WO2007031860A1

WO2007031860A1 - Indane substituted benzimidazoles and their use as acid pump inhibitors

Info

Publication number: WO2007031860A1
Application number: PCT/IB2006/002553
Authority: WO
Inventors: Takeshi Hanazawa; Hiroki Koike; Sachiko Sakakibara
Original assignee: Pfizer Japan Inc.; Pfizer Inc.
Priority date: 2005-09-15
Filing date: 2006-09-08
Publication date: 2007-03-22

Abstract

This invention relates to compounds of the formula (I): a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein: A, X, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each as described herein 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 antagonisitic 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, hypersalivation, airway disorders or asthma.

Description

INDANE SUBSTITUTED BENZIMIDAZOLES AND THEIR USE AS ACID PUMP INHIBITORS

Background of the Invention

This invention relates to indane substituted benzimidazole derivatives. These compounds have selective acid pump inhibitory activity. 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 acid pump modulating activity; in particular acid pump inhibitory activity.

It has been well established that proton pump inhibitors (PPIs) are prodrugs that undergo an acid-catalyzed chemical rearrangement that permits them to inhibit H⁺/K⁺-ATPase by covalently biding to its Cystein residues(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, acid pump antagonists inhibit acid secretion via reversible potassium-competitive inhibition of H⁺/K⁺-ATPase. SCH28080 is one of such reversible inhibitors and has been studied extensively. Other newer agents (revaprazan, soraprazan, AZD-0865 and CS-526) have entered in clinical trials confirming their efficacy in human (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 found to be useful for the treatment of a variety of diseases, including gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, non-steroidal anti-inflammatory drug(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, hypersalivation, airway disorders or asthma(hereinafter, referred as "APA Diseases", Kiljander, Toni O, American Journal of Medicine, 2003, 115(Suppl. 3A), 65S-71S.).

WO04/054984 discloses some compounds, such as indan-1-yl oxy benzimidazole derivatives, as acid pump antagonists. There is a need to provide new acid pump antagonists that are good drug candidates and address unmet needs by PPIs for treating diseases. In particular, preferred compounds should bind potently to the acid pump whilst showing little affinity for other receptors and show functional activity as inhibitors of acid-secretion in stomach. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic. Furthermore, 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 found out that the new class of compounds having an indan-2-yl moiety show acid pump inhibitory activity and good bioavailability as drug candidates, and thus are useful for the treatment of disease conditions mediated by acid pump inhibitory activity such as APA Diseases.

The present invention provides a compound of the following formula (I):

a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein: -A- represents -CH₂- or -CH₂-CH₂-; X represents an oxygen atom or NH;

R¹ represents a hydrogen atom or a C₁-C₆ alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and a C₁-C₆ alkoxy group;

R² represents a C₁-C₆ alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and a C_rC₆ alkoxy group; R³ and R⁴ independently represent a hydrogen atom or, a C₁-C₆ alkyl or a C₃-C₇ cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C₁-C₆ alkoxy group and a C₃-C₇ cycloalkyl group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ acyl group, and a hydroxy Ci-C₆ alkyl group;

R R⁵⁵ rreepprresents a hydrogen atom, a hydroxy group, a C₁-C₆ alkyl group or a C₁-C₆ alkoxy group; and

R⁶, R⁷, R⁸ and R⁹ independently represent a hydrogen atom or a halogen atom.

Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound.

Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, further comprising other pharmacologically active agent(s).

Also, the present invention provides a method of treatment of a condition mediated by acid pump inhibitory activity, 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 acid pump inhibitory activity include, but are not limited to,

APA Diseases.

Further, the present invention provides the use of a compound of 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 acid pump inhibitory activity.

Preferably, the present invention also provides the use of a compound of 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 APA Diseases.

The compounds of the present invention may show good bioavailability, less toxicity, good absorption, distribution, good solubility, less protein binding affinity other than acid pump, 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 and R⁵ are the C₁-C₆ alkyl group, this C₁-C₆ alkyl group may be a straight or branched chain group having one to four carbon atoms, and examples include, but are not limited to, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, pentyl, 1-ethylpropyl and hexyl. Of these, C₁-C₂ alkyl is preferred and methyl is more preferred for R¹, R², R⁴ and R⁵; C_rC₃ alkyl is preferred and methyl and ethyl are more preferred for R³.

Where R³ and R⁴ are the C₃-C₇ cycloalkyl group, this represents cycloalkyl group having three to seven carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Of these, C₃-C₅ cycloalkyl group is preferred; cyclopropyl is more preferred. Where R⁵ and the substituents of R¹, R², R³ and R⁴ are the C₁-C₆ alkoxy group, this represents the oxygen atom substituted with the said C₁-C₆ alkyl group, and examples include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, n-butoxy, isobutoxy, sec-butoxy and terf-butoxy, pentyloxy and hexyloxy. Of these, a C₁-C₂ alkoxy is preferred; methoxy is more preferred.

Where R³ and R⁴ taken together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic group, this 4 to 6 membered heterocyclic group represents a saturated heterocyclic group having three to five ring atoms selected from carbon atom, nitrogen atom, sulfur atom and oxgen atom other than the said nitrogen atom, and examples include, but are not limited to, a azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino,. Of these, azetidinyl, a prrolidinyl and piperazinyl group are preferred. Where the substituent of the 4 to 6 membered heterocyclic group is the hydroxy C₁-C₆ alkyl group, this represents the said Ci-C₆ alkyl group substituted with a hydroxy group, and examples include, but are not limited to, a hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybuthyl, 3-hydroxybuthyl, 2-hydroxybuthyl, 3-hydroxy-2-methtlpropyl, 3-hydroxy-1-methylpropyl, 5-hydroxypentyl and 6-hydroxyhexyl group. Of these, a hydroxy C₁-C₂ alky group is preferred; a hydroxymethyl group is more preferred.

Where the substituent of the 4 to 6 membered heterocyclic group is the C₁-C₆ acyl group, this represents a carbonyl group substituted with the said C₁-C₆ alkyl group, and examples include, but are not limited to, a formyl, acetyl, propionyl, butyryl, pentanoyl and hexanoyl group. Of these, an acetyl group is preferred. Where R⁶, R⁷, R⁸, R⁹ and the substituent of R³ and R⁴ are the halogen atom, they may be a fluorine, chlorine, bromine or iodine atom. Of these, a fluorine atom and a chlorine atom are preferred. 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 term applies, or one or more symptoms of such disorder or condition.

Prodrug of the compound of formula (I) refers to certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs may 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).

The prodrug can be readily prepared from the compounds of formula (I) using methods known in the art. See, e.g. See Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309- 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3):165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1 , pp. 172-178, 949-982 (1995).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

In particular, prodrug of the compound of formula (I) means a compound replaced a hydroxy group(s) thereof with a moiety convertible in vivo into a hydroxy group or a compound replaced a hydrogen atom of R¹ with a substituted sulfonyl moiety.

Further explanation of prodrugs in accordance with the invention as follows: (i) where the compound of formula (I) contains one or more hydroxy group(s), a prodrug of the compound of formula (I) means a compound wherein the hydroxy group(s) is replaced with a moiety convertible in vivo into the hydroxy group.

(ii) where R¹ is a hydrogen atom, a prodrug of the compound of formula (I) means a compound wherein the hydrogen binding to the nitrogen atom at the 1 -position on the benzimidazole ring of the compound of formula (I) is replaced by a substituted sulfonyl moiety.

Where the "moiety convertible in vivo into a hydroxy group" means a moiety transformable in vivo by e.g. hydrolysis and/or by an enzyme, e.g. an esterase into a hydroxyl group. Examples of the moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo. Such moieties have known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Preferred moieties convertible in vivo into a hydroxyl group are e.g. C₁-C₆ alkyl carbonyl oxy group and C₁-C₆ alkyl carbonyl oxy methyl oxy group.

Where the "substituted sulfonyl moiety" means a moiety cleavable between a nitrogen atom at

1 -position on the benzimidazole ring and sulfur atom in vivo. Preferred is a phenyl sulfonyl moiety being substituted with 1 to 4 substituents independently selected from the group consisting of a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a carboxy group, a carboxy C₁-C₆ alkyl group and a carboxy C₁-C₆ alkyl oxy group, and the preparation methods to induce them into the benzimidazole structure are described in WO 04/09583.

Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Preferred class of compounds of the present invention are those compounds of formula (I) or pharmaceutically acceptable salts thereof, each as described herein, in which:

(a) -A- is -CH₂- or -CH₂-CH₂-;

(b) A- Is -CH₂-;

(c) X is an oxygen atom; (d) R¹ is a hydrogen atom or a C₁-C₆ alkyl group;

(e) R¹ is a hydrogen atom or a C₁-C₂ alkyl group;

(f) R¹ is a hydrogen atom or a methyl group;

(g) R¹ is a methyl group;

(h) R² is a C₁-C₆ alkyl group; (i) R² is a C₁-C₂ alkyl group; 0) R² is a methyl group; (k) R³ is a C₁-C₆ alkyl group being unsubstituted or substituted with one substituent selected from the group consisting of a hydroxy group and a C₁-C₆ alkoxy group; (I) R³ is a C₁-C₃ alkyl group being unsubstituted or substituted with a hydroxy group; (m) R³ is a methyl group, an ethyl group, 2-hydroxyethyl group, a 2-hydroxypropyl group or a

2-methoxyethyl group;

(n) R⁴ is a hydrogen atom or a C_rC₆ alkyl group; (o) R⁴ is a C₁-C₂ alkyl group; (p) R⁴ is a methyl group; (q) R³ and R⁴ taken together with the nitrogen atom to which they are attached form a azetidinyl, a pyrrolidinyl or a piperazinyl group being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ acyl group and a hydroxy C₁-C₆ alkyl group;

(r) R³ and R⁴ taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group and a hydroxy C₁-C₂ alkyl group;

(s) R³ and R⁴ taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group and a 2-hydroxyethyl group; (t) R⁵ is a hydrogen atom or a hydroxy group; (u) R⁵ is a hydrogen atom; (v) R⁶ is a hydrogen atom or halogen atom; (w) R⁶ is a hydrogen atom; (x) R⁷ is a hydrogen atom or a halogen atom; (y) R⁷ is a hydrogen atom, a chlorine atom or a fluorine atom; (z) R⁷ is a hydrogen atom or a fluorine atom; (aa)R⁸ is a hydrogen atom or a halogen atom; (bb)R⁸ is a hydrogen atom, a chlorine atom or a fluorine atom; (cc)R⁸ is a hydrogen atom or a fluorine atom; (dd)R⁹ is a hydrogen atom or halogen atom; (ee)R⁹ is a hydrogen atom;

Of these classes of compounds, any combination among (a) to (ee) is also preferred.

