MX2008007030A - Chromane substituted benzimidazoles and their use as acid pump inhibitors - Google Patents

Abstract

This invention relates to compounds of the formula (I):or a pharmaceutically acceptable salt thereof, wherein X is O or NH, and -A-B- is -0-CH2-, -CH2-O-, -S-CH2- or -CH2-S- or a pharmaceutically acceptable salt, and compositions containing such compounds and the use of such compounds In the treatment of a condition mediated by acid pump antagonistic activity such as;but not limited to, as gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID- induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non- erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, hypersalivatioÏÇ, airway disorders or asthma.

Description

BENZ IDAZOL DERIVATIVES REPLACED WITH CRQ ANQ FIELD OF THE INVENTION This invention relates to benzimidazole derivatives substituted with chroman. These compounds have a selective inhibitory activity of the pump for acid. The present invention also relates to a pharmaceutical composition, method of treatment and use, comprising the above derivatives for the treatment of disease conditions mediated by the modulating activity of the pump for acid; in particular an inhibitory activity of the pump for acid. BACKGROUND OF THE INVENTION It has been properly established that proton pump inhibitors (PPIs) are prodrugs that undergo chemical redisposition catalyzed by acids that allow them to inhibit H + / K * -ATPase by covalently binding to their residues. of Cysteine (Sachs, G. et al., Digestive Diseases and Sciences, 1995, 40, 3S-23S; Sachs et al., Annu Rev Pharmacol Toxicol, 1995, 35, 277-305.). However, unlike PPIs, pump antagonists for acid inhibit acid secretion through the reversible competitive inhibition with potassium of H7K + -ATPase. SCH28080 is one such reversible inhibitor and has been extensively studied. Other recent agents (revaprazan, soraprazan, AZD-0865 and CS-526) have entered clinical trials confirming their efficacy in humans (Pope, A., Parsons, M., Trends in Pharmacological Sciences, 1993,14, 323- 5; Vakil, N., Alimentary Pharmacology and Therapeutics, 2004, 19, 1041-1049.). In general, acid pump antagonists are useful for the treatment of a variety of diseases, including gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer , ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, cancer, gastric acidity, nausea , esophagitis, dysphagia, hypersalivation, respiratory tract disorders or asthma (referred to below as "APA Diseases"; Kiljander, Toni O, American Journal of Medicine, 2003, 115 (Suppl 3A), 65S-71S; Ki-Baik Hahm et al., J. Clin. Biochem. Nutr., 2006, 38, (1), 1-8.). WO04 / 054984 refers to some compounds, such as indan-1-xloxybenzimidazole derivatives, as antagonists of the pump for acid. There is a need to provide new acid pump antagonists that are good drug candidates and meet the unmet needs for PPIs to treat diseases. In particular, preferred compounds should be potently bound to the pump for acid while showing little affinity for other receptors and show functional activity as inhibitors of stomach acid secretion. They must be well absorbed from the gastrointestinal tract, be metabolically stable and have favorable pharmacokinetic properties. They must be non-toxic. Additionally, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.

SUMMARY OF THE INVENTION In this invention, it has now been discovered that the new class of compounds having a benzimidazole structure, substituted with a chroman portion, shows an inhibitory activity of the pump for acid and favorable properties as candidates for drugs and, in this way, they are useful for the treatment of disease conditions mediated by an inhibitory activity of the pump for acid, such as the APA Diseases. The present invention provides a compound of the following formula (I): (I) or a pharmaceutically acceptable salt thereof, or prodrug thereof, wherein; -A-B- represents -0-CH2-, -S-CH2-, -CH2-0- or -CH2-S-; X represents an oxygen atom or NH; R1 represents an alkyl group of 1 to 6 carbon atoms which is unsubstituted or is substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and an alkoxy group of 1 to 6 carbon atoms; R2 and R3 independently represent a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms or a heteroaryl group, the alkyl group of 1 to 6 carbon atoms, the cycloalkyl group of 3 to 7 carbon atoms and the heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, an amino group, an alkylamino group of 1 to 6 carbon atoms and a di (alkyl of 1 to 6 carbon atoms) amino group; or R2 and R3 taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group which is unsubstituted or is substituted with 1 to 2 substituents selected from the group consisting of a hydroxy group, an alkyl group from 1 to 6 carbon atoms, an acyl group of 1 to 6 carbon atoms and a hydroxy-alkyl group of 1 to 6 carbon atoms; R4, R5, R6 and R7 independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms; and R8 represents a hydrogen atom, a hydroxy group or an alkoxy group of 1 to 6 carbon atoms. Also, the present invention provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, together with a pharmaceutically acceptable carrier for the compound.

Also, the present invention provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, which further comprises another pharmacologically active agent or agents. Also, the present invention provides a method of treating a condition mediated by an inhibitory activity of the pump for acid in a mammalian subject, which comprises administering, to a mammal in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, each as described herein. Examples of conditions mediated by an inhibitory activity of the pump for acid include, but are not limited to, APA Diseases. In addition, the present invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of a condition mediated by an activity. inhibitor of the pump for acid. Preferably, the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of diseases selected from the APA diseases. The compounds of the present invention can show a good bioavailability, less toxicity, good absorption, good distribution, good average life, good solubility, less protein binding affinity than the pump for acid, less drug-drug interaction and good metabolic stability .

DETAILED DESCRIPTION OF THE INVENTION In the compounds of the present invention: Where R1, R2, R3, R4, R5, R6, R7 or R8 is an alkyl group of 1 to 6 carbon atoms, or the substituents of the heterocyclic group of 4 to 6 members are an alkyl group of 1 to 6 carbon atoms carbon, this alkyl group of 1 to 6 carbon atoms can be a straight or branched chain group having one to six carbon atoms, and examples include, but are not limited to, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl and hexyl. Of these, alkyl of 1 to 3 carbon atoms is preferred; methyl is more preferred for R 1, R 4 R 5, R 6, R 7 and R 8 and alkyl of 1 to 3 carbon atoms is preferred for R 2; methyl and ethyl are more preferred for R2. Where R2 or R3 is a cycloalkyl group of 3 to 7 carbon atoms, or the substituents ofR2 or R3 are a cycloalkyl group of 3 to 7 carbon atoms, this represents a cycloalkyl group having three to seven carbon atoms, and examples include a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group. Of these, cycloalkyl of 3 to 5 carbon atoms is preferred; Cyclopropyl is preferred more. Where R2 or R3 is a heteroaryl group, this represents a 5- to 6-membered ring containing at least one heteroatom selected from N, O and S, and examples include, but not limited to, 2-thienyl, 2-thiazolyl , 4-thiazolyl, 2-furyl, 2-oxazoliol, .1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl. Of these, the heteroaryl group containing at least one nitrogen atom is preferred; 1-pyrazolyl and 2-pyridyl are more preferred. Where R2 and R3 taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group, this 4-6 membered heterocyclic group represents a saturated heterocyclic group having three to five ring atoms selected from an atom carbon, nitrogen atom, sulfur atom and oxygen atom other than the nitrogen atom, and examples include, but are not limited to, an azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, thiomorpholino. Of these, azetidinyl, pyrrolidinyl, morpholino and piperazinyl are preferred; pyrrolidinyl is more preferred. Where the substituent of the 4- to 6-membered heterocyclic group is a hydroxy-alkyl group of 1 to 6 carbon atoms, this represents the alkyl group of 1 to 6 carbon atoms substituted with a hydroxy group, and examples include, but are not limited to, are limited to a hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl-3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-2-methylpropyl group , 3-hydroxy-1-methylpropyl, 5- hydroxypentyl and 6-hydroxyhexyl. Of these, hydroxy-alkyl of 1 to 3 carbon atoms is preferred; hydroxymethyl is more preferred. Where the substituents of the 4- to 6-membered heterocyclic group are an acyl group of 1 to 6 carbon atoms, this represents a carbonyl group substituted with the alkyl group of 1 to 6 carbon atoms, and examples include, but are not limited to a, a formyl, acetyl, propionyl, butyryl, pentanoyl and hexanoyl group. Of these, acetyl is preferred. Where R4, R5, R6, R7, R8 or the substituents of R1, R2 and R3 are an alkoxy group of 1 to 6 carbon atoms, this represents the oxygen atom substituted with the alkyl group of 1 to 6 carbon atoms, and examples include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, pentyloxy and hexyloxy. Of these, alkoxy of 1 to 3 carbon atoms is preferred; methoxy is preferred more. Where the substituents of R2 or R3 are an alkylamino group of 1 to 6 carbon atoms, this alkylamino group of 1 to 6 carbon atoms represents an amino group substituted with the alkyl group of 1 to 6 carbon atoms. Examples include, but are not limited to, a methylamino, ethylamino, propylamino, isopropylamine, butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino. Of these, alkylamine of 1 to 3 carbon atoms is preferred; Methylamino is preferred more. Where the substituents of R2 or R3 are a di (C 1-6) alkyl amino group, this di (C 1-6) alkyl group represents an amino group substituted with two of the alkyl groups of 1 to 6 carbon atoms. Examples include, but are not limited to, a dimethylamino, N-methyl-N-ethylamine, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamine and N, N-d, (1-methylpropyl) amino. Of these, di (1 to 3 carbon atoms) alkylamino is preferred; dimethylamino and diethylamino are more preferred. Where R4, R5, R6 or R7, or the substituents of R2 or R3 are a halogen atom, this may be a fluorine, chlorine, bromine or iodine atom. Of these, fluorine is preferred. Where -A-B- is -0-CH2- or -S-CH2-, -A- corresponds to O- or -S- and -B- corresponds to -CH2-.

Where -A-B- is -CH2-0- or -CH2-S-, -A- corresponds to -CH2- and -B- corresponds to -O- or -S-.

The term "treating" and "treatment", as used herein, refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such a term applies, or one or more symptoms of such disorder or condition. The preferred class of compounds of the present invention are those compounds of the formula (I) or pharmaceutically acceptable salts thereof, each as described herein, wherein: (a) -AB- is -0-CH2 -, -S-CH2-, -CH2-0- or -CH2-S-; (b) -A-B- is -0-CHr or -CH2-O-; (c) -A-B- is -CH2-O-; (d) X is an oxygen atom or NH; (e) X is an oxygen atom; (f) R1 is an alkyl group of 1 to 6 carbon atoms which is unsubstituted or is substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and an alkoxy group of 1 to 6 carbon atoms; (g) R1 is an alkyl group of 1 to 6 carbon atoms; (h) R1 is a methyl group; (i) R 2 is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms or a heteroaryl group, the alkyl group of 1 to 6 carbon atoms, the cycloalkyl group from 3 to 7 carbon atoms and the heteroaryl group being unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, a group cycloalkyl of 3 to 7 carbon atoms, an amino group, an alkylamino group of 1 to 6 carbon atoms and a di (alkyl of 1 to 6 carbon atoms) amino group; (j) R 2 is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms which is unsubstituted or is substituted with 1 to 3 substituents independently selected from the group consisting of a hydroxy group, an alkoxy group of 1 to 6 carbon atoms and a di (alkyl of 1 to 6 carbon atoms) amine group; (k) R2 is an alkyl group of 1 to 3 carbon atoms which is unsubstituted or is substituted with 1 to 3 substituents independently selected from the group consisting of a hydroxy group and an alkoxy group of 1 to 3 carbon atoms; (I) R 2 is a methyl group or ethyl group, the methyl group and the ethyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group and a methoxy group; (m) R3 is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms or a heteroaryl group, the alkyl group of 1 to 6 carbon atoms, the cycloalkyl group from 3 to 7 carbon atoms and the heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, a group cycloalkyl of 3 to 7 carbon atoms, an amine group, an alkylamino group of 1 to 6 carbon atoms and a group di (alkyl of 1 to 6 carbon atoms) amino; (n) R3 is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; (o) R3 is a hydrogen atom or a methyl group; (p) R2 and R3 taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group which is unsubstituted or is substituted with 1 to 2 substituents selected from the group consisting of a hydroxy group, a group alkyl of 1 to 6 carbon atoms, an acyl group of 1 to 6 carbon atoms and a hydroxy-alkyl group of 1 to 6 carbon atoms; (q) R2 and R3 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a piperazinyl group or a morpholino group, the azetidinyl group, the pyrrolidinyl group, the piperazinyl group and the morpholino group being unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of a hydroxy group, an alkyl group of 1 to 6 carbon atoms, an acyl group of 1 to 6 carbon atoms and a hydroxy-alkyl group of 1 to 6 carbon atoms; (r) R2 and R3 taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group which is unsubstituted or is substituted with a substituent selected from the group consisting of a hydroxy group and a hydroxy-alkyl group of 1 to 3 carbon atoms; (s) R4 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms; (t) R4 is a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; (u) R 4 is a hydrogen atom, a halogen atom or an alkyl group of 1 to 3 carbon atoms; (v) R4 is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group; (w) R5 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms; (x) R5 is a hydrogen atom; (y) R6 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms; (z) R6 is a hydrogen atom or a halogen atom; (aa) R6 is a hydrogen atom or a fluorine atom or a chlorine atom; (bb) R7 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms; (ce) R7 is a hydrogen atom or a halogen atom; (dd) R7 is a hydrogen atom or a fluorine atom or a chlorine atom; (ee) R8 is a hydrogen atom, a hydroxy group or an alkoxy group of 1 to 6 carbon atoms; (ff) R8 is a hydrogen atom or a hydroxy group; and (gg) R8 is a hydrogen atom. Of these classes of compounds, any combination between (a) and (gg) is also preferred.

The preferred compound of the present invention are those compounds of the formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, wherein: (A) -AB- is -0-CH2- , -S-CH2-, -CH2-0- or -CH2-S-; X is an oxygen atom; R1 is an alkyl group of 1 to 6 carbon atoms which is unsubstituted or is substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and an alkoxy group of 1 to 6 carbon atoms; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms, the alkyl group of 1 to 6 carbon atoms and the cycloalkyl group of 3 to 7 carbon atoms being not substituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms and a di ( alkyl of 1 to 6 carbon atoms) amine; or R2 and R3 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a piperazinyl group or a morpholino group, the azetidinyl group, the pyrrolidinyl group, the piperazinyl group and the morpholino group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, an alkyl group of 1 to 6 carbon atoms, an acyl group of 1 to 6 carbon atoms and a hydroxy alkyl group of 1 to 6 carbon atoms; R4, R5, R6 and R7 are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R8 is a hydrogen atom; (B) -A-B- is -0-CH2- or -CH2-0-; X is an oxygen atom; R1 is an alkyl group of 1 to 6 carbon atoms; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms which is unsubstituted or is substituted with 1 to 3 substituents independently selected from the group consisting of a hydroxy group and an alkoxy group of 1 to 6 carbon atoms and; or R2 and R3 taken together with the nitrogen atom to which they are bound form a pyrrolidinyl group which is unsubstituted or is substituted with a substituent selected from the group consisting of a hydroxy group, an alkyl group of from 1 to 6 carbon atoms and a hydroxy-alkyl group of 1 to 6 carbon atoms; R4, R5, R6 and R7 are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R8 is a hydrogen atom; (C) -A-B- is -CH2-0-; X is an oxygen atom; R1 is an alkyl group of 1 to 6 carbon atoms; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms; or R2 and R3 taken together with the nitrogen atom to which they bind form a pyrrolidinyl group; R4, R5, R6 and R7 are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R8 is a hydrogen atom; (D) -A-B- is -CH2-0-; X is an oxygen atom; R1 is an alkyl group of 1 to 6 carbon atoms; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms; or 2 R and R taken together with the nitrogen atom to which they are bound form a pyrrolidinyl group; R4, R6 and R7 are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R5 and R8 are a hydrogen atom; (E) -A-B- is -CH2-0-; X is an oxygen atom; R1 is an alkyl group of 1 to 6 carbon atoms; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms; R4, R6 and R7 are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R5 and R8 are a hydrogen atom; One embodiment of the invention provides a compound selected from the group consisting of: 4 - [(5J-d.fluoro-3,4-dihydro-2 / - -chromen-4-yl) oxy] -? /, ? /, 2-thmethyl-1H-benzimidazole-6-carboxamide; 4 - [(5J-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1 - / - benzimidazole; 4 - [(5-fluoro-3,4-dihydro-2 - / - chromen-4-yl) oxy] -? /, / V, 2-trimethyl-1H-benzimidazole-6-carboxamide; or an acceptable pharmaceutical salt thereof. Another embodiment of the invention provides a compound selected from the group consists of: (-) - 4 - [((4S) -5J-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -? /,? /, 2-trimethyl-1H-benzimidazole- 6-carboxamide; (-) - 4 - [(5J-difluoro-3,4-dihydro-2 / - -chromen-4-yl) oxy] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole; (-) - 4 - [(5-fluoro-3,4-dihydro-2 - / - chromen-4-yl) oxy] -? /,? /, 2-trimethyl-1 / - / - benzimidazole-6 -carboxamide; or an acceptable pharmaceutical salt thereof. The pharmaceutically acceptable salts of a compound of the formula (I) include the acid addition salts and salts of bases (including disalts) thereof. Suitable salts of acid addition are formed from acids, which form non-toxic salts. Examples include the salts acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybietylate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / phosphate acid / diacid phosphate , pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. The base addition salts include alkali metal salts, for example lithium salts, sodium salts and potassium salts; metal salts of alkaline earths, for example calcium salts and magnesium salts; ammonium salts; salts of organic bases, for example triethylamine salts, diisopropylamine salts and cyclohexylamine salts; and similar. The preferred salts are alkali metal salts and the most preferred salts are sodium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). A pharmaceutically acceptable salt of a compound of the formula (I) can be easily prepared by mixing together solutions of the compound of the formula (I) and the desired acid or base, as appropriate. Salt can precipitate from the solution and collect by filtration or can recover by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to almost non-ionized. The pharmaceutically acceptable salts of the compounds of the formula (I) thereof include both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is used when the solvent is water. The pharmaceutically acceptable solvates according to the invention include hydrates and solvates wherein the crystallization solvent can be substituted isotopically, for example D20, d6-acetone, d6-DMSO. Included within the scope of the invention are complexes such as clathrates, drug inclusion-release system complexes wherein, in contrast to the aforementioned solvates, the drug and delivery system are presented in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 for Haleblian (August 1975). The compounds of the formula (I) may exist in one or more crystalline forms. These polymorphs, including mixtures thereof, are also included within the scope of the present invention. The compounds of the formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Within the scope of the present invention all stereoisomers of the compounds of the formula (I) are included, including compounds that exhibit more than one type of isomerism, and mixtures of one or more thereof. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the formula (I), wherein one or more atoms are replaced by atoms that have the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chloro, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 1 5l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P and sulfur, such as 35S. Certain isotopically labeled compounds of the formula (I), for example, those that incorporate a radioactive isotope, are useful in studies of drug distribution and / or tissue substrate. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes, such as deuterium, ie, 2H, may offer certain therapeutic advantages, resulting from increased metabolic stability, for example, increased half-life in vivo or reduced dosage requirements and, therefore, may be preferred. in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the examples and adjunct preparations, using an appropriate reagent labeled isotopically in place of the unlabeled reagent previously used. Also, within the scope of the invention are so-called "prodrugs" of the compounds of the formula (I). Thus, certain derivatives of compounds of the formula (I), which may have little or no pharmacological activity by themselves, when administered in or on the body may be converted to compounds of the formula (I) having the activity desired, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information about the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs according to the invention, for example, can be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain known portions, by those skilled in the art, as 'pro-portions', as described, by example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985). Some examples of prodrugs according to the invention include: (i) wherein the compound of formula (I) contains an alcohol functionality (-OH), compounds wherein the hydroxy group is replaced with a portion convertible in vivo to the hydroxy group. The in vivo convertible portion in the hydroxy group means a portion transformable in vivo in a hydroxyl group, for example, by hydrolysis and / or by an enzyme, for example, an esterase. Examples of the portion include, but are not limited to, ester and ether groups which can be readily hydrolyzed in vivo. Preferred are the hydrogen-substituted portions of the hydroxy group with acyloxyalkyl, 1- (alkoxycarbonyloxy) alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl. (ii) wherein the compound of the formula (I) contains an amino group, an amide derivative, prepared by being reacted with a suitable acid halide or a suitable acid anhydride, is exemplified as a prodrug. A particularly preferred amide derivative as a prodrug is -NHC0 (CH2) 20CH3) -NHC0CH (NH2) CH3 or the like. Additional examples of replacement groups according to the preceding examples and examples of other types of prodrugs can be found in the aforementioned references. All compounds of the formula (I) can be prepared by the methods described in the general methods presented in the following, or by the specific methods described in the examples section and the preparations section, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the compounds of the formula (I), in addition to any novel intermediates used therein.

