 ° C for 15 minutes. The resulting mixture was concentrated in vacuo and purified by flash column chromatography, eluting with 2% ammonia in a methanol / dichloromethane system at a ratio of 1:49 to give a brown gum. The resin was dissolved in dichloromethane (0.5 ml), then hydrogen chloride (1M solution in diethyl ether; 0.5 ml) was added and the mixture was concentrated in vacuo to give the title compound as the hydrochloride salt, 1: 1 (32 mg) .

¹ H NMR (400 MHz, CD ₃ OD) δ 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 (1H, d, J = 8.2), 7.23 (1H, t, J = 8.0), 7 74 (1H, d, J = 8.0), 8.00 (1H, s). EsIMS: m / z 410.3 [M + H] ⁺ , 337.1.

Example 32

1- (Cyclohexyl) methyl-3- {2 - [(diethylamino) methyl] - [1,3] oxazol-5-yl} -7-methoxy-1 H -indole, hydrochloride salt

To a solution of (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -oxoacetonitrile (prepared as described in Example 28; 2.39 g, 8.06 mmol) in acetic acid (50 ml) in an atmosphere nitrogen was added 10% palladium on activated carbon (240 mg). The reaction mixture was placed in a hydrogen atmosphere and stirred overnight. Then the reaction mixture was filtered through a loose layer of dicalite. Dicalit was washed with acetic acid and the combined filtrate was evaporated to give a red oil. Red oil was transferred to dichloromethane (50 ml), chloroacetyl chloride (0.77 ml, 9.67 mmol) was added to it, and then triethylamine (3.4 ml, 24.2 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and placed in a separatory funnel. The organics were washed successively with 5% aqueous sodium carbonate (2 × 30 ml) and brine (30 ml). The organics were dried over magnesium sulfate, filtered, the solvent was removed in vacuo to give a red / brown oil. The oil was purified by flash column chromatography using 20-100% (v / v) dichloromethane in heptane and then 25-50% (v / v) diethyl ether in heptane to give 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) was added and the reaction mixture was microwaved at 150 ° C. for 15 minutes. The reaction mixture was poured into a separatory funnel and dichloromethane (30 ml) was added. The organics were washed successively with 5% aqueous sodium carbonate and brine. The organics were dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give a brown solid. The brown solid was dissolved in tetrahydrofuran (2 ml) and triethylammonium hydroxide (methoxycarbonylsulfamoyl), internal salt (505 mg, 2.12 mmol) were added. The resulting reaction mixture was microwaved at 150 ° C. for 15 minutes and quenched with methanol (20 ml). The solvent was removed in vacuo and the precipitate was purified by flash chromatography using 50% (v / v) ethyl acetate in heptane followed by semi-preparative HPLC [method (ii)] to give a white solid. The solid was dissolved in dichloromethane (≈5 ml) and hydrogen chloride (1M solution in diethyl ether; 1 ml) was added. The mixture was concentrated in vacuo to give the title compound as the hydrochloride salt, 1: 1 (77 mg, 0.2 mmol).

¹ H NMR (400 MHz, CD ₃ OD) δ 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), 1.77-1.9 (1H, m), 3.36 (4H, q, J = 6.7), 3.95 (3H, s), 4.26 (2H, d, J = 7), 4.64 (2H, s), 6.77 (1H, d, J = 8) 7.11 (1H, t, J = 8), 7.38 (1H, s), 7.41 (1H, d, J = 8), 7.56 (1H, s); EsIMS: m / z 396.1 [M + H] ⁺ , 323.4, 268.4.

Example 33

1- (Cyclohexyl) methyl-3- (5-ethyl-5,6-dihydro-4 H -pyrrolo [3,4- d ] isothiazol-3-yl) -7-methoxy-1 H -indole, hydrochloride salt

To a suspension of 5- (1-cyclohexylmethyl-7-methoxy-1 H- indole) - [1,3,4] oxathiazol-2-one (obtained as described in Example 7; 100 mg, 0.25 mmol) in m -xylene (0.5 ml) was added diethylacetylene dicarboxylate (0.2 ml, 1.25 mmol) and the reaction mixture was microwaved at 200 ° C. for 5 minutes. The reaction mixture was then immediately purified by flash column chromatography using 0-100% (v / v) dichloromethane in heptane to give 3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) - diethyl ether isothiazole-4,5-dicarboxylic acid (141 mg, 0.3 mmol). This reaction was repeated at 1.255 mmol, all combined and purified by flash column chromatography using 50-60% (v / v) dichloromethane in heptane to give the above intermediate (882 mg, 1.87 mmol).