Preferred compounds of the present invention are those compounds of formula (I) or pharmaceutically acceptable salts thereof, each as described herein, in which:

(A) -A- is -CH₂- or -CH₂-CH₂-; X is an oxygen atom; R¹ is a hydrogen atom or a C₁-C₆ alkyl group; R² is a Ci-C₆ alkyl group; R³ and R⁴ are independently a C₁-C₆ alkyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group and a C₁-C₆ alkoxy group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form an azetidinyl, a pyrrolidinyl or a piperazinyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ acyl group and a hydroxy C₁-C₆ alkyl group; R⁵ is a hydrogen atom or a hydroxy group; and R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom or a halogen atom;

(B) -A- is -CH₂-; X is an oxygen atom; R¹ is a hydrogen atom or methyl group; R², R³ and R⁴ are a methyl group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form an azetidinyl or a pyrrolidinyl group being unsubstituted or substituted with a hydroxy C₁-C₂ alkyl group; R⁵, R⁶ and R⁹ are a hydrogen atom; and R⁷ and R⁸ are independently a hydrogen atom or a halogen atom;

(C) -A- is -CH₂- or -CH₂-CH₂-; X is an oxygen atom; R¹ is a hydrogen atom or a C₁-C₂ alkyl group; R² is a C₁-C₂ alkyl group; R³ is a Ci-C₃ alkyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group and a C₁-C₂ alkoxy group; R⁴ is a C₁-C₂ alkyl group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form an azetidinyl, a pyrrolidinyl or a piperazinyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C₁-C₂ alkyl group, a C₁-C₂ acyl group and a hydroxy C₁-C₂ alkyl group; R⁵ is a hydrogen atom, a hydroxy group, a C₁-C₂ alkyl group or a C₁-C₂ alkoxy group; and R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom or a halogen atom; (D) -A- is -CH₂-; X is an oxygen atom; R¹ is a hydrogen atom or methyl group; R² and R⁴ are a methyl group; R³ is a C_rC₂ alkyl group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form an azetidinyl, a pyrrolidinyl group; R⁵ is a hydrogen atom or a hydroxy group; R⁶ and R⁹ are a hydrogen atom; and R⁷ and R⁸ are independently a hydrogen atom or a halogen atom;

(E) -A- is -CH₂- or -CH₂-CH₂-; X is an oxygen atom; R¹ is a hydrogen atom or a C₁-C₂ alkyl group; R² is a C_rC₂ alkyl group; R³ is a C₁-C₃ alkyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group and a C₁-C₂ alkoxy group; R⁴ is a C₁-C₂ alkyl group; R⁵ is a hydrogen atom or a hydroxy group; and R⁶, R⁷, R⁸ and R⁹ are independently a hydrogen atom or a halogen atom;

(F) -A- is -CH₂-; X is an oxygen atom; R¹ is a hydrogen atom or methyl group; R², R⁴ are a methyl group; R³ is a C₁-C₂ alkyl group; R⁵ is a hydrogen atom or a hydroxy group; R⁶ and R⁹ are a hydrogen atom; and R⁷ and R⁸ are independently a hydrogen atom or a halogen atom; One embodiment of the invention provides a compound selected from the group consisting of: 4-(2,3-Dihydro-1 H-inden-2-yloxy)-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide; 4-(2,3-Dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-6-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole; 4-(2,3-Dihydro-1H-inden-2-yloxy)-Λ/,Λ/,2-trimethyl-1H-benzimidazole-6-carboxamide; 4-[(5-Fluoro-2,3-dihydro-1 H-inden-2-yl)oxy]-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide; or a pharmaceutically acceptable salt thereof.

A compound of formula (I) or a prodrug thereof may form an acid addition salt (including disalts). When a compound of formula (I) is a prodrug having carboxy group, it may form a base salt thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Also included are acid addition salts wherein the counterion is optically active, for example,

D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

The base addition salts include alkali metal salts, for example lithium salts, sodium salts and potassium salts; alkaline earth metal salts, for example calcium salts and magnesium salts; ammonium salts; organic base salts, for example triethylamine salts, diisopropylamine salts and cyclohexylamine salts; and the like. Preferred salts are alkali metal salts and more preferred salts are sodium salts.

For a review on 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 formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

Pharmaceutically acceptable salts of the compounds of fomula (I) or the prodrugs 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 employed when said solvent is water.

Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci. 64 (8), 1269-1288 by Haleblian (August 1975).

The compounds of 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 formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.

Included within the scope of the present invention are all stereoisomers of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having 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 isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. 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, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of 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 accompanying examples and preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

All of the compounds of the formula (I) can be prepared by the procedures described in the general methods presented below 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 formula (I), in addition to any novel intermediates used therein.

General Synthesis

The compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following Method A.

Unless otherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, A and X in the following methods are as defined above.

Method A This illustrates the preparation of compounds of formula (Ia) wherein X is an oxygen atom. Reaction Scheme A

In Reaction Scheme A, R

^1a is R¹ as defined above or R¹ wherein hydroxy group is protected by a hydroxy-protecting group; R^2a is R² as defined above or R² wherein hydroxy group is protected by a hydroxy-protecting group; R^3a is R³ as defined above or R³ wherein hydroxy group is protected by a hydroxy-protecting group; R^4a is R⁴ as defined above or R⁴ wherein hydroxy group is protected by a hydroxy-protecting group; R^5a is R⁵ as defined above or R⁵ wherein hydroxy group is protected by a hydroxy-protecting group; and the same shall apply hereinafter.

The term "hydroxy-protecting groups", as used herein, signifies a protecting group capable of being cleaved by various means to yield a hydroxy group, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such hydroxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). Such as for example, Ci-C₄ alkoxycarbonyl, C₁-C₄ alkylcarbonyl, W-C₁-C₄ alkylsilyl or tri-C_rC₄ alkylarylsilyl groups, and C₁-C₄ alkoxy- C₁-C₄ alkyl groups. Suitable hydroxy-protecting groups include acetyl and terf-butyldimethylsilyl.

(Step A-1)

In this step, the compound (Ia) is prepared by ether formation reaction of the compound of formula (Ha), which is commercially available or may be prepared by the methods described in WO 04/054984, with the compound (III), which is commercially available or may be prepared by the method as described in the following Method F or as described in Synthesis 595 (1983).

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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; 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 likewise no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type may equally be used here. Examples of such condensing agents include: azodicarboxylic acid di-lower alkyl esters, such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and di-fe/f-butyl azodicarboxylate (DTAD); azodicarboxamides, such as N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), 1 ,1'-(azodicarbonyl)dipiperidine (ADDP) and N,N,N',N'-tetramethylazodicarboxamide (TMAD); phosphoranes, such as

(cyanomethylene)tributylphosphorane (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 these, triphenylphosphine or tributylphosphine is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 120⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 48 hours, will usually suffice.

Introduction of the hydroxy-protecting group

In the case where R¹, R², R³, R⁴ or R⁵ has a hydroxy group, if necessary, the reaction may be accomplished after protecting the hydroxy group, before the reaction affected by the hydroxy group. The introduction of the hydroxy-protecting group can be carried out at an appropriate step. This reaction is described in detail by T. W. Greene et al., Protective Groups in Organic Synthesis, 369-453, (1999), the disclosures of which are incorporated herein by reference. The following exemplifies a typical reaction involving the protecting group fert-butyldimetylsisyl. For example, when the hydroxy-protecting group is a " te/f-butyldimetylsilyl ", this step is conducted by reacting with a desired hydroxy- protecting group halide in an inert solvent in the presence of a base.

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, tetrahydrofuran or N,N-dimethylformamide is preferred.

Examples of the hydroxy-protecting group halide usable in the above reaction include trimethylsilyl chloride, triethylsilyl chloride, terf-butyldimethylsilyl chloride, tert-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 triethylamine, tributylamine, N- methylmorpholine, pyridine, imidazole, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Out of these, triethylamine, imidazole, or pyridine is preferred. Upon use of an organic amine in the liquid form, it also serves as a solvent when used in large excess.

Although the reaction temperature differs with the nature of the starting compound, the halide and the solvent, it usually ranges from 0⁰C to 80°C (preferably 0 to 30°C). Although the reaction time differs with the reaction temperature or the like, it ranges from 10 minutes to 2 days (preferably 30 minutes to 1 day). Deprotecting step

In the case where R^1a, R^2a, R^3a, R^4a or R^5a has a protected hydroxy group, the deprotection reaction will follow to yield a hydroxy group. This reaction is described in detail by T. W. Greene et al., Protective Groups in Organic Synthesis, 369-453, (1999), the disclosures of which are incorporated herein by reference. The following exemplifies a typical reaction involving the protecting group terf-butyldimetylsisyl.

The deprotection of the hydroxyl groups is carried out with an acid, such as acetic acid, hydrogen fluoride, hydrogen fluoride-pyridine complex, or fluoride ion, such as tetrabutylammonium fluoride (TBAF). The deprotection reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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 deprotection reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 100⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 24 hours, will usually suffice.

Method B This illustrates the preparation of compounds of formula (Ia) wherein X is an oxygen atom.

Reaction Scheme B

In Reaction Scheme B, R^a is a carboxy-protecting group. The term "carboxy-protecting group", as used herein, signifies a protecting group capable of being cleaved by various means to yield a carboxy group, such as for example, a Ci-C₆ alkyl group, halo C₁-C₆ alkyl group or aryl C₁-C₆ alkyl group. Of these, a C₁-C₆ alkyl group and an aryl C₁-C₆ alkyl group are preferred.

(Step B-l)

In this step, the compound (V) is prepared by ether formation reaction of the compound of formula (IV), which is commercially available or may be prepared by the methods described in WO

04/054984, with the compound (III), which is commercially available, may be prepared by the method described in the following Method F or described in Synthesis 595(1983). The reaction may be carried out under the same condition as described in Step A1 of Method A.

(Step B2)

In this step, the compound (Vl) is prepared by hydrolysis of the ester group of the compound of formula (V) with a base or an acid.

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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, N,N-dimethylformamide, 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; water; or mixed solvents thereof. Of these solvents, methanol, ethanol or tetrahydrofuran is preferred.

The reaction may be carried out in the 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 may 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 reaction may be carried out in the presence of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally 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 range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 120⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 24 hours, will usually suffice. (Step B3)

In this step, the compound (Ia) is prepared by amidation of the compound of formula (Vl) with the compound of formula (VII), which is commercially available or described in J. Org. Chem., 5935 (1990) and Canadian Journal of Chemistry, 2028 (1993). If the compound of formula (Vl) and/or (VII) has hydroxy-protecting groups, the deprotection reaction described in Method A will be applied in an appropriate step.

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve reagents, at least to some extent. 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-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 is preferred.

The reaction is carried out in the 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 may equally be used here. Examples of such bases include: amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(terf-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, DBN, 1 ,4-diazabicyclo[2.2.2]octane (DABCO) and DBU. Of these, triethylamine or diisopropylethylamine is preferred.

The reaction is carried out in the presence of a condensing agent. There is likewise no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type may equally be used here. Examples of such condensing agents include: 2-halo-1 -lower alkyl pyridinium halides, such as 2-chloro-1-methy pyridinium iodide and 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP); diarylphosphorylazides, such as diphenylphosphorylazide (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 Λ/,Λ/'-dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI); iminium salts, such as 2-(1/-/-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU) and tetramethyl fluoroformamidinium hexafluoro phosphate (TFFH); and phosphonium salts, such as benzotriazol-1-yloxytris(dimethylamino)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), may be employed for this step. Of these, HOBt is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 48 hours, will usually suffice.

Method C

This illustrates the preparation of compounds of formula (Ia) wherein X is an oxygen atom. Reaction Scheme C

In Reaction scheme C, Hal is a halogen atom and the same shall apply hereinafter.

(Step CI )

In this step, the compound of formula (IX) is prepared by ether formation reaction of the compound of formula (III) which is commercially available or may be prepared by the method as described in the following Method F or described in Synthesis 595 (1983) with the compound of formula (VIII), which is commercially available. The reaction may be carried out under the same condition as described in Step A1 of Method A.

(Step C2)

In this step, the compound of formula (X) is prepared by halogenation to the benzene ring of the compound of formula (IX).

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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, acetonitrile is preferred.

The reaction is carried out in the presence of a halogenating agent. There is likewise no particular restriction on the nature of the halogenating agents used, and any halogenating agent commonly used in reactions of this type may equally be used here. Examples of such halogenating agents include: succinimides, such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS); bromine. Of these, NBS is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 100⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours will usually suffice.

(Step C3)

In this step, the compound of formula (XII) is prepared by amide formation of the amino group of the compound of formula (X) with acid anhydride (Xl).

Λ/,Λ/-dimethylformamide, Λ/,Λ/-dimethylacetamide and hexamethylphosphoric triamide; Of these solvents, the reaction in the absence of solventis preferred.

The reaction is carried out in the presence or absence 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 may equally be used here. Examples of such bases include: amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(terf-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, DBN, DABCO and DBU. Of these, the reaction in the absence of base is preferred.

(Step C4)

In this step, the compound of formula (XIII) is prepared by substitution of the halogen atom of the compound of formula (XII) with metal cyanide.

