MXPA00010239A - Imidazo pyridine derivatives which inhibit gastric acid secretion - Google Patents

Abstract

The present invention relates to imidazo pyridine derivatives of formula (I), in which the phenyl moiety is substituted, and in which the imidazo pyridine moiety is substituted with a carboxyamide group in 6-position, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

Description

DERIVATIVES OF IMIDAZOPIRIDINE THAT INHIBIT THE SECRETION OF GASTRIC ACID TECHNICAL FIELD The present invention relates to the novel compounds, and to the therapeutically acceptable salts thereof, which inhibit the secretion of exogenously or endogenously stimulated gastric acid and can thus be used in the prevention and treatment of gastrointestinal inflammatory diseases. In additional aspects, the invention relates to the compounds of the invention for use in therapy; to the processes for the preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as an active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above. The invention also relates to novel intermediates for the preparation of novel compounds. Ref: 123828 BACKGROUND OF THE INVENTION Substituted imidazo [1, 2-a] pyridines, useful in the treatment of peptic ulcer diseases, are known in the art, for example from EP-B-0033094 and US / 450,164 (Schering Corporation); EP-B-020 285 and US 4,725,601 (Fujisawa Pharmaceutical Co.); and from publications by JJ Kaminski et al in Journal of Medical Chemistry (vol 28, 876-892; 1985; vol 30, 2031-2046; 1987; vol 30, 2047-2051 1987, vol 32, 1686). 1700, 1989, and vol 34, 533-541, 1991). For a review of the pharmacology of the gastric acid pump (H +, K + -ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol 35: 277-305.

DESCRIPTION OF THE INVENTION It has surprisingly been found that the compounds of the formula I, which are imidazopyridine derivatives in which the phenyl portion is substituted, and in which the imidazopyridine portion is substituted with a group carboxamide in position 6, are particularly effective as inhibitors of gastrointestinal H +, K + -ATPase and therefore are inhibitors of gastric acid secretion. In one aspect, the invention thus relates to the compounds of the general Formula I or a pharmaceutically acceptable salt thereof, wherein R1 is (a) H, (b) CH3, or (c) CH20H; R2 is (a) CH3 (b) CH2CH3 RJ is (a) H (b) alkyl of 1 to 6 carbon atoms (c) alkyl of 1 to 6 carbon atoms hydroxylated (d) halogen R 4 is (a) H, (b) alkyl of 1 to 6 carbon atoms, (c) alkyl of 1 to 6 carbon atoms hydroxylated, or ( d) halogen; R5 is (a) H, or (b) halogen; R6, R7 are the same or different (a) H, (b) alkyl of 1 to 6 carbon atoms (c) alkyl of 1 to 6 hydroxy carbon atoms; (d) alkyl of 1 to 6 carbon atoms substituted with alkoxy of 1 to 6 carbon atoms X is (a) NH, or (b) O. As used herein, the term "alkyl of 1 to 6 carbon atoms" denotes a linear or branched alkyl group having from 1 to 6 carbon atoms. Examples of said alkyl of 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and straight and branched chain pentyl and hexyl. The term "halogen" includes fluorine, chlorine, bromine and iodine. Pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It should be understood that all possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Also included in the invention are derivatives of the compounds of the formula I which have the biological function of the compounds of the formula I, such as prodrugs. It may also be appreciated by those skilled in the art, although derivatives of the compounds of the formula I may not possess pharmacological activity as such, that these can be administered parenterally or orally, and thereafter metabolized in the body to form the compounds of the invention that are pharmacologically active. Such derivatives can therefore be described as "prodrugs". All prodrugs of the compounds of formula I are included within the scope of the invention. Depending on the process conditions, the final products of formula I are obtained either in neutral or salt form. The free base and the salts of these final products are within the scope of the invention. The acid addition salts of the novel compounds can, in a manner known per se, be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained can also form salts with organic or inorganic acids. In the preparation of the acid addition salts, such acids which form the therapeutically acceptable, suitable salts are preferably used. Examples of such acids are hydrohalogenic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymeleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane sulfonic acid, halogenobenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. Preferred compounds according to the invention are those of Formula I wherein R1 is CH3, or CH20H; R2 is CH3 or CH2CH3; R3 is CH3 or CH2CH3; R4 is CH3 or CH2CH3; R5 is H, Br, Cl, or F. Particularly preferred compounds according to the invention are: • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N-propyl-imidazo [1,2] -a] pyridine-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -N - hydroxyethyl-imidazo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [l, 2-a] py and din-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -N, 2 , 3-trimethylimidazo [1,2- a] pyridine-6-caboxbox • 8- (2-ethyl-6-methylbenzylamino) -N, N, 2, 3-tetrame -limidazo [1, 2-a] py din-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [l, 2-a] py and din-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-4- mesylate f luoro-6-methylbenzyl ami no) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-methylbenzyl amino) -imidazofl, 2- a] pi r idi n- 6-carboxamide • 2,3-dimethyl-8- (2,6-dimethyl-4-f luorobenzyl amino) -imidazo [l, 2-a] pyridine-6-ca rbox amide mesylate • 2,3-dimethyl-8- (2-methyl-6-isopropylbenzyl amino) -imide mesylate zo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2, 6) diethylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethylbenzylamino) -imidazo [l, 2-a] pyridin-6-carboxamide • 2,3-dimethyl -8- (2-ethyl-6-methylbenzylamino) -N-hydroxyethyl-imidazo [l, 2-a] iridin-6- ca boxamide • N- (2,3-dihydroxypropyl) -2,3-dimethyl-8- (2-ethyl-6-ethylbenzylamino) - [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N- (2-methoxyethyl) -imidazo [1,2- a] pyridine-6-carboxamide • 2-methyl-8- (2- ethyl-6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carbo-amide • 2,3-dimethyl-8- (2-bromo-6-methylbenzylamino) -imidazo [1,2- a] pyridine- 6-carboxamide • 2,3-dimethyl-8- (2- (2-hydroxyethyl) -6-methylbenzylamino) -imidazo [1,2- a] pyridin-6-carboxamide • 8- (2-ethyl-6-methylbenzylamine ) -N, N-bis (2-hydroxyethyl) -2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -N- (2-hydroxyethyl) - N, 2, 3-trimethylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzyloxy) -imidazo [1,2-a] pyridine-6-carboxamide The most preferred compounds according to the invention are: • 8- (2-ethyl) -6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -N-hydroxyethyl-imidazo [l , 2-a] iridin-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazofl, 2-a] pyridine-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -N, 2, 3-trimethylimidazo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8 - (2-ethyl-4-fluoro-6-methylbenzylamino) -imidazotl, 2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethyl-4-fluoro-benzylamino) -imidazo [1, 2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-diethylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N - hydroxyethyl-imidazo [l, 2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N- (2-methoxyethyl) -imidazo [1,2- a] pyridine-6-carboxamide Preparation The present invention also provides the following processes A, B and C for the manufacture of the compounds with general Formula I.

Process A The process A for the manufacture of the compounds with the general formula I wherein X is NH comprises the following steps: a) The compounds of the general formula II they can be reacted with the amino compounds of the general Formula III NH III where R6 and R7 are as defined for the Formula I, to the corresponding amide of Formula IV. The reaction can be carried out under standard conditions in an inert solvent. b) the compounds of the general formula IV can be reacted with ammonia to form the compounds of the Formula V wherein R6 and R7 are as defined for Formula I. The reactions can be carried out under standard conditions in an inert solvent. c) Compounds of formula V can be reduced for example by the use of hydrogen and a catalyst such as Pd / C to the compounds of Formula VI SAW wherein R6 and R7 are as defined for Formula I. The reaction can be carried out under standard conditions in an inert solvent. d) The imidazo [1,2-a] pyridine compounds of Formula VIII can be prepared by reacting the compounds of general Formula VI with the compounds of general Formula VII wherein R is as defined in formula I and Z is a leaving group such as halogen, esyl, tosyl and R9 represents hydrogen, CH3 or an ester group such as C00H3, COOC2H5, etc. The reaction is carried out under standard conditions in an inert solvent such as acetone, acetonitrile, alcohol, dimethylformamide, etc., with or without a base. e) Compounds of Formula VIII can be reacted with the compounds of Formula IX wherein R, R and R are as defined for Formula I and Y is a leaving group, such as a halide, tosyl or mesyl group, to the compounds of formula X. wherein R2, R3, R4, R5, R6 and R7 are as defined for Formula I and R9 is hydrogen, CH3 or an ester group such as COOCH3, COOC2H5, etc. It is convenient to conduct this reaction in an inert solvent, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without a base. The base is for example an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide, an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine such as triethylamine. f) The reduction of the compounds of the general Formula X wherein R9 is an ester group for example by the use of lithium borohydride in an inert solvent such as tetrahydrofuran or ether diethyl, to the compounds of the general Formula I wherein R1 is CH2OH.

Process B The process B for the manufacture of the compounds with the general formula I wherein R1 is hydrogen or CH3 and X is NH, comprises the following steps: a) The compounds of the general formula II they can be reacted with an alcohol-like compound of the general Formula R10-OH wherein R10 is an alkyl group such as methyl, ethyl, etc., to the corresponding ester of Formula XI.

The reactions can be carried out under standard conditions. b) The compounds of the general formula XI can be reacted with ammonia to the compounds of the general Formula XII wherein R is an alkyl group such as methyl or ethyl, etc. The reactions can be carried out under standard conditions in an inert solvent. c) The compounds of Formula XII can be reduced, by the use of hydrogen and a catalyst such as Pd / C to the compounds of Formula XIII wherein R is an alkyl group such as methyl, ethyl, etc. The reaction can be carried out under standard conditions in an inert solvent. d) The imidazo [1,2-a] pyridine compounds of Formula XV wherein R 10 is an alkyl group, such as methyl, ethyl, etc., can be prepared by reacting the compounds of general Formula XIII with the compounds of general Formula XIV. wherein R is as defined for formula I, Z is a leaving group such as halogen, mesyl or tosyl, and R 11 represents hydrogen or CH 3. The The reaction is carried out under standard conditions in an inert solvent such as acetone, acetonitrile, alcohol, dimethylformamide, etc., with or without a base. e) The compounds of the formula XV can be reacted with the compounds of the Formula IX wherein R3, R4 and R5 are as defined for Formula I and Y is a leaving group, such as a halide, tosyl, or mesyl group, to the compounds of Formula XVI.