To a cooled solution (ice / methanol bath) of 3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -isothiazole-4,5-dicarboxylic acid diethyl ester (400 mg, 0.85 mmol) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (1M solution in THF; 1.91 ml, 1.91 mmol) and the reaction mixture was stirred for 20 minutes. An excess of sodium sulfate decahydrate was added to the reaction mixture, and the reaction mixture was vigorously stirred for 1.5 hours. The resulting mixture was filtered through a loose layer of dicalite, washing with diethyl ether. The filtrate was concentrated in vacuo and the resulting oil was purified by flash column chromatography to give 3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -4-hydroxymethylisothiazol-5-yl] methanol (141 mg, 0, 3 mmol). To a solution of 3- (1-cyclohexylmethyl-7-methoxy-1 H- indol-3-yl) -4-hydroxymethylisothiazol-5-yl] methanol (194 mg, 0.5 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride ( 0.182 ml, 1.16 mmol), then triethylamine (0.175 ml, 1.26 mmol) and the reaction mixture was stirred for 45 minutes. An additional portion of methanesulfonyl chloride (0.07 ml, 0.44 mmol) and triethylamine (0.15 ml, 1 mmol) was added and the reaction mixture was stirred for the next 2 hours. The reaction mixture was placed in a separatory funnel, washed with a 5% aqueous solution of sodium carbonate, then with brine, dried over magnesium sulfate, and the solvent was evaporated in vacuo. The resulting precipitate was purified by flash column chromatography using 33-100% (v / v) dichloromethane in heptane and then diethyl ether to give {4-chloromethyl-3- [1- (cyclohexyl) methyl-7-methoxy- methyl ester 1 H- indol-3-yl] isothiazol-5-yl} methanesulfonic acid (113 mg, 0.23 mmol).

To a solution of {4-chloromethyl-3- [1- (cyclohexyl) methyl-7-methoxy-1 H- indol-3-yl] isothiazol-5-ylmethanesulfonic acid methyl ester (90 mg, 0.19 mmol) in tetrahydrofuran ( 1 ml) ethylamine (0.186 ml, 0.37 mmol) and triethylamine (0.05 ml, 0.37 mmol) were added and the reaction mixture was microwaved at 150 ° C. for 15 minutes. The reaction mixture was placed in a separatory funnel, diluted with dichloromethane (30 ml) and washed with 5% aqueous sodium carbonate (2 × 10 ml), brine (10 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The reaction was repeated at 0.166 mmol to give the above intermediate. The crude products were 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 was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) was added. The mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt, 1: 1.

¹ H NMR (400 MHz, CD ₃ OD): 0.97-1.15 (2H, m), 1.15-1.27 (3H, m), 1.47 (3H, t, J = 7) 1.52-1.61 (2H, m), 1.62-1.77 (3H, m), 1.81-1.95 (1H, m), 3.63 (2H, q, J = 7), 3.95 (3H, s), 4.28 (2H, d, J = 7), 4.62-4.75 (2H, m), 4.95-5.12 (2H, m) 6.77 (1H, d, J = 8), 7.09 (1H, t, J = 8), 7.43 (1H, s), 8.01 (1H, d, J = 8); EsIMS: m / z 396.0 [M + H] ⁺ , 353.4, 351.3, 320.3.

Example 34

1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(pyrrolidin-1-yl) methylisoxazol-3-yl] -1 H -indole, trifluoroacetic acid salt

Phosphorus oxychloride (12 ml, 0.13 mol) was slowly added over 30 minutes to dimethylformamide (30 ml) at -10 ° C. The solution was allowed to warm to 0 ° C for 1 hour, then 1- (cyclohexyl) methyl-7-methoxy-1 H -indole (obtained as in Example 26; 3.2 g, 13 mmol) was added portionwise and the solution was stirred at room temperature for 16 hours. The solution was cooled in an ice bath and diluted with water, then carefully neutralized with sodium bicarbonate and extracted with ethyl acetate (3 × 50 ml). The organic extracts were combined and the solvent was removed in vacuo. The precipitate (3.5 g) was dissolved in an aqueous solution of sodium hydroxide (5M; 100 ml) and the mixture was refluxed at 100 ° C for the next 16 hours. The solution was cooled and extracted with ethyl acetate (3 × 50 ml). The organic extracts were combined and the solvent was 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) was added hydroxylamine hydrochloride (403 mg, 5.8 mmol) and sodium acetate (713 mg, 8.7 mmol) and the solution was stirred for 64 hours at room temperature. The mixture was concentrated in vacuo, the precipitate was diluted with water (50 ml) and extracted with ethyl acetate (3 × 50 ml). The product was recrystallized from diethyl ether / hexane to give 1-cyclohexylmethyl-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, was added N- chlorosuccinimide (119 mg, 0 , 89 mmol) and the mixture was allowed to warm to room temperature with stirring for 1 hour. Propargyl bromide (8 μl, 0.65 mmol) and triethylamine (9 μl, 0.65 mmol) were added and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 60-80% (v / v) dichloromethane in n-heptane to give 3- (5-bromomethylisoxazol-3-yl) -1-cyclohexylmethyl-7- methoxy-1 H -indole (150 mg, 0.37 mmol) as a yellow solid.