General Synthesis The compounds of the present invention can be prepared by a variety of well-known processes for the preparation of compounds of this type, for example, as shown in the following Method A to B. All starting materials in the following general syntheses they may be commercially available or obtained by the following Method C to D or conventional methods known to those skilled in the art, such as WO 2000078751 and WO 2004054984 and the descriptions of which are incorporated herein by reference.

Method A This illustrates the preparation of compounds of the formula (I). Reaction Scheme A In Reaction Scheme A, R1, R2, R3, R4, R5, R6, R7, R8, A and B are each as defined above; Hal is a halogen atom, preferably a bromine atom; Prot is a hydroxy protecting group or an amino protecting group; Prot2 is a nitrogen protection group; Lv is an exit group; R1a is R1 as defined above or R1 wherein the hydroxy group is protected by a hydroxy protecting group; R2a is R2 as defined in the above, R wherein the hydroxy group is protected by a hydroxy protecting group, or R2 wherein the amino group or alkylamine group of 1 to 6 carbon atoms is protected by an amino protecting group; R3a is R3 as defined above, R3 wherein the hydroxy group is protected by a hydroxy protecting group, or R3 wherein the amino group or alkylamino group of 1 to 6 carbon atoms is protected by an amino protecting group; R 4a is R 4 as defined in the above or R 4 wherein the hydroxy group is protected by a hydroxy protecting group; R5a is R5 as defined above or R5 wherein the hydroxy group is protected by a hydroxy protecting group; R6a is R6 as defined above or R6 wherein the hydroxy group is protected by a hydroxy protecting group; R7a is R7 as defined above or R7 wherein the hydroxy group is protected by a hydroxy protecting group; R8a is R8 as defined above or R8 where the hydroxy group is protected by a hydroxy protecting group; and the same should apply next. The term "leaving group", as used herein, means a group capable of being substituted by nucleophilic groups, such as a hydroxy group or amines and examples of such leaving groups include a halogen atom, an alkylsulfonyloxy group, a halogenoalkylsulfonyloxy group and a phenylsulfonyloxy group. Of these, a bromine atom, a chlorine atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group and a 4-methylphenylsulfonyloxy group are preferred. The term "hydroxy protecting groups", as used herein, means a protecting group capable of being cleaved by various means to produce a hydroxy group, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such hydroxy protecting groups are describe in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley &Sons, 1999).

Such as, for example, alkoxycarbonyl groups of 1 to 4 carbon atoms, alkylcarbonyl groups of 1 to 4 carbon atoms, tri-alkylsilyl of 1 to 4 carbon atoms or tri-alkylarylsilyl of 1 to 4 carbon atoms, and alkoxy groups of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms. Suitable hydroxy protecting groups include acetyl and tert-butyldimethylsilyl. The term "amino or nitrogen protecting groups", as used herein, means a protecting group capable of cleaving by various means to produce a hydroxy group, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such protecting groups. amino or nitrogen are described in Protective Groups in Organic Synthesis edited by TW Greene et al. (John Wiley &Sons, 1999). Such as, for example, the alkoxycarbonyl group of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, tri-alkylsilyl of 1 to 4 carbon atoms, phenylsulfonyloxy or aralkyl groups. Suitable amino or nitrogen protecting groups include benzyl, tert-butoxycarbonyl and toluenesulfonyl.

(Step A1) In this step, the compound (IV) is prepared by amide formation of the amino group of the compound of the formula (II), which is commercially available or can be prepared by the methods described in WO 2004054984, with anhydride acid (III). The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-dimethylformamide,? /,? / - dimethylacetamide and hexamethylphosphoric triamide; carboxylic acids, such as acetic acid, formic acid, propanoic acid; Of these solvents, acetic acid is preferred or the reaction in the absence of solvents. The reaction can be carried out in the presence or absence of a base. There is also a particular restriction about the nature of the bases used, and any basis commonly used in reactions of this type can also be used here. Examples of such bases include: amines, such as N-methylmorpholine, triethylamine, tripropylamine, thbutylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, , 6-di (ér-butyl) -4-methylpyridine, quinoline, NN-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4 -diazabicyclo [2.2.2] octane (DABCO) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Of these, the reaction is preferred in the absence of the base.

The reaction can be carried out in the presence of an acid. There is also no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type can also be used here. Examples of such acids include: acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid; sulfonic acids, such as methanesulfonic acid or toluenesulfonic acid. Of these, sulfuric acid is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 100 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 10 minutes to about 24 hours will usually suffice.

(Step A2) In this step, the compound of the formula (V) is prepared by substitution of the halogen atom of the compound of the formula (IV) with metal cyanide. The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least up to a certain point. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-dimethylformamide,? /, / -dimethylacetamide, 1-methylpyrrolidin-2-one and hexamethylphosphoric triamide; Of these solvents, A /,? / - dimethylformamide is preferred. The reaction is carried out in the presence of a metal cyanide reagent. There is no particular restriction on the nature of the metal cyanide reagent to be employed, and any metal cyanide reagent commonly used in reactions of this type can also be used here. Examples of such metal cyanide reagents include: zinc cyanide (ll), copper cyanide (1), potassium cyanide and sodium cyanide; Of these, zinc cyanide (II) is preferred. The reaction is carried out in the presence or absence of a palladium catalyst. There is no particular restriction on the nature of the palladium catalyst to be employed, and any palladium catalyst commonly used in reactions of this type can also be used here. Examples of such palladium catalysts include: a palladium metal, palladium chloride, palladium acetate (11), tris (dibenzylidene ketone) d-palladium chloroform, allyl palladium chloride, [1,2-bis (diphenylphosphino) ethane] palladium dichloride, bis (tri-o-tolylphosphine) palladium dichloride, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, dichloro [1,1'-bis (diphenylphosphino) ferrocene] or a catalyst produced in solution by adding a ligand in the reaction solution of these. The ligand added in the reaction solution can be a phosphoric ligand such as triphenylphosphine, 1,1 '-bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphinophenyl) ether, 2,2'-bis (diphenylfosphin) -1, 1 -binaftol. 1, 3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, tri-o-tolylfosphine, 2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl or 2,2-bis (diphenylphosphino) -1, 1 '-bubble. Of these, tetrakis (triphenylphosphine) palladium is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. Without However, in general, it is convenient to carry out the reaction at a temperature of about 50 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 30 minutes to about 24 hours will usually suffice. In this reaction, microwaves can be used to accelerate the reaction. In the case of using sealed tube microwaves, the reaction may be at a temperature of about 50 ° C to about 180 ° C, and the reaction time of about 5 minutes to about 12 hours will usually suffice.

(Step A3) In this step, the compound of the formula (VI) is prepared by reduction and cyclization of the compound of the formula (V). The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, düsopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide,? , / V-dimethylformamide, A /,? / - dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles, such as acetonitrile and benzonitrile; Of these solvents, ethanol is preferred or the reaction in the absence of solvent. The reaction is carried out in the presence of a reducing agent. There is also no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type can also be used here. Examples of such reducing agents include: a combination of metals, such as zinc or iron, and acids, such as hydrochloric acid, acetic acid and acetic acid-ammonium chloride complex. Of these, the combination of iron and acetic acid is preferred.

The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 30 minutes to about 24 hours will usually suffice.

(Step A4) In this step, the compound (VII) is prepared by hydrolysis of the cyanide group of the compound of the formula (VI) with a base or an acid. The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide,? /, W-dimethylformamide,? /,? / - dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; Water; or mixed solvents thereof. Of these solvents, ethylene glycol is preferred. The reaction can be carried out in the presence of a base. There is also no particular restriction on the nature of the bases used, and any basis commonly used in reactions of this kind can equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, potassium hydroxide is preferred.

The reaction can be carried out in the presence of an acid. There is also no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type can also be used here. Examples of such acids include: carboxylic acids, such as acetic acid or propionic acid; acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid. Of these, hydrochloric acid is preferred.

The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 60 minutes to about 24 hours will usually suffice. In this reaction, microwaves can be used to accelerate the reaction. In the case of using sealed tube microwaves, the reaction may be at a temperature of about 50 ° C to about 180 ° C, and the reaction time of about 5 minutes to about 12 hours will usually suffice.

(Step A5) In this step, the compound (IX) is prepared by amidation of the compound of the formula (VII) with the compound of the formula (VIII), which is commercially available or described in J. Org. Chem., 5935 (1990) and Canadian Journal of Chemistry, 2028 (1993), followed by the introduction of protection group 2 (Prot2) and deprotection of protection group 1 (Prot1). The compound of the formula (IX) can be prepared alternatively by the following Method E. The reaction is carried out normally and preferably in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least up to a certain point. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-d-methylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof. Of these, N, N-dimethylformamide is preferred. The reaction is carried out in the presence of a base. There is also no particular restriction on the nature of the bases used, and any basis commonly used in reactions of this kind can equally be used here. Examples of such bases include: amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picolin, 4- (N, N-dimethylamino) pyridine, , 6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, NN-diethylaniline, DBN, DABCO and DBU. Of these, triethylamine or diisopropylethalamine is preferred. The reaction is carried out in the presence of a condensing agent. There is also no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type can also be used here. Examples of such condensing agents include: lower 2-halo-1-alkylpyridinium halides, such as 2-chloro-1-methylpyridinium iodide and 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP); diarylphosphoryl azides, such as diphenylphosphoryl azide (DPPA); chloroformates, such as ethyl chloroformate and isobutyl chloroformate; phosphorocyanidates, such as diethyl phosphorocyanidate (DEPC); imidazole derivatives, such as N, N'-carbonyldiimidazole (CDI); carbodiimide derivatives, such as? /,? / '- dicyclohexylcarbodiimide (DCC) and hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI); salts, such as 2- (1 - / - benzothazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HBTU) and tetramethylfluoroformamidinium hexafluorophosphate (TFFH); and phosphonium salts, such as benzotriazole-1-yloxytris (dithylamine) phosphonium hexafluorophosphate (BOP) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop). Of these, EDCI or HBTU is preferred. Reagents such as 4- (N, N-dimethylamino) pyridine (DMAP) and 1-hydroxybenztriazole (HOBt) they can be used for this stage. Of these, HOBt is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 30 minutes to about 48 hours will usually suffice.

(Introduction of the Prot2 nitrogen protection group) This reaction is described in detail by T. W. Greene et al., Protective Groups in Organic Synthesis, 369-453, (1999), the descriptions of which are incorporated herein by reference. The following exemplifies a typical reaction involving the alkoxycarbonyl or arylsulfonyl protecting group. Examples of the nitrogen protecting halide or anhydride group that can be used in the above reaction include 4-methylphenylsulfonyl chloride, phenylsulfonyl chloride or di-t-butyl-dicarbonate; of these, 4-methylsulfonyl chloride or di-fer-butyl-dicarbonate is preferred. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide,? /,? / - dimethylformamide,? /,? / - dimethylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; alcohols, such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; or mixed solvents thereof. Of these, N, N-dimethylformamide is preferred. Examples of such bases include: alkali metal hydroxides, such as hydroxide lithium, sodium hydroxide and potassium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; Alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal acid carbonates, such as lithium acid carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyrridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-d, (ter- butyl) -4-methy1pyridine, quinolipa, N, N-dimethylaniline, N, N-diethylaniline, DBN, DABCO and DBU; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and bs (trimethylsilyl) amide of potassium; or mixed bases thereof. Of these, sodium hydride or triethylamine is preferred.

(Deprotection of Prot1) The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide,? /,? / - dimethylformamide,? /,? / - dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; carboxylic acid, such as acetic acid or formic acid; Of these solvents, acetic acid or tetrahydrofuran is preferred. The reaction is carried out in the presence of a palladium catalyst under the hydrogen gas. There is no particular restriction on the nature of the palladium catalyst to be employed, and any palladium catalyst commonly used in reactions of this type can also be used here. Examples of such palladium catalysts include: palladium metal, palladium-carbon, palladium hydroxide. Of these, palladium-carbon or palladium hydroxide is preferred.

The reaction can take place over a wide variety of temperatures, and the Precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 100 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 10 minutes to about 24 hours will usually suffice.

(Step A6) In this step, the compound (I) is prepared by coupling the reaction of the compound of the formula (IX) and the compound of the formula (Xa) (A6-a) or the substitution reaction using the same material of start and the compound of formula (Xb) (A6-b), with the proviso that, when X is NH, only Method A6-b is available. The compounds of the formula (Xa) and (Xb) are commercially available or can be prepared by the methods described in the following Method C, D or Synthesis 595 (1983) (A6-a) Coupling reaction The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-dimethylformamide,? /,? / - d? methylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; or mixed solvents thereof. Of these, tetrahydrofuran or toluene is preferred. The reaction is carried out in the presence of a condensing agent. There is also, a particular restriction about the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type can also be used here. Examples of such condensing agents include: lower di-alkyl esters of azodicarboxylic acid, such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and di-tert-butyl azodicarboxylate (DTAD); azodicarboxamides, such as N, N, N ', N'-tetraisopropylazodicarboxamide (TIPA), 1,1' - (azodicarbonyl) dipiperidine (ADDP) and N, N, N ', N'-tetramethylazodicarboxamide (TMAD); phosphorus, such as (cyanomethylenetributylphosphorane (CMBP) and (cyanomethylene) trimethylphosphorane (CMMP) Of these, DIAD or ADDP is preferred Phosphine reagents, such as triphenylphosphine, trimethylphosphine and tributylphosphine, may be employed for this step, of which triphenylphosphine or tributylphosphine is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention.The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. , it is convenient to carry out the reaction at a temperature from about 0 ° C to about 120 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the materials start and solvent employed, however, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of approximately 60 minutes to approximately 48 hours will usually suffice. (A6-b) Substitution reaction The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N- dimethylformamide,? /,? / - d.methylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; ketones, such as acetone and diethyl ketone; or mixed solvents thereof. Of these solvents,? /,? / - dimethylacetamide or acetone is preferred. The reaction is carried out in the presence or absence of a base. There is also no particular restriction on the nature of the bases used, and any basis commonly used in reactions of this kind can equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; Alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium io-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal acid carbonates, such as lithium acid carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethalamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (e) -butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, NN-diethylaniline, DBN, DABCO and DBU; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Of these, sodium hydride or potassium carbonate is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 100 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 30 minutes to about 24 hours will usually suffice.

(Deprotectof Prot2) The deprotectreactis carried out normally and preferably in the presence of solvent. There is no particular restricton the nature of the solvent to be employed, provided that it has no adverse effect on the reactor reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; Water; or mixed solvents thereof. Of these solvents, methanol, tetrahydrofuran, water, or mixed solvents thereof are preferred. The reactcan be carried out in the presence of a base. There is also no particular restricton the nature of the bases used, and any basis commonly used in react of this kind can equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, lithium hydroxide or sodium hydroxide is preferred. The deprotectreactcan take place over a wide variety of temperatures, and the precise reacttemperature is not critical to the invent The preferred reacttemperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reactat a temperature from about 0 ° C to about 100 ° C. The time required for the reactcan also vary widely, depending on many factors, especially the reacttemperature and the nature of the starting and solvent materials used. However, as long as the reactis carried out under the preferred condit detailed in the foregoing, a period of about 10 minutes to about 24 hours will usually suffice.

(Deprotectof the hydroxy protecting group) In the case where R1a, R2a, R3a, R4a, R5a, R6a, R7a, R8a have a protected hydroxy group, the deprotectreactwill continue to produce a hydroxy group. This reactis described in detail by T. W. Greene et al., Protective Groups in Organic Synthesis, 369-453, (1999), the descript of which are incorporated herein by reference. The following exemplifies a typical reactinvolving the protectgroup fer-butyldimethylsilyl. The deprotectof the hydroxyl groups is carried out with an acid, such as acetic acid, hydrogen fluoride, hydrogen fluoride-pyridine complex or fluoride such as tetrabutylammonium fluoride (TBAF). The deprotectreactis carried out normally and preferably in the presence of solvent. There is no particular restricton the nature of the solvent to be employed, provided that it has no adverse effect on the reactor reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: alcohol, such as methanol, ethanol or mixed solvents thereof. The deprotectreactcan take place over a wide variety of temperatures, and the precise reacttemperature is not critical to the invent The preferred reacttemperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reactat a temperature from about 0 ° C to about 100 ° C. The time required for the reactcan also vary widely, depending on many factors, especially the reacttemperature and the nature of the starting and solvent materials used. However, as long as the reactis carried out under the preferred condit detailed in the foregoing, a period of about 10 minutes to about 24 hours will usually suffice.

Method B This illustrates the preparation of compounds of the formula (I).

Reaction Scheme B In Reaction Scheme B, Alk is an alkyl group of 1 to 6 carbon atoms, preferably a methyl group and the same should be applied next. (Step B1) In this step, the compound of the formula (XI) is prepared by esterification of the compound of the formula (VII), which can be prepared by Step A4 of Method A, with the corresponding alcohol, followed by the introduction of Prot2 and the deprotection of Prot1. The introduction and deprotection of the protecting groups can be carried out under the same condition as described in Step A5 of Method A. The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide,? /,? / - dimethylformamide,? /,? / - d -methylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; ketones, such as acetone and diethyl ketone; Of these solvents, the reaction is preferred in the absence of solvents. The reaction can be carried out in the presence of an acid. There is also no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type can also be used here. Examples of such acids include: acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid; sulfonic acids, such as methanesulfonic acid or toluenesulfonic acid; acid chloride, such as oxalyl chloride or thionyl chloride. Of these, hydrochloric acid or thionyl chloride is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the above, a period of 5 minutes to 24 hours will usually suffice.

(Step B2) In this step, the compound (XII) is prepared by reaction of the compound of the formula (XI) with the compound of the formula (Xa) or (Xb), which is commercially available or can be prepared by the methods described in the following Method C, D or Synthesis 595 (1983). The reaction can be carried out under the same condition as described in Step A6 of Method A.

(Step B3) In this step, the compound (XIII) is prepared by hydrolysis of the compound of the formula (XII). The reaction can be carried out under the same condition as described in Step A4 of Method A.

(Step B4) In this step, the compound (I) is prepared by amidation of the compound of the formula (Xlll) with the compound of the formula (VIII). The reaction can be carried out under the same condition as described in Step A5 of Method A.

Method C This illustrates the preparation of compounds of the formula (Xa-1) and (Xb-1) wherein A is CH2. Reaction scheme C (Xa-1) (Xb-1) In Reaction Scheme C, Hal is a halogen atom, Ralk is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms and the same should be applied next.