XVI wherein R2, R3, R4 and R5 are as defined for Formula I, R10 is an alkyl group such as methyl, ethyl, etc., and R11 is hydrogen, or CH3. It is convenient to conduct this reaction in an inert solvent, for example in acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without a base. The base is for example an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide, an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine. f) The compounds of formula XVI can be reacted with the amino compounds of general formula III wherein R6 and R7 are as defined in formula I to the corresponding amide of formula I wherein R1 is hydrogen or CH3 and X is NH. The reaction can be carried out by heating the .. * ** .. ^. TO, reagents in the pure amino compound or in an inert solvent under standard conditions.

Process C The process C for the manufacture of the compounds with the general Formula I comprises the following steps: a) The treatment of the compounds of the formula XVII XVII wherein R1, R2, R3, R4, R5 and X are as defined in formula I, and R10 is an alkyl group such as methyl, ethyl, etc., with acid or base under standard conditions can be hydrolyzed to the corresponding carboxylic acid compounds of Formula XVIII XVIII b) Compounds of Formula XVIII wherein R1, R2, R3, R4, R5 and X are as defined in Formula I can be reacted with amino compounds of Formula III in the presence of a coupling reagent to the compounds of the corresponding amide of Formula I. The reaction can be carried out in an inert solvent, under standard conditions.

Medical use In a further aspect, the invention relates to the compounds of the formula I for the use in therapy, in particular for use against gastrointestinal inflammatory diseases. The invention also provides the use of a compound of formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases. The compounds according to the invention can thus be used for the prevention and treatment of gastrointestinal inflammatory diseases, and diseases related to gastric acid in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. In addition, the compounds can be used for the treatment of other gastrointestinal disorders where the gastric antisecretory effect is desirable, for example in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. These can also be used in patients in situations of intensive care, and pre- and postoperatively to prevent aspiration of acid and ulceration by stress or tension.

The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral doses will be in the range of 5 to 1000 mg per day of the active substance.

Pharmaceutical Formulations In a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as an active ingredient. The compounds of the invention can also be used in formulations together with other active ingredients, for example antibiotics such as amoxicillin. For clinical use, the compounds of the invention are formulated in pharmaceutical formulations for oral, rectal, parenteral, or other administration administration. The pharmaceutical formulation contains at least one compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier can be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further objective of the invention. Usually, the amount of active compounds is between 0.1 to 95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration. In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of unit doses for oral administration, the selected compound can be mixed with solid or powdered ingredients, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into pellets or pressed into tablets.

Soft gelatin capsules can be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatin capsules may contain granules of the active compound. Hard gelatin capsules may also contain the active compound in combination with solid powder ingredients, such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. The dose units for rectal administration can be prepared (i) in the form of suppositories, which contain the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a ready-to-use microenema; (iv) in the form of an anhydrous microenema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing from 0.1% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agent. Liquid preparations for oral administration can also be prepared in the form of a dry powder to be reconstituted with a suitable solvent before use. Solutions for parenteral administration can be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration of 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and / or buffering ingredients and are supplied in unit doses in the form of ampoules or flasks. Solutions for parenteral administration can also be prepared as an anhydrous preparation to be reconstituted with a suitable solvent extemporaneously before use. The compounds according to the present invention can also be used in formulations, together or in combination for simultaneous, separate or sequential use, with other active ingredients, for example for the treatment or prophylaxis of conditions involving Hel i coba infection. ct er pyl ori of the human gastric mucosa. Other active ingredients such may be antimicrobial agents, in particular: ß-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; • macrolides such as erythromycin, or clarithromycin; • tetracyclines such as tetracycline or doxycycline; • aminoglycosides such as gentamicin, kanamycin or ikacin; • quinolones such as norfloxacin, ciprofloxacin or enoxacin; • others such as metronidazole, nitrofurantoin or chloramphenicol; or • preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate. The compounds according to the present invention can also be used together or in combination for simultaneous, separate or sequential use with antacids such as aluminum hydroxide, magnesium carbonate and magnesium hydroxide or alginic acid, or together or in combination for the simultaneous, separate or sequential use with pharmaceutical products that inhibit acid secretion, such as H2 blockers (eg cytidine, ranitidine), H + / K + -ATPase inhibitors (eg omeprazole, pantoprazole, lansoprazole or rabeprazole) or together or in combination for simultaneous, separate or sequential use with gastroprokinetics (eg, cisapride or mosapride).

Intermediaries A further aspect of the invention is the novel intermediate compounds that are useful in the synthesis of the compounds according to the invention. In this way, the invention includes (a) a compound of formula VIII wherein R2, R6 and R7 are as defined for Formula I, and R9 is hydrogen, CH3 or an ester group such as COOCH3, COOC2H5, etc .; (b) a compound of formula X wherein R2, R3, R4, R5, R6 and R7 are as defined for formula I, and R9 is an ester group such as COOCH3, COOC2H5, etc .; (c) a compound of the formula XV wherein R2 is as defined for formula I, R1 is an alkyl group and R11 is hydrogen or CH3; (d) a compound of formula XVI wherein R, R, R and R are as defined for Formula I, R10 is an alkyl group and R11 is hydrogen or CH3; (e) a compound of formula XVIII XVIII wherein R1, R2, R3, R4, R5 and X are as defined for Formula I.

EXAMPLES 1. PREPARATION OF THE COMPOUNDS OF THE INVENTION Example 1.1 Synthesis of 2, 3-dimethyl-β- (2-ethyl-6-me t i-benzylamino) -N-propyl-imidazofl, 2-a] pyridine-6-carboxamide The ethyl 2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxylate (0.12 g, 0.33 mmol), propylamine (1.0 g, 17 mmol) and a catalytic amount of sodium cyanide it was heated to reflux in 20 ml of methanol for 24 hours. An additional amount of propylamine (1.0 g, 17 mmol) was added and the reaction mixture was heated to reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using diethyl ether as eluent. Crystallization from diethyl ether gave 0.053 g (42%) of the title compound. 1 H NMR (300 MHz, CDC13): d 1.0 (t, 3H), 1.2 (t, 3H), 1.65-1.75 (m, 2H), 2.3 (s, 3H), 2.35 (s, 3H), 2.38 (s) , 3H), 2.7 (q, 2H), 3.4-3.5 (m, 2H), 4.35 (d, 2H), 4.9 (s broad, 1H), 6.2 (broad s, 1H), 6.35 (s, 1H), 7.0-7.2 (m, 4H), 7.85 (s, 1H).

Example 1.2 Synthesis of 8- (2-ethyl-6-methylbenzylamino) -3-hydroxyin? Ethyl-2-methyl? dazo / ~ l, 2-a] pyridine-6-carboxamide Ethyl 6- (aminocarbonyl) -8- (2-ethyl-6-methylbenzylamino) -2-methyl imidazo [l, 2-a] pyridine-3-carboxylate (280 mg, 0.71 mmol) and lithium borohydride (16 mg, 0.71 mmol) were added to 10 ml of tetrahydrofuran and the reaction mixture was heated to reflux for 70 minutes. Additional amounts of lithium borohydride (16 mg) and methanol (34 mg, 1.42 mmol) were added and the mixture was heated to reflux for 80 minutes. Additional amounts of lithium borohydride (16 mg) and methanol (22 mg, 71 mmol) were added and the mixture was heated to reflux for 4 hours. The reaction mixture was allowed to reach room temperature and 1 ml of water and 5 ml of methanol was added, and it was stirred for 40 minutes at room temperature. The solvents were evaporated under reduced pressure and the residue was added to the water and stirred for 80 minutes. minutes The crystals were filtered and washed with water, ethyl acetate / ethanol and diethyl ether to give the desired product (115 mg, 46%).

H-NMR (300 MHz, DMSO-de): d 1.15 (t, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.7 (q, 2H), 4.35 (d, 2H), 4.75 (d , 2H), 4.85 (t, 1H), 5.1 (t, 1H), 6.8 (s, 1H), 7.1-7.25 (, 3H), 7.4 (broad s, 1H), 8.05 (s broad, 1H), 8.3 (s, 1H).

Example 1.3 Synthesis of 2,3-dimethyl-8- (2,6-dimethylbenzylamino) N-hydroxyethyl-imidazofl, 2-a] pi-ridin-6-carboxamide 2, 3-Dimethyl-8- (2,6-dimethylbenzylamino) -im? Dazo [1,2-a] pyridine-6-carboxylic acid methyl ester (0.12 g, 0.33 mmol), ethanola (0.2 g, 3.3 mmol) ) and sodium cyanide (10 mg, 0.2 mmol) were heated to reflux in 2 ml of dimethoxyethane for 20 hours. The solvent was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride: methanol (92: 8) as eluent gave the product which was washed with diethyl ether to give 103 mg (79%) of the title compound.

NMR JH (300 MHz, CDC13): d 2.3 (s, 6H), 2.35 (s, 6H), 3. 5-3.6 (m, 2H), 3.75-3.8 (m, 2H), 4.3 (d, 2H), 4.95 (t, 1H), 6.4 (s, 1H), 6.85 (t, 1H), 7.0-7.2 ( m, 3H), 7.75 (s 1H).

Example 1.4 Synthesis of 2,3-dimethyl-β- (2-ethyl-6-methylben i lami o) -imidazofl, 2-ajpyridin-6-carboxamide 8-amino-2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide (3.3 g, 16.2 mmol), 2-ethyl-6-ethylbenzylchloride (2.73 g, 16.2 mmol), potassium carbonate ( 8.0 g, 58 mmol) and potassium iodide (1.1 g, 6.6 mmol) were added to 150 ml of acetone and heated to reflux for 20 hours. An additional amount of 2-ethyl-6-methylbenzylchloride (1.0 g, 5.9 mmol) was added and the reaction mixture was heated to reflux for 7 hours. 60 ml of methylene chloride and 30 ml of methanol were added. The reaction mixture was filtered and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (100: 7) as eluent. Crystallization from ethyl acetate gave 2.8 g (50%) of the title compound.