To a solution of 3- (5-bromomethylisoxazol-3-yl) -1-cyclohexylmethyl-7-methoxy-1 H -indole (120 mg, 0.31 mmol) in acetonitrile (3 ml) was added diethylamine (0.024 ml, 0.34 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered and the solvent was removed in vacuo. The precipitate was purified by semi-preparative HPLC [method (ii)] to give the title compound as a trifluoroacetic acid salt (20 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 1.03-1.09 (2H, m), 1.21 (3H, m), 1.57-1.74 (5H, m), 1.83 -1.89 (1H, 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 (1H, d, J = 7.5), 7.02 (1H, s), 7.08-7.12 (1H, m), 7.67 (1H, s), 7.67-7.69 (1H, d, J = 8.1). EsIMS: m / z 394.1 [M + H] ⁺ , 323.4.

Example 35

1- (Cyclohexyl) methyl-7-methoxy-3- (5 - {[bis- (2-hydroxyethyl) amino] methyl} isoxazol-3-yl) -1 H- indole, trifluoroacetic acid salt

The title compound was prepared by the method of Example 34 using diethanolamine instead of pyrrolidine. EsIMS: m / z 428.4 [M + H] ⁺ , 323.4.

Example 36

1- (Cyclohexyl) methyl-7-fluoro-3- {5 - [(pyrrolidin-1-yl) methyl] thiophen-2-yl) -1 H -indole, hydrochloride salt

To a ice-cooled solution of 7-fluorindole (2.0 g, 14.8 mmol) in dimethylformamide (50 ml) was added sodium hydride (60% dispersion in mineral oil; 0.88 g, 22.2 mmol), the mixture was stirred for 15 min and then benzenesulfonyl chloride (2.26 ml, 17.8 mmol) was added dropwise. The mixture was then stirred at room temperature for 18 hours. Then the suspension was diluted with water (200 ml), extracted with tert-butyl methyl ether (3 × 100 ml) and the combined organic layers were washed with water (3 × 100 ml), dried with sodium sulfate and concentrated in vacuo. The precipitate was purified by flash column chromatography, eluting with 20% (v / v) ethyl acetate in isohexane to give 1-benzenesulfonyl-7-fluoroindole as a colorless 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) was added dropwise a solution of bromine (0.75 ml, 14.55 mmol) in dimethylformamide (25 ml) over 3 min. The mixture was then stirred at room temperature for 10 minutes and poured into a mixture of sodium metabisulfite (2 g), a solution of ammonium hydroxide (3 ml), water (100 ml) and crushed ice (100 g). The resulting suspension was stirred until decolorization and extracted with tert-butyl methyl ether (2 × 100 ml). The combined organic layers were washed with water (2 × 100 ml), dried with sodium sulfate and the solvent was removed in vacuo to give 1-benzenesulfonyl-3-bromo-7-fluoroindole as a solid orange-pink substance (2.35 g, 6.64 mmol )

Solution of 1-benzenesulfonyl-3-bromo-7-fluorindole (0.5 g, 1.41 mmol), 5-formyl-2-thiophenboronic acid (0.24 g, 1.55 mmol), palladium bis (triphenylphosphine) palladium dichloride (II) (0.06 g, 0.08 mmol) and triethylamine (0.39 ml, 2.82 mmol) in ethanol (4 ml) were microwaved at 150 ° C for 420 s. The resulting suspension was concentrated under reduced pressure and the precipitate was passed through a pad of silica 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-fluorindol-3-yl) thiophene-2-carboxaldehyde was added 4 E 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). Then, the resulting mixture was stirred at room temperature for 18 hours, filtered, and the filter cake was washed with methanol (2 × 30 ml) and dichloromethane (2 × 30 ml). The combined filtrate was concentrated in vacuo, dissolved in dichloromethane (20 ml), washed with aqueous sodium hydroxide (2M; 15 ml), dried with sodium sulfate and concentrated in vacuo. The precipitate was then purified by flash column chromatography, eluting with 0-10% (v / v) methanol in dichloromethane to give 1-benzene-sulfonyl-7-fluoro-3- (5-pyrrolidin-1-ylmethylthiophen-2-yl ) indole as a yellow oil (0.22 g, 0.46 mmol).