(Step C1) In this step, the compound of the formula (XVII) is prepared by reaction of Michael (C1-a) of the compound of the formula (XIV) with the compound of the formula (XV), by alkylation reaction ( C1-b) of the compound of the formula (XIV) with the compound of the formula (XVI) or by coupling reaction (C1-c) of the compound of the formula (XIV) with the compound of the formula (XXIX) followed by the hydrogenation (C1-d) The compounds of the formulas (XIV), (XV), (XVI) and (XXIX) are commercially available (C1 -a) Michael reaction The reaction is carried out normally and preferably in the presence or absence of solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and which can dissolve the reagents, at least to some extent Examples of suitable solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, amides, such as formamide,? /, / Vd? met? lformam? da , W, / Vd? Methalacetam? Da and tpamide hexamethylphosphoc, alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitnets, such as acetonitide and benzonitide, sulfoxides, such as dimethyl sulfoxide and sulfolane, or mixed solvents thereof. Of these, the reaction is preferred in the absence of solvent. The reaction is carried out in the presence of a base. , a particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can also be used here. Examples of such bases include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and hydroxide. potassium, alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium io-butoxide, alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate, amines, such as N-methylmorphroma, tethylamine, tppropylamine, tributylamine, diisopropylethylamine, dicy lohexylamine, N-methylpipendine, pindine, 4-pyrrolidonepine, picoline, 4- (N, Nd? met? lam? no) p? pd? na, 2,6-d? Ier-but? l) -4-met? lp? r? d? na, quinoline, N, Nd? met? lan? l? na, N, Nd? et? lan? l? na, DBN, DABCO, DBU and benzyl-p-methyl-ammonium hydroxide, alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium dnsopropylamide, potassium dnsopropylamide, sodium dnsopropylamide, b? s (tr? met? l? l? ) amide of lithium and b? s (tr? met? l? l?) amido de potasio Of these, it is preferred hydroxide of benciitpmethylammonium or sodium methoxide The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 20 ° C to about 120 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 60 minutes to about 48 hours will usually suffice. After the above procedure, the hydrolysis is carried out by adding an acid in a solvent to produce the compound of the formula (XIV), and it can be carried out in a usual hydrolysis condition. The acid may include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid. This is preferably hydrochloric acid. The solvent may include, for example, water; alcohols such as methanol, ethanol, propanol and ér-butanol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diethoxymethane and dioxane; or mixed solvents thereof. This one is preferably water. The reaction temperature varies depending on the starting compound, the reagent and the solvent, however, it is usually 20 ° C at the reflux temperature. The reaction time varies depending on the starting compound, the reagent, the solvent and the reaction temperature, however, it is usually from 60 minutes to 24 hours.

(C1-b) alkylation reaction The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-d-methylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; ketones, such as acetone and diethyl ketone; Water; or mixed solvents thereof. Of these, water is preferred. The reaction is carried out in the presence of a base. There is also no particular restriction on the nature of the bases used, and any basis commonly used in reactions of this kind can equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; Alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Of these, sodium hydroxide is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 20 ° C to about 100 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, as long as the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 60 minutes to about 24 hours will usually suffice. (C1-c) coupling reaction The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent Examples of suitable solvents include halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers, such as diethyl ether, dnsopropylether, tetrahydrofuran and dioxane, aromatic hydrocarbons, such as benzene , toluene and nitrobenzene, amides, such as formamide, N, N-dimethylformamide,? /,? / - d? met? lacetam? da and hexamethylphosphatic tpamide, amines, such as N-methylmorpho na, triethylamine, tppropylamine, tributylamine, dnsopropylethylamine , / -met? lp? per? d? na, pindina, 4-p? rrol? d? nop? pd? na,? /,? / - d? met? l? na? na and? /,? / -d? et? lan? n, alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol, nitriles, such as acetonitrile and benzonitrile, sulfoxides, such as dimethyl sulfoxide and sulfolane, and ketones, such as acetone and diethyl ketone. Of these solvents, acetonitrile and tetrahydrofuran are preferred. The reaction is carried out in the presence of a base., likewise, a particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can also be used here Examples of such bases include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium f-butoxide, metal carbonates alkali, such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal acid carbonates, such as lithium acid carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; amines, such as? / -methylmorphine, triethylamine, tppropylamine, tpbutylamine, diisopropylethylamine,? / - met? lp? per? d? na, pindine, 4 - (? /,? / - d? met? lam ? no) p? r? d? na and DBU, and tetralkylammonium fluorides, such as tetra-p-butylammonium fluoride (TBAF) Of these, TBAF is preferred. The reaction can take place over a wide variety of temperatures, and the Precise reaction temperature is not critical to the invention The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 0 ° C. at approximately 100 ° C The time required for the reaction can also vary widely, depending on many factors, especially the temperature of reaction and the nature of the starting materials and solvent employed However, as long as the reaction was carried out under the preferred conditions detailed in the foregoing, a period of about 5 minutes to about 72 hours would usually suffice (C1-d) hydrogenation The reaction is carried out normally and preferably in the presence of solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and which can dissolve the reagents, at least to some extent Examples of suitable solvents include aromatic hydrocarbons, such as toluene, alcohols, such as methanol and ethanol, and carboxylic acids, such as acetic acid. Of these solvents, alcohols and carboxylic acids are preferred. The reaction is carried out under a hydrogen atmosphere and in the presence of a catalyst. There is also a particular restriction on the nature of the catalysts used, and any catalysts commonly used in the reaction of this type can also be used here. Examples of such catalysts include palladium on carbon, palladium hydroxide, platinum and Raney nickel Of these catalysts, palladium on carbon is preferred. In the case where the hydrodehalogenation (of the substituent "Hal" in the Scheme of Reaction C) is a problem sinus, the reaction can be carried out in the presence of an additive, which reduces the activity of the used catalyst. The additive is selected from substances that are known to exhibit a toxic effect to some degree against the catalyst. such additives include a source of the halide ion, such as tetra-n-butylammonium bromide and sodium bromide, and sulfoxides, such as dimethylsulfoxide. Of these, sodium bromide is preferred. The reaction can take place under a wide variety of pressures, and The precise pressure is not critical to the invention. The preferred pressure will depend on factors such as the nature of the starting materials and the solvent. However, in general, it is convenient to carry out the reaction at a pressure of 1 atm to about 10 atm. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and starting materials However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 50 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the pressure of hydrogen, the reaction temperature and the nature of the starting materials and solvent employed However, as long as the reaction was carried out under the preferred condition detailed in the foregoing, a period of about 30 minutes to about 12 hours would usually suffice Introduction of the hydroxy protection group In the case of the compound of the formula (Xa-1) or (Xb-1) having a hydroxy group, if necessary, the reaction can be achieved by protecting the hydroxy group The introduction of the protection group hydroxy can be carried out at an appropriate stage before the reaction is affected by the hydroxy group This reaction is described in detail by TW Greene et al, Protective Groups in Organic Synthesis, 369-453, (1999), whose descriptions are incorporated in the present for reference The following exemplifies a typical reaction involving the tert-butyldimethylsilyl protecting group. For example, when the hydroxy protecting group is a "tert-butyldimethylsilyl", this step is conducted by reacting with a protective halide group. desired hydroxy in an inert solvent in the presence of a base Examples of suitable solvents include halogenated hydrocarbons, such as dichloromethane, chloroform, tetrachloride of carbon and 1,2-d-chloroethane, ethers, such as diethylether, dnsopropylether, tetrahydrofuran and dioxane, aromatic hydrocarbons, such as benzene, toluene and nitrobenzene, amides, such as formamide,? /,? / - d? met? For example, tetrahydrofuran or N, Nd? met? lformam? Examples of the hydroxy protecting halide group that can be used in the above reaction include tpmethylsilyl chloride, tethylsilyl chloride, tert-butyldimethylsilyl chloride, fer-butyldimethylsilyl bromide, acetyl chloride are preferred. Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, and organic amines such as tetylamine, t-butylamine, N-methylmorpholine, pipdine, imidazole, 4-d? Met? Lam? Nop? R? D? Na, picolma, lutidipa, colidina, DBN and DBU Among these, it is preferred tetylamine, imidazole or pindine With the use of an organic amine in liquid form, it also serves as a solvent when used in large excess Although the reaction temperature differs from the nature of the starting compound , the halide and the solvent, usually varies from 0 ° C to 80 ° C (preferably 0 to 30 ° C) Although the reaction time differs from the reaction temperature or the like, it ranges from 10 minutes to 2 days (preferably 30 minutes to 1 day) (Step C2) In this step, the compound of the formula (XVIIIa) is prepared by Friedel Crafts reaction (C2-a) after the halogenation (C2-b) or by cyclization (C2-c) of the compound of the formula (XVII) when Ralk is a hydrogen atom, or by acid cyclization (C2-d) of the compound of the formula (XVII) when Ralk is an alkyl group of 1 to 6 carbon atoms (C2-a) Friedel Crafts reaction The reaction is carried out normally and preferably in the presence or absence of solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and capable of dissolving the reagents, at least to some extent Examples of suitable solvents include halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, 1,1, 2,2-tetrachloroethane and 1,2-d chloroethane, aromatic hydrocarbons, such as benzene, toluene and nitrobenzene, carbon disulfide, or mixed solvents thereof Of these, it prefers dichloromethane or carbon disulfide. The reaction is carried out in the presence of an acid. There is also a particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type can likewise be used here. Examples of such acids include Lewis acids, such as BF3, AICI3, AIBr3, FeCl3, AgCI, ZnL2, ZnCl2, Fe (N03) 3, CF3S03S (CH3) 3, Yb (CF3 S03) 3 and SnCl4 Of these, AICI3 is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is It is convenient to carry out the reaction at a temperature from about 0 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting materials and solvent employed However, with the proviso that the reaction is carried out under the detailed preferred conditions in the foregoing, a period of approximately 30 minutes to approximately 24 hours will usually suffice (C2-b) Halogenation The reaction is carried out normally and preferably in the presence of solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that can dissolve the reagents, at least to a certain extent. Examples of suitable solvents include halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethylether, dnsopropyl ether, tetrahydrofuran and dioxane, amides, such as formamide, N, Nd? met? lformamide, N, Nd? methalacetamide and hexamethylphosphonated tpamide, amines such as nitnets, such as acetonitrile and benzonitrile, or mixed solvents thereof. Of these, 1,2-d-chloroethane or dichloromethane is preferred. The reaction is carried out in the presence of a halogenating agent. There is also a particular restriction on the nature of the halogenation agents used, and any halogenation agent commonly used in reactions of this type can also be used here. Examples of such halogenating agents include: thionyl chloride, oxalyl chloride and phosphorus oxychloride. Of these, thionyl chloride is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 10 minutes to about 8 hours will usually suffice.

(C2-c) Cyclization The reaction is carried out normally and preferably in the presence or absence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; or mixed solvents thereof. Of these, dichloromethane or the absence of solvent is preferred. The reaction is carried out in the presence of an acid. There is also no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type can also be used here. Examples of such acids include: acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid; acids, such as acid trifluoroacetic or polyphosphoric acid. Of these, polyphosphoric acid is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 20 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 30 minutes to about 24 hours will usually suffice. (C2-d) acid cyclization The reaction is carried out normally and preferably in the presence of an acid, which functions as a solvent and reactant. There is no particular restriction on the nature of the acid to be employed, provided that it has no adverse effect on the reaction and that it can dissolve the substrate, at least to some extent. Examples of suitable acids include: sulfuric acid and trifluoromethanesulfonic acid. Of these, trifluoromethanesulfonic acid is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. Nevertheless, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of about 30 minutes to about 5 hours will usually suffice.

(Stage C3) In this step, the compound (Xa-1) is prepared by reduction of the carbonyl group of the compound of the formula (XVIIIa). In case of using the optically active reducing agent, the resulting compound of the formula (XVI Na) can be obtained as an optically active compound. The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; sulfoxides, such as dimethyl sulfoxide and sulfolane; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; or mixed solvents thereof. Of these, methanol or tetrahydrofuran is preferred. The reaction is carried out in the presence of a reducing agent. There is also no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type can also be used here. Examples of such reducing agents include: metal borohydrides, such as sodium borohydride, lithium borohydride and sodium cyanoborohydride; hydride compounds, such as lithium aluminum hydride and diisobutylaluminum hydride; and borane reagents, such as borane-tetrahydrofuran complex, borane-dimethyl sulfide complex (BMS) and 9-borabicyclo [3.3.1] nonane (9-BBN).

Of these, sodium borohydride is preferred. Concerning an optically active reducing agent there is likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type can likewise be used here. Examples of such reducing agents include: the combination of (S) or (f?) - tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1, 2-c] [1, 3.2] oxazaborol and BMS; the combination of the optically active ruthenium catalyst and hydrogen gas. Examples of the optically active ruthenium catalyst include; Dichloro [(S) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] [(S) -1, 1'-b¡s (p-methoxyphenyl) -2-isopropyl-1,2- ethanediamine] ruthenium (ll), Dichloro [(R) -2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl] [(/?) - 1, 1'-bs (p-methoxyphenol) -2-sopropyl- 1, 2-ethanediamine] ruthenium (ll). The ruthenium catalyst is used in the presence of a catalytic amount of potassium tert-butoxide. Of these, the combination of (S) or (R) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1, 2-c] [1, 3,2] oxazaborol and BMS is preferred. . The reaction can take place over a wide vty of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 10 minutes to about 8 hours will usually suffice.

(Step C4) In this step, the compound of the formula (Xb-1) is prepared by halogenation of the hydroxy group of the compound of the formula (Xa-1). The reaction is carried out normally and preferably in the presence or absence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-d? methylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N-dimethylaniline and N, N-diethylaniline; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as sulfoxide dimethyl and sulfolane; or mixed solvents thereof. Of these, diethyl ether or tetrahydrofuran is preferred. The reaction can be carried out in the presence of a base. There is also no particular restriction on the nature of the bases used, and any basis commonly used in reactions of this kind can equally be used here. Examples of such bases include: amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, piccoline, 4- (N, N-dimethylamine) pyridine, 2.6 -di (tert-butyl) -4-methylpyridine, quinolin, N, N-dimethylaniline, N, N-diethylaniline, DBN, DABCO and DBU. Of these, pyridine is preferred. The reaction is carried out in the presence of a halogenating agent. There is also no particular restriction on the nature of the halogenation agents used, and any halogenating agent commonly used in reactions of this type can also be used here. Examples of such halogenating agents include: thionyl chloride, oxalyl chloride, phosphorus pentachloride and phosphorus oxychloride. Of these, thionyl chloride is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 100 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 10 minutes to about 8 hours will usually suffice.

Method D This illustrates the preparation of compounds of the formula (Xa-2) and (Xb-2) wherein B is CH2.

Diagram of Reaction D (XXIII) (XVlilb) (Xa-2) (Xb-2) In Reaction Scheme D, Rc and Rd independently represent an alkyl group of 1 to 6 carbon atoms. (Step D1) In this step, the compound of the formula (XX) is prepared by halogenation of the methyl group of the compound of the formula (XIX). The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof. Of these, carbon tetrachloride or 1,2-dichloroethane is preferred. The reaction is carried out in the presence of a halogenating agent. There is not, likewise, a particular restriction about the nature of the halogenation agents used, and any halogenation agent commonly used in reactions of this type can likewise be used here. Examples of such halogenating agents include: succinimides, such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS); bromine. Of these, NBS is preferred. Reagents such as benzoyl peroxide and 2,2'-azobis (isobutyronitrile) (AIBN) can be used for this step. Of these, benzoyl peroxide is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. Nevertheless, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 100 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 30 minutes to about 24 hours will usually suffice.

(Step D2) In this step, the compound of the formula (XXII) is prepared by ether forming reaction of the compound of the formula (XX) with the compound of the formula (XXI), which is commercially available. The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof. Of these, N, N-dimethylformamide or tetrahydrofuran is preferred. The reaction is carried out in the presence of a base. There is also no particular restriction on the nature of the bases used, and any basis commonly used in reactions of this kind can equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; Alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Of these, sodium hydride is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 20 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 60 minutes to about 48 hours will usually suffice.

(Step D3) In this step, the compound of the formula (XXIII) is prepared by cyclization (Dieckmann Condensation) of the compound of the formula (XXII). The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent Examples of suitable solvents include ethers, such as diethylether, dnsopropylether, tetrahydrofuran and dioxane, aromatic hydrocarbons, such as benzene, toluene and nitrobenzene, alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol, or mixed solvents thereof. Of these, toluene is preferred. The reaction is carried out in the presence of a base. There is also a particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can also be used here Examples of such bases include alkali metal, such as lithium and sodium, alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride, alkali metal amides, such as amide of lithium, sodium amide, potassium amide, lithium dnsopropylamide, potassium dusopropylamide, sodium diisopropylamide, b? s (tr? met? l? l?) lithium ammonium and b? s (tr? met? l? l) ammonia. Of these, sodium is preferred. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and starting materials However, in general, it is convenient to carry out the reaction at a temperature from about 0 ° C to about 150 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of reaction and the nature of the starting materials and solvent employed However, with the proviso that the reaction was carried out under the preferred conditions detailed in the foregoing, a period of from about 30 minutes to about 24 hours. hours will usually suffice (Step D4) In this step, the compound of the formula (XVIIIb) is prepared by decarboxylation of the compound of the formula (XXIII) The reaction is carried out normally and preferably in the presence of solvent There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include ethers, such as diethylether, dnsopropylether, tetrahydrofuran and dioxane, amides, such as formamide, / V, / Vd? met? lformamide, N? / -d? met? lacetam? da and tpamide hexamethylphosphonate, alcohols, such as methanol, ethanol , propanol, 2-propanol, ethylene glycol and butanol, nitrites, such as acetonitrile and benzonitide, sulfoxides, such as dimethyl sulfoxide and sulfolane, water, or mixed solvents thereof. Of these, ethanol is preferred. The reaction can be carried out in presence of a base There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can equally be used here Examples of such bases include alkali metal hydroxides, such as hydroxide lithium, sodium hydroxide and potassium hydroxide, alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, sodium hydroxide is preferred. The reaction can be carried out in the presence of an acid There is also a particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type can also be used here Examples of such acids include carboxylic acids, such as acetic acid or acid propionic, acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid Of these, hydrochloric acid is preferred The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention The preferred reaction temperature it will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 20 ° C to about 120 ° C. The time required for the reaction can also vary widely , depending on many factors, especially the reaction temperature and the natur However, with the proviso that the reaction was carried out under the preferred conditions detailed in the foregoing, a period of about 60 minutes to about 48 hours will usually suffice.

(Step D5) In this step, the compound of the formula (Xa-2) is prepared by reduction of the compound of the formula (XVIIIb). The reaction can be carried out under the same condition as described in Step C3 of Method C.

(Step D6) In this step, the compound of the formula (Xb-2) is prepared by halogenation of the compound of the formula (Xa-2). The reaction can be carried out under the same condition as described in Step C4 of Method C. If the compound of the formula (Xb-2) has hydroxy groups, the reaction to introduce the hydroxy protecting group described in Method D it will be applied at an appropriate stage.

(Step D7) In this step, the compound of the formula (XXVI) is prepared by reaction of ether formation of the compound of the formula (XXIV) with the compound of the formula (XXV), which is commercially available. The reaction can be carried out under the same condition as described in Step D2 of Method D.

(Step D8) In this step, the compound of the formula (XXVII) is prepared by hydrolysis of the compound of the formula (XXIV). The reaction can be carried out under the same condition as described in Step A4 of Method A.