NMR 1 (300 MHz, CDCl 3): d 1.2 (t, 3H), 2.34 (s, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 4.4 (d, 2H) ), 4.9 (broad s, 1H), 6.0 (broad s, 2H), 6.45 (s, 1H), 7.0-7.2 (m, 3H), 7.9 (s, 1H).

Ex empl o 1.5 Synthesis of 8- (2-ethyl-6-methylbenzylamino) -N, 2, 3-trimethylimidazofl, 2-aJpi idin-6-carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-benzotriazole tetrafluoroborate-l- IL-N, N, N ', N' -tetramethyluronium (TBTU) (0.14 g, 0.44 mmol) were added to 10 ml of methylene chloride and the reaction mixture was stirred at room temperature for 15 minutes. Added methylamine (0.1 g, 3.2 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate: methylene chloride (1: 1) as the eluent. The product was treated with diethyl ether to give 40 mg (26%) of the desired product.

NMR XH (300 MHz, CDC13): d 1.2 (t, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 3.05 (d, 3H) ), 4.35 (d, 2H), 4.9 (t, 1H), 6.3 (broad s, 1H), 6.4 (s, 1H), 7.0-7.2 (m, 3H), 7.85 (s, 1H).

Example 1.6 Synthesis of 8- (2-ethyl-6-methylbenzylamino) -N, N, 2, 3-tetrametílimidazofl, 2-aJpi ridin- 6 -carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-benzotriazole tetrafluoroborate-l- IL-N, N, N ', N' -tetramethyluronium (TBTU) (0.14 g, 0.44 mmol) were added to 10 ml of methylene chloride. Dimethylamine (0.063 g, 1.4 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. An additional amount of 0.1 ml of dimethylamine was added and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography using methylene chloride: methanol (9: 1) as eluent. The oily product was treated with heptane and the solid that formed was filtered to give 0.1 g (62%) of the title compound. 2 H NMR (300 MHz, CDC13): d 1.2 (t, 3H), 2.35 (s, 6H), 2. 4 (s, 3H), 2.7 (q, 2H), 3.15 (s, 6H), 4.4 (d, 2H), 4.9 (t, 1H), 6.25 (s, 1H), 7.0-7.2 (m, 3H) 7.45 (s, 1 HOUR) .

Example 1 . 1 Synthesis of 2, 3-dimethyl-8 - (2,6-dimethylbenzylamino) -imi dazofl, 2 -ajpi ri din - 6 -carboxami da 8-amino-2,3-dimethylimidazo [1,2-a] pyridine-6-carboxamide (0.6 g, 2.9 mmol), 2,6-dimethylbenzylchloride (0.45 g, 2.9 mmol), sodium carbonate (1.0 g) , 9.4 mmol) and potassium iodide (0.2 g, 1.3 mmol) were added to 25 ml of acetone and heated to reflux for 19 hours. Methylene chloride was added and the inorganic salts were filtered. The solution was washed with a bicarbonate solution, the organic layer was separated, dried and the solvents were evaporated under reduced pressure. The residue was purified by chromatography on column over silica gel using methylene chloride: methanol (100: 5) as eluent and the product washed with diethyl ether to give 0.78 g (82%) of the title compound.

NMR? E (500 MHz, CDC13): d 2.33 (s, 3H), 2.4 (s, 6H), 2.42 (s, 3H), 4.4 (d, 2H), 2.95 (s broad, 1H), 6.45 (s) , 1H), 7.05-7.15 (m, 3H), 7.95 (s, 1H).

Ex empl o 1.8 Synthesis of 2,3-dimethyl-8- (2-ethyl-4-fluoro-6-methylbenzylamino) -imidazofl, 2-a] pyridine-6-carboxamide mesylate The mesylate of 8-amino-2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide (0.7 g, 1.9 mmol), 2-ethyl-4-fluoro-6-methylbenzylchloride (0.26 g, 1.9 mmol) and diisopropylethylamine (0.54 g, 4.2 mmol) were added to 5 ml of dimethylformamide and stirred at room temperature for 1 hour. Methylene chloride and water were added to the reaction mixture, the organic layer was separated, dried and evaporated under reduced pressure. The residue was solvated in ethyl acetate and ethanol and methanesulfonic acid (0.2 g, 2 mmol) was added. The product was filtered and dissolved in methylene chloride: methanol (2: 1) and an excess of potassium carbonate. The solids were filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (10: 1) as eluent. The residue was dissolved in ethyl acetate and methanesulfonic acid (0.04 g, 0.4 mmol) was added. The salt was filtered to give 0.2 g (23%) of the title compound. 1K NMR (300 MHz, DMSO-d6): d 1.15 (t, 3H), 2.25 (s, 3H), 2.4 (s 3H), 2.45 (s, 3H), 2.6 (q, 2H), 4.35 (d, 2H), 6.15 (s, broad, 1H), 6.95-7.05 (m, 2H), 7.4 (s, 1H), 7.8 (s broad, 1H), 8.3 (s, broad, 1H), 8.45 (s, 1H).

Example 1.9 Synthesis of 2, 3-dimethyl-8- (2-methylbenzylamino) imidazofl, 2 -ajpi ridin- 6 -carboxamide The mesylate of 8-amino-2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide (1.0 g, 2.7 mmol), a-chloro-o-xylene (0.38 g, 2.7 mmol) and diisopropylethylamine (0.76 g) g, 5.9 mmol) in 7 ml of dimethylformamide was stirred at 50 ° C for 7 hours and at room temperature for 72 hours. The solvent was evaporated and the residue was treated with a mixture of methylene chloride, water and a small amount of diisopropylethylamine. The solid that formed isolated by filtration and washed with ethyl acetate to give 0.11 g (13%) of the title compound.

H NMR (300 MHz, DM? 0-d6): d 2.3 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 4.45 (d, 2H), 6.3-6.4 (m, 2H), 7. 1-7.25 (m, 4H), 7.3 (broad s, 1H), 7.85 (broad s, 1H), 8.05 (s, 1H).

Ex empl o 1.10 Synthesis of 2,3-dimethyl-8- (2,6-dimethyl-4-fluoro-benzyllamino) -imidazofl, 2-a] pyridine-6-carboxamide mesylate The mesylate of 8-amino-2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide (5.0 g, 13.4 mmol), 2,6-dimethyl-4-fluorobenzylbromide (2.91 g, 13.4 mmol), diisopropylethylamine (3.8 g, 29.5 mmol) and a catalytic amount of potassium iodide were stirred in 20 ml of dimethylformamide at room temperature overnight. 70 ml of water and 2 50 ml portions of methylene chloride were added to the reaction mixture, and the organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. The product was dissolved in isopropanol and 0.3 g of methanesulfonic acid was added. The salt that formed was isolated by filtration and washed with isopropanol and diethyl ether to give 1.4 g (24%) of the title compound. 1 H NMR (500 MHz, DMSO-de): d 2.25 (s, 3H), 2.35 (s, 6H), 2.4 (s, 3H), 2.5 (s, 3H), 4.4 (d, 2H), 6.1 (s) broad, 1H), 7.0 (d, 2H), 7.35 (s, 1H), 7.8 (s broad, 1H), 8.3 (broad s, 1H), 8.45 (s, 1H).

Ex empl o 1.11 Synthesis of 2,3-dimethyl-8- (2-methyl-6-isopropylbenzylamino) -imidazofl, 2-a] pyridine-6-carboxamide mesylate The mesylate of 8-amino-2,3-dimethylimidazo [1,2-a] -6-carboxamide (3.0 g, 8.0 mmol), 2-methyl-6-isopropylbenzylchloride (1.47 g, 8.0 mmol), diisopropylethylamine (2.4 g) , 18.6 mmol) and a catalytic amount of potassium iodide in 15 ml of dimethylformamide. The title compound was prepared according to Example 1.10 (Yield: 1.3 g, 36%) 2 H NMR (300 MHz, DMSO-de): d 1.2 (d, 6H), 2.25 (s, 3H), 2.4 (s, 3H), 2.45 (s, 3H), 2.5 (s, 3H), 3.2 (m , 1H), 4.45 (d, 2H), 6.15 (broad s, 1H), 7.15-7.3 (m, 3H), 7.4 (s, 1H), 7.85 (s, broad, 1H), 8.35 (s broad, 1H) 8.45 (s, 1H).

Ex empl o 1.12 Synthesis of 2, 3-dimethyl-8- (2,6-diethylbenzylamino) -imi azofl, 2-aJpi ri din-6-carboxami da The mesylate of 8-amino-2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide (4.0 g, 10.7 mmol), 2,6-diethylbenzylchloride (1.8 g, 9.9 mmol), diisopropylethylamine (3.0 g, 23.3 mmol) were stirred in 20 ml of dimethylformamide at 50 ° C overnight and at 70 ° C for 3 hours. 60 ml of water and methylene chloride were added, and the organic layer was separated, dried and evaporated under reduced pressure.

The residue was treated with diethyl ether and the product was filtered to give 1.7 g (45%) of the title compound.

NMR JH (300 MHz, CDC13): d 1.2 (t, 6H), 2.35 (s, 3H), 2. 4 (s, 3H), 2.7 (q, 4H), 4.4 (d, 2H), 4.95 (s, broad, 1H), 6.15 (s broad, 2H), 6.5 (s, 1H), 7.05-7.25 (, 3H), 7.95 (s, 1H).