1-benzenesulfonyl-7-fluoro-3- (5-pyrrolidin-1-ylmethylthiophen-2-yl) indole (0.20 g, 0.46 mmol) and potassium carbonate (0.25 g, 1.82 mmol) were treated a mixture of methanol and water (3: 1 v / v; 4 ml) and subjected to microwave irradiation at 100 ° C for 600 s. Then, the resulting suspension was concentrated under reduced pressure and partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (10 ml). The combined organic layers were dried with sodium sulfate and concentrated in vacuo. The precipitate was purified by flash column chromatography, eluting with 0-10% (v / v) methanol in dichloromethane to give 7-fluoro-3- (5-pyrrolidin-1-ylmethylthiophen-2-yl) indole as a colorless solid (0.10 g, 0.35 mmol).

To a solution of 7-fluoro-3- (5-pyrrolidin-1-ylmethylthiophen-2-yl) indole (0.10 g, 0.35 mmol) in dimethylformamide (3 ml) was added sodium hydride (60% dispersion in mineral oil; 0.03 g, 0.71 mmol) and the mixture was stirred at room temperature for 15 minutes. Bromomethylcyclohexane (0.05 ml, 0.39 mmol) was added and the mixture was stirred at 60 ° C for 18 hours. Then the suspension was diluted with water (30 ml), extracted with tert-butyl methyl ether (2 × 30 ml), the combined organic layers were washed with water (2 × 20 ml), dried with sodium sulfate and evaporated under reduced pressure. The precipitate was purified by flash chromatography, eluting with 5% (v / v) dichloromethane in methanol to give the title compound (free base) as a colorless solid (0.05 g, 0.13 mmol). The resulting material was dissolved in diethyl ether (3 ml) and treated with hydrochloric acid (1M solution in diethyl ether) to give the title compound (1: 1 with hydrochloric acid salt) by evaporation as a colorless solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 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); EsIMS: m / z 396.9 [M + H] ⁺ , 326.0.

Example 37

1- (Cyclohexyl) methyl-3- {5 - [(diethylamino) methyl] - [1,3,4] oxadiazol-2-yl} -7-methoxy-1 H -indole, hydrochloride salt

To a suspension of 1-cyclohexylmethyl-7-methoxy-1 H- indole-3-carboxylic acid (1.0 g, 3.48 mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.6 ml, 6.96 mmol) and the reaction mixture was stirred for 3.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was redissolved in dichloromethane (20 ml). Chloroacetic acid hydrazide (1.3 g, 8.97 mmol) and triethylamine (2.9 ml, 20.9 mmol) were added to the solution, and the reaction mixture was stirred for 4 hours and then allowed to stand overnight. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography, eluting with 50-100% (v / v) ethyl acetate in heptane to give N - (2-chloroacetyl) hydrazide 1-cyclohexylmethyl-7-methoxy-1 H -indole-3-carboxylic acid (397 mg, 1.05 mmol).

To a solution of N ' - (2-chloroacetyl) 1-cyclohexylmethyl-7-methoxy-1 H -indole-3-carboxylic acid hydrazide (250 mg, 0.662 mmol) in tetrahydrofuran (3 ml) was added the internal salt of triethylammonium hydroxide (methoxycarbonylsulfamoyl) ( 315 mg, 1.32 mmol) and the resulting reaction mixture was microwaved at 150 ° C. for 15 minutes. The reaction was quenched with methanol and the solvent was evaporated. The resulting precipitate was 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- 1H- indole (169 mg, 0.47 mmol) as a yellow solid. This reaction was repeated at an amount of 0.53 mmol to give the above intermediate compound (total 276 mg, 0.77 mmol).

To a solution of 3- (5-chloromethyl [1,3,4] oxadiazol-2-yl) -1-cyclohexylmethyl-7-methoxy-1 H- indole (92 mg, 0.26 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0.134 ml, 1.28 mmol) and the reaction mixture were microwaved at 150 ° C. for 15 minutes. The resulting mixture was purified by flash column chromatography to give the title compound (87 mg, 0.22 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) was added. Excess reagent and solvent were removed by evaporation to give the title compound (1: 1 with hydrochloric acid salt) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD): 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 (1H, m), 3.44 (4H, q, J = 7), 3.98 (3H, s), 4.33 (2H, d, J = 7), 4.84 (2H, s), 6.85 (1H, d, J = 7), 7.19 (1H, t, J = 7.9), 7.73 (1H, d, J = 8), 7.94 (1H, s). EsIMS: m / z 397.1 [M + H] ⁺ , 324.4, 270.5.

