HK1144554B - Process for the preparation of compounds useful as inhibitors of sglt - Google Patents

Description

Process for the preparation of compounds useful as SGLT inhibitors

Cross reference to related patent applications

This application claims us provisional application 60/971,067 filed on 9/10 of 2007; and priority of U.S. provisional application 61/018,822 filed on 3.1.2008, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to a novel process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporters (SGLT) located in the intestine or kidney.

Background

Diet therapy and exercise therapy are essential in the treatment of diabetes. When these therapies fail to effectively control the condition of the patient, additional insulin or oral antidiabetic agents are required to treat diabetes. Currently, as antidiabetic agents, there have been used: biguanide compounds, sulfonylurea compounds, insulin resistance improvers and alpha-glucosidase inhibitors. However, these antidiabetic agents have various side effects. For example, biguanides cause lactic acidosis, sulfonylureas cause significant hypoglycemia, insulin resistance improvers cause edema and heart failure, and α -glucosidase inhibitors cause abdominal distension and diarrhea. Under these circumstances, it is necessary to develop a new drug for treating diabetes mellitus without these side effects.

Recently, hyperglycemia has been reported to be associated with the onset and progressive impairment of diabetes, the theory of glucotoxicity. That is, chronic hyperglycemia may lead to decreased insulin secretion and further decreased insulin sensitivity, resulting in increased blood glucose concentration leading to worsening of diabetes itself [ see Diabetologia, volume 28, page 119 (1985); diabetes Care, volume 13, page 610 (1990), etc. ]. Therefore, by treating hyperglycemia, the aforementioned self-worsening cycle can be blocked, thereby making it possible to prevent or treat diabetes.

As one of the methods for treating hyperglycemia, it is considered that an excessive amount of glucose is directly excreted into urine to normalize the blood glucose concentration. For example, glucose reabsorption by the kidney can be inhibited by inhibiting sodium-dependent glucose transporters located in the renal proximal convoluted tubules, thereby facilitating excretion of glucose into the urine resulting in a decrease in blood glucose levels. In fact, it has been demonstrated that continuous subcutaneous administration of phlorizin having SGLT inhibitory activity to diabetic animal models normalizes hyperglycemia and maintains its blood glucose level normal for a longer period of time, thereby improving insulin secretion and insulin resistance [ see Journal of Clinical Investigation, volume 79, page 1510 (1987); volume 80, page 1037 (1987); volume 87, page 561(1991), et al.

Furthermore, by treating a diabetic animal model with an SGLT inhibitor for a long period of time, the insulin secretion response and insulin sensitivity of the animal are improved without causing any adverse effect on the kidney or imbalance in blood electrolyte level, and therefore, the onset and development of diabetic nephropathy and diabetic neuropathy can be prevented [ see Journal of Medicinal Chemistry, volume 42, page 5311 (1999); british Journal of Pharmacology, Vol.132, p.578 (2001), Ueta, Ishihara, Matsumoto, Oku, Nawano, Fujita, Saito, Arakawa, Life Sci., pay-per-impression (2005), etc. ].

As can be seen from the above, SGLT inhibitors are expected to improve insulin secretion and insulin resistance by lowering blood glucose levels in diabetic patients, and further prevent onset and progression of diabetes and diabetic complications.

Disclosure of Invention

The present invention relates to processes for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

wherein ring a and ring B are one of the following:

(1) ring a is an optionally substituted unsaturated monocyclic heterocycle, and ring B is an optionally substituted unsaturated monocyclic heterocycle, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; or

(2) Ring a is an optionally substituted phenyl ring and ring B is an optionally substituted unsaturated monocyclic heterocycle, or an optionally substituted unsaturated fused heterobicyclic ring, wherein Y is connected to the heterocycle of the fused heterobicyclic ring; or

(3) Ring a is an optionally substituted unsaturated fused heterobicyclic ring, wherein both the sugar moiety X- (sugar) and the-Y- (ring B) moiety are located on the same heterocycle of the fused heterobicyclic ring, and ring B is an optionally substituted unsaturated monocyclic heterocycle, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring;

x is a carbon atom;

y is- (CH)₂)_n-; wherein n is 1 or 2;

provided that, in ring a, X is part of an unsaturated bond;

the method comprises the following steps:

reacting a compound of formula (V) with a compound of formula (VI-S) in the presence of an alkyllithium in an organic solvent at a temperature in the range of from about 0 ℃ to about-78 ℃; to produce the corresponding compound of formula (VII);

reacting said compound of formula (VII) with BF₃OEt₂In the presence of a trialkylsilane in an organic solvent to give the corresponding compound of formula (VIII); and

reacting the compound of formula (VIII) with acetic anhydride or acetyl chloride in the presence of an organic base, either without addition of a solvent or in an organic solvent, to yield the corresponding compound of formula (IX); and

deprotecting the compound of formula (IX) to give the corresponding compound of formula (I).