Example 1.13 Synthesis of 2, 3-dimethyl-8- (2-ethylbenzylamino) -imidazofl, 2-aJpiri in-6-carboxami The mesylate of 8-amino-2,3-dimethylimidazo [1,2- a] pyridine-6-carboxamide (4.0 g, 10.7 mmol), 2-ethylbenzylchloride (1.65 g, 10.7 mmol). diisopropylethylamine (3.0 g, 23.3 mmol) in 20 ml of dimethylformamide. The title compound was prepared according to Example 1.12 (Yield: 1.15 g, 26%) 2 H-NMR (300 MHz, CDC13): d 1.2 (t, 3 H), 2.3 (s, 3 H), 2.35 (s, 3 H), 2.75 (q, 2 H), 4.5 (d, 2 H), 6.3 (t, 1 H) ), 6.4 (s, 1H), 7.05-7.25 (m, 4H), 7.3 (s broad, 1H), 7.85 (broad s, 1H), 8.05 (s, 1H).

Ex empl o 1.14 Synthesis of 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N-hydroxyethyl-imidazofl, 2-aJpyridine-6-carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methylbenzylamino) imidazo [1,2-a] pyridine-6-carboxylic acid (0.3 g, 0.88 mmol) and o-benzotriazole-1-yl- tetrafluoroborate N, N, N ', N' -tetramethyluronium (TBTU) (0.29 g, 0.90 mmol) were added to 15 ml of methylene chloride and the mixture was stirred for 5 minutes. Ethanolamine (0.11 g, 1.8 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Crystallization from diethyl ether gave 0.2 g (59%) of the desired product.

NMR LH (500 MHz, CDC13): d 1.2 (t, 3H), 2.3 (s, 6H), 2.35 (s, 3H), 2.7 (q, 2H), 3.55-3.6 (, 2H), 3.8-3.85 ( m, 2H), 4.35 (d, 2H), 4.9 (t, 1H), 6.4 (s, 1H), 6.85 (t, 1H), 7.05-7.2 (, 3H), 7.75 (s, 1H).

Example 1.15 Synthesis of N- (2,3-dihydroxypropyl) -2,3-dimethyl-8- (2-ethyl-6-meth i 1 benzyl) -fl, 2-aJpyridine-6-carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxylic acid (0.3 g, 0.88 mmol), o-benzotriazole tetrafluoroborate-l- il-N, N, N ', N' -tetramethyluronium (TBTU) (0.29 g, 0.90 mmol) and 3-amino-1,2-propanediol (0.16 g, 1.81 mmol) in 10 ml of dimethylformamide. The title compound was prepared according to Example 1.14 (Yield: 0.2 g, 54%) NMR: H (500 MHz, CDC13): d 1.2 (t, 3H), 1.82-1.85 (m, 1H), 2.32 (s, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.7 ( q, 2H), 3.5-3.65 (m, 4H), 3.72-3.77 (m, 1H), 3.85-3.91 (m, 1H), 4.34 (d, 2H), 5.04 (t, 1H), 6.4 (d, 1H), 6.89 (t, 1H), 7.04-7.12 (m, 2H), 7.18 (t, 1H), 7.78 (d, 1H).

Ex empl o 1.16 Synthesis of 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N- (2-methoxyethyl) -imidazofl, 2-aJpyririn-6-carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methyIbene-amino) -imidazo [1,2-a] pyridine-6-carboxylic acid (0.15 g, 0.44 mmol), o-benzotriazole tetrafluoroborate-l- il-N, N, N ', N' -tetramethyluronium (TBTU) (0.14 g, 0.44 mmol) and 2-methoxyethylamine (0.11 g, 1.4 mmol) in 10 ml of methylene chloride. The title compound was prepared according to Example 1.14 Crystallization from hexane: ethyl acetate (Yield: 0.09 g, 53%) H-NMR (400 MHz, CDCl 3): d 1.22 (t, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.71 (q, 2H), 3.42 (s, 3H) ), 3.6-3.72 (m, 4H), 4.38 (d, 2H), 4.91 (t, 1H), 6.42 (s, 1H), 6.58 (t, 1H), 7.04-7.2 (, 3H), 7.88 (s) , 1 HOUR) .

Ex empl o 1.11 Synthesis of 2-methyl-8- (2-ethyl-6-methylbenzylamino) -imidazofl r2-aJpyridine-6-carboxamide 8-Amino-2-methylimidazo [1,2-a] pyridine-6-carboxamide (3.8 g, 20 mmol), 2-ethyl-6-methylbenzylchloride (2.8 g, 17 mmol), potassium carbonate (5.5 g, 40 mmol) and sodium iodide (0.1 g, 0.6 mmol) were added 75 ml of dimethylformamide and the mixture was stirred at 50 ° C for 4 hours, and at room temperature for 48 hours. The reaction mixture was filtered through silica gel and the gel was washed with methylene chloride. The solvents were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Crystallization from a mixture of methylene chloride and hexane gave 0.13 g (2%) of the title compound. 2 H NMR (400 MHz, CDC13): d 1.15 (t, 3H), 2.31 (s, 6H), 2.64 (q, 2H), 4.32 (d, 2H), 4.89 (broad s, 1H), 6.36 (s, 1H), 7.0-7.15 (m, 3H), 7.23 (s, 3H), 8.03 (s, 1H).

Example 1 . 18 Synthesis of 2, 3-dimethyl-8- (2-bromo-6-methyl-benzyl amino-1-dazofl, 2-a] pyridin-6-carboxamide The mesylate of 8-amino-2,3-dimethylimidazole [1,2- a] pyridine-6-carboxamide (1.0 g, 5.0 mmol), 2-bromo-6-methylbenzylchloride (45%) (3.0 g, 5.0 mmol) and diisopropylethylamine (2.2 g, 17 mmol) were added to 50 ml of dimethylformamide and stirred at 50 ° C for 48 hours. Methylene chloride and water were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel using methylene chloride: methanol (10: 1) and ethyl acetate as eluent gave 0.18 g (1%) of the desired product.

H-NMR (300 MHz, CDC13): d 2.28 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 4.48 (d, 2H), 5.0 (s broad, 1H), 6.05 (s, broad, 2H), 6.41 (d, 1H), 6.95-7.1 (m, 2H), 7.37 (d, 1H), 7.87 (d, 1H).

Ex empl o 1.19 Synthesis of, 3-dimethyl-8- (2- (2-hydroxyethyl) -6-methylbenzylamino) -imidazofl, 2-a] pyridine-6-carboxamide 2, 3-Dimethyl-8- (2- (2-benzyloxy) ethyl) -6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide (0.13 g, 0.29 mmol), 1 ml of cyclohexane , Catalytic Pd (OH) 2 (25 mg) was added to 5 ml of ethanol and the mixture was heated to reflux overnight. An additional 1 ml of cyclohexane was added and 25 mg of catalytic Pd (OH) 2 and the mixture was heated to reflux for 4 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Treatment of the residue with chloroform and filtration gave 0.1 g (99%) of the title compound.

NMR? (400 MHz, CD3OD): d 2.29 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.94 (t, 2H), 3.74 (t, 2H), 4.47 (s, 2H), 6.83 (d, 1H), 711-7.20 (m, 3H), 8.12 (d, 1H).

Example 1.20 Synthesis of 8- (2-ethyl-6-methylbenzylamino) -N, N-bis (2-hydroxyethyl) -2, 3-d? Methylimidazofl, 2-a] pyridine-6-carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methylbenzylamino) imidazo [1,2-a] pyridine-6-carboxylic acid (0.3 g, 0.88 mmol) o-benzotriazole-1-yl- tetrafluoroborate N, N, N ', N' -tetramethyluronium (TBTU) (0.3 g, 0.94 mmol) and diethanolamine (0.2 g, 1.9 mmol) in 10 ml of methylene chloride. The title compound was prepared according to Example 1.14 (Yield: 0.19 g, 50%) AH NMR (400 MHz, CDC13): d 1.2 (t, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 2.7 (q, 2H), 3.65 (s, broad) , 4H), 3.9 (broad s, 4H), 4.35 (d, 2H), 4.95 (broad s, 1H), 6.35 (s, 1H), 7.0-7.2 (m, 3H), 7.7 (s, 1H).

Example 1.21 Synthesis of 8- (2-ethyl-6-methylbenzylamino) -N- (2-hydroxyethyl) -N, 2, 3-trimethylimidazo [1,2, -aJpyridine-6-carboxamide 2,3-Dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxylic acid (0.3 g, 0.88 mmol), and o-benzotriazole tetrafluoroborate -il-N, N, N ', N' -tetramethyluronium (TBTU) (0.3 g, 0.94 mmol) and 2- (methylamino) ethanol (0.2 g, 2.66 mmol) in 10 ml of methylene chloride. The title compound was prepared according to Example 1.14 (Yield: 0.25 g, 71%). 1K NMR (600 MHz, CDC13): d 1.2 (t, 3H), 2.25 (s, 6H), 2. 35 (s, 3H), 2.7 (q, 2H), 3.15 (s, 3H), 3.65 (s, broad, 2H), 3.9 (s broad, 2H), 4.35 (d, 2H), 5.0 (s broad, 1H), 6.25 (broad s, 1H), 7.0-7.25 (m, 3H), 7.45 (broad s, 1H).

Ex empl o 1.22 Synthesis of 2, 3-dimethyl-8- (2-ethyl-6-methylbenzyloxy) imidazofl, 2 -ajpi ridin -6 -carboxamide 6-Amino-5- (2-ethyl-6-methylbenzyloxy) nicotinamide (0.14 g, 0.49 mmol), 3-bromo-2-butanone (0.075 g, 0.49 mmol) and sodium bicarbonate (0.1 g, 1.2 mmol) ) were added to 3 ml of acetonitrile and heated to reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. Crystallization from acetonitrile gave 0.058 g, (35%) of the title compound.