Example 38

1- (Cyclohexyl) methyl-7-methoxy-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,3,4] thiadiazol-2-yl} -1 H- indole, hydrochloride salt

To a solution of N ' - (2-chloroacetyl) 1-cyclohexylmethyl-7-methoxy-1 H -indole-3-carboxylic acid hydrazide (prepared as described in Example 37; 50 mg, 0.139 mmol) in tetrahydrofuran (0.5 ml ) phosphorus pentasulfide (62 mg, 0.139 mmol) was added and the reaction mixture was microwaved at 150 ° C for 5 minutes. The reaction was repeated two times with an amount of 0.7 mmol. The combined reaction mixture was placed in a separatory funnel and diluted with dichloromethane (60 ml). The organic phase was washed with 5% aqueous sodium carbonate (2 × 30 ml), brine (30 ml), dried over sodium sulfate and the solvent was removed in vacuo. The resulting precipitate was purified by flash column chromatography to give 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 was added pyrrolidine (0.101 ml , 1.235 mmol) and the mixture was microwaved at 150 ° C for 5 minutes. The resulting reaction mixture was purified by flash column chromatography to give the title compound (42 mg, 0.1 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (1M solution in diethyl ether; 1 ml, 1 mmol) was added. Excess reagent and solvent were removed in vacuo to afford the title compound as the hydrochloride salt, 1: 1.

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, J = 7), 6.73 (1H, d, J = 7.8), 7.17 (1H, t, J = 8), 7.66 (1H, s), 7.77 (1H, d, J = 8); EsIMS: m / z 411.1 [M + H] ⁺ , 340.0, 324.4, 286.1, 270.5.

Example 39

7-Chloro-3- {5 - [(2,2-dimethylpyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl-1- (tetrahydropyran-4-yl) methyl-1 H -indole, hydrochloride salt

The method of synthesis of 2,2-dimethylpyrrolidinone:

To a stirred and cooled solution (0 ° C) of NiCl ₂ · 6H ₂ O in methanol (200 ml) was added sodium borohydride (3.36 g, 89 mmol) in portions. The reaction mixture was stirred for 30 minutes and then methyl 4-methyl-4-nitropentanoate was added as a solution in methanol (100 ml). The reaction temperature was maintained at 0 ° C. prior to the addition of sodium borohydride (7.86 g, 208 mmol) in portions. The reaction mixture was allowed to settle for 72 hours before being filtered through a pad of celite. The resulting precipitate was washed with methanol (150 ml) and the filtrate was evaporated to dryness. The resulting solid was triturated with dichloromethane (400 ml) and filtered through a pad of celite. After washing the precipitate with dichloromethane (200 ml), the filtrate was evaporated to give the product 2,2-dimethylpyrrolidinone as a light green gum (6.8 g).

The method of synthesis of 2,2-dimethylpyrrolidine hydrochloride:

Lithium aluminum hydride (1M solution in tetrahydrofuran; 120 ml, 120 mmol) was slowly added to a stirred solution of 2,2-dimethylpyrrolidinone (6 g, 53 mmol) in tetrahydrofuran (150 ml). Upon completion of the addition, the reaction was heated to the boiling temperature under reflux and stirred at the boil under reflux in an argon atmosphere for 16 hours. The reaction mixture was allowed to cool to 0 ° C and then water (2.2 ml), 10% sodium hydroxide solution (2.2 ml) and water (6.6 ml) were added at 45 minute intervals. The resulting pasty mixture was diluted with diethyl ether (150 ml) and filtered through a pad of celite. The precipitate was washed with diethyl ether (250 ml) and the filtrate was acidified with hydrochloric acid (1M solution in diethyl ether; 63 ml). The resulting yellow solid was filtered off to give 2,2-dimethylpyrrolidine hydrochloride (4.8 g).

The method of synthesis of ethyl ester (2,2-dimethylpyrrolidin-1-yl) acetic acid:

Ethyl chloroacetate (0.15 ml, 1.37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2,2-dimethylpyrrolidine (0.280 mg, 2.06 mmol) were suspended in ethanol (3 ml) and microwaved at 120 ° C for 45 minutes The resulting mixture was suspended in diethyl ether (30 ml), extracted with 2M hydrochloric acid (30 ml) and the organic layer was taken. The aqueous layer was treated with a slight excess of 4 N. sodium hydroxide solution and was extracted with diethyl ether (3 × 30 ml). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give ethyl (2,2-dimethylpyrrolidin-1-yl) acetic acid (156 mg).