(Step D9) In this step, the compound of the formula (XVIIIb) is prepared by cyclization (D9-a) of the compound of the formula (XXVII) or by acid halide formation (D9-b) followed by Friedel Crafts reaction (D9-c) of the compound of the formula (XXVII). The reaction can be carried out under the same condition as described in Step C2 of Method C.

Method E This illustrates the preparation of compounds of the formula (IX). Reaction Scheme E (Step E1) In this step, the compound of the formula (XXVIII) is prepared by the reduction and cyclization (E1-a) of the compound of the formula (IV), which can be prepared by Step A1 of Method A, followed for the protection of the nitrogen atom (E1-b). The reduction and cyclization (E1-a) can be carried out under the same condition as described in Step A3 of Method A and the protection of the nitrogen atom can be carried out under the same condition described in Step A5 of Method A .

(Step E2) In this step, the compound of the formula (IX) is prepared by the amidation of the compound of the formula (XXVIII) with the compound of the formula (Vllll) under the atmosphere of carbon monoxide, followed by the deprotection of protection group 1 (Prot1). The deprotection of the protection group (Prot1) can be carried out under the same condition described in Step A5 of method A. The reaction is carried out normally and preferably in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such such as benzene, toluene and nitrobenzene; amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; and ketones, such as acetone and diethyl ketone. Of these solvents, tetrahydrofuran is preferred. The reaction is carried out in the presence of a palladium catalyst. There is no particular restriction on the nature of the palladium catalyst to be employed, and any palladium catalyst commonly used in reactions of this type can also be used here. Examples of such palladium catalysts include: palladium metal, palladium-carbon, palladium (II) acetate, tris (dibenzylidene ketone) dipaladiochloroform, [1,2-bis (diphenylphosphino) ethane] palladium dichloride, bis (tri-o) dichloride -toluylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, dichlorotl. V-bisidiphenylphosphinoJferrocenjpaladium or a catalyst produced in solution by adding a ligand in the reaction solution thereof. The ligand added in the reaction solution can be a phosphoric ligand such as 1,1'-bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphinophenyl) ether, 2,2'-bis (diphenylphosphino) -1, 1 ' -blackphol, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, tri-o-toluylphosphine, triphenylphosphine, 2-diphenylfosphino-2'-methoxy-1,1'-biphenyl or 2, 2 -bis (difenílfosfino) -1,1 '-binaftilo. The above palladium catalyst is preferably tetrakis (triphenylphosphine) palladium. The reaction can take place over a wide variety of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of about 20 ° C to about 120 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the starting and solvent materials used. However, with the proviso that the reaction is carried out under the preferred conditions detailed in the foregoing, a period of from about 60 minutes to about 72 hours will usually suffice. The compounds of the formula (I) and the intermediates in the aforementioned preparation methods in the above can be isolated and purified by conventional procedures, such as distillation, recrystallization or chromatographic purification The compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid seals, powders or films by methods such as precipitation, crystallization, freeze drying, dehydration by spray or evaporative drying Microwave or radio frequency drying can be used for this purpose Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, an optical resolution method of a racemate (or a racemic precursor) can be appropriately selected from conventional methods, eg, preferential crystallization. to or resolution of diastereomeric salts between an alkaline portion of the compound of the formula (I) and a suitable optically active acid such as tartaric acid. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a pharmaceutical composition or formulation in association with one or more carriers. or pharmaceutically acceptable excipients The term "carrier" or "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of carrier or excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the present invention, and methods for their preparation, will be readily apparent to those skilled in the art. Such compositions and the methods for your pre can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995) ORAL ADMINISTRATION The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as, for example, tablets, capsules containing particles, liquids or powders, dragees (including liquid-filled), chewable, multi- and nano-particles, gels, solid solution, liposome, films (including muco-adhesives), ovules, sprays and liquid formulations. Liquid formulations include, for example, suspensions, solutions, syrups and elixirs. Such formulations can be used as soft or hard capsule fillers and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a small sack. The compounds of the invention can also be used to rapidly dissolve, rapidly disintegrate dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001). For dosage forms in tablets, depending on the dose, the drug can be from about 1% by weight to about 80% by weight of the dosage form, most commonly from about 5% by weight to about 60% by weight of the dosage form. In addition to the drug, the tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from about 1% by weight to about 25% by weight, preferably from about 5% by weight to about 20% by weight of the form of dosage. Generally binders are used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diuretics, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally comprise surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.

When presented, the surfactants may comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet. The tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from about 0.25% by weight to about 10% by weight, preferably from about 0.5% by weight to about 3% by weight of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets contain up to about 80% of the drug, from about 10% by weight to about 90% by weight of the binder, from about 0% by weight to about 85% by weight of the diluent, from about 2% by weight to about 10% by weight. % by weight of the disintegrant and from about 0.25% by weight to about 10% by weight of the lubricant. Tablet preparations can be compressed directly or by roll to form the tablets. The preparations of tablets or portions of preparations, alternatively, can be granulated in wet, dry or melt, freeze by fusion or extruded before the tablet formation The final formulation may comprise one or more layers and may be coated or uncoated, it may even be encapsulated. The tablet formulation is discussed in "Pharmaceutical Dosage Forms Tablets, Vol 1", by H Lieberman and L Lachman, Marcel Dekker, NY , NY, 1980 (ISBN 0-8247-6918-X) Solid formulations for oral administration can be formulated to be immediate and / or modified release Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release Suitable modified release formulations, for the purposes of the invention, are described in US Patent No. 6,106,864. Details of other suitable release technologies, such as high energy dispersions and osmotic and coated particles will be found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) The use of chewing gum to achieve controlled release is described in WO 00/35298 PARENTERAL ADMINISTRATION The compounds of the invention can also be administered directly into the blood stream, into the muscle or into an internal organ. Suitable means for parenteral administration include intravenous, intraartenal, intrapentoneal, intrathecal, intraventular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. suitable for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of about 3 to about 9), but, for some applications, they can be formulated more conveniently as a sterile non-aqueous solution or as a dry form for use in conjunction with a suitable vehicle such as sterile, pyrogen-free water. Parenteral ions under sterile conditions, for example, by lyophilization, can be easily achieved using standard pharmaceutical techniques well known to those skilled in the art The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of agents that increase solubility. Formulations for parenteral administration can be formulated to be immediate and / or modified release Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. In this manner, the compounds of the invention can be formulated as a solid, semi-solid or liquid. thixotropic for administration as an implanted reservoir, which provides a modified release of the active compound Examples of such formulations include drug-coated stents and PGLA microspheres TOPICAL ADMINISTRATION The compounds of the invention can also be administered topically to the skin or mucosa, i.e., in dermal or transdermal form. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, drying powders, dressings , foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, petrolatum, glycine, ethylene glycol and propylene glycol. penetration - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999) Other means of topical administration include delivery by electroporation, lontophoresis, phonophoresis, sonophoresis and injection with microneedles or without needles (eg Powderject ™, Bioject ™, etc.) Formulations for topical administration can be Formulated to be immediate and / or modified release Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release INHALED / INTRANASAL ADMINISTRATION The compounds of the invention can also be administered in intranasal form or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry preparation with lactose, or as a dry particle). mixed components, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhalant or as an aerosol spray from a container, pump, sprinkler, atomizer (preferably an atomizer using electrohydrodynamics to produce fine vaporization) or pressurized nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprinkler, atomizer or nebulizer contains a solution or suspension of the compound or compounds of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersing, solubilizing or extending the release of the active, one or propellants such as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligoláctico acid. Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any appropriate grinding method, such as spiral jet grinding, fluid bed jet grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules (made, for example, of gelatin or HPMC), blisters and cartridges for use in an inhalant or nsufflator can be formulated to contain a mixture of powders of the compound of the invention, a suitable powder base such as lactose or starch. and a performance modifier such as / -leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextrin, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce fine vaporization may contain about 1 μg. to about 20mg of the compound of the invention by activation and the activation volume can vary from about 1μl to about 100μl. A typical formulation may comprise a compound of the formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents, which may be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to those formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, poly (DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In the case of inhalants and dry powder aerosols, the dosage unit is determined by means of a valve which supplies a measured quantity. The units according to the invention are typically arranged to deliver a metered dose or "puff" containing from about 1 to about 100 μg of the compound of the formula (I). The overall daily dose will typically be in the range of about 50 μg to about 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

RECTAL / INTRAVAGINAL ADMINISTRATION The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional base for suppositories, but various alternatives can be used as appropriate. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

OTHER TECHNOLOGIES The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability. for use in any of the aforementioned modes of administration. It is found that drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to the direct formation of complexes with e '> drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in. WO 91/11172, WO 94/02518 and WO 98/55148.

SET OF PARTS Whereas it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of the which contains a compound according to the invention, can conveniently be combined in the form of a suitable equipment for the co-administration of the compositions. In this way, the equipment of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the formula (I) according to the invention, and means for separately retaining the compositions, such as a container, divided bottle or divided metallic paper package. An example of such equipment is the family blister used for the packaging of tablets, capsules and the like. The equipment of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, to administer the separate compositions in different dosage ranges or to title the compositions separated against each other. To aid compliance, the equipment typically comprises addresses for administration and can be provided with a so-called memory assistant.

DOSAGE For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of about 0.5 mg to about 300 mg depending, of course, on the mode of administration, preferred in the range of about 1 mg to about 100 mg and more preferred in the range of about 1 mg to about 20 mg. For example, oral administration may require a total daily dose of about 1 mg to about 20 mg, while an intravenous dose may require only about 0.5 mg to about 10 mg. The total daily dose can be administered in single or divided doses. These dosages are based on an average human subject who weighs approximately 65kg to approximately 70kg. The doctor will be able to easily determine the doses for subjects whose weight falls outside this range, such as infants and the elderly.

COMBINATIONS As discussed in the foregoing, a compound of the invention exhibits an inhibitory activity of the pump for acid. An antagonist of the acid pump of the present invention can be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of gastroesophageal reflux disease. For example, an acid pump antagonist, particularly a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above, can be administered simultaneously, in sequence or separately, in combination with one or more agents selected from: (i) Histamine H2 receptor antagonists, eg, ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine; (ii) proton pump inhibitors, for example, omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole; (iii) antacid oral mixtures, for example, Maalox®, Aludrox® and Gaviscon®; (iv) mucosal protective agents, for example, polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate, sucralfate, chlorophyllin-copper and plaunotol; (v) gastric anti-acid agents, for example, anti-gastrin vaccine, itriglumide and Z-360; (vi) 5-HT3 antagonists, for example, dolasetron, palonosetron, alosetron, azasetron, ramosetron, mithrazapine, granisetron, tropisetron, E-3620, ondansetron and ndisetron; (vii) 5-HT agonists, for example, tegaserod, mosapride, cinitapride and oxtriptan; (viii) laxatives, for example, Trifyba®, Fybogel®, Konsyl®, Isogel®, Regulan®, Celevac® and Normacol®; (ix) GABAB agonists, for example, baclofen and AZD-3355; (x) GABAB antagonists, for example, GAS-360 and SGS-742; (xi) calcium channel blockers, for example, aranidipine, lacidipine, falodipine, azelnidipine, clinidipine, lomerizine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine and fasudil; (xii) dopamine antagonists, for example, metoclopramide, domperidone and levosulpiride; (xiii) Tachykinin (NK) antagonists, particularly antagonists of NK-3, NK-2 and NK-1, for example, nepadutanto, saredutanto, talnetanto, (aR, 9R) -7- [3,5-bis ( trifluoromethyl) benzyl] - 8,9,10,11 -tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2, 1 -g] [1 J] naftridin-6- 13-dione (TAK-637), 5 - [[(2R, 3S) -2- [(1 R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4 - morpholinyl] methyl] -1,2-dihydro-3H-1, 2,4-triazole-3-one (MK-869), lanepitanto, dapitanto and 3 - [[2- methoxy-5 - (trifluoromethoxy) phenyl] methylamino] -2-phenyl-pperidine (2S.3S); (xiv) agents for Helicobacter pylori infection, e.g. clarithromycin, roxithromycin, roquitamycin, fluritromycin, telithromycin, amoxicillin, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, piperacillin, lenampicillin, tetracycline, metronidazole, bismuth citrate, and bismuth subsalicylic acid; (xv) nitric oxide synthase inhibitors, for example, GW-274150, tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen; (xvi) vanilloid 1 receptor antagonists, eg, AMG-517 and GW-705498; (xvii) muscarinic receptor antagonists, for example, trospium, solifenacin, tolterodine, tiotropium, cimetropium, oxitropium, ipratropium, tiquizium, dalifenacin and imidafenacin; (xviii) calmodulin antagonists, for example, squalamine and DY-9760; (xix) potassium channel agonists, for example, pinacidyl, tilisolol, nicorandil, NS-8 and retigabine; (xx) beta-1 agonists, for example, dobutamine, denopamine, xamoterol, denopamine, docarpamine and xamoterol; (xxi) beta-2 agonists, for example, salbutamol; terbutaline, arformoterol, meluadrine, mabuterol, rhytodrine, fenoterol, clenbuterol, formoterol, procaterol, tulobuterol, pirbuterol, bambuterol, tulobuterol, dopexamine and levosalbutamol; (xxii) beta agonists, eg, isoproterenol and terbutaline; (xxiii) alpha 2 agonists, for example, clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine; (xxiv) endothelin A antagonists, for example, bonsetan, atrasentan, ambrisentan, clazosentan, sitaxsentan, fandosentan and darusentan; (xxv) opioid agonists μ, for example, morphine, fentanyl and loperamide; (xxvi) opioid antagonists μ, for example, naloxone, buprenorphine and alvimopan; (xxvii) motilin agonists, for example, erythromycin, mitemcinal, SLV-305 and atilmotin; (xxviii) ghrelin agonists, for example, capromorelin and TZP-101; (xxix) AchE release stimulants, eg, Z-338 and KW-5092; (xxx) CCK-B antagonists, eg, itriglumide, YF-476 and S-0509; (xxxi) glucagon antagonists, for example, NN-2501 and A-770077; (xxxii) piperacillin, lenampicillin, tetracycline, metronidazole, bismuth citrate and bismuth subsalicylate; (xxxiii) Antagonists of glucagon-like peptide-1 (GLP-1), for example, PNU-126814; (xxxiv) Channel 3 antagonists of small conductance calcium activated potassium (SK-3), for example, apamin, decualinium, atracurium, pancuronium, and tubocurarine (xxxv) anatagonists of mGluR5, for example, ADX-10059 and AFQ-056; (xxxvi) 5-HT3 agonists, for example, pumosetrag (DDP733); (xxxvii) mGluR8 agonists, for example, (S) -3,4-DCPG and mGluR8-A.

Method for assessing biological activities: The inhibitory activity of the pump for acid and other biological activities of the compounds of this invention were determined by the following procedures. The symbols have their usual meanings in the specification: mL (milliliter or milliliters), μL (microliter or microliter), Kg (kilogram or kilogram), g (gram or gram), mg (milligram or milligram), μg (microgram or microgram) ), pmol (picomolar or picomolar), mmol (millimolar or millimolar), M (molar mass (m3 / mol)), mM (millimolar mass), μM (micromolar mass), atm (standard atmospheric pressure), rpm (revolutions per minute), quant. (quantitative performance), nm (nanometer or nanometer), min (minute or minute), Cat # (catalog number).

Preparation of gastric vesicles from fresh porcine stomachs The porcine gastric vesicles for the H + / K + - porcine gastric ATPase inhibition assays were prepared from mucous membrane in fresh porcine stomachs by homogenization with a polytetrafluoroethylene homogenizer (Teflone®) from forced adjustment in sucrose 0.25 M at 4 ° C. The unpurified granule was removed with centrifugation at 20,000 g for 30 min. Then the supernatant was centrifuged at 100,000 g for 30 min. The resulting granule was re-suspended in 0.25 M sucrose, and then subjected to centrifugation by density gradients at 132,000 g for 90 min. Gastric vesicles were harvested from the interface in the 0.25 M sucrose layer containing 7% Ficoll ™ PM400 (Amersham Biosciences). This procedure was performed in a cold room.

Inhibition of H + / K + - porcine gastric ATPase due to ion leakage Inhibition of H + / K + - porcine gastric ATPase by ion leakage was measured according to the modified method described in Biochemical Pharmacology, 1988, 37, 2231-2236. The isolated vesicles were lyophilized, and then kept in an ultra freezer until its use. For the enzymatic assay, lyophilized vesicles were reconstituted with 3 mM MgSO 3 containing 40 mM Bis-tris (pH 6.4 at 37 ° C). The enzymatic reaction was performed by incubating 5 mM KCl, 3 mM Na 2 ATP, 3 mM MgSO 3 and 1.0 μg of the vesicles reconstituted for 30 minutes at 37 ° C in 60 μl final reaction mixture (40 mM Bis-tris, pH 6.4) with or without the test compound. The enzymatic reaction was stopped by adding 10% sodium dodecyl sulfate (SDS). The inorganic phosphate released from ATP was detected by incubation with a mixture of 1 part of 35 mM ammonium molybdate tetrahydrate in 15 mM zinc acetate hydrate and 4 parts of 10% ascorbic acid (pH 5.0), resulting in phosphomolybdate , which has optical density at 750 nm.

Inhibition of H + / K + - porcine gastric ATPase impermeable to ions Inhibition of H + / K + - porcine gastric ATPase impermeable to ions was measured according to the modified method described in Biochemical Pharmacology, 1988, 37, 2231-2236. The isolated vesicles were kept in an ultra freezer until use. For the enzymatic assay, the vesicles were diluted with 3 mM MgSO 3 containing 5 mM Tris (pH 7.4 at 37 ° C). The enzymatic reaction was performed by incubating 150 mM KCl, 3 mM Na 2 ATP, 3 mM MgSO 4, 15 μM valinomycin and 3 μg of the vesicles for 30 minutes at 37 ° C in the final 60 μl of the reaction mixture (5 mM Tris, pH 7.4 ) with or without the test compound. The enzymatic reaction was stopped by adding 10% SDS. Inorganic phosphate released from ATP was detected by incubating with a mixture of 1 part of 35 mM ammonium molybdate tetrahydrate in 15 mM zinc acetate hydrate and 4 parts of 10% ascorbic acid (pH 5.0), resulting in phosphomolybdate , which has optical density at 750 nm. The results of the IC 50 values of the inhibition activity for the compounds of the Examples are shown in Table 1.

Table 1.

Inhibition of canine kidney Na * / K * -ATPase Na + / K + -ATPase from powdered canine kidney (Sigma) was reconstituted with 3 mM MgSO4 containing 40 mM Tris (pH 7.4 at 37 ° C). The enzymatic reaction was performed by incubating 100 mM NaCl, 2 mM KCl, 3 mM Na 2 ATP, 3 mM MgSO 4 and 12 μg of the enzyme for 30 minutes at 37 ° C in 60 μl final reaction mixture (40 mM Tris, pH 7.4 ) with or without the test compound. The enzymatic reaction was stopped by adding 10% SDS. Inorganic phosphate released from ATP was detected by incubating with a mixture of 1 part of 35 mM ammonium molybdate tetrahydrate in 15 mM zinc acetate hydrate and 4 parts of 10% ascorbic acid (pH 5.0), resulting in phosphomolybdate , which has optical density at 750 nm.

Inhibition of acid secretion in the perfused rat in gastric lumen The secretion of acid in the perfused rat in the gastric lumen was measured according to Watanabe et al. [Watanabe K et al., J. Physiol. (Paris) 2000; 94: 111-116].