In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I-S)

Or a pharmaceutically acceptable salt thereof; (also known as 1- (β -D-glucopyranosyl) -4-methyl-3 [5- (4-fluorophenyl) -2-thienylmethyl ] benzene);

the method comprises the following steps:

reacting a compound of formula (V-S) with a compound of formula (VI-S) in the presence of an alkyllithium in an organic solvent at a temperature in the range of from about 0 ℃ to about-78 ℃; to produce the corresponding compound of formula (VII-S);

reacting said compound of formula (VII-S) with BF₃OEt₂In the presence of a trialkylsilane in an organic solvent to give the corresponding compound of formula (VIII-S);

reacting the compound of formula (VIII-S) with acetic anhydride or acetyl chloride in the presence of an organic base, either without addition of a solvent or in an organic solvent, to yield the corresponding compound of formula (IX-S); and

deprotecting the compound of formula (IX-S) to give the corresponding compound of formula (I-S).

The invention also relates to a process for recrystallizing the compounds of formula (I-S). In one embodiment of the invention, the compound of formula (I-S) is recrystallized from a mixture of ethyl acetate and water using heptane as the anti-solvent.

The invention also relates to crystalline forms of the compounds of formula (I-S),

characterized by the powder X-ray diffraction pattern peaks described herein. In one embodiment, the present invention relates to a crystalline form of the compound of formula (I-S) prepared by recrystallizing the compound of formula (I-S) from a mixture of ethyl acetate and water using heptane as the antisolvent.

In another embodiment, the present invention relates to methods for preparing compounds of formula (I-K)

Or a pharmaceutically acceptable salt thereof; (also known as 1- (beta-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl) benzene),

the method comprises the following steps:

reacting a compound of formula (V-K) with a compound of formula (VI-S) in the presence of an alkyllithium in an organic solvent at a temperature in the range of from about 0 ℃ to about-78 ℃; to give the corresponding compound of formula (VII-K);

deprotecting the compound of formula (VII-K) to give the corresponding compound of formula (X-K);

reacting said compound of formula (X-K) with BF₃OEt₂In the presence of a trialkylsilane in an organic solvent to give the corresponding compound of formula (VIII-K);

reacting the compound of formula (VIII-K) with acetic anhydride or acetyl chloride in the presence of an organic base, either without addition of a solvent or in an organic solvent, to yield the corresponding compound of formula (IX-K); and

deprotecting the compound of formula (IX-K) to give the corresponding compound of formula (I-K).

The invention further relates to compounds of the formula (I-K)

Or a crystalline form of a pharmaceutically acceptable salt thereof; (also known as 1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl ] benzene), its crystalline form can be characterized by its powder X-ray diffraction pattern peaks, as described herein. In one embodiment, the present invention relates to a process for the preparation and/or isolation of a crystalline form of a compound of formula (I-K).

The invention also relates to a product prepared according to any of the methods described herein.

An example of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a product prepared according to any of the methods described herein. An example of the invention is a pharmaceutical composition prepared by mixing a product prepared according to any of the methods described herein with a pharmaceutically acceptable carrier. An example of the invention is a process for preparing a pharmaceutical composition comprising admixing a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.

An example of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of a compound of formula (I-S) or a crystalline form of a compound of formula (I-K) as described herein. An example of the invention is a pharmaceutical composition prepared by mixing a crystalline form of a compound of formula (I-S) or a crystalline form of a compound of formula (I-K) as described herein with a pharmaceutically acceptable carrier. An example of the invention is a process for preparing a pharmaceutical composition comprising mixing a crystalline form of a compound of formula (I-S) or a crystalline form of a compound of formula (I-K) as described herein with a pharmaceutically acceptable carrier.

The present invention illustrates a method of treating a disorder mediated by SGLT (including treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension), comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds, crystalline forms, or pharmaceutical compositions described above.

The present invention also illustrates a method of treating type 1 and type 2 diabetes comprising administering to a subject in need of treatment a therapeutically effective amount of any of the compounds, crystalline forms, or pharmaceutical compositions described above, alone or in combination with at least one anti-diabetic agent, agent for treating diabetic complications, anti-obesity agent, anti-hypertensive agent, anti-platelet agent, anti-atherosclerotic agent, and/or hypolipidemic agent.