RMN 1 ?? (300 MHz, DM? O-de): d 1.14 (t, 3H), 2.24 (s, 3H), 2.33 (s, 3H), 2.40 (s, 3H), 2.69 (q, 2H), 5.25 (s) , 2H), 7.1-7.3 (m, 4H), 7.51 (broad s, 1H), 8.08 (broad s, 1H), 8.42 (s, 1H). 2. PREPARATION OF INTERMEDIARIES Ex empl o 2. 1 Synthesis of 6-amino-5-ni troni cotina to meti l o 6-Chloro-5-nitronicotinoyl chloride (22.0 g, 0.1 mol) was cooled to + 5 ° C. Methanol was added dropwise over 30 minutes and the reaction mixture was stirred for 60 minutes. The temperature was not allowed to rise above + 10 ° C. Ammonium hydroxide (25%, 400 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 20 hours. The product was filtered, washed with water and dried to give 9.0 g (45.9%) of the title compound. 1 H NMR (300 MHz, CDC13): d 3.95 (s, 3H), 6.3 (broad s, 1H), 8.0 (broad s, 1H), 8.95 (s, 1H), 9.05 (s, 1H).

Ex empl o 2. 2 Synthesis of 5, 6-di aminoni cotina to methyl o The methyl 6-amino-5-nitronicotinate (9.0 g, 46 mmol) and a small amount of catalytic Pd / C were added to 200 ml of methanol and the mixture was hydrogenated at room temperature and at atmospheric pressure until the uptake of hydrogen. After filtration through celite, the methanol was evaporated under reduced pressure to give 7.0 g (92%) of the title compound.

X H NMR (300 MHz, CDC13): d 3.3 (s, 2H), 3.9 (s, 3H), 4.75 (s, 2H), 7.45 (s, 1H), 8.35 (s, 1H).

Ex empl o 2. 3 Synthesis of 8-amino-2, 3-dimeti limi dazo [l, 2 -aJpi ri din -6-carboxyl to meti l o Methyl 5,6-diaminonicotinate (0.9 g, 5.4 mmol) and 3-bromo-2-butanone (0.9 g, 6.0 mmol) were added to 30 mL of acetonitrile and heated to reflux for 24 hours. After cooling, some of the product was filtered as the hydrobromide salt. 20 ml of the filtrate were evaporated under reduced pressure and diethyl ether was added. More product was filtered as the hydrobromide salt. The salt was dissolved in methylene chloride and washed with a sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give 0.7 g, (59%) of the desired compound.

AH NMR (300 MHz, CDC13): d 2.4 (s, 6H), 3.9 (s, 3H), 4.5 (s, 2H), 6.85 (s, 1H), 8.1 (s, 1H).

Ex empl o 2. 4 Synthesis of 2, 3-dimethyl -8- (2-ethyl-6-methylbenzyl amino) -zimide, 2 -jpi-ri-din-6-carboxyl methyl ester Methyl 8-amino-2, 3-dimethylimidazo [1,2- a] pyridine-6-carboxylate (0.7 g, 3.2 mmol), 2-ethyl-6-methylbenzylchloride (0.54 g, 3.2 mmol), potassium carbonate (0.9 g, 6.4 mmol) and a catalytic amount of potassium iodide were added to 20 ml of acetonitrile and heated to reflux for 6 hours. After filtration, the acetonitrile was evaporated under reduced pressure to give an oil. The oily residue was dissolved in methylene chloride and washed with water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give a solid. Purification by column chromatography on silica gel using methylene chloride: ethyl acetate (10: 1) as eluent gave 0.42 g (38%) of the title compound. 2 H NMR (500 MHz, CDC13): d 1.15 (t, 3H), 2.35 (s, 3H), 2.4 (s, 3H), 2.43 (s, 3H), 2.75 (q, 2H), 4.0 (s, 3H), 4.25 (d, 2H), 4.9 (s broad, 1H), 6.8 (s, 1H), 7.05-7.2 (m, 3H), 8.1 (s, 1H).

Ex empl o 2.5 Synthesis of 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazofl, 2-a] pyridine-6-carboxylic acid The methyl 2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxylate (0.4 g, 1.1 mmol) was added to a mixture of 6 ml of 1,4-dioxane and 6 ml of sodium hydroxide 2 M, and heated to reflux for 30 minutes. The dioxane was evaporated under reduced pressure and the aqueous solution was acidified by the addition of 2M hydrochloric acid. The aqueous acidic solution was made alkaline by the addition of a saturated solution of sodium bicarbonate and the solid that formed was isolated by filtration. give 0.35 g (91%) of the title compound. 1 H NMR (400 MHz, DMSO-de): d 1.15 (t, 3H), 2.2 (s, 3H), 2.35 (s, 6H), 2.7 (q, 2H), 4.35 (d, 2H), 4.65 (t , 1H), 6.8 (s, 1H), 7.05-7.2 (m, 3H), 7.95 (s, 1H).

Ex empl o 2. 6 Synthesis of 8-amino-2,3-dimethylamine dazo [1, 2-aJpyridine-6-carboxyl to ethyl or The ethyl 5,6-diaminonicotinate (1.4 g, 7.7 mmol) and 3-bromo-2-butanone (1.16 g, 7.2 mmol) were added to 50 ml of 1,2-dimethoxyethane and heated to reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride: methanol (10: 1) as eluent to give 0.3 g (17%) of the title compound. 2 H NMR (300 MHz, CDC13): 1.4 (t, 3H), 2.4 (s, 6H), 4.35 (q, 2H), 4.6 (s, 2H), 6.75 (s, 1H), 8.2 (s, 1H) ).

Ex empl o 2. 1 Synthesis of 2, 3-dimethyl-8- (2-ethyl-6-methyl-benzyl amino) -imino-dazofl, 2-a] pi-ri-din-6-carboxylic acid Ethyl 8-amino-2, 3-dimethylimidazo [1,2- a] pyridine-6-carboxylate (0.7 g, 3.0 mmol), 2-ethyl-6-methylbenzylchloride (0.5 g, 3.0 mmol), sodium carbonate (0.64 g, 6.0 mmol) and a catalytic amount of potassium iodide were added to 50 ml of acetone and heated to reflux for 20 hours. After filtration, the acetone was evaporated under reduced pressure to give an oil. The oily product was purified by column chromatography on silica gel using diethyl ether: petroleum ether (1: 1) as eluent to give 0.12 g (9%) of the title product. 1 H NMR (300 MHz, CDC13): d 1.25 (t, 3H), 1.5 (t, 3H), 2.5 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 2.75 (q, 2H) ), 4.45-4.5 (m, 4H), 4.9 (s broad, 1H), 6.8 (s, 1H), 7.05-7.2 (m, 3H), 8.1 (s, 1H).

Ex empl o 2. 8 Synthesis of 6-amino-5-nor troni cotinamide A solution of 6-chloro-5-nitronicotinoyl chloride (38 g, 0.2 mmol) in 500 ml of tetrahydrofuran was stirred at + 5 ° C and ammonia was bubbled into the solution. After 1 hour, the reaction mixture was allowed to warm to room temperature and ammonia was bubbled into the solution for an additional 2.5 hours. The reaction mixture was stirred at room temperature for 20 hours. The solids were removed by filtration, washed thoroughly with water and dried under reduced pressure to give 18.5 g (51%) of the title compound. 2 H NMR (400 MHz, DMSO-d 6): d 7.4 (s, 1 H), 8.05 (s, 1 H), 8.3 (s, 2 H), 8.8 (s, 2 H).

Example 2.9 Synthesis of 5,6-diaminonicotinamide A suspension of 6-amino-5-nitronicotinamide (18 g, 99 mmol) and a catalytic amount of Pd / c in 600 ml of methanol and the mixture was hydrogenated at room temperature and at atmospheric pressure until the uptake of hydrogen ceased. After filtration through celite, the methanol was evaporated under reduced pressure to give the title compound, 14.5 g (96%). 1 H NMR (300 MHz, DMSO-de): d 5.0 (broad s, 2H), 6.1 (broad s, 2H), 6.9 (broad s, 1H), 7.15 (s, 1H), 7.55 (broad s, 1H) 7.9 (s, 1H).

Ex empl o 2.10 Synthesis of 8-amino-2, 3-dimethylimidazofl, 2-aJpiridin-6-carboxamide ,6-diaminonicotinamide (12.5 g, 82 mmol), 3-Bromo-2-butanone (13.6 g, 90 mmol) and 150 ml of acetonitrile were heated to reflux for 20 hours.

^ ^ Additional 3-bromo-2-butanone (4.0 g, 26.5 mmol) was added and the reaction mixture was heated to reflux for 5 hours. After cooling the solids were removed by filtration. The solids were added to 150 ml of methylene chloride, 150 ml of methanol and potassium carbonate (22 g, 160 mmol) and stirred for 30 minutes. The solids were removed by filtration and evaporation of the solvents under reduced pressure gave an oily residue. Purification by column chromatography on silica gel eluting with methylene chloride: methanol (5: 1) gave 3.3 g (20%) of the title compound. 1 E NMR (400 MHz, DMSO-d6): d 2.25 (s, 3H), 2.35 (s, 3H), 5.6 (s, 2H), 6.65 (s, 1H), 7.15 (s broad, 1H), 7.85 (s) s broad, 1H), 8.05 (s, 1H).

Ex empl o 2. 11 Synthesis of ethyl 8-amino-6- (aminocarbonyl) -2-methylimidazofl, 2-a] pyridine-3-carboxylate , 5-diaminonicotinamide (2.0 g, 13.4 mmol), ethyl-2-chloroacetoacetate (2.38 g, 14.4 mmol) and 40 ml of ethanol were heated to reflux for 20 hours. The precipitate was isolated by filtration and washed with ethanol and diethyl ether. The solids were suspended in water, made alkaline with a sodium hydroxide solution and isolated by filtration. Washing the solids with water and diethyl ether gave 0.42 g (12%) of the desired product.

NMR XH (500 MHz, DMSO-de): d 1.4 (t, 3H), 2.6 (s, 3H), 4.35 (q, 2H), 5.95 (s broad, 2H), 6.9 (s, 1H), 7. 35 (s broad, 1H), 8.0 (broad s, 1H), 9.0 (s, 1H).