Male Sprague-Dawley rats, 8 weeks old, deprived of food for 18 hours before the experiment with free access to water, were anesthetized with urethane (1.4 g / kg, i.p.) and tracheotomized. After an intermediate abdominal incision, a double polyethylene cannula was inserted into the anterior stomach and the stomach was perfused with saline (37 ° C, pH 5.0) at a rate of 1 ml / min. The production of acid in the perfusate was determined at 5 minute intervals by titration with 0.02 M NaOH at pH 5.0. After the determination of basal acid secretion for 30 min, the secretion of acid was stimulated by a continuous intravenous infusion of pentagastrin (16 μg / kg / h). The test compounds were administered by a rapid intravenous injection or intraduodenal administration after the stimulated secretion of acid reached a stabilization phase. Acid secretion was monitored after administration. The activity was evaluated either as inhibition of total acid secretion from 0 hours to 1.5 or 3.5 hours after administration or maximal inhibition after administration.

Inhibition of gastric acid secretion in dog Heidenhain bag Male Beagle dogs weighing 7 - 15 kg were used with Heidenhain bag [Heidenhaín R: Arch Ges Physiol. 1879; 19: 148-167]. The animals were allowed to recover from surgery for at least three weeks before the experiments. The animals were kept at a 12-hour light-dark rhythm, individually housed. They received standard feeding once daily at 11:00 a.m. and tap water ad libitum, and fasted overnight before the experiment, with free access to water. Samples of gastric juices were collected throughout the experiment by gravity drainage every 15 min.

The acidity in the gastric juice was measured by titration to the final point of pH 7.0. The secretion of acid was stimulated by a continuous intravenous infusion of histamine (80 μg / kg / h). Oral administration or rapid intravenous injection of the test compounds was done 90 minutes after the start of the histamine infusion. Acid secretion was monitored after administration. The activity was evaluated by the maximum inhibition with respect to the control value correspondent. The compound of Example 2 showed good inhibitory activity.

Binding to human dofetilide HEK293S cells infected with the human gene related to a-go-go ether (HERG) were prepared and internally grown. A cell paste of HEK-293 cells expressing the HERG product can be suspended in a 10-fold volume of 50 mM Tris buffer adjusted to pH 7.5 at 25 ° C with 2 M HCl containing 1 mM MgCl 2, 10 mM KCl. The cells were homogenized using a Polytron homogenizer (at maximum power for 20 seconds) and centrifuged at 48,000 g for 20 minutes at 4 ° C. The granule was resuspended, homogenized and centrifuged once more in the same way. The resulting supernatant was discarded and the final granule was resuspended (volume 10 times of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds. The membrane homogenate was placed in aliquots and stored at -80 ° C until use. An aliquot was used to determine protein concentration using a Protein Assay Rapid Kit (wako) and Spectra max plate reader (Wallac). All manipulation, reserve solution and equipment were kept on ice at all times. For saturation tests, the experiments were conducted in a total volume of 200 μl. Saturation was determined by incubating 36 μl of [3 H] -dofetilide, and 160 μl of membrane homogenates (20-30 μg of protein per well) for 60 minutes at room temperature in the absence or presence of 10 μM dofetilide at final concentrations ( 4 μl) for total or specific binding, respectively. All incubations were terminated by rapid vacuum filtration on glass fiber filter papers soaked with PEI using a Skatron cell harvester, followed by two washes with 50 mM Tris buffer (pH 7.4 at 25 ° C). The radioactivity bound to receptor was quantified by liquid scintillation counting using a Packard LS counter. For the competition assay, the compounds were diluted in 96-well polypropylene plates as 4-point dilutions in a semi-logarithmic format. All dilutions were made in DMSO first and then transferred to 50 mM Tris buffer (pH 7.4 at 25 ° C) containing 1 mM MgCl 2, 10 mM KCl so that the final concentration of DMSO would become equal to 1%. The compounds were distributed in triplicate on assay plates (4 μl). The total binding and the specific binding wells were prepared in 6 wells as vehicle and 10 μM dofetilide in final concentration, respectively. The radioligand was prepared at a final concentration of 5.6x and this solution was added to each well (36 μl). The assay was initiated by the addition of YSi poly-L-lysine beads (50 μl, 1 mg / well) and membranes (110 μl, 20 μg / well). Incubation continued for 60 minutes at room temperature. The plates were incubated for an additional 3 hours at room temperature for the beads to settle. The radioactivity bound to the receptor was quantified by counting in a Wallac MicroBeta plate counter.

Permeability in Caco-2 The permeability in Caco-2 was measured according to the method described in Shiyin Yee, Pharmaceutical Research, 763 (1997). Caco-2 cells were grown on filter supports (Falcon HTS multi-well insertion system) for 14 days. The culture medium was removed from both the apical and basolateral compartments and the monolayers were pre-incubated with 0.3 ml of apical buffer and 1.0 ml of pre-heated basolateral buffer for 0.5 hour at 37 ° C in a water bath at 50 cycles / min. The apical buffer consisted of Hanks' Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM 2-morpholinoethane sulfonic acid (MES) Biological Buffer, 1.25 mM CaCl2 and 0.5 mM MgCl2 (pH 6.5). The basolateral buffer consisted of Hanks' Salted Solution, 25 mM D-glucose monohydrate, 20 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid (HEPES) Biological Buffer, 1.25 mM CaCl2 and 0.5 mM MgCl2 (pH 7.4). At the end of preincubation, the medium was removed and the solution of test compounds (10μM) in buffer was added to the apical compartment. The insertions were moved to wells containing fresh basolateral buffer in 1 hour. The concentration of the drug in the buffer was measured by LC / MS analysis. The flow rate (F, mass / time) was calculated from the slope of the cumulative appearance of the substrate on the receiver side and the apparent permeability coefficient (Papp) was calculated from the following equation.

Papp (cm / sec) = (F x VD) / (SA x MD) where SA is the surface area for transport (0.3 cm2), VD is the donor volume (0.3ml), MD is the total amount of drug on the donor side at = 0. All data represent the average of 2 inserts. The integrity of the monolayer was determined by transporting Lucifer Yellow.

Mean life in human liver microsomes (HLM -1) Test compounds (1 μM) were incubated with 3.3 mM MgCl2 and 0.78 mg / mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37 ° C in the 96 deep well plate The reaction mixture was divided into two groups, a non-P450 and a P450 group NADPH was added only to the P450 group reaction mixture An aliquot of samples of the P450 group was collected in the point at time 0, 10, 30 and 60 minutes, where the point in time of 0 minutes indicated the time when NADPH was added to the P450 group reaction mixture An aliquot of samples from the non-P450 group was collected at the point in time of -10 and 65 minutes.The collected aliquots were extracted with acetonitrile solution containing an internal standard.The precipitated protein was pelleted in the centrifuge (2000 rpm, 15 min.). the supernatant was measured by the LC / MS / MS system. of the half-life was obtained by plotting the natural logarithm of the ratio of the peak area of the compounds / internal standard versus time. The slope of the line of best fit through the points produces the rate of metabolism (k). This was converted to a half-life value using the following equations: Average life = In 2 / k Half life in human liver microsomes (HLM1-2) Test compounds (1 μM) were incubated with 1 mM MgCl2, 1 mM NADP +, 5 mM isocitric acid, 1U / mL isocitic dehydrogenase and 0.8 mg / mL HLM (HL101 ) in 100 mM potassium phosphate buffer (pH 7.4) at 37 ° C in a series of 384 well plates At various points in time, a plate was removed from the incubator and the reaction was terminated with two volumes incubation of acetonitrile. The concentration of compounds in the supernatant was measured by the LC / MS / MS system. The intrinsic purification value was calculated using the following equations: Cl, nt (ul / min / mg protein) = k x incubation volume Protein concentration Where, k = - slope of ln (concentration) vs. time (min-1) In vitro drug-drug interaction studies for five major CYPs (fDDI) CYP1A2 Test compounds (3 μM) were pre-incubated with recombinant CYP1A2 (Baculosome lot # 21198 Invitrogen, 50 pmol P450 / ml) in Buffer K * 100 mM Phosphate (pH 7.4) and Vivid blue 1A2 probe 10 μM (Invitrogen) as substrate for 5 minutes at 30 ° C. The reaction was initiated by adding a solution of a heated NADPH regenerator system A, which consists of 0.50 mM NADP and 10 mM MgCl2, 6.2 mM DL-lsocyclic acid, and 0.5 U / ml Isocyclic Dehydrogenase (ICD). Plates were placed in the plate reader at 30 ° C and readings were taken every 1.5 minutes, with a stir of 10 seconds between each reading for 15 cycles. The excitation / emission wavelengths were 408/465 nm, respectively. CYP2C9 Test compounds (3 μM) were pre-incubated with recombinant CYP2C9 (Baculosome lot # 20967 Invitrogen, 50 pmol P450 / ml) in Buffer K * 100 mM phosphate (pH 7.4) and 30 μM MFC probe (Gentest) as substrate for 5 minutes at 37 ° C. The reaction was started by adding a solution of the heated NADPH regenerator system A. The plates were placed in the plate reader at 37 ° C and readings were taken every 2.0 minutes, with an agitation of 10 seconds between each reading for 15 cycles. The excitation / emission wavelengths were 408/535 nm, respectively. CYP2C19 Test compounds (3 μM) were pre-incubated with recombinant CYP2C19 (Baculosome lot # 20795 Invitrogen, 5 pmol P450 / ml) in Buffer K + 100 mM Phosphate (pH 7.4) and Vivid blue 2C19 probe 10 μM (Invitrogen) as a substrate for 5 minutes at 37 ° C. The reaction was started by adding a solution of the heated NADPH regenerator system A. The Plates were placed in the plate reader at 37 ° C and readings were taken every 1.5 minutes with a shaking of 10 seconds between each reading for 15 cycles. The excitation / emission wavelengths were 408/465 nm, respectively. CYP2D6 Test compounds (3 μM) were pre-incubated with recombinant CYP2D6 (Baculosome lot # 21248 Invitrogen, 20 pmol P450 / ml) in Buffer K + 100 mM Phosphate (pH 7.4) and probe of 3- [2- (N, N-di-ethyl-N-methylammonium) ethyl] -7-methoxy-4-methylcoumarin (AMMC) 1 μM (Gentest) as substrate for 5 minutes at 37 ° C. The reaction was initiated by adding a solution of a heated NADPH regenerator B system, which consists of 0.03 mM NADP and 10 mM MgCl 2, 6.2 mM DL-lccyctric acid and 0.5.5 U / ml ICD. Plates were placed in the plate reader at 37 ° C and readings were taken every 2.0 minutes with a 10 second shake between each reading for 15 cycles. The excitation / emission wavelengths were 400/465 nm, respectively. CYP3A4 Test compounds (3 μM) were pre-incubated with recombinant CYP3A4 (Baculosome lot # 20814 Invitrogen, 5 pmol P450 / ml) in Buffer K * 100 mM phosphate (pH 7.4) and Vivid Red probe 2 μM (Invitrogen) as substrate for 5 minutes at 30 ° C. The reaction was started by adding a solution of the heated NADPH regenerator system A. Plates were placed in the plate reader at 30 ° C and readings were taken at minimum intervals with a 10 second agitation between each reading for 15 cycles. The excitation / emission wavelengths were 530/595 nm, respectively. The drug-drug interaction was evaluated by the rate of metabolite formation calculated with a slope (Time vs. Fluorescence Units) in the linear region or percent inhibition by the test compounds calculated by the following equation. Inhibition% =. { (v0 -v,) / vo} x100, wherein v0 is a control reaction index (without test compounds) and v, is a reaction index in the presence of the test compound.

IHFR trial? The HEK293 cells so affected with the human gene related to a-go-go ether (HERG) are prepared and cultured internally. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Z.Zhou et al., 1998, Biophysical Journal, 74, 230-241). On the day of experimentation, the cells are harvested from culture flasks and stored as cell suspension in a standard external solution (see the following about its composition). In the ambient atmosphere of 23 ° C. The cells are studied between 0.5-5 hours after harvesting. HERG currents are studied using a standard zonal membrane zonation technique of the whole cell mode. In the course of the experiment, the cells are superfused with a standard external solution of the following composition: (mM) NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole cell logs are made using a zonal membrane clamp amplifier and pipettes for membrane patches which have a resistance of 1-3MOhm when filled with the standard internal solution of the following composition; (mM); KCl, 130; MgATP, 5; MgCl2, 1; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 10 MOhm and seal resistances above 1GOhm are accepted for further experimentation. The series resistance compensation is applied up to a maximum of 80% without any escape subtraction. After achieving complete cell configuration and sufficient time for cell dialysis with pipette solution (> 5 min), the membrane is depolarized from a maintenance potential of -80 mV to + 30mV for 1000 ms, followed by a descending voltage ramp (rate 0.5 mV msec "1) back to the maintenance potential, this depolarization and ramp are applied to the cells continuously every 4 seconds (0.25 Hz).

The amplitude of the peak current produced is measured in response to around -40 mV in the course of the ramp. Once stable current responses evoked from minimal changes in amplitude in the external solution are obtained, the test compound is applied during -20 minutes with multiple dosing in a single cell. The cells are also exposed to a high dose of dofetilide (5 μM), a specific blocker of IKr, to assess the insensitive endogenous current. All experiments are carried out at 23 +/- 1 ° C. The evoked membrane currents are recorded online in a computer, filtered at 500-1000 Hz (Bessel -3dB) and sampled to 1- 2 KHz. The osmolarity and the change in pH induced by the test compound in the external solution will be examined at the highest concentration. The arithmetic mean of these ten values of the peak current is calculated under control conditions and in the presence of the drug. The percentage decrease of lN in each experiment is obtained by the normalized value of the current using the following formula: l N = (lc - I D) / (l e - I_of)? 100, where lc is the average value of the current under control conditions, lD is the average value of the current in the presence of the test compound and ldof is the average value of the current in the application of dofetilide. Separate experiments are performed and the combined data of the arithmetic mean of each experiment are defined as the result of the study.

Rat bioavailability Adult rats of the Sprague-Dawley strain were used. One to two days before the experiments, all rats were prepared by cannula insertion of the right jugular vein under anesthesia. The cannula was exteriorized at the nape of the neck. Blood samples (0.2-0.3 mL) were removed from the jugular vein at intervals up to 24 hours after the intravenous or oral administrations of the test compound. The samples were frozen until analysis. Bioavailability was assessed by calculating the quotient between the area under the plasma concentration curve (AUC) after oral administration or intravenous administration.

Bioavailability in dogs Adult Beagle dogs were used. Blood samples (0.2-0.5 mL) were drawn from the cephalic vein at intervals up to 24 hours after the intravenous or oral administrations of the test compound. The samples were frozen until analysis. Bioavailability was assessed by calculating the quotient between the area under the plasma concentration curve (AUC) after oral administration or intravenous administration.

Plasma protein binding Plasma protein binding of the test compound (1 μM) was measured by the method of equilibrium dialysis using a 96-well plate type equipment. Spectra-Por®, regenerated cellulose membranes (molecular weight cutoff 12,000-14,000, 22 mm x 120 mm) were soaked overnight in distilled water, then for 20 minutes in 30% ethanol, and finally for 15 minutes in dialysis buffer (Dulbecco's phosphate buffered saline solution, pH7.4). The frozen plasma of human, Sprague-Dawley rats and Beagle dogs was used. The dialysis equipment was assembled and 150 μL of compound-fortified plasma was added to one side of each well and 150 μL of dialysis buffer was added to the other side of each well.

After 4 hours of incubation at 37 ° C for 150 r.p.m, aliquots of plasma and buffer were sampled. The compound in the plasma and buffer was extracted with 300 μL of acetonitrile containing internal standard compounds for analysis. The concentration of the compound was determined with the LC / MS / MS analysis. The fraction of the unbound compound was calculated by the following equation: fu = 1 -. { ([plasma] ßq - [buffer] ßq) / ([plasma] ßq)} wherein [plasma] ßq and [buffer] ßq are the concentrations of the compound in plasma and buffer, respectively.

Aqueous Solubility The aqueous solubility in media (a) - (c) was determined by the following method: Whatman mini-UniPrep Chambers (Clifton, NJ, USA) containing more than 0.5 mg of the compound and 0.5 mL of each medium were shaken overnight (for 8 hours) at room temperature. All samples were filtered through a 0.45 μm membrane of difluoride Polyvinylidene (PVDF) in the Whatman mini-UniPrep plunger before analysis. The filtrates were examined by HPLC. < medium > (a) Simulated gastric fluid without enzyme (SGN) at pH 1.2: Dissolve 2.0 g of NaCl in 7.0 mL of 10 M HCl and enough water to make 1000 mL; (b) Saline solution of phosphate buffer (PBS) at pH 6.5: Dissolve 6.35 g of KH2P04, 2.84 g of Na2HP0 and 5.50 g of NaCl in enough water to make 1000 mL, adjust the pH to 6.5; (c) 3.94 mg of sodium taurocholate (NaTC) and 1. 06 mg of 1-palmitoyl-2-oleyl-L-phosphatidylcholine (POPC) in 1 mL of PBS (pH 6.5).

Estimation of hepatic clearance using metabolic stability in human hepatocytes The tested compounds (1 μM) were statically incubated with human hepatocytes at 37 ° C in 95% air / 5% C02 with a target cell density of 0.5 x 106 cells / ml and a total volume of 50 μL. Incubation was stopped at each point in time by the addition of ice cold acetonitrile (ACN). Aliquots of samples were mixed with 10% ACN containing an internal standard for LC / MS / MS analysis. After the samples were sonicated for 10 minutes, the samples were centrifuged at 2,000 rpm for 15 minutes, and then the supernatant was transferred to the other plates for analysis. The concentrations of compounds in the supernatant were measured by the LC / MS / MS system. The disappearance rates of the tested compounds were obtained by plotting the common logarithm of the ratio of the peak area of the compounds / internal standard versus time. The slope of the line of best fit across the points produced the rate of metabolism (kß). This value was scaled to take into account hepatocellularity, liver and body weight to give an intrinsic purification value (CLint) in ml / min / kg as illustrated in Equation 1. Hepatic clearance (CLh) was done before of this intrinsic purification value using the parallel tube model as shown in Equation 2. The predicted depuration divided by the hepatic blood flow (Qh) gave the extraction rate (Eh) (Equation 3). Equation 1: kß x (liver g / kg of body weight) x (ml of incubation / number of cells in incubation) x (cells / g of liver) Equation 2: CLh = Qh x. { 1 - exp (-CL¡n, / Qh)} Equation 3: Eh = CLh / Qh Where, "g of liver weight / kg of body weight" is 21, "Cells / g of liver" is 1.2 x 108, "ml of incubation / number of cells in incubation" is 2.0 x 10'6, and Qh is 20 ml / min / kg. Assume that hepatic metabolism is the main route of drug elimination, systemic exposure (AUCp0) after oral administration is calculated using Equation 4. Equation 4 AUCpo = Dosage x (1-Eh) / CLh Method for examining the phototoxic potential of the compounds: The phototoxic potential was measured in strict accordance with the method described in OECD Guidelines for the Chemical Test 432 (2002). Chlorpromazine (CPZ) and n-Sodium Dodecyl Sulfate (SDS) were used as positive and negative controls, respectively. Balb / 3T3 cells, clone 31 (ATCC, CCL-163) were cultured in 96-well plates (Nunc, 167008) at a density of 1 x 10 4 cells / well. The cells were incubated under a standard condition (37 ° C, a humidified atmosphere of 95% air and 5% C02) within the culture medium-DMEM (GIBCO; cat # 11885-084) for 24 hours. After incubation, the culture medium-DMEM was discarded and the cells were carefully washed with 150 μl of Earle's Balanced Salt Solution (EBSS, Sigma, Cat # E3024), then 100 μl of test compound solution was added. in EBSS or solvent control (the EBSS contained 1% dimethyl sulfoxide or 1% ethanol). The plate was prepared in duplicate. All plates were incubated under the standard condition for 60 min in darkness. One of the duplicate plates was used for cytotoxicity determination (-rr) and kept at room temperature in the dark for 50 min. For the determination of photocytotoxicity (+ lrr), another was exposed to the solar simulator (UVA irradiation: 1. 7mW / cm2; SOL500, Dr. Honle UV Technology, Germany) for 50 min (UVA dose = 5 joules / cm2). Then, the solutions were discarded from the two plates and immediately washed with 150 μl of EBSS carefully. The cells were further incubated with 150 μl / well of DMED medium for 18-22 hr. After incubation, the culture medium was discarded, the cells were carefully washed with 150 μl of EBSS and then immediately incubated with 100 μl / well of 50 μg / ml neutral red (NR) (3-amino-7-d-methylamino-2-methylphenazine hydrochloride, Kanto Chemical Co., Inc., Japan) in DMEM without serum for 3 hours under the standard condition.