The title compound was 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) instead of cyclohexylmethyl bromide and ethyl (2,2-dimethylpyrrolidin-1-yl) ethyl acetate instead of N , N- dimethylglycine methyl ester.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.45 (10H, m), 2.22 (5H, m), 3.35 (2H, m), 3.59 (1H, broad 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, broad 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). EsIMS: m / z 429.5 [M + H] ⁺ .

Example 40

1- (Cyclohexyl) methyl-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1 H- indole-7-carbonitrile, hydrochloride salt

A suspension of [3- (7-bromo-1-cyclohexylmethyl-1 H- indol-3-yl) - [1,2,4] thiadiazol-5-yl] methanol (obtained from 7-bromoindole as described in Example 7; 2 × 250 mg, 0.16 mmol), zinc (II) cyanide (2 × 72 mg, 0.61 mmol) and tetrakis (triphenylphosphine) palladium (0) (2 × 21 mg, 18.3 mol) in DMF ( 2 x 4 ml) was microwaved at 200 ° C for 5 min using the Emrys ™ Optimizer EXP. The reaction mixtures were combined and poured into a separatory funnel, dichloromethane (≈50 ml) was added to them. The organic phase was washed successively with water (2 × 20 ml), 1M aqueous HCl (20 ml) and brine (20 ml), dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The resulting oil was 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 [1,2,4] thiadiazole-3 -yl) -1 H- indole-7-carbonitrile (416 mg, 1.18 mmol) as a pale yellow oil, which crystallized upon standing.

To a solution of 1-cyclohexylmethyl-3- (5-hydroxymethyl [1,2,4] thiadiazol-3-yl) -1 H- indole-7-carbonitrile (416 mg, 1.18 mmol) in dichloromethane (40 ml) sequentially methanesulfonyl chloride (0.110 ml, 1.42 mmol) and triethylamine (0.214 ml, 1.53 mmol) were added. The reaction mixture was stirred for 1 hour and poured into a separatory funnel. The organic phase was washed with 2M aqueous sodium carbonate (20 ml), brine (20 ml), dried over magnesium sulfate, filtered, the solvent was removed in vacuo to give 3- (7-cyano-1-cyclohexylmethyl-1 H- indole- 3-yl) - [1,2,4] thiadiazol-5-ylmethyl methanesulfonic acid ester (503 mg, 1.17 mmol), which was used without further purification.

To a solution of 3- (7-cyano-1-cyclohexylmethyl-1 H- 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) was added and the reaction mixture was microwaved at 100 ° C for 5 minutes. The reaction mixture was immediately purified 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) was dissolved in dichloromethane (2 ml) and hydrogen chloride (1M solution in diethyl ether) was added. The mixture was concentrated in vacuo to afford the title compound as the hydrochloride salt, 1: 1.

¹ H NMR (400 MHz, CD ₃ OD): 1.06-1.36 (7H, m), 1.62-1.80 (5H, m), 1.91-2.07 (1H, m) , 2.09-2.34 (2H, broad m), 3.35-4.20 (4H, broad m), 4.42 (2H, d, J = 7), 5.07 (2H, s), 7.37 (1H, t, J = 8), 7.69 (1H, dd, J = 7, 1), 8.23 (1H, s); 8.84 (1H, dd, J = 8.1). EsIMS: m / z 406.4 [M + H] ⁺ .

Example 41

In vitro determination of potency and efficacy against the human CB1 receptor expressed in CHO cells

Chinese Hamster Ovary (CHO) cells expressing the human CB1 receptor and luciferase reporter gene were suspended in serum-free phenol red / DMEM / F-12 nutrient mixture containing penicillin / streptomycin (50 units / 50 μg / ml) and fungicone (1 μg / ml), and plated in 96-well plates at a concentration of 3 × 10 ⁴ cells per well (final volume 100 μl). Before testing, cells were incubated overnight (approximately 18 hours at 37 ° C, 5% CO ₂ /95% air). The test compound (10 mm solution in dimethyl sulfoxide) was diluted with F12 nutrient mixture to obtain mother liquors in the range from 0.11 mm to 0.11 nm. Stock solutions (10 μl) were directly added to the corresponding wells. To obtain agonist-induced luciferase expression, the plates were incubated at 37 ° C for 5 hours. Under dim light, a LucLite substrate (Packard; reproduced according to manufacturer's instructions; 100 μl) was added to each well. The plates were covered with a top lid and then incubated at room temperature for 5 minutes before counting on a TopCount, Packard device (counting single photons, counting time 0.01 minutes, 5 minute delay).