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: aliphatic hydrocarbons, such as 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, Λ/,Λ/-dimethylformamide, Λ/,Λ/-dimethylacetamide, 1-methylpyrrolidin-2-one and hexamethyl phosphoric triamide; Of these solvents, A/,Λ/-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 may equally be used here. Examples of such metal cyanide reagents include: zinc(ll) cyanide, copper(l) cyanide, potassium cyanide and sodium cyanide; Of these, zinc(ll) cyanide 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 may equally be used here. Examples of such palladium catalysts include: a palladium metal, palladium chloride, palladium (II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, allyl palladium chloride,

[1 ,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)pa!ladium dichloride, tetrakis(triphenylphosphine) palladium, dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium, or a catalyst produced in solution by adding a ligand into the reaction solution of these. The ligand added into the reaction solution may be a phosphoric ligand such as triphenylphosphine, 1 ,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl) ether, 2,2'-bis(diphenylphosphino)-1 ,1^l-binaphthol, 1 ,3-bis(diphenylphosphino)propane,

1 ,4-bis(diphenylphosphino)butane, tri-o-toluylphosphine, 2-diphenylphosphino-2'-methoxy-1 ,1'-binaphthyl or 2,2- bis (diphenylphosphino)-1 ,1'-binaphthyl. Of these, tetrakis(triphenylphosphine) palladium is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 50⁰C to about 150⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours will usually suffice.

In this reaction, microwave can be employed to accelerate the reaction. In the case of employing microwave in sealed tube, the reaction at a temperature may be from about 50⁰C to about 180⁰C and the reaction time from about 5 minutes to about 12 hours will usually suffice.

(Step C5)

In this step, the compound of formula (XIV) is prepared by reduction and cyclization of the compound of formula (XIII).

The reaction is normally and preferably effected 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 the reagents involved and that it can d issol ve 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, Λ/,Λ/-dimethylformamide, Λ/,Λ/-dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles, such as acetonitrile and benzonitrile; Of these solvents, the reaction in the absence of solvent or ethanol is preferred.

The reaction is carried out in the presence of a 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 may equally be used here. Examples of such reducing agents include: a combination of metals, such as zinc and 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 range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 120°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 24 hours will usually suffice. (Step C6)

In this step, the compound of formula (XV) is prepared by hydrolysis of the compound of formula (XIV). The reaction may be carried out under the same condition as described in Step B2 of Method B.

(Step C7)

In this step, the compound of formula (Ia) is prepared by amidation of the compound of formula (XV) with the compound of formula (VII), which is commercially available. The reaction may be carried out under the same condition as described in Step B3 of Method B. If the compound of formula (XV) has hydroxy-protecting groups, the deprotection reaction described in Method A will be applied in an appropriate step.

Method D

This illustrates the preparation of compounds of formula (Ib) wherein R⁵ is a hydroxy group or a C₁-C₆ alkoxy group. Reaction Scheme D

In Reaction group.

The term "leaving group", as used herein, signifies a substitutable group by nucleophilic groups, such as a hydroxy group or amines and examples of such leaving groups include a halogen atom, a 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. (Step D1) Step A1

In the Step D1 , the compound of formula (XVII) is prepared by nucleophilic substitution with Lv of the compound of formula (XVI), which is commercially available or may be prepared by the method described in WO 00/078751 or US 20050038032, with the compound of formula (II), which is commercially available or may be prepared by the methods described in WO 04/054984.

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline and N, N- diethylamide; 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 diethylketone; or mixed solvents thereof. Of these solvents, tetrahydrofuran, N,N-dimethylformamide or ethanol is preferred. The reaction is carried out in the 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 may 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 terf-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(terf-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, DBN, DABCO and DBU; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, sodium hydride, potassium carbonate or potassium terf-butoxide is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 120⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 48 hours, will usually suffice.

(Step D2)

In this step, the compound (Ib) wherein R^5b is a hydroxy group is prepared by reduction of the carbonyl group (D2-a) of the compound of formula (XVII). After this reaction, alkylation of hydroxy group (D2-b) with halo(C₁-C₆)alkyl may follows, and then, the compound (Ib) wherein R^5b is a C₁-C₆ alkoxy group may be obtained.

(D2-a) Reduction The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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 likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type may equally 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 diisobutyl aluminum hydride. Of these, sodium borohydride is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0°C to about 8O⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 8 hours will usually suffice.

(D2-b) Alkylation

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; 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 likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may 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 terf-butoxide; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, sodium hydride is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0°C to about 100⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 48 hours, will usually suffice. Method E

This illustrates the preparation of compounds of formula (Ic) wherein X is NH. Reaction Scheme E

(Step EI)

In this step, the compound of formula (XX) is prepared by reductive amination of the compound of formula (XVIII), which is commercially available or may be prepared by the method described in WO 04/054984, with the compound of formula (XIX) which is commercially available or may be prepared by the method described in JP 10072397 and JP 06263663.

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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, dimethoxyethane, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; acetic acid; and water. Of these solvents, dichloromethane is preferred..

The reaction is carried out in the presence of a reducing reagent. There is likewise no particular restriction on the nature of the reducing reagents used, and any reducing reagent commonly used in reactions of this type may equally be used here. Examples of such reducing reagent include: sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Of these, we prefer sodium triacetoxyborohydride.

The reaction may be carried out in the presence or absence of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally 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, acetic acid is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about O⁰C to about 100⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 48 hours, will usually suffice.

(Step E2)

In this step, the compound of formula (XXI) is prepared by substitution of the halogen atom of the compound of formula (XX). The reaction may be carried out under the same condition as described in Step C4 of Method C.

(Step E3)

In this step, the compound of formula (XXII) is prepared by hydrolysis of the compound of formula (XXI). The reaction may be carried out under the same condition as described in Step B2 of Method B.

(Step E4)

In this step, the compound of formula (Ic) is prepared by amidation of the compound of formula (XXII) with the compound of formula (VII), which is commercially available. The reaction may be carried out under the same condition as described in Step B3 of Method B. If the compound of formula (XXII) has hydroxy-protecting groups, the deprotection reaction described in Method A will be applied in an appropriate step.

Method F

This illustrates the preparation of compounds of formula (Ilia). Reaction Scheme F

(Step FI )

In this step, the compound of formula (XXIV) is prepared by bromohydrination of the compound of formula (XXIII), which is commercially available or as described in Bulletin De La Societe Chimique De France 3092 (1973).

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichioromethane, 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; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; ketones, such as acetone and diethylketone; water; or mixed solvents thereof. Of these, a mixed solvent of tetrahydrofuran and water is preferred.

The reaction is carried out in the presence of a halogenating agent. There is likewise no particular restriction on the nature of the halogenating agents used, and any halogenating agent commonly used in reactions of this type may equally be used here. Examples of such halogenating agents include: succinimides, such as NBS; haloacetamide, such as N-bromoacetamide; bromine. Of these, N-bromoacetamide is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about O⁰C to about 100⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 24 hours, will usually suffice.

(Step F2)

In this step, the compound of formula (XXV) is prepared by cyclization of the compound of formula (XXIV)

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichioromethane, 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; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4- pyrrolidinopyridine, N,N-dimethylaniline and N₁N- diethylaniline; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof. Of these, diethyl ether is preferred.

The reaction is carried out in the 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 may 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; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(ferf-butyl)-4-methylpyridine, quinoline, N.N-dimethylaniline, N.N-diethylaniline, DBN, DABCO and DBU. Of these, potassium hydroxide is preferred. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about 0⁰C to about 10fJ⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 60 minutes to about 48 hours, will usually suffice.

(Step F3) In this step, the compound of formula (XXV) is prepared by epoxydation of the compound of formula (XXIII).

The reaction is normally and preferably effected 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 the reagents involved and that it can dissolve 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; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; ketones, such as acetone and diethylketone; water; or mixed solvents thereof. Of these, dichloromethane is preferred.

The reaction is carried out in the 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 may 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; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(ferf-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, DBN, DABCO and DBU. Of these, sodium hydrogencarbonate is preferred.

The reaction is carried out in the presence of an oxidizing agent. There is likewise no particular restriction on the nature of the oxidizing agents used, and any oxidizing agent commonly used in reactions of this type may equally be used here. Examples of such oxidizing agents include: peroxy acids, such as 3-chloroperbenzoic acid (MCPBA), perbenzoic acid, peracetic acid and trifluoroperacetic acid; peroxides, such as hydrogen peroxide and ferf-butyl hydroperoxide. Of these, MCPBA is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors 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 from about -78⁰C to about 100⁰C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 24 hours, will usually suffice.

(Step F4) In this step, the compound of formula (Ilia) is prepared by epoxy opening reaction of the compound of formula (XXV). The reaction may be carried out under the same condition as described in Step D2 of Method D.

The compounds of formula (I), and the intermediates in the above-mentioned preparation methods can be isolated and purified by conventional procedures, such as distillation, recrystallization or chromatographic purification.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray drying, or evaporative drying. Microwave or radio frequency drying may 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, a method of optical resolution of a racemate (or a racemic precursor) can be appropriately selected from conventional procedures, for example, preferential crystallization, or resolution of diastereomeric salts between a basic moiety of the compound of formula (I) and a suitable optically active acid such as tartaric acid.

They may 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 pharmaceutically acceptable carriers or 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 to a large extent depend 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 methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995). ORAL ADMINISTRATION

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as, for example, tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include, for example, suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules 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 may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents. X\_ (6), 981-986 by Liang and Chen (2001 ).

For tablet dosage forms, depending on dose, the drug may make up from about 1 wt% to about 80 wt% of the dosage form, more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from about 1 wt% to about 25 wt%, preferably from about 5 wt% to about 20 wt% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface-active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from about 0.25 wt% to about 10 wt%, preferably from about 0.5 wt% to about 3 wt% of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted 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 are to be found in Verma et a/, Pharmaceutical Technology On-line. 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

PARENTERALADMINISTRATION

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished 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 may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

TOPICALADMINISTRATION The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - 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, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

INHALED/INTRANASAL ADMINISTRATION

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, 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, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. .

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix 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 dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from about 1μg to about 20mg of the compound of the invention per actuation and the actuation volume may vary from about 1//I to about 100//I. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from about 1 to about 100 μg of the compound of formula (I).

The overall daily dose will typically be in the range 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 may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

OTHER TECHNOLOGIES

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in. WO 91/11172, WO 94/02518 and WO

98/55148.