After incorporation of neutral red in the cell lysosomes, the NR-DMED medium was discarded and the cells were carefully washed with 150 μl of EBSS. The exact 150μl of ethanol / acetic acid / water (50: 1: 49) was added to each well of the plate and extraction was carried out for 10 minutes by shaking gently at room temperature. Then, the optical density (OD) of the NR extract was measured at 540 nm using a spectrophotometer (Plate reader, POLARstar OPTIMUM; BMG Labtechnologies, Germany). The OD values were used to calculate the mean value of the photoeffect (MPE) using the "3T3 NRU Phototox" software provided by OECD. (Version 2.0, Federal Institute for Risk Assessment, Germany).

The results for the control (CPZ and SDS) were used for the quality control of the assay. The MPE value < 0.1 was evaluated as "no phototoxicity"; the MPE value > 0.1 and < 0.15 was evaluated as "probable phototoxicity" and the MPE value > 0.15 was evaluated as "phototoxicity".

EXAMPLES The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the described invention. Unless otherwise stipulated in the following examples, the general experimental conditions are as follows: all operations were carried out at room or ambient temperature, i.e., in the range of 18-25 ° C; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 ° C; the reactions were monitored by thin layer chromatography (TLC) and the reaction times are given for illustration only; the given melting points (mp) are uncorrected (the polymorphism can result in different melting points); the structure and purity of all the isolated compounds was guaranteed by at least one of the following techniques: TLC (TLC plates precoated with silica gel 60 F25 Merck or TLC plates precoated with NH2 gel (a silica gel coated with amine) Merck F254s ), mass spectrometry, nuclear magnetic resonance (NMR) spectra, infrared absorption (IR) spectra or microanalysis. The returns are given for illustrative purposes only. Flash column chromatography was carried out using Biotage KP-SIL (40-63 μm), Biotage KP-NH (an silica gel coated with amine) (40-75 μM), Fuji Silysia amino gel (30-50 μm) ) or silica gel Wako 300HG (40-60 μM). Microwave reactions were carried out using Personal Chemistry Emrys Optimizer or Biotage Initiator. Preparative TLC was carried out using TLC plates precoated with Merck silica gel 60 F254 (0.5 or 1.0 mm thick). All mass data were obtained in low resolution mass spectral data (ESI) using ZMD ™ or ZQ ™ (Waters) and mass spectrometer. The NMR data is determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (spectrometer JEOL JNM-LA300) using deuterated chloroform (99.8%) or dimethyl sulfoxide (99.9%) as solvent unless otherwise indicated, with respect to tetramethylsilane (TMS) as an internal standard in parts per million (ppm); the conventional abbreviations used are: s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublet, br. = broad, etc. The IR spectra were measured by an infrared Fourier transformation spectrophotometer (Shimazu FTIR-8300). Optical rotations were measured using a JASCO DOP-370 and Digital Polarimeter P-1020 (Japan Spectroscopic CO, Ltd.).

Example 1 4-r (5.7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl- / V.A / .2-trimethyl-1H-benzimidazole-6-carboxamide STEP 1: / V- (4-Bromo-2-nitro-6 - [(phenylmethyl) oxylphenyl) acetamide To a solution of 4-bromo-2-nitro-6 - [(phenylethyl) oxy] aniline ( 33.0 g, 102 mmol, WO 2004054984) and acetic anhydride (14.5 mL, 153 mmol) in acetic acid (90 mL) was added concentrated sulfuric acid (2 drops) at 70 ° C. The mixture was stirred at 70 ° C for 20 minutes. After cooling to room temperature, water (800 mL) was added, and the formed precipitate was collected by filtration and washed with diisopropyl ether to give the title compound as a brown solid (30.9 g, 83%). 1 H NMR (CDCl 3, 270 MHz) d: 7.69 (d, J = 2.0 Hz, 1 H), 7.56 (br. S, 1 H), 7.47-7.38 (m, 5 H), 7.34 (d, J = 2.0 Hz, 1 H), 5.14 (s, 2H), 2.16 (s, 3H) ppm. MS (ESI) m / z: 365 (M + H) \ STAGE 2? - (4-C? Ano-2-n? Tro-6- [(fen? Lmet? L) ox? Lfen? Llacetam? Da A mixture of? / - {4-bromo-2-n ? -6- [(fen? lmet? l) ox?] phenol.] acetamide (6.5 g, 17.8 mmol, STAGE 1), zinc cyanide (418 g, 35.6 mmol) and tetrak? s (tr? phen? lfosfin) paladin (2 06 g, 1.78 mmol) In? /,? / - d? met? lformamide (100 mL) was heated at 170 ° C for 20 minutes in the microwave synthesizer (Biotage, Emrys Optimizer) After cooling to room temperature, the suspension was filtered and washed with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated in vacuum The residual solid was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (3 1) to afford the title compound as a white solid (5 5 g, 99%) 1 H NMR (300 MHz CDCI3l) ) d 7 92 (s, 1 H), 7 83 (s, 1H), 7 53-7 33 (m, 5H), 7 39 (s, 1 H), 21 (s, 2H), 2 21 (s, 3H) ppm MS (ESI) m / z 312 (M + H) \ 310 (M-H) ' STAGE 3 2-Met? L-4 - [(phen? Lmet? L) ox? 1-1 H-benz? M? Dazol-6-carbon? Tr? Lo A mixture of? / -. { 4-c? Ano-2-n? Tro-6 - [(fen? Lmet? L) ox?] Phen? L} acetamido (5 g, 17 7 mmol, STEP 2) and iron powder (2 96 g, 53 mmol) in acetic acid (90 mL) was refluxed with stirring for 2 hours After cooling to room temperature, the mixture was filtered through a pad of Celite. and the filtrate was concentrated in vacuo. The residue was poured into water and the aqueous layer was extracted with ethyl acetate / methanol (20 l). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated vacuum to give the title compound as a brown solid (3 82 g, 82%) 1 H NMR (DMSO-d 6, 300 MHz) d 7 64 (s, 1 H), 7 64-7 27 (m, 6 H), 7.19 (1H). 5 34 (s, 2H), 2 50 (s, 3H) ppm MS (ESI) m / z 264 (M + H) 262 (M-H) STEP 4 Acid 2-met? L-4 - [(fen? Lmet? L) ox? L-1 H -benz? M? Dazole-6-carboxyl? Co A solution of 2-met? L-4 - [(phen ? lmet? l) ox?] - 1 H -benz? m? dazol-6-carbonyl (3 82 g, 14 5 mmol, STAGE 3) and potassium hydroxide (85%, 10 2 g, 15 4 mmol) in ethylene glycol (50 mL) was heated at 170 ° C for 20 minutes on the microwave synthesizer (Biotage, Emrys Optimizer). After cooling to room temperature, the mixture was acidified with 2M hydrochloric acid aqueous solution (pH = 3). The precipitated solid was collected by filtration to give the title compound as a white solid (3.83 g, 93%). 1 H NMR (DMSO-d 6, 270 MHz) d: 12.68 (br. S, 1 H), 7.74 (s, 1 H), 7.64-7.01 (m, 7 H), 5.33 (s, 2H), 2.50 (s, 3H) ppm. MS (ESI) m / z: 283 (M + H) *, 281 (M-H). " STEP 5:? /. A /, 2-Trimethyl-4 - [(phenylmethyloxy-1 / - -benzimidazole-6-carboxamide A mixture of 2-methyl-4 - [(phenylmethyl) oxy] -1 / - - benzimidazole-6-carboxylic acid (5.0 g, 17.7 mmol, STAGE 4), dimethylamine hydrochloride (4.33 g, 53.1 mmol), 2- [1 H-benzotriazol-1-yl] -1, 1, 3,3- hexafluorophosphate tetramethyluronium (10.1 g, 26.6 mmol) and triethylamine (10.7 g, 106 mmol) in? /,? / - dimethylformamide (80 mL) was stirred at room temperature for 1 hour.The mixture was diluted with ethyl acetate / methanol (20 mL). 1) and washed with saturated aqueous ammonium chloride solution The organic layer was dried over magnesium sulfate and concentrated in vacuo The residue was purified by column chromatography on silica gel (gradient elution of ethyl acetate only to ethyl acetate: methanol 5: 1) to afford the title compound as a white solid (4.90 g, 89%). 1 H NMR (CDCl 3, 270 MHz) d: 7.47-7.23 (m, 5 H), 7.20 (s, 1 H), 6.75 (s, 1 H), 5.22 (s, 2 H), 2.95 (br. S, 6 H), 2.54 (s, 3H) ppm (-NH was not observed). MS (ESI) m / z: 310 (M + H) \ 308 (M-H). " STEP 6: / V, /, 2-Trimethyl-1 - [(4-methylphenyl) sulfonyl-4 - [(phenylmethyl) oxy-1H-benzimidazole-6-carboxamide To a suspension of? /,? /, 2-trimethyl -4 - [(Phenylmethyl) oxy] -1H-benzimidazole-6-carboxamide (928 mg, 3.0 mmol, STEP 5) in? /,? / - d.methylformamide (20 mL) was added sodium hydride (60% in mineral oil, 180 mg, 4.50 mmol) at 0 ° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled to 0 ° C. 4-chloride was added to the mixture methylbenzenesulfonyl (572 mg, 3 00 mmol) at 0 ° C and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution of dichloromethane gradients only to ethyl acetate only) to give the title compound as a white solid ( 100 g, 72%) 1 H NMR (CDCl 3, 270 MHz) d 7 80 (d, J = 8 1 Hz, 2 H), 7 70 (s, 1 H), 7 45 (d, J = 8 1 Hz, 2H), 7 40-7 22 (m, 5H), 6 86 (s, 1H), 5 32 (s, 2H), 3 11 (br s, 3H), 2 89 (br s, 3H), 2 81 (s, 3H), 2 40 (s, 3H) ppm MS (ESI) m / z 464 (M + H) + STAGE 7 4-H? Drox? -?,? /, 2-tr? Met? L-1-f (4-met? Lfen? L) sulfon? Ll-1 H -benz? Dazole-6-carboxam? A mixture of? /, v, 2-tr? met? l-1 - [(4-met? lfen? l) sulfon? l] -4 - [(phen? lmet? l) ox?] - 1 - / -benz? m? dazol-6-carboxamide (350 mg, 0 756 mmol, STAGE 6) and 20% palladium hydroxide (1 20 g) in acetic acid (20 mL) was stirred under hydrogen gas (4). atmospheres) for 4 hours. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution of ethyl acetate only to ethyl acetate methanol 5 1) to afford the title compound as a white solid (131 mg, 36%) 1 H NMR (CDCl 3, 270 MHz) d 7 82 (d, J = 8 1 Hz, 2 H), 7 63 (s, 1 H), 7 31 (d , J = 8 1 Hz, 2H), 6 92 (s, 1H), 3 14 (br s, 3H), 3 01 (br s, 3H), 2 79 (s, 3H), 2 40 (s, 3H) ppm (-OH not observed) MS (ESI) m / z 374 (M + H) \ 372 (MH) STEP 8 4 - [(5.7-D? Fluoro-3,4-d? H? Dro-2H-chromen-4? L) ox? L -? /.? /. 2-tpmet? L-1-f (4 - met? lfen? l) sulfon? p-1H-benz? m? dazol-6-carboxam? da STAGE 8-1 5,7-D? fluoro-3,4-d? h? dro-2H-chromen- 4-ol To a solution of 5,7-d? Fluoro-2,3-d? -hydro-4H-chromen-4-one (14 2 g, 77 0 mmol, US 20050038032) in methanol (200 mL) was added sodium borohydride (3.50 g, 92.5 mmol) to 0 ° C. The reaction mixture was stirred at the same temperature for 1 hour and evaporated to remove the methanol. The residue was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 1 as eluent) to afford the title compound as a pale gray solid (9.64 g, 67%). 1 H NMR (CDCl 3, 270 MHz) d: 6.47-6.36 (m, 2H), 5.05-4.97 (m, 1 H), 4.36-4.20 (m, 2H), 2.16-1.92 (m, 3H) ppm.

STEP 8-2: 4-f (5.7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl -? /.? .2-trimethyl-1-((4-methylphenyl) sulfonyl-1 / - / - benzimidazole-6-carboxamide To a stirred mixture of 4-hydroxy -? /,? /, 2-trimethyl-1 - [(4- methylphenyl) sulfonyl] -1 / - / - benzimidazole-6-carboxamide (110 mg, 0.294 mmol, STAGE 7), 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (164 mg, 0.884 mmol, STEP 8-1) and triphenylphosphine (232 mg, 0.884 mmol) in toluene (5 mL) was added diisopropyl azodicarboxylate (DIAD) (179 mg, 0.884 mmol) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution ethyl acetate: hexane from 1: 20 to 10: 1) to give a mixture of the title compound and triphenylphosphine oxide (280 mg, unpurified) as white solids, which were used in the next step without further purification. 1 H NMR (CDCl 3, 270 MHz) d: 7.81 (d, J = 8.1 Hz, 2 H), 7.51 (s, 1 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.07 (s, 1 H), 6.54. -6.22 (m, 2H), 5.93 (br. S, 1H), 4.40 (t, J = 10.8 Hz, 1H), 4.27 (t, J = 10.8 Hz, 1 H), 3.15 (br. S, 3H) , 3.03 (br. S, 3H), 2.79 (s, 3H), 2.39 (s, 3H), 2.40-2.21 (m, 1 H), 2.19-1.73 (m, 1H) ppm. MS (ESI) m / z: 542 (M + H) \ 540 (M-H) '.

STAGE 9: 4-α (5,7-D-fluoro-3,4-dihydro-2H-chromen-4-yl) oxy-1-γ / γ-γ-2-trimethyl-1H-benzimidazole-6-carboxamide To a solution of 4 - [(5J-d.fluoro-3,4-dihydro-2H-chromen-4-yl) oxy] - / v, / V, 2-trimethyl-1 - [(4-methylphenyl) - sulfonyl] -1H-benzimidazole-6-carboxamide (280 mg, unpurified, STAGE 8) in tetrahydrofuran (8 mL) and methanol (4 mL) was added sodium hydroxide (165 mg, 4.1 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution of dichloromethane gradients only to ethyl acetate: methanol 10: 1) to give the title compound as a white solid (74 mg, 65% for 2 steps). 1 H NMR (CDCl 3, 270 MHz) d: 7.27 (s, 1 H), 6.95 (s, 1 H), 6.51-6.33 (m, 2 H), 5.87-5.69 (m, 1H), 4.41-4.25 (m, 2H), 3.10 (br. S, 6H), 2.56 (s, 3H), 2.44-2.34 (m, 1 H), 2.14-1.98 (m, 1 H) ppm (- NH was not observed). MS (ESI) m / z: 388 (M + H) +, 386 (M-H) '.

Example 2 (-) - 4 - [((4S) -5,7-D-fluoro-3,4-dihydro-2 H -chromen-4-yl) oxy] -? / ,? , 2-trimethyl-1H-benzimidazole-6-carboxamide and Example 3 (+) - 4-r ((4?) - 5,7-Difluoro-3,4-d, hydroxy-2-yl-chromen-4-yl) oxyl- /V.?/.2-trimethyl-1H- benzimidazole-6-carboxamide Example 2 Fraction-1 (582 mg) and fraction-2 (562 mg) were prepared from 4- [(5J-difluoro-3,4-dihydro-2 / - / - chromen-4-yl) oxy] -? / l, 2,4-trimethyl-1 / - / - benzimidazole-6-carboxamide racemic (1.63 g, STAGE 9 in Example 1) by HPLC as follows. Insulation condition Column: CHIRALCEL OJ-H (20 mm x 250 mm, DAICEL) Mobile phase: n-Hexane / Ethanol / Diethylamine (95/5 / 0.1) Flow rate: 18.9 mL / min (-) - 4-i ((4S) -5,7-Difluoro-3,4-dihydro-2 H -chromen-4-yl) oxyl-, rV, 2-trimethyl-1H-benzimidazole-6-carboxamide (fraction-1) 1H NMR: the spectra data were identical with those of the optical rotation racemate: [a] D23 = -101.1 ° (c = 1.00, Methanol) retention time: 14 min (- * -) - 4-í ((4f?) - 5.7 -Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-? ,? , 2-trimethyl-1H-benzimidazole-6-carboxamide (fraction-2) 1H NMR: the spectral data were identical with those of the racemate optical rotation: [a] D23 = +104.2 ° (c = 1.00, Methanol) time retention: 18 min. The following is the alternative method to synthesize (-) - 4 - [((4S) -5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -? / , V, 2-trimethyl-1 / - / - benzyl | dazol-6-carboxamide. STEP 1: 6-Bromo-2-methyl-4 - [(phenylmethyl) oxyl-1 / - / - benzimidazole A mixture of? / -. { 4-bromo-2-nitro-6 - [(phenylmethyl) oxy] phenyl} acetamide (120 g, 329 mmol, STEP 1 in Example 1) and iron powder (55.1 g, 986 mmol) in acetic acid (500 mL) was refluxed with stirring for 6 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (1.5 L). The resulting precipitates were filtered through a pad of Celite and washed with ethyl acetate (500 mL). The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate (200 mL). The brine (800 mL) was added to the organic mixture, the resulting white precipitates were collected by filtration and washed with water (200 mL) and diethyl ether (200 mL). The white solid was dissolved with dichloromethane / methanol (10: 1, 1.0 L), dried over magnesium sulfate and concentrated. The solid was triturated with diethyl ether (300 mL), collected by filtration and dried in vacuo to give the title compound as a white solid (54.7 g, 53%). 1 H NMR (DMSO- / ß 270 MHz) d: 7.63-7.28 (m, 7H), 5.38 (s, 2H), 2.69 (s, 3H) ppm. (NH was not observed.) MS (ESI) m / z: 317 (M + H) \ 315 (M-H) ".