Example 2.12 Synthesis of ethyl 6- (aminocarbonyl) -8- (2-ethyl-6-methylbenzylamino) -2-methylimidazofl, 2-a] pyridine-3-carboxylate 8-amino-6- (aminocarbonyl) -2-methylimidazo [1,2- a] pipd? N-3-carboxylic acid ethyl ester (0.41 g, 1.6 mmol), 2-ethyl-6-methybenzylchloride, Sodium carbonate (0.7 g, 6.6 mmol), sodium iodide (0.15 g, 1.0 mmol) and 20 ml of acetone were added. heated to reflux * »for 44 hours. Methylene chloride was added and the solids were removed by filtration. The filtrate was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel eluting with methylene chloride: methanol (100: 4) gave 0.35 g (56%) of the title compound.

X H NMR (300 MHz, CDC13): d 1.25 (t, 3H), 1.45 (s, 3H), 2.35 (s, 3H), 3.65 (s, 3H), 2.7 (q, 2H), 4.4-4.45 (m , 4H), 5.0 (t, 1H), 6.95 (s, 1H), 7.0-7.2 (m, 3H), 9.2 (s, 1H).

Ex empl o 2. 13 Syntheses of the mesylation of 8-amino-2-methylimide zo [l, 2-a] pyridine-6-carboxamide The 5,6-diaminonicotinamide (10 g, 66 mmol), chloroacetone (6.1 g, 66 mmol) and sodium bicarbonate (11.2 g, 132 mmol) were added to 200 ml of dimethylformamide and the mixture was stirred for 72 hours at room temperature. ambient. The majority of the solvent was evaporated under reduced pressure and methanesulfonic acid (6 g, 63 mmol) was added. It evaporated more solvent under reduced pressure and ethanol was added to the residue. After heating the mixture to 60 ° C, the product crystallized as a salt and was filtered to give 6 g (32%) of the title compound. 1 H NMR (400 MHz, CDC13): d 2.3 (s, 6H), 7.25 (s, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.75 (s, 1H), 7.85 (s, 1H) ), 7.9 (s, 1H), 8.15 (s, 1H), 8.6 (s, 1H).

Ex empl o 2. 14 Synthesis of l -bromo-2 -i sopropi l -6-methylbenzene The 2-isopropyl-6-methylaniline (14.9 g, 0.1 mmol) was dissolved in 40 ml of concentrated hydrobromic acid and the mixture was cooled to 5 ° C. Sodium nitrite (7.0 g, 0.1 mol) was added in 15 ml of water so that the temperature was below ° C. A solution of copper (I) bromide in 10 ml of concentrated hydrobromic acid was added to the reaction mixture, and the temperature was allowed to rise to room temperature. The mixture was stirred for 1 hour at room temperature and 30 minutes at 40 ° C. Hexane was added and the organic layer was separated and evaporated under reduced pressure. The purification by column chromatography on silica gel using hexane as eluent gave 6.9 g (32%) of the title compound as an oil.

X H NMR (300 MHz, CDC13): d 1.23 (d, 6H), 2.43 (s, 3H), 3.4-3.55 (m, 1H), 7.05-7.2 (m, 3H).

Ex empl o 2. 15 Synthesis of 2-i sopropil-6-methylbenzaldehyde To a solution of l-bromo-2-isopropyl-6-ethylbenzene (6.9 g, 32.4 mmol) in 50 ml of diethyl ether were added magnesium chips (0.9 g, 37 mmol) and the mixture was heated to reflux in an atmosphere of nitrogen until the reaction was started and then stirred overnight at room temperature. 4 ml of dimethylformamide was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes. 30 ml of a saturated solution of ammonium chloride was added and the mixture was stirred for 1 hour. The organic layer was separated, filtered and evaporated under reduced pressure. Purification by column chromatography on silica gel using hexane: methylene chloride (3: 2) as eluent gave 1.75 g (33%) of the title compound.

X H NMR (500 MHz, CDC13): d 1.25 (d, 6H), 2.55 (s, 3H), 3.7-3.8 (m, 1H), 7.1-7.4 (m, 3H), 10.65 (s, 1H).

E empl o 2. 1 6 Synthesis of the alcohol 2-i sopropil-6-meti lbencil i co To a solution of 2-isopropyl-6-methylbenzaldehyde (1.75 g, 10.8 mmol) in 15 ml of methanol was added sodium borohydride (0.35 g, 9.5 mmol) and the mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure and hexane and water were added to the residue. The organic layer was separated and evaporated under reduced pressure to give 1.73 g (98%) of the title compound as an oil.

X H NMR (500 MHz, CDCl 3): d 1.25 (d, 6H), 2.45 (s, 3H), 3.3-3.4 (m, 1H), 4.8 (s, 2H), 7.05-7.2 (m, 3H).

Ex empl o 2.11 Synthesis of 2-isopropyl-6-methylbenzylchloride To a solution of 2-isopropyl-6-methylbenzyl alcohol (1.7 g, 10.4 mmol) in 20 ml of methylene chloride was added thionyl chloride (1.7 g, 14 mmol) and the reaction was stirred for 1 hour at room temperature. ambient. The solvent was evaporated under reduced pressure and the residue was filtered through the silica gel using methylene chloride as eluent. The solvent was evaporated under reduced pressure to give 1.83 g (96%) of the title compound as an oil.

JH NMR (500 MHz, CDC13): d 1.25 (d, 6H), 2.45 (s, 3H), 3.25-3.35 (m, 1H), 4.75 (s, 2H), 7.05-7.25 (m, 3H).

Example 2.18 Synthesis of 2-bromo-6-methylbenzyl bromide A mixture of 3-bromo-o-xylene (15 g, 81 mmol), N-bromosuccinimide (15.1 g, 85.1 mmol), Dibenzoyl peroxide (0.65 g) and 150 ml of tetrachloromethane were heated to reflux for 5 hours. After filtration, the filtrate was washed with sodium acid sulfite and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. Chromatography on silica gel (petroleum ether: ethyl acetate) gave a fraction of 16.8 g of a mixture containing 45% of the title compound. This mixture was used without further purification.

NMR: H (300 MHz, CDC13): d 2.5 (s, 3H), 4.65 (s, 2H), 7.05-7.45 (m, 3H).

Ex empl o 2. 19 Synthesis of 2- (2-bromo-3-methyl phenyl) acetoni tril or 2-Bromo-l- (bromoethyl) -3-methylbenzene (15 g, 0.057 mmol) and potassium cyanide (9.6 g, 0.148 mol) were added to 75 ml of dimethylformamide and stirred at 90 ° C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between 150 ml of water and methylene chloride. The aqueous layer was extracted twice with methylene chloride, the organic extracts were separated, washed twice with water and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane: methylene chloride (3: 7) as eluent gave 8.0 g (67%) of the title compound. 1 H NMR (500 MHz, CDC13): d 2.44 (s, 3 H), 3.86 (s, 2 H), 7.22-7.37 (m, 3 H).

Example 2. 20 Synthesis of acid 2 - (2-bromo-3-methyl-ethyl) acetic acid The 2- (2-bromo-3-methylphenyl) acetonitrile (8.0 g, 0.038 mol) was added to a mixture of 60 ml of water and 50 ml of sulfuric acid, and the mixture was heated to reflux overnight. After cooling to room temperature, 200 ml of water were added and the mixture was extracted twice with methylene chloride. The methylene chloride extracts were combined, washed twice with water, dried and evaporated under reduced pressure to give 7.9 g (90.8%) of the title compound.

NMR: H (400 MHz, CDCl 3): d 2.42 (s, 3 H), 3.86 (s, 2 H), 7.09-7.18 (m, 3 H).

Ex empl o 2. 21 Synthesis of 2- (2-bromo-3-methyl-methyl) acetates 2- (2-Bromo-3-methylphenyl) acetic acid (7.9 g, 0.034 mol) and 0.1 ml of sulfuric acid were added to 25 ml of ethanol and the mixture was heated to reflux overnight. The solvent was evaporated and saturated sodium carbonate was added to the residue. The aqueous solution was extracted twice with diethyl ether, the organic extracts were combined, washed twice with water, dried and evaporated under reduced pressure to give the desired product as an oil (8.5 g, 97.7%).

X H NMR (400 MHz, CDCl 3): d 1.24 (t, 3 H), 2.40 (s, 3 H), 3.78 (s, 3 H), 4.16 (q, 2 H), 7.06-7.14 (m, 3 H).

Ex empl o 2. 22 Synthesis of 2- (2-bromo-3-methylphenyl) -l-ethanol LiAlH4 (3.1 g, 0.083 mol) was suspended in 100 ml of tetrahydrofuran under an argon atmosphere. The ethyl 2- (2-bromo-3-methylphenyl) acetate (8.5 g, 0.033 mol) dissolved in 50 ml of anhydrous tetrahydrofuran was added and the mixture was stirred at room temperature for 4 hours. The mixture was cooled on ice and 3.1 ml of water was added dropwise, followed by 3.1 ml of 15% sodium hydroxide and then 9.3 ml of water. After 15 hours, the solids were removed by filtration and washed thoroughly with tetrahydrofuran. The filtrate was removed under reduced pressure. Purification of the residue by filtration through silica gel using methylene chloride: methanol (9: 1) as eluent gave 7.0 g (98.6%) of the title compound as an oil.

X H NMR (400 MHz, CDC13): d 2.39 (s, 3 H), 3.00 (t, 2 H), 3.81 (t, 2 H), 7.04-7.10 (m, 3 H).

Ex empl o 2. 23 Synthesis of 2-bromo-3-methyl phenethyl benzyl ether The 50% sodium hydride in oil (1.7 g, 0.036 mol) was suspended in 75 ml of anhydrous tetrahydrofuran under an argon atmosphere. The 2- (2-bromo-3-methylphenyl) -1-ethanol (7.0 g, 0.033 mol) dissolved in 25 ml of tetrahydrofuran was added dropwise over 30 minutes at room temperature. Benzyl bromide (6.2 g) was added, 0.036 mol) and the reaction mixture was stirred at room temperature overnight. 1 ml of water was added carefully and the solvent was evaporated under reduced pressure. The residue was partitioned between water and diethyl ester and the aqueous layer was extracted twice with diethyl ether. The ether extracts were combined, washed twice with water, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane: methylene chloride (7: 3) as eluent gave 7.5 g (74.3%) of the title compound. 1 H NMR (400 MHz, CDC13):? 2.38 (s, 3H), 3.10 (t, 2H), 3.69 (t, 2H), 4.51 (s, 2H), 7.04-7.08 (m, 3H), 7.21-7.30 (m, 5H).