KlT-OF-PARTS Inasmuch as 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 which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

DOSAGE

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of about 0.05 mg to about 100 mg depending, of course, on the mode of administration, preferred in the range of about 0.1 mg to about 50 mg and more preferred in the range of about 0.5 mg to about 20 mg. For example, oral administration may require a total daily dose of from about 1 mg to about 20 mg, while an intravenous dose may only require from about 0.5 mg to about 10 mg. The total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65kg to about

70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

COMBINATIONS As discussed above, a compound of the invention exhibits acid pump inhibitory activity. An acid pump antagonist of the present invention may 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), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from: (i) histamine H₂ receptor antagonists, e.g. ranitidine, lafutidine, nizatidine, cimetidine, famotidine and roxatidine;

(ii) proton pump inhibitors, e.g. omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;

(iii) oral antacid mixtures, e.g. Maalox^®, Aludrox^® and Gaviscon^®;

(iv) mucosal protective agents, e.g. polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper and plaunotol;

(v) anti-gastric agents, e.g. Anti-gastrin vaccine, itriglumide and Z-360; (vi) 5-HT₃ antagonists, e.g. dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron; (vii) 5-HT₄ agonists, e.g. tegaserod, mosapride, cinitapride and oxtriptane; (viii) laxatives, e.g. Trifyba^®, Fybogel^®, Konsyl^®, Isogel^®, Regulan^®, Celevac^® and Normacol^®; (ix) GABAB agonists, e.g. baclofen and AZD-3355; (x) GABA₅ antagonists, e.g. GAS-360 and SGS-742;

(xi) calcium channel blockers, e.g. 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, e.g. metoclopramide, domperidone and levosulpiride;

(xiii) Tachykinin (NK) antagonists, particularly NK-3, NK-2 and NK-1 antagonists, e.g. nepadutant, saredutant, talnetant, (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9, 10,11 -tetrahydro-θ-methyl-S- (4-methylphenyl)-7H-[1 _I4]dlazoclno[2,1-g][1 ,7]naphthrldlne-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-3 H-1 ,2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3-[[2-methoxy-5-(trifluoromethoxy)phenyl] methylamino]-2-phenyl-piperidine (2S.3S);

(xiv) Helicobacter pylori infection agents, e.g. clarithromicyn, roxithromycin, rokitamycin, flurithromycin, telithromycin, amoxicillin, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, piperacillin, lenampicillin, tetracycline, metronidazole, bithmuth citrate and bithmuth subsalicylate; (xv) nitric oxide synthase inhibitors, e.g. GW-274150, tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen;

(xvi) vanilloid receptor 1 antagonists, e.g. AMG-517 and GW-705498;

(xvii) muscarinic receptor antagonists, e.g. trospium, solifenacin, tolterodine, tiotropium, cimetropium, oxitropium, ipratropium, tiquizium, dalifenacin and imidafenacin; (xviii) calmodulin antagonists, e.g. squalamine and DY-9760; (xix) potassium channel agonists, e.g. pinacidil, tilisolol, nicorandil, NS-8 and retigabine;

(xx) beta-1 agonists, e.g. dobutamine, denopamine, xamoterol, denopamine, docarpamine and xamoterol;

(xxi) beta-2 agonists, e.g. salbutamol; terbutaline, arformoterol, meluadrine, mabuterol, ritodrine, fenoterol, clenbuterol, formoterol, procaterol, tulobuterol, pirbuterol, bambuterol, tulobuterol, dopexamine and levosalbutamol;

(xxii) beta agonists, e.g. isoproterenol and terbutaline;

(xxiii) alpha 2 agonists, e.g. clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine;

(xxiv) endthelin A antagonists, e.g. bonsetan, atrasentan, ambrisentan, clazosentan, sitaxsentan, fandosentan and darusentan;

(xxv) opioid μ agonists, e.g. morphine, fentanyl and loperamide; (xxvi) opioid μ antagonists, e.g. naloxone, buprenorphine and alvimopan; (xxvii) motilin agonists, e.g. erythromycin, mitemcinal, SLV-305 and atilmotin; (xxviii) ghrelin agonists, e.g. capromorelin and TZP-101 ; (xxix) AchE release stimulants, e.g. Z-338 and KW-5092;

(xxx) CCK-B antagonists, e.g. itriglumide, YF-476 and S-0509; (xxxi) glucagon antagonists, e.g. NN-2501 and A-770077;

(xxxii) piperacillin, lenampicillin, tetracycline, metronidazole, bithmuth citrate and bithmuth subsalicylate; (xxxiii) Glucagon-like peptide-1 (GLP-1 ) antagonists, e.g. PNU-126814; (xxxiv) small conductance calcium-activated potassium channel 3 (SK-3) antagonists, e.g. apamin, dequalinium, atracurium, pancuronium and tubocurarine.

Method for assessing biological activities:

The acid pump inhibitory activity and other biological activities of the compounds of this invention were determined by the following procedures. Symbols have their usual meanings: mL (milliliter(s)), μl_

(microlitter(s)), Kg (kirogram(s)), g (gram(s)), mg (milligram(s)), μg (microgram(s)), pmol (pico molar(s)), mmol (milli molar(s)), M (molar mass (m³/mol)), mM (milli molar mass), μM (micro molar mass), quant, (quantitative yield), nm (nanometer(s)), min (minute(s)) Cat# (catalog number).

Preparation of gastric vesicles from fresh porcine stomachs The porcine gastric vesicles for Porcine gastric H⁺/K⁺-ATPase inhibition assays were prepared from mucous membrane in fresh porcine stomachs by homogenization with a tight-fitted polytetrafluoroethylene (Teflone®) homogenizer in 0.25 M sucrose at 4⁰C. The crude pellet was removed with centrifugation at 20,000 g for 30 min. Then supernatant was centrifuged at 100,000 g for 30 min. The resulting pellet was re-suspended in 0.25 M sucrose, and then subjected to density gradient centrifugation at 132,000 g for 90 min. The gastric vesicles were collected from interface on 0.25 M sucrose layer containing 7% Ficoll™ PM400(Amersham Biosciences). This procedure was performed in a cold room.

Ion-leaky Porcine gastric H+/K+-ATPase inhibition

Ion-leaky porcine gastric H⁺/K⁺-ATPase inhibition was measured according to the modified method described in Biochemical Pharmacology, 1988, 37, 2231-2236.

The isolated vesicles were lyophilized , and then kept in deep-freezer until use. For enzyme assay, lyophilized vesicles were reconstituted with 3 mM MgSO₄ containing 40 mM Bis-tris (pH 6.4 at 37°C).

Enzyme reaction was performed incubating 5 mM KCI, 3 mM Na₂ATP, 3 mM MgSO₄ and 1.0 μg of reconstituted vesicles for 30 minutes at 37⁰C in a final 60 μl of reaction mixture (40 mM Bis-tris, pH 6.4) with or without the test compound. Enzyme reaction was stopped by adding 10% sodium dodecyl sulphate (SDS). Released inorganic phosphate from ATP was detected by incubation with 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.

Ion-tight porcine gastric H+/K+-ATPase inhibition

Ion-tight porcine gastric H⁺/K⁺-ATPase inhibition was measured according to the modified method described in Biochemical Pharmacology, 1988, 37, 2231-2236.

The isolated vesicles were kept in deep-freezer until use. For enzyme assay, vesicles were diluted with 3 mM MgSO₄ containing 5 mM Tris (pH 7.4 at 37⁰C).

Enzyme reaction was performed incubating 150 mM KCI, 3 mM Na₂ATP, 3 mM MgSO_4, 15 μM valinomycin and 3.0 μg of vesicles for 30 minutes at 37⁰C in a final 60 μl of reaction mixture ( 5mM Tris, pH 7.4) with or without the test compound. Enzyme reaction was stopped by adding 10% SDS. Released inorganic phosphate from ATP was detected by incubating with 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 IC₅₀ values of the inhibition activity for the compounds of Examples are shown in Table 1.

Table 1.

Canine kidney Na*/K*-ATPase inhibition

The powdered canine kidney Na⁺/K⁺-ATPase (Sigma) was reconstituted with 3 mM MgSO₄ containing 40 mM Tris (pH 7.4 at 37⁰C). Enzyme reaction was performed incubating 100 mM NaCI, 2 mM

KCI, 3 mM Na₂ATP, 3 mM MgSO₄ and 12 μg of enzyme for 30 minutes at 37⁰C in a final 60 μl of reaction mixture (40 mM Tris, pH 7.4) with or without the test compound. Enzyme reaction was stopped by adding

10% SDS. Released inorganic phosphate from ATP was detected by incubating with 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 gastric lumen-perfused rat

Acid secretion in the gastric lumen-perfused rat 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 a middle abdominal incision, a dual polyethylene cannula was inserted into the forestomach and the stomach was perfused with saline (37 ⁰C, pH 5.0) at a rate of 1 ml/min. The acid output in the perfusate was determined at 5 minutes interval by titration with 0.02 M NaOH to pH 5.0. After the determination of basal acid secretion for 30 min, the acid secretion was stimulated by a continuous intravenous infusion of pentagastrin (16 μg/kg/h). The test compounds were administered by an intravenous bolus injection or intraduodenal administration after the stimulated acid secretion reached a plateau phase. The acid secretion was monitored after the administration.

The activity was evaluated either inhibition of total acid secretion from 0 hours to 1.5 or 3.5 hours after administration or the maximum inhibition after administration.

Inhibition of gastric acid secretion in the Heidenhain pouch dog Male Beagle dogs weighing 7 - 15 kg with Heidenhain pouch [Heidenhain R: Arch Ges Physiol.

1879; 19: 148-167] were used. 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, housed singly. They received standard food once daily at 11 :00 a.m. and tap water ad libitum, and were fasted overnight prior to the experiment, with free access to water. Gastric juice samples were collected throughout the experiment by gravity drainage every 15 min. Acidity in the gastric juice was measured by titration to the end point of pH 7.0. Acid secretion was stimulated by a continuous intravenous infusion of histamine (80 μg/kg/h). Oral or intravenous bolus administration of the test compounds was done 90 minutes after commencement of the histamine infusion. The acid secretion was monitored after the administration. The activity was evaluated by the maximum inhibition relative to the corresponding control value.

The compound of Example 13 showed a good inhibitory activity.

Human dofetilide binding

Human ether a-go-go related gene (HERG) transfected HEK293S cells were prepared and grown in-house. Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25 ⁰C with 2 M HCI containing 1 mM MgCI₂, 10 mM KCI. The cells were homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,000 g for 20 minutes at 4°C. The pellet was resuspended, homogenized and centrifuged once more in the same manner. The resultant supernatant was discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds. The membrane homogenate was aliquoted and stored at -8O⁰C until use. An aliquot was used for protein concentration determination using a Protein Assay Rapid Kit (wako) and Spectra max plate reader (Wallac). All the manipulation, stock solution and equipment were kept on ice at all times. For saturation assays, experiments were conducted in a total volume of 200 μ\. Saturation was determined by incubating 36 μ\ of [³H]-dofetilide, and 160 μl of membrane homogenates (20-30 μg protein per well) for 60 minutes at room temperature in the absence or presence of 10 μM dofetilide at final concentrations (4 μ\) for total or nonspecific binding, respectively. All incubations were terminated by rapid vacuum filtration over PEI soaked glass fiber filter papers using Skatron cell harvester followed by two washes with 50 mM Tris buffer (pH 7.4 at 25 "C). Receptor-bound radioactivity was quantified by liquid scintillation counting using Packard LS counter.

For the competition assay, compounds were diluted in 96 well polypropylene plates as 4-point dilutions in semi-log format. All dilutions were performed in DMSO first and then transferred into 50 mM Tris buffer (pH 7.4 at 25 °C) containing 1 mM MgCi₂, 10 mM KCI so that the final DMSO concentration became equal to 1 %. Compounds were dispensed in triplicate in assay plates (4 μl). Total binding and nonspecific binding wells were set up in 6 wells as vehicle and 10 μM dofetilide at final concentration, respectively. The radioligand was prepared at 5.6x final concentration and this solution was added to each well (36 μl). The assay was initiated by addition of YSi poly-L-lysine SPA beads (50 μl, 1 mg/well) and membranes (110 μl, 20 μg/well). Incubation was continued for 60 minutes at room temperature. Plates were incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity was quantified by counting Wallac MicroBeta plate counter. Caco-2 permeability

Caco-2 permeability was measured according to the method described in Shiyin Yee, Pharmaceutical Research, 763 (1997).

Caco-2 cells were grown on filter supports (Falcon HTS multiwell insert system) for 14 days. Culture medium was removed from both the apical and basolateral compartments and the monolayers were preincubated with pre-warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.5 hour at 37°C in a shaker water bath at 50 cycles/min. The apical buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM 2-morpholinoethanesulphonic acid (MES) Biological Buffer, 1.25 mM CaCI₂ and 0.5 mM MgCI₂ (pH 6.5). The basolateral buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) Biological Buffer, 1.25 mM CaCI₂ and 0.5 mM MgCI₂ (pH 7.4). At the end of the preincubation, the media was removed and test compound solution (10μM) in buffer was added to the apical compartment. The inserts were moved to wells containing fresh basolateral buffer at 1 hour. Drug concentration in the buffer was measured by LC/MS analysis. Flux rate (F, mass/time) was calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (P_app) was calculated from the following equation.

P_app (cm/sec) = (F x VD) / (SAx MD) where SA is 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 t = 0. All data represent the mean of 2 inserts. Monolayer integrity was determined by Lucifer Yellow transport.