To obtain the EC ₅₀ value by the least squares method, the curve of the best fit was selected for the count per second (CPS) versus compound concentration (M) curve. Table 1 shows the pEC ₅₀ values obtained for some representative compounds of the present invention.

Table 1 Example Chemical name chemical structure pEC _fifty 2G ( R ) -1- (cyclohexyl) methyl-7-methoxy-3- [5- (1-methylpyrrolidin-2-yl) - [1,2,4] oxadiazol-3-yl] -1 H- indole, hydrochloride salt

7.5 13 ( R ) -3-cyclohexyl-6- {5 - [(diethylamino) methyl] - [1,2,4] thiadiazol-3-yl-2,3-dihydropyrrolo [1,2,3- de ] -1, 4-benzoxazine hydrochloride salt

8.1 14B 7-fluoro-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1- (tetrahydropyran-4-yl) methyl-1 H -indole, hydrochloride salt

7.3 15A 7-chloro-3- (5 - {[N -ethyl -N- (2-methoxyethyl) amino] methyl} - [1,2,4] thiadiazol-3-yl) -1- (tetrahydropyran-4-yl) methyl 1 H -indole, hydrochloride salt

8.0 15B 7-chloro-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,2,4] thiadiazol-3-yl} -1- (tetrahydropyran-4-yl) methyl-1 H -indole, hydrochloride salt

7.7 15C 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

8.0 twenty 7-chloro-1- (cyclohexyl) methyl-3- (4 - {[N-isopropyl -N- (2-methoxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -1 H -indole hydrochloride salt

8.3 23B 7-chloro-3- {4 - {{ N - (2-hydroxyethyl) -N- isopropylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl-1 H is indole

8.0 23C 7-chloro-3- (4 - {[N -ethyl -N- (2-hydroxyethyl) amino] methyl} - [1,3] -thiazol-2-yl) -1- (tetrahydropyranyl-4-yl) methyl- 1 H -indole

7.9 23D 7-chloro-3- (4 - {[ N - (2-methoxyethyl) -N- methylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl-1 H- indole, hydrochloride salt

8.2 32 1- (cyclohexyl) methyl-3- {2 - [(diethylamino) methyl] - [1,3] oxazol-5-yl} -7-methoxy-1 H -indole, hydrochloride salt

7.3 33 1- (cyclohexyl) methyl-3- (5-ethyl-5,6-dihydro-4 H -pyrrolo [3,4- d ] isothiazol-3-yl) -7-methoxy-1 H -indole, hydrochloride salt

7.1 38 1- (cyclohexyl) methyl-7-methoxy-3- {5 - [(pyrrolidin-1-yl) methyl] - [1,3,4] thiadiazol-2-yl} -1 H- indole, hydrochloride salt

7.1 39 7-chloro-3- {5 - [(2,2-dimethylpyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl-1- (tetrahydropyran-4-yl) methyl-1 H -indole, hydrochloride salt

7.5

Example 42

The tail latency of mice

Mice were trained to sit quietly in a tail pull test device (Ugo Basile, Italy) during the measurement of the tail pull latency period. The tail was heat-irradiated with a focused beam at a point approximately 2.5 cm from the end of the tail. The latent period of tail pullback was defined as the time interval between the application of thermal stimulus and tail pullback. 12 second intervals were used to prevent tissue damage. Four groups, eight mice each, were treated with a vehicle or one of three doses of the test compound administered intravenously (vehicle: 10% Tween-80 in saline; volume of administration 10 ml / kg). The latency of tail tail withdrawal was measured before administration of the test compound, and also at regular intervals (typically 20, 40, and 60 minutes) after administration of the compound. ED _{50 was} calculated at T _max .

The compounds of Examples 2G, 13, 14B, 15A, 15B, 15C, 20, 23B, 23C, 23D and 39 significantly increased the latency period of tail withdrawal with ED ₅₀ <5 μmol / kg.