STEP 2: 6-Bromo-2-methyl-1-f (4-methylphenyl) sulfonyl-4-y (phenylmethyl) oxyl-1H-benzimidazole To a suspension of 6-bromo-2-methyl-4 - [(phenylmethyl) oxy] -1H-benzimidazole (79.2 g, 250 mmol, STAGE 1) in? /,? / - dimethylformamide (500 mL) was added sodium hydride (60% in mineral oil, 12.0 g, 300 mmol) at 0 ° C. After stirring at room temperature for 20 minutes, the reaction mixture was cooled to 0 ° C. To the mixture was added 4-methylbenzenesulfonyl chloride (47.6 g, 250 mmol) at 0 ° C and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water (800 mL) and the white precipitates were collected by filtration, washed with diisopropyl ether (500 mL) and dried in vacuo at 70 ° C for 7 hours to give the title compound as a white solid ( 116 g, 98%). H NMR (DMSO-d6, 270 MHz) d: 7.98 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 1.9 Hz, 1 H), 7.53- 7.34 (m, 7H), 7.22 (d, J = 1.9 Hz, 1 H), 5.28 (s, 2H), 2.74 (s, 3H), 2.38 (s, 3H) ppm. MS (ESI) m / z: 471 (M + H) \ 469 (M-H). " STEP 3: V,? 2-Trimethyl-1-f (4-methylphenyl) sulfonin-4-y (phenylmethyl) oxyl-1H-benzimidazole-6-carboxamide A mixture of 6-bromo-2-methyl-1- [ (4-methylphenyl) sulfonyl] -4 - [(phenylmethyl) oxy] -1H-benzimidazole (53.0 g, 112 mmol, STAGE 2) and tetrakis (triphenylphosphine) palladium (0) (25.9 g, 22.4 mmol) in dimethylamine solution - 2M tetrahydrofuran (580 mL) was stirred at 65 ° C under carbon monoxide gas (1 atmosphere) for 32 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (600 mL). The organic mixture was washed with an aqueous solution of saturated ammonium (800 mL) and brine (500 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution of hexane: ethyl acetate from 1: 2 to 1: 3) to give the title compound as a white solid (21.8 g, 42%). 1H NMR: Spectra data were identical with STAGE 6 in Example 1.

STEP 4: 4-Hydroxy - ?, A /, 2-trimethyl-1-f (4-methylphenyl) sulfonyl1-1 - / - benzimidazole-6-carboxamide A mixture of? /,? /, 2-trimetyl- 1 - [(4-methylphenyl) sulfonyl] -4 - [(phenylmethyl) oxy] -1- -benzimidazole-6-carboxamide (29.0 g, 62.6 mmol, STAGE 3) and 10% palladium on carbon (6.0 g ) in tetrahydrofuran (200 mL) was stirred under hydrogen gas (1 atmosphere) at room temperature for 24 hours. Another 4.0 g of 10% palladium on carbon was added and the mixture was stirred under hydrogen gas (1 atmosphere) at room temperature for an additional 6 hours. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give the title compound as a white solid (23.0 g, 98%). 1 H NMR: the spectrum data were identical with STEP 7 in Example 1.

STEP 5: 3- (3,5-Difluorophenoxy) methyl acrylate A solution of 3,5-difluorophenol (35.5 g, 273 mmol) and methyl propiolate (25.0 mL, 300 mmol) in acetonitrile (109 mL) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (commercial solution 1.0 M, 109 mL, 109 mmol) at room temperature over a period of 2 hours. After finishing the addition of the solution, the mixture was stirred for 1 hour. The reaction mixture was diluted with toluene (350 mL) and the organic mixture was washed twice with water (250 mL x 2), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on amino gel (hexane: ethyl acetate = 3: 2 as eluent) to afford the title compound as a yellow solid (60.0 g, quant, 1: 1 mixture of cis- and trans isomers) -). 1 H NMR (CDCl 3, 270 MHz,) d: 7.72 (d, J = 10.8 Hz, 0.5 H), 6.83 (d, J = 5.4 Hz, 0.5 H), 6.74- 6.49 (m, 3 H), 5.68 (d, J = 10.8 Hz, 0.5H), 5.28 (d, J = 5.4 Hz, 0.5H), 3.76 (s, 3H) ppm.

STAGE 6 3- (3,5- Difluorophenoxy) methyl propanoate A mixture of methyl 3- (3,5-difluorophenoxy) acrylate (60.0 g, 280 mmol, STAGE 5) and 10% palladium on carbon (1.0 g) in methanol (300 mL) was stirred under hydrogen gas (1 atmosphere) at room temperature for 18 hours. The reaction mixture was filtered through a pad of Celite and washed with toluene (100 mL). The filtrate was concentrated in vacuo to give the title compound (61.0 g, quant) as a colorless oil, which was used in the next step without further purification. 1 H NMR (CDCl 3, 270 MHz) d: 6.56-6.21 (m, 3 H), 4.21 (t, J = 5.4 Hz, 2 H), 3.74 (s, 3 H), 2. 80 (t, J = 5.4 Hz, 2H) ppm.

STEP 7: 5,7-Difluoro-2,3-dihydro-4 / - / - chromen-4-one A mixture of methyl 3- (3,5-difluorophenoxy) propanoate (11.6 g, 53.7 mmol, STAGE 6) and trifluoromethanesulfonic acid (23.2 mL, 2.0 mL / g of substrate) was stirred at 80 ° C for 2 hours.

After cooling to room temperature, the reaction mixture was diluted with water (120 mL), and extracted with toluene (120 mL). The organic layer was washed successively with aqueous potassium carbonate solution (50 mL), water (50 mL) and dried over magnesium sulfate. The organic mixture was concentrated in vacuo to provide the title compound (8.75 g, 88%) as a white solid, which was used in the next step without further purification. 1 H NMR (CDCl 3l 270 MHz) d: 6.51-6.40 (m, 2H), 4.55-4.50 (m, 2H), 2.86-2.75 (m, 2H) ppm.

STEP 8: (+) - 5,7-Difluoro-3,4-dihydro-2H-chromen-4-ol To a mixture of (S) -tetrahydro-1-methyl-3,3-diphenyl-1H solution, 3 H-pyrrolo [1, 2- c] [1,3,2] oxazaborol-toluene 1 M (5.43 mL, 5.43 mmol) and tetrahydrofuran (40 mL) was added borane-methyl sulfide-tetrahydrofuran complex solution 2M (29.8 mL, 59.7 mmol) at 0 ° C and the mixture was stirred for 20 minutes. To the mixture was added a solution of 5,7-d.fluoro-2,3-dihydro-4H-chromen-4-one (10.0 g, 54.3 mmol, STAGE 7) in tetrahydrofuran (70 mL) at 0 ° C for a period of 1 hour and the mixture was stirred at the same temperature for 1 hour. The mixture of The reaction was quenched with methanol (50 mL) and stirred for 30 minutes at room temperature. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 4: 1 as eluent) to give white solids without purification (8.85 g, 86% ee). The solids were recrystallized from hexane (300 mL) to give the title compound as a colorless acicular crystal (5.90 g, 58%, > 99% ee). 1 H NMR: the spectral data were identical with those of the racemate (STEP 8-1 in Example 1). Optical rotation: [a] D24 = +143.6 ° (c = 1.00, Methanol).

STEP 9: (-) - 4-r ((4S) -5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl -? /.? /. 2-trimethyl-1- [ (4-methylphenyl) sulfonyl1-1 / - / - benzimidazole-6-carboxamide To a stirred mixture of 4-hydroxy-? ,? /, 2-trimethyl-1 - [(4-methylphenyl) sulfonyl] -1H-benzimidazole-6-carboxamide (21.2 g, 56.8 mmol, STAGE 4), (+) - 5,7-d-fluoro-3 , 4-dihydro-2H-chromen-4-ol (15.86 g, 85.1 mmol, STAGE 8) and tributylphosphine (22.9 g, 113 mmol) in toluene (840 mL) was added 1.1% - (azodicarbonyl) ) dipiperidine (ADDP) (19.3 g, 76.5 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (300 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution of ethyl acetate: hexane from 1: 20 to 20: 1) to give unpurified solids (27.0 g). The solids were recrystallized from 2-propanol (130 mL) to give the title compound as a colorless crystal (23.2 g, 75%, > 99% ee) 1 H NMR: the spectrum data were identical with those of the racemate (STEP 8-2 in Example 1). Optical rotation: [a] D24 = -80.4 ° (c = 0.50, Methanol).

STEP 10: (-) - 4-r ((4S) -5.7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl -? /.? /. 2-trimethyl-1-fluoxy-6-carboxamide To a solution of (-) - 4 - [((4S) -5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] - / V, / V, 2-tr Methyl-1- [(4-methylphenyl) -sulfonyl] -1H-benzimidazole-6-carboxamide (24.2 g, 44.7 mmol, STAGE 9) in tetrahydrofuran (65 mL) and 2-propanol (220 mL) was added aqueous sodium hydroxide solution 2M (220 mL, 440 mmol) at room temperature. After stirring at room temperature for 4 hours, the mixture was diluted with ethyl acetate (1.20 L) and washed with saturated aqueous solution of ammonium chloride (500 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on amino gel (gradient elution of ethyl acetate: methanol from 50: 1 to 20: 1) to afford the title compound as a white solid (15.2 g, 87%, > 99 % ee). H NMR: the spectral data were identical with those of the racemate (STAGE 9 in Example 1). The optical rotation and retention time were identical with the previous.

Example 4 4-r (5.7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1W-benzimidazole STAGE 1: methyl 2-methyl-4-f (phenylmethyl) oxy-1H-benzimidazole-6-carboxylate A mixture of 2-methyl-4 - [(phenylmethyl) oxy] -1H-benzimidazole-6-acid carboxylic acid (10.0 g, 35.4 mmol, STAGE 4 in Example 1) and thionyl chloride (5.2 mL, 7.1 mmol) in methanol (300 mL) was stirred at 80 ° C for 3 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was diluted with methanol, filtered to remove the precipitate and the The filtrate was concentrated in vacuo. The resulting solid was washed with dichloromethane to give the title compound as a brown solid (29.8 g, unpurified), which was used in the next step without further purification. MS (ESI) m / z: 297 (M + H) +, 295 (M-H). " STEP 2: 2-Methyl-4 - [(phenylmethyl) oxyl-1H-benzimidazole-1- (1,1-dimethylethyl) -6-methyl-dicarboxylate A mixture of 2-methyl-4 - [(phenylmethyl) oxy] -1H methyl-benzimidazole-6-carboxylate (29.8 g, unpurified, STAGE 1), di-tert-butyl-dicarbonate (69 g, 315 mmol), 4-dimethylaminopyridine (366 mg, 3.0 mmol) and triethylamine (100 mL, 717 mmol) in? /,? / - dimethylformamide (100 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution of ethyl acetate: hexane gradients from 1: 20 to 3: 2) to give the title compound (12.1 g, unpurified) as a white solid, which it was used in the next step without further purification. 1 H NMR (CDCl 3, 270 MHz) d: 8.29 (s, 1 H), 7.54 (s, 1 H), 7.60-7.50 (m, 2 H), 7.40-7.31 (m 3 H), 5.37 (s, 2 H), 3.92 (s, 3H), 2.86 (s, 3H), 1.73 (s, 9H) ppm. MS (ESI) m / z: 397 (M + H) +.

STAGE 3: 4-Hydroxy-2-methyl-1H-benzimidazole-1,6-dicarboxylate of 1 -M. 1 -dimethylethyl .6-methyl A mixture of 2-methyl-4 - [(phenylmethyl) oxy] 1- (1,1-dimethylethyl) -6-methyl-1H-benzimidazole-1,6-dicarboxylate (12.1 g, unpurified, STAGE 2) and 20% palladium hydroxide (6.0 g) in tetrahydrofuran (250 mL) it was stirred under hydrogen gas for 2 hours. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was washed with hexane / diethylether (10: 1) to give the title compound as a white solid (3.02 g, 28% for 3 steps). 1 H NMR (CDCl 3, 270 MHz) d: 10.38 (br. S, 1 H), 8.21 (s, 1 H), 7.62 (s, 1 H), 3.94 (s, 3 H), 2. 87 (s, 3H), 1.73 (s, 9H) ppm. MS (ESI) m / z: 307 (M + H) +, 305 (M-H). " STEP 4: 4 - [(5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-2-methyl-1H-benzimidazole-6-carboxylic acid To a stirred mixture of 4-hydroxy-2- 1- (1,1-dimethyl-ethyl) -6-methyl-methyl-1H-benzimidazol-1,6-dicarboxylate (1.50 g, 4.90 mmol, STAGE 3), 5,7-d, fluoro-3,4-dih Dro-2H-chromen-4-ol (1.82 g, 9.79 mmol, STAGE 8-1 in Example 1) and triphenylphosphine (2.57 g, 9.79 mmol) in toluene (50 mL) was added diisopropyl azodicarboxylate (DIAD) ( 1.98 g, 4.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and tetrahydrofuran (5 mL) and an aqueous solution of 4M lithium hydroxide (20 mL, 80 mmol) was added to the mixture at room temperature. After stirring for 4 hours at 80 ° C, the reaction mixture was concentrated in vacuo. The residue was dissolved with water, washed with ethyl acetate and acidified (pH = 6) with 2M hydrochloric acid aqueous solution. The precipitated solid was filtered and dried in vacuo to give the title compound as a white solid (1.67 g, unpurified), which was used in the next step without further purification. 1 H NMR (DMSO-d 6, 270 MHz) d: 7.76 (s, 1 H), 7.51 (s, 1 H), 6.79 (t, J = 10.8 Hz, 1 H), 6.66 (t, J = 10.8 Hz, 1 H), 5.99 (br. S, 1 H), 4.39-4.17 (m, 2H), 2.46 (s, 3H), 2.28-2.05 (m, 2H) ppm (-COOH and -NH were not observed). MS (ESI) m / z: 361 (M + H)? 359 (M-H) '.

STEP 5: 4 - [(5J-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole The title compound was prepared as a solid white (70 mg, 56% yield for 3 steps) from 4 - [(5J-difluoro-3,4-dihydro-2 - / - chromen-4-yl) oxy] -2-methyl-1 / - / - benzimidazole-. 6-carboxylic acid (100 mg, unpurified, STAGE 4) and pyrrolidine (59 mg, 0.832 mmol) in the same manner as in STEP 5 of Example 1. 1 H NMR (CDCl 3, 270 MHz) d: 7.33 (s, 1 H), 7.03 (s, 1 H), 6.47-6.07 (m, 2 H), 5.90-66 (m, 1 H), 4.40-4.18 (m, 2H), 3.73-3.40 (m, 4H), 2.48 (s, 3H), 2.37-2.22 (m, 1 H), 2.11-1.78 (m, H) ppm (-NH was not observed). MS (ESI) m / z: 414 (M + H) \ 412 (M-H). " Example 5 (+) - 4 - [(5,7-D-Fluoro-3,4-dihydro-2 H -chromen-4-yl) oxy] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) - 1 H - benzimidazole and Example 6 (-) - 4-r (5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxy-2-methyl-6- (pyrrolidin-1-ylcarbonyl) - 1H-benzim Dazol Fraction-1 (152 mg) and fraction-2 (146 mg) were prepared from 4 - [(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] - Racemic 2-methyl-6- (pyrrolidin-1-ylcarbonyl) -l 7-benzamidazole (0.35 g, STEP 5 in Example 4) by HPLC as follows. Insulation condition Column: CHIRALPAK AD-H (20 mm x 250 mm, DAICEL) Mobile phase: n-Hexane / iso-Propanol / Diethylamine (85/15 / 0.1) Flow rate: 20 mL / min (+) - 4 - [(5J-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxy-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole (fraction-1) 1H NMR: the data of spectra were identical with those of the racemate optical rotation: [ct] D23 = +105.0 ° (c = 0.50, Methanol) retention time: 12 min (-) - 4 - [(5J-Difluoro-3,4-dihydro-2H- chromen-4-yl) oxy1-2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole (fraction-2) 1H NMR: the spectral data were identical with those of the optical rotation racemate: [a] D23 = -106.5"(c = 0.50, Methanol) retention time: 14 min Example 7 4-r (5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-rV- (2-hydroxyethyl) -? /, 2-dimethyl-1H-benzimidazole-6-carboxamide The title compound was prepared as a white solid (50 mg, 40% yield for 3 steps) from 4 - [(5J-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -2-methyl-1 / -benzimidazole-6-carboxylic acid (100 mg, unpurified, STAGE 4 in Example 4) and 2- (methylamino) ethanol (63 mg, 0.83 mmol) in the same manner as in the PHASE 5 of Example 1. 1 H NMR (CDCl 3 270 MHz) d: 6.91 (br. S, 2H), 6.49-6.23 (m, 2H), 5.88-5.65 (m, 1H), 4.37-4.11 (m, 2H), 3.99-3.60 (m, 3H), 3.07 (s, 3H), 2.41 (s, 3H), 2.36-2.17 (m, 1 H), 2.08-1.89 (m, 2H) ppm (-OH and -NH) observed). MS (ESI) m / z: 418 (M + H) *, 416 (M-H). " EXAMPLE 8 4-r (5,7-Difluoro-3,4-dihydro-2 H -chromen-4-yl) oxyl-α / - r 2 - (dimethylamino) ethyl-N 2 -dimethyl-1 H -benzimidazole-6 carboxamide The title compound was prepared as a white solid (10 mg, 13% yield for 3 steps) from 4 - [(5J-difluoro-3,4-dihydro-2 / - / - chromen-4-yl) ) oxy] -2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, unpurified, STAGE 4 in Example 4) and / V,? /, / v "-trimethyl-1,2-ethanediamine (45 mg , 0.44 mmol) in the same manner as in STEP 5 of Example 1. 1 H NMR (CDCl 3 270 MHz) d: 7.27 (s, 1 H), 6.94 (s, 1 H), 6.50-6.31 (m, 2 H), 5.76 (br. s, 1H), 4.44-4.24 (m, 2H), 3.76-3.32 (m, 2H), 3.09 (s, 3H), 2.56 (s, 3H), 2.61-1.94 (m, 10H) ppm ( -NH was not observed.) MS (ESI) m / z: 445 (M + H) +, 443 (MH). " Example 9 4-f (5-Fluoro-3,4-dihydro-2 H -chromen-4-yl) oxy-JV, / V, 2-trimethyl-1H-benzylmidazole-6-carboxamide STEP 1: 6-r (Dimethylamino) carbonip-2-methyl-4-f (phenylmethyl) oxyl-1H-benzimidazole-1-carboxylate 1,1-dimethylethyl The title compound was prepared as a white solid in 67% yield (5.68 g) from α /, / /, 2-trimethyl-4 - [(phenylmethyl) oxy] -1 - / - benzimidazole-6-carboxamide (6.4 g, 20.7 mmol, STAGE 5 in Example 1) and di-tert-butyl-dicarbonate (6.77 g, 31.0 mmol) in the same manner as in STEP 2 of Example 4. 1 H NMR (CDCl 3 270 MHz) d: 7.64 (s, 1 H), 7.47 (d, J = 8.1 Hz, 2H), 7.38-7.28 (m, 3H), 6.83 (s, 1H), 5.38 (s, 2H), 2.97 (br. S, 6H), 2.83 (s, 3H), 1.69 (s, 9H) ppm; MS (ESI) m / z: 410 (M + H) +.

STEP 2: 6 - [(Dimethylamino) carbonyl 1-4-hydroxy-2-methyl-1 H-benzimidazole-1-carboxylate 1,1-dimethylethyl The title compound was prepared as a white solid in 92% yield (4.10). g) from 6 - [(dimethylamino) carbonyl] -2-methyl-4 - [(phenylmethyl) oxy] -1H-benzamidazol-1-carboxylate 1,1-dimethylethyl (5.68 g, 13.9 mmol, STEP 1) and 20% palladium hydroxide (2.4 g) in the same manner as in STEP 3 of Example 4. 1 H NMR (CDCl 3 270 MHz) d: 10.39 (s, 1 H), 7.56 (s, 1 H), 6.97 (s, 1H), 3.13 (br. S, 3H), 3.04 (br.s, 3H), 2.82 (s, 3H), 1.69 (s, 9H) ppm. MS (ESI) m / z: 320 (M + H) \ 318 (M-H). " STEP 3: 4 - [(5-Fluoro-3,4-dihydro-2 / - / - chromen-4-yl) oxyl -? / ./ .. 2-trimethyl-1H-benzimidazole-6-carboxamide STAGE 3-1: 5-Fluoro-3,4-dihydro-2H-chromen-4-ol The title compound was prepared as a black oil in quantitative yield (0.9 g) from 5-fluoro-2,3-dihydro-4 / - / -chromen-4-one (0.9 g, 5 mmol, GB 2355264) in the same manner as in STEP 8-1 of Example 1. 1 H NMR (CDCl 3, 300 MHz) d: 7.25-7.11 (m, 1H) , 6.75-6.60 (m, 2H), 5.13-5.02 (m, 1H), 4.40-4.18 (m, 2H), 2.25-1.95 (m, 3H) ppm.