Half-life in human liver microsomes (HLM)

Test compounds (1 μM) were incubated with 3.3 mM MgCI₂ and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37°C on the 96-deep well plate. The reaction mixture was split into two groups, a non-P450 and a P450 group. NADPH was only added to the reaction mixture of the P450 group. An aliquot of samples of P450 group was collected at 0, 10, 30, and 60 minutes time point, where 0 minutes time point indicated the time when NADPH was added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group was collected at -10 and 65 minutes time point. Collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated protein was spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant was measured by LC/MS/MS system.

The half-life value was obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yields the rate of metabolism (k). This was converted to a half-life value using following equations: Half-life = In 2 / k

In vitro drug-drug interaction studies for five major CYPs (fPDI)

CYP1A2 Test compounds (3 μM) were pre-incubated with recombinant CYP1A2 (Baculosome lot#21198 Invitrogen, 50 pmol P450/ml) in 100 mM K⁺Phosphate Buffer (pH 7.4) and 10 μM Vivid blue 1A2 probe (Invitrogen) as a substrate for 5 minutes at 3O⁰C. Reaction was initiated by adding a solution of a warmed NADPH-regenerating system A, which consists of 0.50 mM NADP and 10 mM MgCI₂, 6.2 mM DL-lsocitric acid and 0.5U/ml lsocitric Dehydrogenase (ICD). Plates were placed in the plate reader at 3O⁰C and were taken readings every 1.5 minutes, with a 10 second shake in between each reading for 15 cycles. Wavelengths of excitation/emission 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 100 mM K⁺Phosphate Buffer (pH 7.4) and 30 μM MFC probe (Gentest) as a substrate for 5 minutes at 37⁰C. Reaction was initiated by adding a solution of the warmed NADPH-regenerating system A. Plates were placed in the plate reader at 37°C and were taken readings every 2.0 minutes, with a 10 second shake in between each reading for 15 cycles. Wavelengths of excitation /emission 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 100 mM K⁺Phosphate Buffer (pH 7.4) and 10 μM Vivid blue 2C19 probe (Invitrogen) as a substrate for 5 minutes at 37⁰C. Reaction was initiated by adding a solution of the warmed NADPH-regenerating system A. Plates were placed in the plate reader at 37⁰C and were taken readings every 1.5 minutes with a 10 second shake in between each reading for 15 cycles. Wavelengths of excitation /emission 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 100 mM K⁺Phosphate Buffer (pH 7.4) and 1 μM 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) probe (Gentest) as a substrate for 5 minutes at 37⁰C. Reaction was initiated by adding a solution of a warmed NADPH-regenerating system B, which consists of 0.03 mM NADP and 10 mM MgCI₂, 6.2 mM DL-lsocitric acid and 0.5 U/ml ICD. Plates were placed in the plate reader at 37°C and were taken readings every 2.0 minutes with a 10 second shake in between each reading for 15 cycles. Wavelengths of excitation /emission 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 100 mM K⁺Phosphate Buffer (pH 7.4) and 2 μM Vivid Red probe (Invitrogen) as a substrate for 5 minutes at 30⁰C. Reaction was initiated by adding a solution of the warmed NADPH-regenerating system A. Plates were placed in the plate reader at 30⁰C and were taken readings minimum intervals with a 10 second shake in between each reading for 15 cycles. Wavelengths of excitation /emission were 530 /595 nm, respectively. Drug-drug interaction was evaluated by the rate of metabolite formation calculated with a slope (Time vs. Fluorescence units) in the linear region or the percentage of inhibition by test compounds calculated by the following equation.

Inhibition % = {(v₀ -Vj)/v_o}x100, wherein V₀ is a rate of control reaction (no test compounds) and v, is a rate of reaction in the presence of test compound.

lHFpg assay

Human ether a-go-go related gene (HERG) transfected HEK293 cells are prepared and cultured in-house. 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 below of its composition), in the room atmosphere of 23°C. Cells are studied between 0.5-5 hours after harvest.

HERG currents are studied using a standard patch clamp technique of the whole-cell mode. During the experiment, the cells are superfused with a standard external solution of the following composition;(mM) NaCI, 130; KCI, 4; CaCI₂, 2; MgCI₂, 1 ; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings is made using a patch clamp amplifier and patch pipettes which have a resistance of 1-3MOhm when filled with the standard internal solution of the following composition; (mM); KCI, 130; MgATP, 5; MgCI₂, 1 ; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 10 MOhm and seal resistances over 1GOhm are accepted for further experimentation. Series resistance compensation is applied up to a maximum of 80% without any leak subtraction. Following the achievement of whole cell configuration and sufficient time for cell dialysis with pipette solution (>5 min), the membrane is depolarized from a holding potential of - 80 mV to + 3OmV for 1000 ms followed by a descending voltage ramp (rate 0.5 mV msec^'1) back to the holding potential. This depolarization and ramp is applied to the cells continuously every 4 seconds (0.25 Hz). The amplitude of the peak current elicited around -40 mV during the ramp is measured. Once stable evoked current responses of minimal changes in the amplitude are obtained in the external solution, the test compound is applied for 10-20 minutes with multiple dosing in a single cell. The cells are also exposed to high dose of dofetilide (5 μM), a specific IKr blocker, to evaluate the insensitive endogenous current.

All experiments are performed at 23+/-1°C. Evoked membrane currents are recorded online on a computer, filtered at 500-1000 Hz (Bessel -3dB) and sampled at 1-2 KHz. Osmolarity and pH change induced by the test compound in external solution will be examined at the highest concentration.

The arithmetic mean of these ten values of peak current is calculated under control conditions and in the presence of drug. Percent decrease of I _N in each experiment is obtained by the normalized current value using the following formula: I N = (Ic - ' D)/( I C - l_dof)^χ 100, where Ic is the mean current value under control conditions, I_D is the mean current value in the presence of test compound and I _dot is the mean current value in dofetilide application. Separate experiments are performed and pooled data of arithmetic mean from each experiment is defined as the result of the study.

Bioavailability in rat

Adult rats of the Sprague-Dawley strain were used. One to two days prior to the experiments all rats were prepared by cannulation 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 drawn from the jugular vein at intervals up to 24 hours after 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 plasma concentration curve (AUC) following oral administration or intravenous administration.

Bioavailability in dog 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 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 plasma concentration curve (AUC) following 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 96-well plate type equipment. Spectra-Por®, regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm x 120 mm) were soaked for over night in distilled water, then for 20 minutes in 30% ethanol, and finally for 15 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, pH7.4). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs were used. The dialysis equipment was assembled and added 150 μL of compound-fortified plasma to one side of each well and 150 μL of dialysis buffer to the other side of each well. After 4 hours incubation at 37⁰C for 150 r.p.m, aliquots of plasma and buffer were sampled. The compound in plasma and buffer were extracted with 300 μL of acetonitrile containing internal standard compounds for analysis. The concentration of the compound was determined with LC/MS/MS analysis. The fraction of the compound unbound was calculated by the following equation: fu = 1-{ ( [plasma]_eq - [buffer]_eq ) / ( [plasma]_eq)} wherein [plasma]_eq and [buffer]_eq are the concentrations of the compound in plasma and buffer, respectively.

Aqueous solubility

Aqueous solubility in the mediums (a)-(c) was determined by following method: Whatman mini-UniPrep chambers (Clifton, NJ, USA) containing more than 0.5 mg of compound and 0.5 mL of each medium were shaken overnight (over 8 hours) at room temperature. All samples were filtered through a 0.45 μm Polyvinylidene Difluoride (PVDF) membrane into the Whatman mini-UniPrep plunger before analysis. The filtrates were assayed by HPLC.

<medium>(a) Simulated gastric fluid with no enzyme (SGN) at pH 1.2: Dissolve 2.0 g of NaCI in 7.0 mL of 10 M HCI and sufficient water to make 1000 mL; (b) Phosphate buffer saline (PBS) at pH 6.5: Dissolve 6.35 g of KH₂PO₄, 2.84 g of Na₂HPO₄ and 5.50 g of NaCI in sufficient water to make 1000 mL, adjusting 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 the metabolic stability in human hepatocytes

Tested compounds (1 μM) were incubated statically with hepatocytes from human at 37 °C in a 95 % air/ 5 % CO₂ with target cell density of 0.5 x 10⁶ cells/ml and a total volume of 50 μL. Incubation was stopped at each time point 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 samples were sonicated for 10 minutes, samples were centrifuged at 2,000 rpm for 15 minutes, and then the supernatant was transferred to the other plates for analysis. The compound concentrations in supernatant were measured by LC/MS/MS system. The disappearance rates of tested compounds were obtained by plotting the common logarithm of the peak area ratio of compounds / internal standard versus time. The slope of the line of best fit through the points yielded the rate of metabolism (k_e). This value was scaled to take hepatocellularity, liver and body weight into account to give an intrinsic clearance value (CL_int) in ml/min/kg as illustrated in Equation 1. Hepatic clearance (CL_h) was predicted from this intrinsic clearance value using the parallel tube model as shown in Equation 2. The predicted clearance divided by the hepatic blood flow (Q_h) afforded the extraction ratio (E_h) (Equation 3). Equation 1 : k_e x (g liver/kg body weight)x(ml incubation/ number of cells in incubation)x(cells/g liver)

Equation 2: CL_h = Q_h x { 1 - exp (-CL_int/ Q_h) }

Equation 3: E_h = CL_h / Q_h Wherein, "gliver weight /kg body weight" is 21 , "Cells / g liver" is 1.2 x 10⁸, "ml incubation/ number of cells in incubation" is 2.0 x 10^"6, and Q_h is 20 ml/min/kg.

Supposing that hepatic metabolism is the main route of drug elimination, systemic exposure (AUC_p0) after oral administration is calculated using Equation 4. Equation 4 AUC_po = Dose x (1 -E_h) / CL_h

All compounds of Examples showed the extraction ratio of less than 0.253.

Examples

The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. Unless stated on otherwise in the following examples, general experimental conditions are as follows: all operations were carried out at room or ambient temperature, that is, in the range of 18-25 ⁰C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 °C; reactions were monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points (mp) given are uncorrected (polymorphism may result in different melting points); the structure and purity of all isolated compounds were assured by at least one of the following techniques: TLC (Merck silica gel 60 F₂₅₄ precoated TLC plates or Merck NH₂ gel (an amine coated silica gel) F_254S precoated TLC plates), mass spectrometry, nuclear magnetic resonance spectra (NMR), infrared absorption spectra (IR) or microanalysis. Yields are given for illustrative purposes only. Flash column chromatography was carried out using Biotage KP-SIL (40-63 μm), Biotage KP-NH (an amine coated silica gel) (40-75 μM) or Wako silica gel 300HG (40-60 μM). Preparative TLC was carried out using Merck silica gel 60 F₂₅₄ precoated TLC plates (0.5 or 1.0 mm thickness). Low-resolution mass spectral data (ESI) were obtained on ZMD™ or ZQ™ (Waters) and mass spectrometer. NMR data were determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8%) or dimethylsulfoxide (99.9%) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br. = broad, dd = doublet of doublet, dt = doublet of triplet, br s = broad singlet, etc. IR spectra were measured by a Fourier transform infrared spectrophotometer (Shimazu FTIR-8300). Optical rotations were measured using a JASCO P-1020 Polarimeter (Japan Spectroscopic CO, Ltd.).

Example 1

4-(2,3-Dihydro-1 f/-inden-2-yloxy)-JV,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide

To a stirred mixture of 4-hydroxy-Λ/,Λ/,1 _I2-tetramethyl-1 H-benzimidazole-6-carboxamide (0.10 g,

0.62 mmol, WO 04/054984), indan-2-ol (0.17 g, 1.2 mmol) and triphenylphosphine (0.32 g, 1.2 mmol) in tetrahydrofuran (10 ml_) was added diisopropyl azodicarboxylate (DIAD) (0.25 g, 1.2 mmol) at 0⁰C. The reaction mixture was stirred at room temperature for 18 hours. The residue was diluted with water, and extracted with ethyl acetate. The extract was washed with 2M sodium hydroxide aqueous solution and saturated ammounium chloride aqueous solution. The organic layer was dried over sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate : methanol = 10 : 1 as an eluent), and recrystallized from ethyl acetate/diethyl ether (1 : 10) to afford the title compound as a white solid (68 mg, 32%).