Claims (10)

1. Derived (indol-3-yl) heterocyclic compounds of General formula I

where A represents a 5-membered aromatic heterocyclic ring, where X ₁ , X ₂ and X ₃ independently selected from N, O, S and CR;
R represents H or (C _1-4 ) alkyl; or
R, when present in X ₂ or X ₃ , may form a 5-8 membered ring together with R ₃ ;
R ₁ represents a 5-8 membered saturated carbocyclic ring optionally containing an O heteroatom;
R ₂ represents H; or
R _{2 is} attached to R ₇ to form a 6-membered ring optionally containing an O heteroatom, and wherein said heteroatom is bonded to position 7 of the indole ring;
R ₃ and R ₄ independently represent H or (C _1-6 ) alkyl optionally substituted with OH or (C _1-4 ) alkyloxy; or
R ₃ together with R ₄ and N to which they are attached forms a 4-8 membered ring, optionally containing an additional heteroatom selected from O and S, and optionally substituted with OH, (C _1-4 ) alkyl, (C _{1- 4} ) alkyloxy or (C _1-4 ) alkyloxy (C _1-4 ) alkyl; or
R ₃ together with R ₅ forms a 4-8 membered ring optionally substituted by OH, (C _1-4 ) alkyl, (C _1-4 ) alkyloxy; or
R ₃ together with R, when present in X ₂ or X ₃ , forms a 5-8 membered ring;
R ₅ represents H; or
R ₅ together with R ₃ forms a 4-8 membered ring optionally substituted with OH, (C _1-4 ) alkyl or (C _1-4 ) alkyloxy;
R ₅ ′ represents H;
R ₆ represents one substituent selected from H, (C _1-4 ) alkyl, (C _1-4 ) alkyloxy or halogen;
R ₇ represents H, (C _1-4 ) alkyl, (C _1-4 ) alkyloxy or halogen; or
R _{7 is} connected to R ₂ to form a 6-membered ring, optionally containing an additional O heteroatom, and wherein the heteroatom is bonded to position 7 of the indole ring; or a pharmaceutically acceptable salt thereof. 2. The derivative (indol-3-yl) of the heterocyclic compound according to claim 1, wherein R ₂ is H or is attached to R ₇ to form a 6-membered ring, optionally containing an O heteroatom, attached to position 7 of the indole ring. 3. The derivative (indol-3-yl) of the heterocyclic compound according to claim 1 or 2, where R, R ₅ , R ₅ ′ and R ₆ are N. 4. The derivative of (indol-3-yl) heterocyclic compound according to claim 1, wherein R ₁ is cyclohexyl or tetrahydropyranyl. 5. The derivative (indol-3-yl) of the heterocyclic compound according to claim 4, where heterocycle A is 1,2,4-oxadiazole (X ₁ represents N, X ₂ represents O, X ₃ represents N), 1 , 2,4-thiadiazole (X ₁ represents N, X ₂ represents S, X ₃ represents N) or thiazole (X ₁ represents S, X ₂ represents CR, X ₃ represents N). 6. The derivative (indol-3-yl) of the heterocyclic compound according to claim 1, selected from:
7-chloro-3- (5 - {[N-ethyl-N- (2-methoxyethyl) amino] methyl} - [1,2,4] thiadiazol-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-1H-indole;
7-chloro-3- (5 - {[N-ethyl-N- (2-hydroxyethyl) amino] methyl} - [1,2,4] thiadiazol-3-yl) -1- (tetrahydropyran-4-yl) methyl 1H-indole;
7-chloro-3- (4 - {[N- (2-hydroxyethyl) -N-isopropylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl-1H -indole;
7-chloro-3- (4 - {[N-ethyl-N- (2-hydroxyethyl) amino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl- 1H-indole;
7-chloro-3- (4 - {[N- (2-methoxyethyl) -N-methylamino] methyl} - [1,3] thiazol-2-yl) -1- (tetrahydropyran-4-yl) methyl-1H -indole;
7-chloro-3- {5 - [(2,2-dimethylpyrrolidin-1-yl) methyl] - [1,2,4] oxadiazol-3-yl} -1- (tetrahydropyran-4-yl) methyl-1H -indole;
or their pharmaceutically acceptable salts. 7. The derivative (indol-3-yl) of the heterocyclic compound according to claim 1, showing agonist activity at the CB1 cannabinoid receptor. 8. A pharmaceutical composition exhibiting CB1 cannabinoid receptor agonist activity, comprising the derivative of (indol-3-yl) heterocyclic compound according to any one of claims 1 to 6 in a mixture with pharmaceutically acceptable additives. 9. The use of a derivative (indol-3-yl) of a heterocyclic compound of the formula I as defined in claim 1, in the manufacture of a medicament for the treatment of pain. 10. A method of treating pain, such as chronic pain, neuropathic pain and cancer pain, comprising administering to a patient in need thereof a therapeutically effective amount of a derivative (indol-3-yl) of a heterocyclic compound according to any one of claims 1 to 6.