STEP 3-2: 4-r (5-Fluoro-3,4-dihydro-2H-chromen-4-yl) oxyl -? /.? /. 2-trimethyl-1H-benzamidazole-6-carboxamide A stirring mixture of 6-f (dimethylamino) carbonyl-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester (1.00 g, 3.13 mmol, STAGE 2), 5-fluoro-3 , 4-dihydro-2H-chromen-4-ol (948 mg, 5.64 mmol, STEP 3-1) and triphenylphosphine (2.57 g, 9.79 mmol) in toluene (50 mL) was added diisopropyl azodicarboxylate (DIAD) (1.98 g, 4.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue is dissolved in tetrahydrofuran (30 mL) and methanol (15 mL) and sodium hydroxide (750 mg, 18.8 mmol) was added to the mixture at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane only then ethyl acetate: methanol 10: 1 as eluent) to afford the title compound as a white solid (510 mg, 50%). 1 H NMR (CDCl 3, 270 MHz) d: 7.20-7.11 (m, 1 H), 7.13 (s, 1 H), 6.90 (s, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 6.52 ( d, J = 8.1 Hz, 1H), 5.76 (br. s, 1H), 4.28-4.07 (m, 2H), 3.04 (br. s, 6H), 2.38 (s, 3H), 2.29-2.18 (m, 1 H), 2.04-1.90 (m, 1 H) ppm (-NH was not observed). MS (ESI) m / z: 370 (M + H) +, 368 (M-H) '.

Example 10 (-) - 4 - [(5-Fluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -iV, W, 2-trimethyl-1H-benzimidazole-6-carboxamide and Example 11 (+) - 4-r (5-Fluoro-3,4-dihydro-2H-chromen-4-yl) oxy-A /,? /, 2-trimethyl-1H-benzimidazole-6-carboxamide Fraction-1 (126 mg) and fraction-2 (114 mg) were prepared from 4 - [(5-fluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -? /, 1, 2-trimethyl-1H racemic-benzimidazole-6-carboxamide (510 mg, STEP 3-2 in Example 9) by HPLC as follows. Insulation condition Column: CHIRALCEL OJ-H (20 mm x 250 mm, DAICEL) Mobile phase: n-Hexane / Ethanol / Diethylamine (90/10 / 0.1) Flow rate: 20.0 mL / min (-) - 4- [ (5-Fluoro-3,4-dihydro-2H-chromen-4-yl) oxp-v, / V, 2-trimethyl-1H-benzimidazole-6-carboxamide (fruct-1) 1H NMR: the spectral data were identical with those of the racemate optical rotation: [a] D23 = -106.8 ° (c = 0.50, Methanol) retention time: 7 min (+) - 4 - [(5-Fluoro-3,4-dihydro-2H-chromen-4-yl) oxy1-? .A /, 2-trimethyl-1H-benzimidazole-6-carboxamide (frustration-2) 1H NMR: the spectral data were identical with those of the racemate optical rotation: [a] D23 = +103.6 '(c = 0.50, methanol ) retention time: 9 min Example 12 4- (3,4-Dihydro-2-chromen-4-yloxy) - / V./V.2-trimethyl-1H-benzimidazole-6-carboxamide The title compound was prepared as a white solid (58 mg, 53% yield for 2 steps) from 6-r (dimethylamino) carbonyl-4-hydroxy-2-methyl-1 - / - benzimidazole-1-carboxylate. of 1,1-dimethylethyl (100 mg, 0.313 mmol, STAGE 2 in Example 9) and 3,4-dihydro-2H-chromen-4-ol (141 mg, 0.939 mmol) in the same manner as in STEP 3 -2 of Example 9: 1 H NMR (CDCl 3, 270 MHz) d: 7.22-7.12 (m, 3H), 6.90-6.75 (m, 3H), 5.62-5.57 (m, 1H), 4.29-4.08 (m, 2H ), 3.12-2.95 (m, 6H), 2.40 (s, 3H), 2.28-2.07 (m, 2H) ppm (-NH was not observed). MS (ESI) m / z: 352 (M + H) +, 350 (M-H) '.

EXAMPLE 13 4-R (8-Fluoro-5-methyl-3,4-dihydro-2H-chromen-4-yl) oxy-A / .A / .2-trimethyl-1H-benzimidazole-6-carboxamide STEP 1: 8-Fluoro-5-methylchroman-4-ol STAGE 1-1: 3- (2-Fluoro-5-methylphenoxy) propanoic acid To a solution of sodium hydroxide (3.2 g, 79 mmol) in water (16 mL) was added 2-fluoro-5-methylphenol (5.0 g, 40 mmol) at room temperature. After the solution was stirred for 5 minutes, 3-iodopropionic acid (7.9 g, 40 mmol) was added to the pale yellow solution and the mixture was refluxed with stirring for 18 hours. The mixture was cooled to room temperature, poured into 2M hydrochloric acid aqueous solution (100 mL) at 0 ° C and extracted with ethyl acetate (60 mL x2). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution of hexane / ethyl acetate 3: 1 to ethyl acetate only). The resulting pale yellow solid was triturated with hexane, collected by filtration and dried in vacuo to give the title compound as a pale yellow solid (2.45 g, 31%). 1 H NMR (CDCl 3, 270 MHz) d: 6.95 (dd, J = 11.2, 8.6 Hz, 1 H), 6.81 (dd, J = 7.9, 2.0 Hz, 1 H), 6.75-6.66 (m, 1H), 4.30 (t, J = 6.6 Hz, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.30 (s, 3H) ppm. (-OH was not observed.) STAGE 1-2: 8-Fluoro-5-methyl-2,3-dihydro-4H-chromen-4-one A mixture of 3- (2-fluoro-5-methylphenoxy) propanoic acid (2.45 g, 12.4 mmol, STAGE 1-1) in polyphosphoric acid (35 g) was stirred at 100 ° C for 2 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x2). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (2.30 g, quant.). 1 H NMR (CDCl 3, 270 MHz) d: 7.15 (dd, J = 9.9, 8.6 Hz, 1H), 6.73 (dd, J = 8.6, 5.3 Hz, 1 H), 4. 59 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.59 (s, 3H) ppm.

STEP 1-3: 8-Fluoro-5-methylchroman-4-ol The title compound was prepared as a white solid in 93% yield (2.16 g) from 8-fluoro-5-methyl-2,3- dihydro-4H-chromen-4-one (2.30 g, 12.8 mmol, STAGE 1-2) in the same manner as in STEP 8-1 of Example 1. 1 H NMR (CDCl 3, 270 MHz) d: 6.94 (dd, J = 11.2, 7.9 Hz, 1H), 6.68 (dd, J = 7.9, 4.6 Hz, 1H), 4.90-4.82 (m, 1 H), 4.47-4.36 (m, 1 H), 4.30-4.17 (m, 1 H), 2.38 (s, 3H) 2.15-2.00 (m, 2H) 1.85-1.75 (m, 1H) ppm.

STEP 2: 4 - [(8-Fluoro-5-methyl-3,4-dihydro-2H-chromen-4-yl) oxyl -? /, / V, 2-trimethyl-1H-benzimidazole-6-carboxamide The compound of the title was prepared as a white solid in 32% yield (38 mg) from 6 - [(dimethylamino) carbonyl 1-4-hydroxy-2-methyl-1 H-benzimidazole-1-carboxylate 1,1-dimethylethyl (100 mg, 0.31 mmol, STAGE 2 in Example 9) and 8-fluoro-5-methylchroman-4-ol (0.23 g, 1.2 mmol, STAGE 1-3) in the same manner as in STAGE 3-2 of the Example 9: 1 H NMR (CDCl 3, 270 MHz) d: 9.61 (br.s, 1 H), 7.45-7.22 (m, 1 H), 7.08-6.90 (m, 2H), 6.75-6.60 (m, 1H) , 5.70-5.50 (m, 1H), 4.43-4.05 (m, 2H), 3.11 (br. S, 6H), 2.55 (s, 3H) 2.50-2.33 (m, 1H), 2.28-2.05 (m, 1 H), 2.20 (s, 3H) ppm. MS (ESI) m / z: 384 (M + H)? 382 (M-H). " Example 14 4-r (5.8-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxy-1 /? .2-trimethyl-1H-benzimidazole-6-carboxamide STEP 1: 5,8-Difluorochroman-4-ol STAGE 1-1: 3- (2,5-Difluorophenoxy) propanoic acid The title compound was prepared as a white solid in 37% yield (4.6 g) from 2,5-difluorophenol (8.0 g, 61 mmol) in the same manner as in STAGE 1-1 of Example 13. 1 H NMR (CDCl 3, 300 MHz) d: 7.10-6.95 (m, 1 H), 6.80-6.68 ( m, 1H), 6.67-6.55 (m, 1H), 4.29 (t, J = 6.3 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H) ppm. (-OH was not observed.) STEP 1-2: 5.8-Difluoro-2,3-dihydro-4H-chromen-4-one The title compound was prepared as a brown oil in 91% yield (3.8 g) from 3- (2.5-) acid. difluorophenoxy) pro-anoic (4.6 g, 23 mmol, STAGE 1-1) in the same manner as in STEP 1-2 of Example 13. 1 H NMR (CDCl 3, 270 MHz) d: 7.30-7.18 (m, 1 H ), 6.72-6.60 (m, 1H), 4.65 (t, J = 6.3 Hz, 2H), 2.87 (t, J = 6.3 Hz, 2H) ppm.

STEP 1-3: 5,8-Difluorochroman-4-ol The title compound was prepared as a brown oil in 91% yield (3.3 g) from 5,8-difluoro-2,3-dihydro-4H- chromen-4-one (3.8 g, 21 mmol, STAGE 1-2) in the same manner as in STAGE 8-1 of Example 1. 1 H NMR (CDCl 3, 270 MHz) d: 7.05-6.93 (m, 1H) , 6.62-6.52 (m, 1H), 5.10-5.02 (m, 1H), 4. 47-4.38 (m, 1 H), 4.35-4.23 (m, 1 H), 2.33-2.03 (m, 3H) ppm. STEP 2: 4-α (5.8-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl -? /.? /. 2-trimethyl-1 H-benzimidazole-6-carboxamide The title compound was prepared as a white solid in 48% yield (87 mg) from 6-α- (dimethylamino) carbonin-4-hydroxy-2-methyl-1 / - / - benzimidazole-1-carboxylate. 1,1-dimethylethyl (150 mg, 0.47 mmol, STAGE 2 in Example 9) and 5,8-difluorochroman-4-ol (0.26 g, 1.4 mmol, STAGE 1-3) in the same manner as in STAGE 3 -2 of Example 9: 1 H NMR (CDCl 3, 270 MHz) d: 7.33-7.18 (, 1H), 7.08-6.90 (m, 2H), 6.58-6.48 (m, 1H), 5.90-5.75 (m, 1 H ), 4.45-4.30 (m, 2H), 3.12 (br. S, 3H), 3.06 (br. S, 3H), 2.52 (s, 3H) 2.44-2.34 (m, 1H), 2.18-2.00 (m, 1H) ppm (-NH was not observed.). MS (ESI) m / z: 388 (M + H) +, 386 (M-H). " The following Examples 15 to 21 were prepared according to the procedure described in Example 22 (.). 6- (Azetidin-1-ylcarbonyl) -4-r (5,7-difluoro-3,4-dihydro-2 H -chromen-4-yl) oxyl-2-methyl-H-benzimidazole active STEP 1: (-) - 4-f (5J-Difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-2-methyl-1H-benzimidazole-6-carboxylic acid To a stirred mixture of 4-hydroxy- 2-Methylene-1 / - / - benzamidozol-1,6-dicarboxylic acid 1- (1,1-dimethylethyl) -methyl ester (1.33 g, 4.34 mmol, STAGE 3 in Example 4) ), (+) - 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (1.82 g, 9.79 mmol, STAGE 8 in Example 2) and triphenylphosphine (2.28 g, 8.69 mmol) in toluene (50 mL) was added diisopropyl azodicarboxylate (DIAD) (1.76 g, 8.70 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and tetrahydrofuran (5 mL) and an aqueous solution of 4M lithium hydroxide (18 mL, 90.0 mmol) was added to the mixture at room temperature. ambient. After stirring for 1 hour at 80 ° C, the reaction mixture was concentrated in vacuo. The residue was dissolved with water (200 mL), acidified with 2M hydrochloric acid aqueous solution (50 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution of ethyl acetate only to ethyl acetate: methanol with 1% by weight of acetic acid = 3: 1) to afford the title compound as a white solid. (1.15 g, 73%, > 99% ee). 1 H NMR: the spectral data were identical with those of the racemate (STAGE 4 in Example 4). Optical rotation: [a] D24 = -78.7 '(c = 0.50, methanol).

STEP 2: (-) - 6- (Azetidin-1-ylcarbonyl) -4 - [(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) oxyl-2-methyl-1 H-benzimidazole The title compound was prepared as a white solid (132 mg, 79%) from (-) - 4 - [(5,7-difluoro-3,4-dihydro-2 - / - chromen-4-yl) oxy] -2-methy1-1H-benzimidazole-6-carboxylic acid (150 mg, STAGE 1) and azetidine hydrochloride (117 mg, 1.25 mmol) in the same manner as in STAGE 5 of the Example 1. 1 H NMR (CDCl 3, 270 MHz) d: 7.40 (s, 1 H), 7.20 (s, 1 H), 6.42-6.25 (m, 2 H), 5.87-5.62 (m, 1 H), 4.46-3.94 (m, 6H), 2.51 (s, 3H), 2.42-2.19 (m, 3H), 2.19-1.78 (m, 1H) ppm (-NH was not observed). MS (ESI) m / z: 400 (M + H)? 398 (M-H) '. Optical rotation: [a] D24 = -98.0 ° (c = 1.00, Methanol).

The following Examples 23 and 24 were prepared from (-) - 4 - [(5,7-difluoro-3,4-dihydro-2 - / - chromen-4-yl) oxy] -2-methyl-1 acid / - / - Bepcimidazole-6-carboxylic acid (Stage 1 in the Example 22) and the various corresponding amines according to the procedure described in Step 5 of Example 1.

The following Example 25 was prepared according to the procedure described in Example 1.

All publications, including but not limited to, patents filed, patent applications and journal articles, cited in this application are each incorporated herein by reference in their entirety. Although the invention has been described in the foregoing with reference to the embodiments described, those skilled in the art will readily appreciate that specific detailed experiments are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims (9)

1. CLAIMS 1. A compound of the formula (I): or a pharmaceutically acceptable salt thereof, or prodrug thereof, wherein; -A-B- represents -0-CH2-, -S-CH2-, -CH2-0- or -CH2-S-; X represents an oxygen atom or NH; R represents an alkyl group of 1 to 6 carbon atoms which is unsubstituted or is substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and an alkoxy group of 1 to 6 carbon atoms; R2 and R3 independently represent a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms or a heteroaryl group, the alkyl group of 1 to 6 carbon atoms, the cycloalkyl group from 3 to 7 carbon atoms and the heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, a group cycloalkyl of 3 to 7 carbon atoms, an amino group, an alkylamino group of 1 to 6 carbon atoms and a di (alkyl of 1 to 6 carbon atoms) amino group; or R2 and R3 taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group which is unsubstituted or is substituted with 1 to 2 substituents selected from the group consisting of a hydroxy group, an alkyl group from 1 to 6 carbon atoms, an acyl group of 1 to 6 carbon atoms and a hydroxy-alkyl group of 1 to 6 carbon atoms;
2. R, R, R and R independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms; and R8 represents a hydrogen atom, a hydroxy group or an alkoxy group of 1 to 6 carbon atoms. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that X is an oxygen atom; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms, the alkyl group of 1 to 6 carbon atoms and the cycloalkyl group of 3 to 7 carbon atoms are not substituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms and a di ( alkyl of 1 to 6 carbon atoms) amino; or R2 and
3. R3 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a piperazinyl group or a morpholino group, the azetidinyl group, the pyrrolidinyl group, the piperazinyl group and the morpholino group are unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, an alkyl group of 1 to 6 carbon atoms, an acyl group of 1 to 6 carbon atoms and a hydroxy-alkyl group of 1 to 6 carbon atoms; R4, R5, R6 and R7 are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R8 is a hydrogen atom. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that -A-B- is -0-CH2- or -CH2-0-; X is an oxygen atom; R1 is an alkyl group of 1 to 6 carbon atoms; R2 and R3 are independently an alkyl group of 1 to 6 carbon atoms which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group which consists of a hydroxy group and an alkoxy group of 1 to 6 carbon atoms and; or R2 and R taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group which is unsubstituted or substituted by a substituent selected from the group consisting of a hydroxy group, an alkyl group of 1 to 6 carbon atoms and a hydroxy alkyl group of 1 to 6 carbon atoms; R, R, R and R are independently a hydrogen atom, a halogen atom or an alkyl group of 1 to 6 carbon atoms; and R is a hydrogen atom.
4. 4. The compound according to claim 1, characterized in that it is selected from: 4 - [(5J-difluoro-3,4-dihydro-2W-chromen-4-yl) oxy] - / V,? /, 2- trimethyl-1H-benzimidazole-6-carboxamide; 4 - [(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1- -benzimidazole; 4 - [(5-fluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -? /,? /, 2-trimethyl-1 / - -benzimidazole-6-carboxamide; or an acceptable pharmaceutical salt thereof. 5. The compound according to claim 1, characterized in that it is selected from: (-) - 4 - [((4S) -5J-difluoro-3,4-dihydro-2H-chromen-4-yl) oxy] -? /, / V, 2-trimethyl-1H-benzamidazole-6-carboxamide; (-) - 4 - [(5,7-difluoro-3,4-dihydro-2 / - / - chromen-4-yl) oxy] -2-methyl-6- (pyrrolidin-1-ylcarbonyl) -1H - benzimidazole; (-). 4 - [(5.flUoro-3,4-dihydro-2H-chromen-4-yl) oxy] -? /,? /, 2-trimethyl-1H-benzimidazole-6-carboxamide; or an acceptable pharmaceutical salt thereof. 6. A pharmaceutical composition characterized in that it comprises the compound or pharmaceutically acceptable salt thereof according to any of the claims 1 to 5, and a pharmaceutically acceptable carrier. 7. The pharmaceutical composition according to claim 6, further characterized in that it comprises another or other pharmacologically active agents. A method of treating a condition mediated by an inhibitory activity of the pump for acid in a mammalian subject, including a human, characterized in that it comprises administering, to a mammal in need of such treatment, a therapeutically effective amount of the compound or The pharmaceutically acceptable salt according to any one of claims 1 to
5. 5. The method according to claim 8, characterized in that the condition is gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcer, gastric ulcer, duodenal ulcer, ulcers induced by NSAID, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, cancer, gastric acidity, nausea , esophagitis, dysphagia, hypersalivation, respiratory tract disorders asthma or asthma.