¹H NMR (CDCI₃, 300 MHz) δ: 7.27-7.15 (m, 4H), 7.05 (s, 1 H), 6.77 (s, 1 H), 5.55-5.48 (m, 1 H), 3.71 (s, 3H), 3.54-3.34 (m, 4H), 3.20-3.00 (m, 6H), 2.59 (s, 3H) ppm. MS (ESI) m/z: 350 (M+H)⁺.

Example 2

N,NA ,2-Tetramethyl-4-(1 ,2,3,4-tetrahvdronaphthalen-2-yloxy)-1 /7-benzimidazole-β-carboxamide

The title compound was prepared as a white solid in 35% yield (78 mg) from 4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide (0.10 g, 0.62 mmol, WO 04/054984) and 1 ,2,3,4-tetrahydronaphthalen-2-ol (0.18 g, 1.2 mmol) by the same manner in Example 1.

¹H NMR (CDCI₃, 300 MHz) δ: 7.21-7.06 (m, 4H), 7.05 (s, 1 H), 6.79 (s, 1 H), 5.17-5.02 (m, 1 H), 3.72 (s, 3H), 3.38-3.29 (m, 1 H), 3.21-2.87 (m, 9H), 2.62 (s, 3H), 2.43-2.28 (m, 1 H), 2.21-2.05 (m, 1 H) ppm. MS (ESI) m/z: 364 (M+H)⁺.

Example 3

4-(2,3-Dihvdro-1H-inden-2-yloxy)-1,2-dimethyl-6-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole

STEP 1 : Methyl 4-(2,3-dihvdro-1rt-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazole-6-carboxylate

To a stirred mixture of methyl 4-hydroxy-1 ,2-dimethyl-1 H-benzimidazole-6-carboxylate (2.0 g, 9.1 mmol, WO 04/054984), indan-2-ol (2.4 g, 18 mmol) and triphenylphoshine (4.7 g, 18 mmol) in tetrahydrofuran (120 mL) was added diisopropyl azodicarboxylate (DIAD) (3.6 g, 18 mmol) at 0⁰C. The reaction mixture was stirred at room temperature for 3 hours. Additional diisopropyl azodicarboxylate (3.6 g, 18 mmol) and triphenylphosphine (4.7 g, 18 mmol) were added to the mixture. After the reaction mixture was stirred at room temperature for 18 hours, indan-2-ol (2.4 g, 18 mmol), diisopropyl azodicarboxylate (1.8 g, 9.1 mmol) and triphenylphosphine (2.4 g, 9.1 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, and concentrated in vacuum. The residue was diluted with water, and extracted with ethyl acetate. The extract was washed with 2M sodium hydroxide aqueous solution and saturated ammounium chloride aqueous solution. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate : hexane gradient elution from 1 : 1 to 4 : 1) to afford a mixture of the title compound and triphenylphosphine oxide (3.5 g, crude) as white solids, which was used in the next step without further purification. MS (ESI) m/z: 337 (M+H)⁺.

STEP 2: 4-(2,3-Dihvdro-1H-inden-2-yloxy)-1 ,2-dimethyl-1H-benzimidazole-6-carboxylic acid To a stirred solution of methyl 4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1H-benzimidazole

-6-carboxylate (3.5 g, crude, STEP 1 ) in methanol (50 mL) and tetrahydrofuran (10 mL) was added 4M lithium hydroxide aqueous solution (20 mL). The mixture was stirred at 50⁰C for 5 hours, cooled to room temperature, and stirred at the same temperature for 18 hours. The reaction mixture was concentrated in vacuum to remove methanol and tetrahydrofuran. The residue was diluted with 4M lithium hydroxide aqueous solution (25 mL) and water, and washed with diethyl ether (50 mL x 3). The aqueous layer was acidified with saturated sodium dihydrogenphosphate dihydrate solution (pH = 4). The precipitated solid was collected by filtration, washed with water, and. dried in vacuum to afford the title compound as a white solid (2.3 g, 79% for 2 steps).

1 H NMR (DMSO-Cf₆, 300 MHz) δ: 7.73 (s, 1 H), 7.33-7.24 (m, 3H), 7.20-7.17 (m, 2H), 5.67-5.61 (m, 1 H), 3.75 (s, 3H), 3.44-3.40 (m, 2H), 3.15-3.04 (m, 2H), 2.50 (s, 3H) ppm (-OH was not observed). MS (ESI) m/z: 323 (M+H)⁺, 321 (M+H)\

STEP 3: 4-(2,3-Dihvdro-1/V-inden-2-yloxy)-1 ,2-dimethyl-6-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole

To a stirred mixture of 4-(2,3-dihydro-1W-inden-2-yloxy)-1 ,2-dimethyl-1f/-benzimidazole -6-carboxylic acid (55 mg, 0.17 mmol, STEP 2) and pyrrolidine (24 mg, 0.34 mmol) in

Λ/,Λ/-dimethylformamide (3 mL) was added O-benzotriazol-1-yl-Λ/,Λ/,/V',Λ/',-tetramethyluronium hexafluorophosphate (HBTU) (97 mg, 0.26 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated sodium hydrogencarbonate aqueous solution (10 ml_) and extracted with ethyl acetate (25 ml_ x 2). The extracts were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from ethyl acetate only to ethyl acetate : methanol 10 : 1). The resulted solid was triturated with ethyl acetate/diisopropyl ether (1 : 2), collected by filtration, and dried in vacuum to afford the title compound as a white solid (25 mg, 39%).

¹H NMR (CDCI₃, 300 MHz) δ: 7.32-7.15 (m, 5H), 6.88 (s, 1 H), 5.58-5.48 (m, 1 H), 3.71 (s, 3H), 3.75-3.64 (m, 2H), 3.57-3.29 (m, 6H), 2.60 (s, 3H), 2.04-1.84 (m, 4H) ppm. MS (ESI) m/z: 376 (M+H)⁺.

Example 4

6-(Azetidin-1 -ylcarbonyl)-4-(2,3-dihvdro-1 H-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazole

The title compound was prepared as a white solid in 59% yield (53 mg) from

4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1/-/-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and azetizine hydrochloride (46 mg, 0.50 mmol) by the same manner in STEP 3 of Example 3. ¹H NMR (CDCI₃, 300 MHz) δ: 7.34-7.13 (m, 5H), 6.98 (s, 1 H), 5.57-5.47 (m, 1 H), 4.47-4.21 (m, 4H), 3.72 (s, 3H), 3.55-3.35 (m, 4H), 2.60 (s, 3H), 2.45-2.30 (m, 2H) ppm. MS (ESI) m/z: 362 (M+H)⁺.

Example 5 4-f2.3-Dihvdro-1H-inden-2-yloxy)-/V-ethyl-/V,1,2-trimethyl-1tf-benzimidazole-6-carboxamide

The title compound was prepared as a white solid in 62% yield (350 mg) from

4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1H-benzimidazole-6-carboxylic acid (500 mg, 1.5 mmol,

STEP 2 of Example 3) and Λ/-methylethanamine (275 mg, 4.7 mmol) by the same manner in STEP 3 of

Example 3. ¹H NMR (CDCI₃, 300 MHz) δ: 7.36-7.11 (m, 4H), 7.02 (s, 1 H), 6.75 (s, 1 H), 5.61-5.43 (m, 1 H), 3.72 (s, 3H),

3.58-3.34 (m, 6H), 3.22-2.98 (m, 3H), 2.59 (s, 3H), 1.37-1.12 (m, 3H) ppm. MS (ESI) m/z: 364 (M+H)⁺.

Example 6

4-(2,3-Dihvdro-1 H-inden-2-yloxy)-JV,JV-diethyl-1 ,2-dimethyl-1 H-benzimidazole-6-carboxamide

The title compound was prepared as a white solid in 59% yield (55 mg) from 4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and Λ/-ethylethanamine (54 mg, 0.74 mmol) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.38-7.12 (m, 4H), 6.99 (s, 1 H), 6.73 (s, 1 H), 5.58-5.47 (m, 1 H), 3.71 (s, 3H), 3.64-3.25 (m, 8H), 2.59 (s, 3H), 1.45-1.09 (m, 6H) ppm. MS (ESI) m/z: 378 (M+H)⁺.

Example 7

4-(2,3-Dihvdro-1f/-inden-2-yloxy)-Λf-(2-hvdroxyethyl)-Λ/,1,2-trimethyl-1H-benzimidazole-6-carboxam ide

The title compound was prepared as a white solid in 43% yield (40 mg) from 4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1H-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol,

STEP 2 of Example 3) and 2-(methylamino)ethanol (44 mg, 0.50 mmol) by the same manner in STEP 3 of

Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.27-7.14 (m, 4H), 7.10 (s, 1 H), 6.61 (s, 1 H), 5.61-5.47 (m, 1 H), 3.93-3.66 (m,

4H), 3.71 (s, 3H), 3.53-3.29 (m, 4H), 3.13 (s, 3H), 2.60 (s, 3H) ppm (-OH was not observed.). MS (ESI) m/z: 380 (M+H)⁺.

Example 8

4-(2,3-Dihvdro-1H-inden-2-yloxy)-/V-r(1R)-2-hvdroxy-1-methylethvn-Λ/,1,2-trimethyl-1tf-benzimidazo le-6-carboxamide

The title compound was prepared as a white solid in 42% yield (65 mg) from 4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1 W-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and (2R)-2-(methylamino)propan-1-ol hydrochloride (125 mg, 0.99 mmol, Canadian Journal of Chemistry 1993, 2028.) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.27-7.14 (m, 4H), 7.10 (s, 1 H), 6.81 (s, 1 H), 5.60-5.49 (m, 1 H), 3.81-3.54 (m,

3H), 3.70 (s, 3H), 3.53-3.30 (m, 4H), 2.97 (s, 3H), 2.59 (s, 3H), 1.33-1.19 (m, 3H) ppm (-OH was not observed).

MS (ESI) m/z: 394 (M+H)⁺.

Example 9

6-IY4-Acetylpiperazin-1 -yl)carbonyl1-4-(2,3-dihvdro-1 H-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazol

The title compound was prepared as a white solid in 56% yield (60 mg) from

4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and 1-acetylpiperazine (64 mg, 0.50 mmol) by the same manner in STEP 3 of Example 3. ¹H NMR (CDCI₃, 300 MHz) δ: 7.26-7.13 (m, 4H), 7.06 (s, 1 H), 6.75 (s, 1 H), 5.61-5.48 (m, 1 H), 3.72 (s, 3H), 3.73-3.49 (m, 8H), 3.50-3.28 (m, 4H), 2.61 (s, 3H), 2.15 (s, 3H) ppm. MS (ESI) m/z: 433 (M+H)⁺.

Example 10

((2R)-1 -(T4-(2,3-Dihvdro-1 H-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazol-6-vncarbonyl}pyrrolidin-2

-vDmethanol

The title compound was prepared as a white solid in 73% yield (73 mg) from 4-(2,3-dihydro-1 H-inden-2-yloxy)-1 ,2-dimethyl-1 H-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and (2R)-pyrrolidin-2-ylmethanol (75 mg, 0.74 mmol) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.26-7.08 (m, 5H), 6.36 (s, 1 H), 5.58-5.49 (m, 1 H), 5.07-4.97 (m, 1 H), 4.51-4.42 (m, 1 H), 3.88-3.72 (m, 2H), 3.72 (s, 3H), 3.71-3.29 (m, 6H), 2.60 (s, 3H), 2.28-2.15 (m, 1 H), 1.95-1.72 (m, 2H) ppm (-OH was not observed). MS (ESI) m/z: 406 (M+H)⁺.