Example 2.24 Synthesis of 2- [2-benzyl oxy) ethyl J- 6-methylbenzal dehyde To a solution of benzyl 2-bromo-3-methylphenethyl ether (3.2 g, 0.0105 mol) in anhydrous tetrahydrofuran under a nitrogen atmosphere at -65 ° C was added tert-butyllithium (1.7 M in pentane) (10.5 ml. , 0.018 mol) and the mixture was stirred at -20 ° C for 30 minutes. Dimethylformamide (1.5 g, 0.021 mol) was added dropwise at -65 ° C and the mixture was stirred at -20 ° C for 30 minutes and at room temperature for 1 hour. Water and 2M hydrochloric acid were carefully added to the solution to acidify it, and the mixture was stirred for 30 minutes. To the mixture was added 50 ml of diethyl ether, the organic layer was separated and washed with saturated sodium carbonate and water. The organic layer was separated, dried and evaporated under reduced pressure. The purification of the residue by column chromatography on gel silica using heptane: methylene chloride (2: 8) as eluent, gave 1.0 g (38.5%) of the title compound.

H-NMR (300 MHz, CDC13): d 2.55 (s, 3H), 3.23 (t, 2H), 3.66 (t, 2H), 4.46 (s, 2H), 7.05-7.31 (m, 8H), 10.54 (s) , 1 HOUR) .

Ex empl o 2. 25 Synthesis of 8- ((2 - [2-benzyl oxy) ethyl] 6-methylbenzyl) amino-2, 3-dimethyl imi zofl, 2-aJpi ridin-6-carboxamide To a solution of 8-amino-2,3-dimethylimidazo [1,2-a] pyridine-6-carboxamide mesylate (1.4 g, 0.0038 mol) in 20 ml of methanol under a nitrogen atmosphere was added zinc chloride ( 1.0 g, 0.0039 mol) dissolved in 10 ml of methanol and the mixture was stirred for 30 minutes. To the mixture was added 2- [2-benzyloxy) ethyl] -6-methylbenzaldehyde (1.0 g, 0.0039 mol) and sodium cyanoborohydride (0.48 g, 0.0076 mol) and the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, 4 ml of triethylamine and the The mixture was stirred for 30 minutes, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (9: 1) as eluent. The residue was dissolved in diethyl ether, treated with diethyl ether / hydrochloric acid and the product precipitated as the hydrochloride salt and filtered. The salt was dissolved in methylene chloride and washed with saturated sodium carbonate. The organic layer was separated, washed with water, dried and evaporated under reduced pressure to give 0.13 g (7.7 g) of the title compound.

NMR aH (300 MHz, CDC13): d 2.31 (s, 3H), 2.33 (s, 3H), 2.34 (s, 3H), 2.98 (t, 2H), 3.66 (t, 2H), 4.37 (d, 2H), 4.46 (s, 2H), 5.02 (s broad, 1H), 6.29 (s broad, 2H), 6.47 (s, 1H), 7.03-7.26 (m, 8H), 7.91 (s, 1H) ).

Ex empl o 2. 26" Synthesis of 5- (2-ethyl-6-methylbenzyloxy) - 6-ni troni cotina to 2-ethyl-6-methylbenzyl or The 5-hydroxy-6-nitronicotinic acid (1 g, 5 mmol), the 2-ethyl-6-methylbenzyl chloride (1.85 g, 11 mmol), N, -diisopropylamine (1.75 g, 14 mmol) and 0.1 g of iodide of tetrabutylammonium was added to 10 ml of acetonitrile and heated to reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed with water. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using n-hexane: methylene chloride (1: 1) as eluent gave 0.7 g (29%) of the title compound. 1N NMR (300 MHz, CDC13): d 1.2 (t, 3H), 1.25 (t, 3H), 2. 35 (s, 3H), 2.45 (s, 3H), 2.7 (q, 2H), 2.8 (q, . 25 (s, 2H), 5.55 (s, 2H), 7.05-7.3 (, 6H), 8.2 (s, 8.65 (s, 1H).

Ex empl o 2. 21 Synthesis of 6-amino-5- (2-eti l-6-methylbenzyl oxy) or cotinami da The 5- (2-ethyl-6-methylbenzyloxy) -6-nitronicotinate of 2-ethyl-6-methylbenzyl (0.7 g, 2 mol) was added to a solution of ammonia in methanol (5-10%) (40 ml). and the mixture was stirred at 35 ° C for 96 hours. The solvent was evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel using ethyl acetate: methylene chloride (1: 1) and methanol: methylene chloride (1: 9) as eluent gave 0.14 g (31%) of the Title .

XH NMR (500 MHz, CDC13): d 1.21 (t, 3H), 1.87 (s, 2H), 2.37 (s, 3H), 2.72 (q, 2H), 5.11 (s, 2H), 5.99 (s broad 2H), 7.1-7.3 (m, 3H), 7.67 (d, 1H), 8.09 (d , 1 HOUR) .

BIOLOGICAL TESTS I. Experiments in vi tro Inhibition of acid secretion in gastric glands of a rabbit.

The inhibitory effect on in vitro acid secretion in isolated gastric glands of rabbit was measured as described by Berglindh et al. (1976) Acta Physiol. Scand. 97, 401-414.

Determination of the activity of H *, K * -ATPase Membrane vesicles (2.5 g, 5 μg) were incubated for 15 minutes at + 37 ° C in 18 mM Pipes buffer / Tris pH 7.4 containing 2 mM magnesium chloride, 10 mM potassium chloride and ATP. 2 mM. ATPase activity was estimated as the release of inorganic phosphate from ATP, as described by LeBel et al. (1978) Anal. Biochem. 85, 86-89. 2. Live ip experiments. »- Inhibitory effect on the secretion of acid in female rats Female rats of the Sprague-Dawley strain are used. These were equipped with cannulated fistulas in the stomach (lumen) and the upper part of the duodenum, for the collection of gastric secretions and the administration of test substances, respectively. A recovery period was left 14 days after the surgery, before the test began. Before the secretory tests, the animals were deprived of food but not of water for 20 hours. The stomach is repeatedly washed through the gastric cannula with tap water (+ 37 ° C), and 6 ml of Ringer-glucose were administered subcutaneously. Acid secretion is stimulated with infusion for 2.5-4 hours (1.2 ml / h subcutaneously) of pentagastrin and carbacol (20 and 110 nmol / kg h, respectively), during which time gastric secretions are collected in fractions of 30 minutes. The test substances or the vehicle are administered either at 60 minutes after the start of the stimulation (intravenous and intraduodenal dosing, 1 ml / kg), or 2 hours before the start of the stimulation (oral dose, 5 ml / kg, closed gastric cannula). The time interval between dosing and stimulation can be increased in order to study the duration of the action. Samples of gastric juice at pH 7.0 are titrated with 0.1 M sodium hydroxide, and the acid output is calculated as the product of the volume of the titrant and the concentration. The additional calculations are based on the average group responses of 4 to 6 rats. In the case of administration during stimulation; the acid exit during the periods after the administration of the test substance or the vehicle are expressed as fractional responses, adjusting the acid exit in the period of 30 minutes preceding the administration, to 1.0. The percent inhibition is calculated from the fractional responses promoted by the test compound and the vehicle. In the case of administration before stimulation, the percentage inhibition is calculated directly from the output or yield of acid registered after the test compound and the vehicle.

Bi odi sponibili ty in ra ta Adult rats of the Sprague-Dawley strain are used. One to three days before the experiments all rats are prepared by cannulation of the left carotid artery under anesthesia. The rats used for the intravenous experiments are also cannulated in the jugular vein (Popovic (1960) J. App. Physiol. 15.277-728). The cannulas are exteriorized in the neck. Blood samples (0.1-0.4 g) are drawn repeatedly from the carotid artery at intervals up to 5.5 hours after the dose is administered. The samples are frozen until the analysis of the test compound. Bioavailability is evaluated by calculating the quotient between the area under the blood / plasma concentration (AUC) curve after (i) intraduodenal (id) or oral (po) administration and (ii) intravenous (iv) administration from the rat or the dog, respectively.

The area under the curve of blood concentration vs. time, AUC, is determined by the trapezoidal logarithmic / linear rule and extrapolated to infinity by dividing the last blood concentration determined by the constant of the rate of elimination in the terminal phase. The systemic bioavailability (F%) after intraduodenal or oral administration is calculated as F (%) = (AUC (p.o. or i.d.) / AUC (i.v.)) x 100.

Inhibition of gastric acid secretion and bi-availability in consci ent dogs.

Labrador or Harrier retrievers of either sex are used. These are equipped with a duodenal fistula for the administration of test compounds or vehicle, and a cannulated gastric fistula or a bag of Heidenhaim for the collection of gastric secretion. Before the secretion tests the animals are fasted for approximately 18 hours but they are given water freely. The secretion of gastric acid is stimulated by up to 6. 5 hours infusion of histamine dihydrochloride (12 ml / h) at a dose that produces approximately 80% of the individual maximum secretory response, and gastric juice collected in consecutive fractions of 30 minutes. The test substance or vehicle is administered orally, i.d. or i.v., 1 or 1.5 hours after the initiation of the histamine infusion in a volume of 0.5 ml / kg of body weight. In the case of oral administration, it should be noted that the test compound is administered to the main stomach secretor of dog acid with Heidenham bag. The acidity of the gastric juice samples is determined by titration up to pH 7.0, and the gastric acid output is calculated. The acid exit in the collection periods after the administration of the test substance or the vehicle are expressed as the fractional responses, adjusting the acid exit in the fraction that precedes the administration to 1.0. The percent inhibition is calculated from the fractional responses promoted by the test compound and the vehicle. Blood samples are collected for analysis of the concentration of the test compound in plasma, at intervals up to 4 hours after dosing. The plasma separates and freezes within 30 minutes after collection and subsequently analyzed. The systemic bioavailability (F%) after oral administration or i.d., is calculated as described above in the rat model.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (23)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of the formula I or a pharmaceutically acceptable salt thereof, wherein R1 is (a) H, (b) CH3, or (c) CH2OH; R2 is (a) CH3 (b) CH2CH3 R3 is (a) H (b) alkyl of 1 to 6 carbon atoms (c) alkyl of 1 to 6 carbon atoms hydroxylated (d) halogen R4 is (a) H, (b) alkyl of 1 to 6 carbon atoms, (c) alkyl of 1 to 6 hydroxy carbon atoms, or (d) halogen; R5 is (a) H, or (b) halogen; R6, R7 are the same or different (a) H, (b) alkyl of 1 to 6 carbon atoms (c) alkyl of 1 to 6 hydroxy carbon atoms; (d) alkyl of 1 to 6 carbon atoms substituted with alkoxy of 1 to 6 carbon atoms X is (a) NH, or (b) 0

. A compound according to claim 1, characterized in that R1 is CH3 or CH2OH: R2, R3 and R4, independently are CH3 or CH2CH3; and R5 is H, Br, Cl, or F.