Drawings

Figure 1 shows a representative XRD pattern of a crystalline form of a compound of formula (I-S).

FIG. 2 shows a representative X-ray powder diffraction pattern of a crystalline form of the compound of formula (I-K) as measured on a RINT-ULTIMA3(Rigaku, Tokyo, Japan) X-ray diffractometer.

FIG. 3 shows a representative X-ray powder diffraction pattern of the crystalline form of the compound of formula (I-K) as measured on an X-ray diffractometer X' PertProMPD, Philips X-ray diffractometer. FIG. 4 shows a representative infrared spectrum of crystals of the compound of formula (I-K) in mineral oil.

FIG. 5 shows a representative infrared spectrum of crystals of the compound of formula (I-K) in potassium bromide compressed tablets.

Detailed Description

The present invention relates to a process for the preparation of a compound of formula (I),

wherein X, Y, ring A and ring B are as defined herein. The compounds of formula (I) are shown to have inhibitory activity against sodium-dependent glucose transporters present in the intestine and kidney of mammalian species and are useful in the treatment of diabetes or diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and delayed wound healing. One skilled in the art will further recognize that any of the compounds or crystalline forms described herein may be used in combination with one or more other antidiabetic agents, antihyperglycemic agents and/or agents used to treat other diseases, as desired; and may be administered in the same dosage form or in a separate oral dosage form or by injection.

PCT publication WO2005/012326 discloses a class of compounds which are sodium-dependent glucose transporter (SGLT) inhibitors, including compounds of formula (I-K), also known as 1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene, and compounds of formula (I-S), also known as 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene. PCT publication WO2005/012326 also discloses the use of such compounds, including compounds of formula (I-K) and compounds of formula (I-S), in the treatment of diabetes, obesity, diabetic complications, and the like.

The present invention further relates to compounds of formula (I-S) or a pharmaceutically acceptable salt thereof; and a process for the preparation of a compound of formula (I-K) or a pharmaceutically acceptable salt thereof.

The invention further relates to novel crystalline forms of the compounds of formula (I-S) and novel crystalline forms of the compounds of formula (I-K), as detailed herein. The invention further relates to processes for the preparation of the compounds of formula (I-S) and crystalline forms of the compounds of formula (I-K), as detailed herein.

The term "halogen atom" or "halogen" means chlorine, bromine and fluorine, and preferably chlorine and fluorine.

The term "alkyl" means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms. Preferably a linear or branched alkyl group having 1 to 6 carbon atoms, more preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl and the various branched isomers thereof. Further, the alkyl group may be optionally and independently substituted with 1 to 4 substituents listed below, as necessary.

The term "alkylene group" or "alkylene" means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms. Preferably a linear or branched alkylene group having 1 to 6 carbon atoms, and more preferably a linear or branched alkylene group having 1 to 4 carbon atoms. Examples thereof are methylene, ethylene, propylene, trimethylene and the like. If necessary, the alkylene group may be optionally substituted in the same manner as the above-mentioned "alkyl group". When an alkylene group as defined above is attached to two different carbon atoms of the phenyl ring, they form together with the attached carbon atoms a fused five-, six-or seven-membered carbocyclic ring, which may be optionally substituted by one or more substituents as defined below.

The term "alkenyl" means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond. Preferred alkenyl groups are linear or branched alkenyl groups having 2 to 6 carbon atoms, and more preferably linear or branched alkenyl groups having 2 to 4 carbon atoms. Examples thereof are vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl and the like. The alkenyl group may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary.

The term "alkenylene" means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond. It is preferably a straight-chain or branched alkenylene group having 2 to 6 carbon atoms, and more preferably an alkenylene group having 2 to 4 carbon atoms. Examples thereof are vinylene group, propenylene group, butadienylene group and the like. The alkenylene group may be optionally substituted with 1 to 4 substituents mentioned below, if necessary. When an alkenylene group as defined above is attached to two different carbon atoms of a phenyl ring, they form, together with the attached carbon atoms, a fused five-, six-or seven-membered carbocyclic ring (e.g. a fused phenyl ring), and may be substituted by one or more substituents as defined below.