Example 11

4-(2,3-Dihvdro-1H-inden-2-yloxy)-JV-(2-methoxyethyl)-JV,1,2-trimethyl-1tf-benzimidazole-6-carboxa mide

The title compound was prepared as a white solid in 72% yield (70 mg) from 4-(2,3-dihydro-1 /-/-inden-2-yloxy)-1 ,2-dimethyl-1 W-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and 2-methoxy-Λ/-methylethanamine (44 mg, 0.50 mmol) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.27-7.13 (m, 4H), 7.06 (s, 1 H), 6.85-6.74 (m, 1 H), 5.57-5.47 (m, 1 H), 3.81-3.53 (m, 7H), 3.71 (s, 3H), 3.53-3.29 (m, 4H), 3.13 (s, 3H), 2.59 (s, 3H) ppm. MS (ESI) m/z: 394 (M+H)⁺.

Example 12

4-f2,3-Dihvdro-1H-inden-2-yloxy)-/V-r(2R)-2-hvdroxypropyπ-A/,1,2-trimethyl-1H-benzimida2θle-6-car boxamide

The title compound was prepared as a white solid in 17% yield (17 mg) from 4-(2,3-dihydro-1H-inden-2-yloxy)-1 ,2-dimethyl-1/-/-benzimidazole-6-carboxylic acid (80 mg, 0.25 mmol, STEP 2 of Example 3) and (2R)-1-(methylamino)propan-2-oi hydrochloride (125 mmol, 0.99 mmol, J. Org. Chem. 1990, 5935.) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.27-7.12 (m, 4H), 7.09 (s, 1 H), 6.80 (s, 1 H), 5.63-5.44 (m, 1 H), 4.31-3.69 (m,

3H), 3.68 (s, 3H), 3.52-3.26 (m, 4H), 3.13 (s, 3H), 2.58 (s, 3H), 1.30-1.20 (m, 3H) ppm (-OH was not observed).

MS (ESI) m/z: 394 (M+H)⁺.

Example 13

4-(2,3-Dihvdro-1H-inden-2-yloxy)-Λ/,Λ/,2-trimethyl-1/-/-benzimidazole-6-carboxamide

STEP 1 : 2-(2.3-Dihydro-1H-inden-2-yloxy)-6-nitroaniline The title compound was prepared as an orange solid in 80% yield (20.1 g) from

2-amino-3-nitrophenol (14.4 g, 93.4 mmol) and indan-2-ol (18.8 g, 140 mmol) by the same manner in

Example 1.

¹H NMR (CDCI₃, 300 MHz) δ: 7.75 (d, J = 8.8 Hz, 1 H), 7.50-7.18 (m, 4H), 6.98 (d, J = 7.3 Hz, 1 H), 6.62 (dd,

J = 8.8, 7.3 Hz, 1 H), 6.30 (br s, 2H), 5.28-5.18 (m, 1 H), 3.41 (dd, J = 16.9, 5.9 Hz, 2H), 3.22 (dd, J = 16.9, 2.2 Hz, 2H) ppm.

STEP 2: 4-Bromo-2-(2,3-dihydro-1H-inden-2-yloxy)-6-nitroaniline

A mixture of 2-(2,3-dihydro-1H-inden-2-yloxy)-6-nitroaniline (20.1 g, 74.4 mmol, STEP 1) and

N-bromosuccinimide (14.6 g, 81.8 mmol) in acetonitrile (150 mL) was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, silica gel (90 g) was added to the mixture. The black slurry was concentrated in vacuum. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 10 : 1 as an eluent) to afford the title compound as an orange solid (13.2 g,

51 %).

¹H NMR (CDCI₃, 300 MHz) δ: 7.92 (d, J = 2.2 Hz, 1 H), 7.35-7.20 (m, 4H), 7.04 (d, J = 2.2 Hz, 1 H), 6.33 (br s, 2H), 5.26-5.16 (m, 1 H), 3.44 (dd, J = 16.9, 5.9 Hz, 2H), 3.23 (dd, J = 16.9, 2.2 Hz, 2H) ppm. STEP 3: Λ/-r4-Bromo-2-(2.3-dihydro-1 H-inden-2-yloxy)-6-nitrophenyllacetamide

4-Bromo-2-(2,3-dihydro-1H-inden-2-yloxy)-6-nitroaniline (10.0 g, 28.6 mmol, STEP 2) was dissolved in acetic anhydride (50 ml_) at 7O⁰C. To the orange solution was added concentrated sulfuric acid (0.1 ml_) in several portions. The reaction mixture was stirred for 5 minutes, cooled to O⁰C, and diluted with water (80 mL). The precipitated solid was filtered, washed with water (50 mL) and ether (50 ml_), and dried in vacuum to afford the title compound as a pale brown solid (8.4 g, 75%). ¹H NMR (CDCI₃, 300 MHz) δ: 7.67 (d, J = 2.2 Hz, 1 H), 7.35 (d, J = 2.2 Hz, 1 H), 7.33-7.21 (m, 4H), 6.33 (br s, 1 H), 5.28-5.18 (m, 1 H), 3.42 (dd, J = 16.9, 5.9 Hz, 2H), 3.19 (dd, J = 16.9, 2.2 Hz, 2H), 1.99 (s, 3H) ppm.

STEP 4: Λ/-r4-Cvano-2-(2.3-dihvdro-1 H-inden-2-yloxy)-6-nitrophenyllacetamide

A stirred mixture of Λ/-[4-bromo-2-(2,3-dihydro-1H-inden-2-yloxy)-6-nitrophenyl]acetamide (1.1 g, 2.8 mmol, STEP 3), zinc cyanide (0.33 g, 2.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) in Λ/,Λ/-dimethylformamide (8 mL) was heated to 170⁰C for 20 minutes in a microwave synthesizer (Biotage, Emrys Optimizer). The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate/methanol (10 : 1 , 50 mL x 3). The extracts were combined, washed with water (50 mL x 2) and brine (50 mL), dried over magnesium sulfate, and concentrated in vacuum. The solid was triturated with diethyl ether (20 mL), collected by filtration, and dried in vacuum to afford the title compound as a brown solid (0.75 g, 80%). ¹H NMR (DMSO-Of₆, 300 MHz) δ: 10.05 (s, 1 H), 8.06-7.97 (m, 2H), 7.32-7.16 (m, 4H), 5.49-5.37 (m, 1 H), 3.50 (dd, J = 17.6, 7.3 Hz, 2H), 3.15 (dd, J = 17.6, 2.9 Hz, 2H), 1.97 (s, 3H) ppm.

STEP 5: 4-(2,3-Dihvdro-1 H-inden-2-yloxy)-2-methyl-1rt-benzimidazole-6-carbonitrile

A mixture of Λ/-[4-cyano-2-(2,3-dihydro-1H-inden-2-yloxy)-6-nitrophenyl]acetamide (3.1 g, 9.2 mmol, STEP 4) and iron powder (2.6 g, 46 mmol) in acetic acid (50 mL) was heated to 120⁰C for 4 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (10 mL), and filtered through a pad of Celite. The filterate was concentrated in vacuum, diluted with sodium hydrogencarbonate aqueous solution (150 mL), dichloromethane (100 mL) and methanol (10 mL). The mixture was filtered through a pad of Celite. The organic layer was separated, and the aqueous layer was extracted with dichloromethane/methanol (10 : 1 , 100 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuum. The solid was dissolved with dichloromethane/methanol (10 : 1 , 100 mL), silica gel (12 g) was added to the solution, and the slurry was concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate as an eluent) to afford the title compound as a white solid (1.9 g, 70%). ¹H NMR (DMSO-CZ₆, 300 MHz) δ: 7.62 (s, 1 H), 7.33-7.26 (m, 2H), 7.24-7.12 (m, 3H), 5.61-5.48 (m, 1 H), 3.53-3.40 (m, 2H), 3.17-3.07 (m, 2H), 2.45 (s, 3H) ppm (NH was not observed). MS (ESI) m/z : 290 (M+H)⁺, 288 (M-H)^".

STEP 6: 4-(2,3-Dihvdro-1 H-inden-2-yloxy)-2-methyl-1/-/-benzimidazole-6-carboxylic acid hydrochloride A mixture of 4-(2,3-dihydro-1 /-/-inden-2-yloxy)-2-methyl-1 H-benzimidazole-6-carbonitrile (1.68 g,

5.81 mmol) in acetic acid (15 mL) and concentrated hydrochloric acid (25 mL) was refluxed for 4 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuum. The residual solid was triturated with ethyl acetate/diethyl ether (1 : 1 , 30 mL), collected by filtration, and dried in vacuum to afford the title compound as a pale gray solid (1.88 g, 93%). MS (ESI) m/z: 309 (M+H)⁺, 307 (M-H)^'.

STEP 7: 4-(2.3-Dihvdro-1 H-inden-2-yloxy)-Λ/,Λ/,2-trimethyl-1 H-benzimidazole-6-carboxamide

The title compound was prepared as a white solid in 32% yield (185 mg) from 4-(2,3-dihydro-1H-inden-2-yloxy)-2-methyl-1/-/-benzimidazole-6-carboxylic acid hydrochloride (600 mg, 1.74 mmol, STEP 6) and dimethylamine hydrochloride (284 mg, 3.48 mmol) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 300 MHz) δ: 7.28-7.12 (m, 5H), 6.78 (s, 1 H), 5.44-5.27 (m, 1 H), 3.35 (dd, J = 16.9, 5.9 Hz, 2H), 3.27-2.98 (m, 8H), 2.44 (s, 3H) ppm (NH was not observed). MS (ESI) m/z: 336 (M+H)\ 334 (M-H)^'.

Example 14

4-r(5-Fluoro-2.3-dihvdro-1H-inden-2-yl)oxy1-Λ/,Λ/,1,2-tetramethyl-1H-benzimidazole-6-carboxamide

STEP 1 : 2-Bromo-6-fluoroindan-1-ol

To a stirred solution of 5-fluoro-1/-/-indene (5.30 g, 39.5 mmol, Bulletin De La Societe Chimique De France 1973, 3092.) in tetrahydrofuran (130 mL) and water (40 mL) was added Λ/-bromoacetamide (5.45 g, 39.5 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 15 hours, and evaporated to remove tetrahydrofuran. The residue was diluted with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum. The residual solid was triturated with hexane, and collected by filtration to give the title compound as a white solid (8.26 g, 90%).

¹H NMR (CDCI₃, 270 MHz) δ: 7.05-7.24 (m, 2H), 6.86-7.05 (m, 1 H), 5.28 (s, 1 H), 4.27 (q, J = 5.4 Hz, 1 H), 3.53 (dd, J = 8.1 , 5.4 Hz, 1 H), 3.17 (dd, J = 8.1 , 5.4 Hz, 1 H), 2.60 (s, 1 H) ppm.

STEP 2: 3-Fluoro-6,6a-dihvdro-1a/-/-indenoH ,2-tfloxirene To a solution of 2-bromo-6-fluoroindan-1-ol (8.26 g, 35.7 mmol, STEP 1 ) in diethyl ether (300 mL) was added potassium hydroxide (12.5 g, 179 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours, quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum to afford the title compound as a yellow solid (4.75 g, 89%). ¹H NMR (CDCI₃, 300 MHz) δ: 7.13-7.27 (m, 2H), 6.95 (dt, J = 9.0, 3.0 Hz, 1 H), 4.21-4.24 (m, 1 H), 4.13- 4.16 (m, 1 H), 3.17 (d, J = 18.0 Hz, 1 H), 2.93 (d, J = 18.0 Hz, 1 H) ppm. STEP 3: 5-Fluoroindan-2-ol

To a stirred solution of 3-fluoro-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene (4.75 g, 31.6 mmol, STEP

2) in diethyl ether (200 mL) was added diisobutylaluminium hydride (37.0 mL, 0.94 M in hexane, 34.8 mmol) at O⁰C. The reaction mixture was stirred at the same temperature for 20 minutes, quenched with water (32 mL), and stirred for 1 hour at room temperature. To the mixture were added sodium fluoride

(36.0 g, 85.7 mmol), Celite (26.0 g) and ethyl acetate (200 mL). The suspension was stirred for 1 hour at room temperature, and filtered through a pad of Celite. The filtrate was concentrated in vacuum, and the residue was purified by column chromatography on silica gel (hexane : ethyl acetate gradient elution from 10 : 1 to 2 : 3) to afford the title compound as a white solid (4.06 g, 84%).