3. The compound according to claim 1 or 2, characterized in that it is: • 2,3-dimethyl-8- (2-tyl-6-met i Ib ene i lamino) -N-propyl-imidazo [l, 2- a] pyridin-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -N - hydroxyethyl-imidazo [1,2-a] pyridine-6-carboxamide • 2,3-Dimethyl-8- (2-ethyl-6-methylamine) - imidazo [1,2- a] pyridine-6-ca rbo amide • 8- (2-ethyl-6-) methylbenzylamino) -N, 2, 3-trimethylimidazo [l, 2-a] pyridine-6-ca rbox amide • 8- (2-ethyl-6-methylbenzylamino) -N, N, 2, 3-tet amethylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imido z [l, 2-a] pyridine-6-ca rbox amide • N- [2- (dimethylamino) -2-qxoethyl] -8- (2-ethyl-6-methylbenzylamino) -N, 2, 3-trimethylimidazo [l, 2-a] pyridine-6-carboxamide • mesylate 2 , 3-dimethyl-8- (2-ethyl-4-fluoro-6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-methylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethyl-4-f-lurobenzylamino) -imidazo [1,2-a] pyridine-mesylate mesylate carboxamide • 2,3-dimethyl-8- (2-methyl-6-isopropylbenzylamino) -imidazo [1,2-a] pyridine-6-carboxamide mesylate • 2,3-dimethyl-8- (2,6-diethylbenzylamine ) - imidazo [l, 2-a] pi ridin-6-carboxamide • 2,3-dimethyl-8- (2-ethylbenzyl amino) -imide zo [l, 2- a] pi ridin- 6 -carboxamide • 2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N-hydroxyethyl-imidazo [1,2- a] pyridin-6-carboxamide • N- (2,3-dihydroxypropyl) -2, 3-dimethyl- 8- (2-ethyl-6-methylbenzylamino) - [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N- (2-methoxyethyl) -imidazo [l, 2-a] pi-ridin-6-carboxamide • 2-Methyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-bromo-6-methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2- (2-hydroxyethyl) - 6- methylbenzylamino) -imidazofl, 2-a] pyridine-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -N, N-bis (2-hydroxyethyl) -2,3-dimethylimidazo [l, 2- a] pyridine-6-carboxamide • 8- (2-ethyl-6-methylbenzylamino) -N- (2-hydroxyethyl) - N, 2, 3-trimethylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzyloxy) -i idazofl, 2-a] pyridine-6-carboxamide or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 6 2: • 8- (2-ethyl-6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl- 8- (2,6-dimethylbenzylamino) -N-hydroxyethyl-imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1,2- a] pyridin-6-ca boxamide • 8- (2-ethyl-6-methylbenzylamino) -N, 2, 3- trimethylimidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-4-fluoro-6-) methylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-dimethyl-4-fluoro-benzylamino) -imidazofl, 2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2,6-diethylbenzylamino) -imidazo [1,2- a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-et? 1-6-methylbenzylamino) -N-hydroxyethyl-imidazo [1,2-a] pyridine-6-carboxamide • 2,3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N- (2-methoxyethyl) -imidazo [1,2-a] pyridine-6-carboxamide or a pharmaceutically acceptable salt thereof

5. A compound according to any of claims 1-4, characterized in that it is like a hydrochloride or mesylate salt.

6. The products containing at least one compound according to any one of claims 1 to 4, and at least one antimicrobial agent as a combined preparation for the simultaneous, separate or sequential use in the prevention or treatment of gastrointestinal inflammatory diseases.

7. The products containing at least one compound according to any of claims 1 to 4, and at least one proton pump inhibitor as a combined preparation for simultaneous, separate or sequential use in the prevention of the treatment of gastrointestinal inflammatory diseases .

8. A process for the preparation of a compound according to any of claims 1 to 5, wherein X is NH, characterized in that it comprises: (a) the reaction of a compound of the formula II II with a compound of formula III wherein R6 and R7 are as defined according to claim 1, in an inert solvent, to a compound of the formula IV, IV (b) the reaction of a compound of formula IV wherein Rd and R7 are as defined in accordance with claim 1, with ammonia in an inert solvent to a compound of the formula V (c) the reduction of a compound of the formula V, wherein R6 and R7 are as defined in accordance with claim 1, in an inert solvent under standard conditions, to a compound of the formula VI (d) the reaction of a compound of the formula VI wherein R6 and R7 are as defined according to claim 1, with a compound of the formula VII VII wherein R is as defined according to claim 1, Z is a leaving group and R9 represents hydrogen CH3 or an ester group with an inert solvent with or without a base, up to a compound of formula VIII (e) the reaction of a compound of the formula VIII wherein R6, R7 and R2 are as defined according to claim 1, and R9 is hydrogen, CH3 or an ester group, with a compound of the formula IX IX wherein R3, R4 and R5 are as defined according to claim 1, and Y is a leaving group, in an inert solvent with or without a base, up to a compound of the formula X (f) reducing a compound of the formula X wherein R9 is an ester group, in an inert solvent, to a compound of the formula I wherein R1 is CH2OH and X is NH.

9. A process for the preparation of a compound according to any of claims 1 to 5, wherein X is NH and R1 is hydrogen or CH3, characterized in the process because it comprises: (a) the reaction of a compound of formula II with an alcohol compound of the general formula R-OH, wherein R 10 is an alkyl group, under standard conditions, up to a compound of the formula XI (b) the reaction of a compound of the formula XI wherein R10 is an alkyl group, with ammonia in an inert solvent under standard conditions, to a compound of the formula XII (c) the reduction of a compound of the formula XII wherein R10 is an alkyl group, in an inert solvent under standard conditions, to a compound of the formula XIII (d) the reaction of a compound of the formula XIII wherein R10 is an alkyl group, with a compound of the formula XIV wherein R2 is as defined according to claim 1, Z is a leaving group and R represents hydrogen or CH3, in an inert solvent with or without a base to a compound of the formula XV (e) the reaction of a compound of the formula XV wherein R10 is an alkyl group, R2 is as defined according to claim 1, and R11 is hydrogen or CH3 with a compound of the formula IX wherein R, are as defined in accordance with claim 1, and Y is a group salient, in an inert solvent with or without a base to a compound of formula XVI (f) the reaction of a compound of the formula XVI wherein R, are defined according to claim 1, R10 is an alkyl group and R11 is hydrogen or CH3, with a compound of the formula III III wherein R6 and R7 are as defined in accordance with claim 1, under conditions standards, to a compound of formula I, wherein R 1 is hydrogen or CH 3 and X is NH.

10. A process for the preparation of a compound according to any of claims 1 to 5, characterized in that it comprises: (a) the treatment of a compound of the formula XVII wherein R1, R2, R3, R4, R5 and X are as defined according to claim 1, and R10 is an alkyl group, with acid or base under standard conditions, up to a compound of the formula XVIII (b) the reaction of a compound of the formula XVIII wherein R1, R2, R3, R, R5 and X are as defined according to claim 1, with a compound of the formula III III wherein R6 and R7 are as defined in accordance with claim 1, in the presence of a coupling reagent in an inert solvent under standard conditions, up to a compound of the formula I.

11. A compound according to any of claims 1 to 5, for use in therapy.

12. A pharmaceutical formulation, characterized in that it contains a compound according to any of claims 1 to 5, as an active ingredient in combination with a pharmaceutically acceptable diluent or carrier.

13. The use of a compound according to any of claims 1 to 5, for the manufacture of a medicament for the inhibition of gastric acid secretion.

14. The use of a compound according to any of claims 1 to 5, for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.

15. The use of a compound according to any of claims 1 to 5, for the manufacture of a medicament for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of the mucosa human gastric, wherein the salt is adapted to be administered in combination with at least one antimicrobial agent.

16. A pharmaceutical formulation for use in the inhibition of gastric acid secretion, wherein the active ingredient is a compound according to any of claims 1 to 5.

17. A pharmaceutical formulation for use in the treatment of gastrointestinal inflammatory diseases, wherein the active ingredient is a compound according to any of claims 1 to 5.

18. A pharmaceutical formulation for use in the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of the human gastric mucosa, wherein the active ingredient is a compound according to any of claims 1 to 5, in combination for simultaneous use , separate or sequential or together with at least one antimicrobial agent.

19. A compound of formula VIII VIII wherein R2, R6 and R7 are as defined according to claim 1, and R9 is hydrogen, CH3 or an ester group.

20. A compound of formula X Gfe characterized in that R2, R3, R4, R5, R6 and R7 are as defined according to claim 1, and R9 is an ester group.

21. A compound of the formula XV characterized in that R is as defined according to claim 1, R10 is an alkyl group and R11 is hydrogen or CH3.

22. A compound of formula XVI XVI characterized in that R2, R3, R4 and R5 are as is an alkyl group and R is hydrogen or CH3.

23. A compound of the formula XVIII characterized in that R1, R2, R3, R4, R5 and X are as defined in accordance with claim 1.