The term "alkynyl" means a straight or branched monovalent hydrocarbon chain having at least one triple bond. Preferred alkynyl groups are straight or branched chain alkynyl groups having 2 to 6 carbon atoms, and more preferably straight or branched chain alkynyl groups having 2 to 4 carbon atoms. Examples thereof are 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecyynyl, 4-dodecenyl and the like. The alkynyl group may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary.

The term "cycloalkyl" means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and more preferably a monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Examples thereof are monocycloalkyl and bicycloalkyl radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. These groups may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary. The cycloalkyl group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) And the condensed saturated hydrocarbon ring and the condensed unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "cycloalkylene" means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and preferably a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Examples thereof are monocyclic alkylene and bicyclic alkylene such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like. These groups may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary. Further, the cycloalkylene group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) And the condensed saturated hydrocarbon ring and the condensed unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "cycloalkenyl" means a mono-or bicyclic monovalent radical having 4 to 12 carbon atoms and having at least one double bondA saturated hydrocarbon ring. Preferred cycloalkenyl groups are monocyclic unsaturated hydrocarbon groups having 4 to 7 carbon atoms. Examples thereof are monocyclic alkenyl groups such as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group and the like. These groups may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary. Further, the cycloalkenyl group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) And the condensed saturated hydrocarbon ring and the condensed unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "cycloalkynyl" means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms and having at least one triple bond. Preferred cycloalkynyl groups are monocyclic unsaturated hydrocarbon groups having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl such as cyclooctynyl, cyclodecynyl. These groups may be optionally substituted with 1 to 4 substituents mentioned below, if necessary. Further, the cycloalkynyl group may be optionally and independently condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring, if necessary₂) And the condensed saturated hydrocarbon ring or the condensed unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "aryl" means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof are phenyl group, naphthyl group (including 1-naphthyl group and 2-naphthyl group). These groups may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary. Further, the aryl group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) And the condensed saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "unsaturated monocyclic heterocyclic ring" means an unsaturated hydrocarbon ring containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, and preferably a 4-to 7-membered saturated or unsaturated hydrocarbon ring containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms. Examples are pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 4, 5-dihydrooxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole and the like. Among them, pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, oxazole and thiazole are preferably used. The "unsaturated monocyclic heterocycle" may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "unsaturated fused heterobicyclic ring" means a hydrocarbon ring composed of a saturated or unsaturated hydrocarbon ring condensed with the above-mentioned unsaturated monocyclic heterocyclic ring, wherein said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring, if necessary₂. "unsaturated fused heterobicyclic ring" includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydroisoquinoline, and the like. Furthermore, "heterocycle" also includes possible N or S-oxides thereof.

The term "heterocyclyl" means the monovalent group of the unsaturated mono-heterocyclic ring or unsaturated fused heterobicyclic ring mentioned above, and the monovalent group of the saturated type of the unsaturated mono-heterocyclic ring or unsaturated fused heterobicyclic ring mentioned above. The heterocyclic group may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary.

The term "alkanoyl" means formyl and the group formed by bonding an "alkyl" group to a carbonyl group.

The term "alkoxy" means a group formed by bonding an "alkyl" group to an oxygen atom.

Substituents for the above-mentioned groups include, for example, a halogen atom (fluorine, chlorine, bromine), nitro group, cyano group, oxo group, hydroxyl group, mercapto group, carboxyl group, sulfonic group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidene methyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkenyloxy group, cycloalkynyloxy group, aryloxy group, heterocyclyloxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl group, cycloalkynylcarbonyl group, arylcarbonyl group, heterocyclylcarbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group; aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkoxycarbonyloxy, alkynylthio, cycloalkylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkylcarbamoyl, mono-or di-aryl, Alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl. Each of the above-mentioned groups may be optionally substituted with these substituents.

Further, terms such as haloalkyl, halogenated lower alkyl, halogenated alkoxy, halogenated lower alkoxy, halogenated phenyl or halogenated heterocyclic group mean that alkyl, lower alkyl, alkoxy, lower alkoxy, phenyl or heterocyclic group (hereinafter referred to as alkyl and the like) is substituted with one or more halogen atoms, respectively. Preferred are alkyl groups substituted with 1 to 7 halogen atoms and the like, and more preferred are alkyl groups substituted with 1 to 5 halogen atoms and the like. Likewise, terms such as hydroxyalkyl, hydroxy-lower alkyl, hydroxyalkoxy, hydroxy-lower alkoxy and hydroxyphenyl mean alkyl substituted by one or more hydroxy groups, and the like. Preferred are alkyl groups substituted with 1 to 4 hydroxyl groups and the like, and more preferred are alkyl groups substituted with 1 to 2 hydroxyl groups and the like. Furthermore, terms such as alkoxyalkyl, lower alkoxyalkyl, alkoxy-lower alkyl, lower alkoxy-lower alkyl, alkoxyalkoxy, lower alkoxyalkoxy, alkoxy-lower alkoxy, lower alkoxy-lower alkoxy, alkoxyphenyl, and lower alkoxyphenyl mean alkyl substituted with one or more alkoxy groups, and the like. Preferred are alkyl groups substituted with 1 to 4 alkoxy groups and the like, and more preferred are alkyl groups substituted with 1 to 2 alkoxy groups and the like.