¹H NMR (CDCI₃, 270 MHz) δ: 7.14-7.19 (m, 1 H), 6.82-6.95 (m, 2H), 4.72 (s, 1 H), 3.13-3.24 (m, 2H), 2.83-2.93 (m, 2H), 1.74 (s, 1 H) ppm.

STEP 4: 4-r(5-Fluoro-2,3-dihvdro-1 H-inden-2-yl)oxyl-Λ/.Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide)

The title compound was prepared as a white solid in 38% yield (0.99 g) from

4-hydroxy-Λ/,Λ/,1 _>2-tetramethyl-1 H-benzimidazole-6-carboxamide (1.2 g, 5.1 mmol, WO 04/054984) and

5-fluoroindan-2-ol (1.6 g, 10 mmol, STEP 3) by the same manner in STEP 1 of Example 1.

¹H NMR (CDCI₃, 300 MHz) δ 7.00-7.32 (m, 1 H), 7.05 (s, 1 H), 6.72-6.97 (m, 2H), 6.75 (s, 1 H), 5.49-5.59 (m, 1 H), 3.71 (s, 3H), 3.25-3.50 (m, 4H), 3.10 (br s, 6H), 2.59 (s, 3H) ppm.'

MS (ESI) m/z: 368 (M+H)⁺.

Example 15

(^^-rfS-Fluoro-Σ.S-dihvdro-IH-inden-Σ-vDoxyi-yv.Λ/.I.Σ-tetramethyl-ify-bθnzimidazole-e-carboxamid e (fraction -1) and Example 16

(+)-4-r(5-Fluoro-2,3-dihvdro-1H-inden-2-yl)oxy1-Λ/,Λ/,1,2-tetramethyl-1f/-benzimidazole-6-carboxami de (fraction-2)

The fraction-1 (370 mg) and fraction-2 (365 mg) were prepared from racemic 4-[(5-fluoro-2,3-dihydro-1 A7-inden-2-yl)oxy]-Λ/,Λ/,1 ,2-tetramethyl-1 W-benzimidazole-6-carboxamide (985 mg, STEP 4 of Example 14) by HPLC as follows. Isolation condition

Column: CHIRALCEL OJ-H (20 mm x 250 mm, DAICEL) Mobile phase: n-Hexane / Ethanol / Diethylamine (90 / 10 / 0.1 ) Flow rate: 20 mL/min

(-)-4-r(5-Fluoro-2.3-dihvdro-1 /-/-inden-2-yl)oxyl-Λ/./\/,1.2-tetramethyl-1/-/-benzimidazole-6-carboxamide (fraction-1 )

NMR: spectrum data were identical with those of the racemate optical rotation: [α]_D ²⁴ = -0.64 ° (c = 1.0, Methanol) retention time: 23 min

(+)-4-r(5-Fluoro-2.3-dihvdro-1H-inden-2-yl)oxy1-Λ/.Λ/,1.2-tetramethyl-1H-benzimidazole-6-carboxamide (fraction-2)

NMR: spectrum data were identical with those of the racemate optical rotation: [α]_D ²⁴ = +1.37 ° (c = 1.0, Methanol) retention time: 29 min

Example 17

4-f(5-Fluoro-2,3-dihydro-1 H-inden-2-yl)oxy1-1 ,2-dimethyl-6-(1 -pyrrolidinylcarbonyl)-1 H-benzimidaz ole

STEP 1 : Methyl 4-r(5-fluoro-2.3-dihvdro-1 H-inden-2-yl)oxyl-1 ,2-dimethyl-1 H-benzimidazole-6-carboxylate The title compound was prepared as a mixture of triphenylphosphineoxide (660 mg, crude) from methyl 4-hydroxy-1 ,2-dirnethyl-1H-benzimidazole-6-carboxylate (1.12 g, 5.10 mmol, WO 04/054984) and 5-fluoroindan-2-ol (1.57 g, 10.3 mmol, STEP 3 of Example 14) by the same manner in STEP 1 of Example 3. MS (ESI) m/z: 355 (M+H)⁺.

STEP 2: 4-f(5-Fluoro-2,3-dihvdro-1 /-/-inden-2-yl)oxy1-1 ,2-dimethyl-1 /-/-benzimidazole-6-carboxylic acid

The title compound was prepared as a white solid in 6% yield for 2 steps (110 mg) from methyl

4-[(5-fluoro-2,3-dihydro-1/-/-inden-2-yl)oxy]-1 ,2-dimethyl-1/-/-benzimidazole-6-carboxylate (660 mg, crude, STEP 1 ) by the same manner in STEP 2 of Example 3.

¹H NMR (DMSO-Qf₆, 300 MHz) δ: 12.73 (s, 1 H), 7.74 (s, 1 H), 7.23-7.34 (m, 2H), 7.13 (d, J = 12.0 Hz, 1 H),

6.99 (t, J = 9.0 Hz, 1 H), 5.66 (br s, 1 H), 3.74 (s, 3H), 3.36-3.43 (m, 2H), 3.03-3.13 (m, 2H), 2.52 (s, 3H), ppm.

MS (ESI) m/z: 341 (M+H)⁺, 339 (M+Hf.

STEP 3: 4-r(5-Fluoro-2,3-dihydro-1 H-inden-2-yl)oxy1-1 ,2-dimethyl-6-(1 -pyrrolidinylcarbonyl)-1 H-benzimid azole

The title compound was prepared as a white solid in 86% yield (50 mg) from

4-[(5-fluoro-2,3-dihydro-1 /-/-inden-2-yl)oxy]-1 ,2-dimethyl-1/-/-benzimidazole-6-carboxylic acid (50 mg, 5.1 mmol, STEP 2) by the same manner in STEP 3 of Example 3.

¹H NMR (CDCI₃, 270 MHz) δ: 7.06-7.23 (m, 1 H), 7.15 (s, 1 H), 6.57-7.06 (m, 2H), 6.86 (s, 1 H), 5.21-5.64 (m,

1 H), 3.60-3.79 (m, 2H), 3.71 (s, 3H), 3.60-3.79 (m, 2H), 3.16-3.60 (m, 4H), 2.59 (s, 3H), 1.81-2.12 (m, 4H) ppm.

MS (ESI) m/z: 394 (M+H)⁺.

Example 18 4-IY1 -Hvdroxv-2.3-dihvdro-1 H-inden-2-v0oxv1-Λ/.Λ/,1 ,2-tetramethvl-1 H-benzimidazole-6-carboxamid

STEP 1 : Λ/.Λ/.i ^-Tetramethyl-^rfi-oxo-Σ.S-dihvdro-IH-inden^-v^oxyl-IH-benzimidazole-G-carboxamide To a stirred suspension of 4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide (160 mg, 0.69 mmol, WO 04/054984) in Λ/,Λ/-dimethylformamide (4.0 mL) was added sodium hydride (60% dispersion in mineral oil, 33 mg, 0.83 mmol) at room temperature. After the mixture was stirred for 10 minutes, 2-bromoindan-1-one (289 mg, 1.37 mmol) was added to the mixture at room temperature. The reaction mixture was warmed to 70⁰C for 15 hours, quenched with water, and extracted with ethyl acetate (20 mL x 5). The extracts were combined, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate : methanol gradient elution from 10 : 1 to 3 : 1 ) to afford the title compound as a white solid (60 mg, 24%).

¹H NMR (CDCI₃, 270 MHz) δ: 7.81 (d, J = 8.1 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.38-7.47 (m, 2H), 7.13 (s, 1 H), 6.98 (s, 1 H), 5.68-5.72 (m, 1H), 3.70-3.79 (m, 1 H), 3.72 (s, 3H), 3.38 (dd, J = 16.2, 5.4 Hz, 1 H), 3.10 (s, 6H), 2.59 (s, 3H) ppm. MS (ESI) m/z: 364 (M+H)⁺.

STEP 2: 4-r(1-Hvdroxy-2,3-dihvdro-1H-inden-2-yl)oxyl-Λ/.Λ/.1.2-tetramethyl-1H-benzimidazole-6-carboxa mide To a solution of Λ/,Λ/,1 ,2-tetramethyl-4-[(1-oxo-2,3-dihydro-1H-inden-2-yl)oxy]-1H- benzimidazole-6-carboxamide (30 mg, 0.083 mmol, STEP 1) in methanol (1.0 mL) was added sodium borohydride (3.1 mg, 0.083 mmol) at 0⁰C. The reaction mixture was stirred for 30 minutes, quenched with water, and evaporated to remove methanol. The precipitated solid was collected by filtration, and dried in vacuum to afford the title compound as cis/trans (7:1 ) mixture (23 mg, 74%, white solid). MS (ESI) m/z: 366 (M+H)⁺.

The Examples 19 to 21 were prepared according to the procedure described in Example 13, and the following optical resolution (Example 22 and 23).

All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.

Claims

CLAIMS 1. A compound of the following formula (I):

a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein: -A- represents -CH₂- or -CH₂-CH₂-;

X represents an oxygen atom or NH;

R¹ represents a hydrogen atom or a C₁-C₆ alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and a C₁-C₆ alkoxy group; R² represents a C₁-C₆ alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and a C₁-C₆ alkoxy group; R³ and R⁴ independently represent a hydrogen atom or, a C₁-C₆ alkyl or a C₃-C₇ cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C₁-C₆ alkoxy group and a C₃-C₇ cycloalkyl group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a Ci-C₆ alkyl group, a C₁-C₆ acyl group, and a hydroxy C₁-C₆ alkyl group; R R⁵⁵ rreeppresents a hydrogen atom, a hydroxy group, a C₁-C₆ alkyl group or a C₁-C₆ alkoxy group; and R⁶, R⁷, R⁸ and R⁹ independently represent a hydrogen atom or a halogen atom.

2. The compound or the pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein

X is an oxygen atom; R¹ is a hydrogen atom or a C₁-C₆ alkyl group; R² is a C₁-C₆ alkyl group;

R³ and R⁴ are independently a C₁-C₆ alkyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group and a C₁-C₆ alkoxy group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form an azetidinyl, a pyrrolidinyl or a piperazinyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ acyl group and a hydroxy C₁-C₆ alkyl group; and R⁵ is a hydrogen atom or a hydroxy group.

3. The compound or the pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein -A- is -CH₂-I

X is an oxygen atom; R¹ is a hydrogen atom or methyl group;

R², R³ and R⁴ are a methyl group; or R³ and R⁴ taken together with the nitrogen atom to which they are attached form an azetidinyl or a pyrrolidinyl group being unsubstituted or substituted with a hydroxy C₁-C₂ alkyl group;

R⁵, R⁶ and R⁹ are a hydrogen atom; and R⁷ and R⁸ are independently a hydrogen atom or a halogen atom;.

4. The compound of claim 1 , which is selected from:

4-(2,3-Dihydro-1H-inden-2-yloxy)-Λ/,Λ/,1 ,2-tetramethyl-1/-/-benzimidazole-6-carboxamide; 4-(2,3-Dihydro-1/-/-inden-2-yloxy)-1 ,2-dimethyl-6-(pyrrolidin-1-ylcarbonyl)-1/-/-benzimidazole; 4-(2,3-Dihydro-1 W-inden-2-yloxy)-Λ/,Λ/,2-trimethyl-1 H-benzimidazole-6-carboxamide;

4-[(5-Fluoro-2,3-dihydro-1/-/-inden-2-yl)oxy]-Λ/,Λ/,1 ,2-tetramethyl-1/-/-benzimidazole-6-carboxamide; or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition as claimed in claim 5 further comprising other pharmacologically active agent(s).

7. A method for the treatment of a condition mediated by acid pump inhibitory activity in a mammalian subject including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4.

8. The method as claimed in claim 7, wherein said condition is 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, hypersalivation, airway disorders or asthma.

9. A use of the compound of formula (I) or the pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, for the manufacture of a medicament for the treatment of a condition mediated by acid pump inhibitory activity.

10. The use as claimed in claim 9, wherein said condition is 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, hypersalivation, airway disorders or asthma.