The terms "aralkyl" and "arylalkoxy" used alone or as part of another group refer to the alkyl and alkoxy groups described above with an aryl substituent.

Unless otherwise defined, the term "lower" used in the present specification for the definition of chemical formula refers to a straight or branched carbon chain having 1 to 6 carbon atoms. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms.

The term "prodrug" means an ester or carbonate formed by reacting one or more hydroxyl groups of a compound of formula I with an acylating agent substituted with an alkyl, alkoxy, or aryl group in a conventional manner to form an acetate, pivalate, methyl carbonate, benzoate, and the like. In addition, prodrugs also include esters or amides, which are likewise formed by reacting one or more of the hydroxyl groups of the compounds of formula I with an α -amino acid or β -amino acid, etc., in a conventional manner using a condensing agent.

Pharmaceutically acceptable salts of the compounds of formula I include, for example, salts with alkali metals such as lithium, sodium, potassium, and the like; salts with alkaline earth metals such as calcium, magnesium, and the like; salts with zinc or aluminum; salts with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methylglucamine, triethanolamine and dehydroabietylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.; or salts with acidic amino acids such as aspartic acid, glutamic acid, and the like.

The compounds of the present invention also include mixtures of stereoisomers, or each pure or substantially pure isomer. For example, the present compounds may optionally have one or more asymmetric centers located at a carbon atom, wherein the carbon atom contains any one of the substituents. Thus, the compounds of formula I may exist as enantiomers or diastereomers or mixtures thereof. When the present compound (I) contains a double bond, the present compound may exist in the form of geometric isomers (cis-compound, trans-compound), and when the present compound (I) contains an unsaturated bond such as carbonyl, the present compound may exist in the form of tautomer, and the present compound also includes these isomers or a mixture thereof. The starting compounds may be used in the preparation of the present compounds in the form of racemic mixtures, enantiomers or diastereomers. When the present compounds are obtained in diastereomeric or enantiomeric forms, they can be separated by conventional methods such as chromatography or fractional crystallization.

Further, the present compound (I) includes an intramolecular salt, hydrate, solvate, or polymorph thereof.

Examples of the optionally substituted unsaturated monocyclic heterocyclic ring in the present invention include unsaturated monocyclic heterocyclic rings which may be optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen atom, nitro group, cyano group, oxo group, hydroxyl group, mercapto group, carboxyl group, sulfonic group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidene methyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, cycloalkenyloxy group, cycloalkynyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkynylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, alkanoyloxy group, alkenylcarbonyloxy group, alkynylcarbonyloxy group, cycloalkylcarbonyloxy group, cycloalkenylcarbonyloxy group, cycloalkynylcarbonyloxy group, arylcarbonyloxy group, heterocyclic carbonyloxy group, Alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, cycloalkylthio, arylthio, heterocyclylthio, alkoxythio, alkoxy, Alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl, wherein each substituent may be optionally further substituted by these substituents.

Examples of the unsaturated fused heterobicyclic ring which may be optionally substituted in the present invention include unsaturated fused heterobicyclic rings optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen atom, nitro group, cyano group, oxo group, hydroxyl group, mercapto group, carboxyl group, sulfonic group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylene-methyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkoxy group, cycloalkenyloxy group, cycloalkynyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenyl-carbonyl group, cycloalkynylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxy-carbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxy-carbonyl group, cycloalkynyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, alkanoyloxy group, alkenylcarbonyloxy group, alkynylcarbonyloxy group, cyclo-alkylcarbonyloxy group, cycloalkenyl carbonyloxy group, cyclo-alkynylcarbonyloxy group, arylcarbonyloxy, heterocyclyl-carbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoyl-amino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkyl-sulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cyclo-alkenylsulfinyl, cycloalkynylsulfinyl, alkynylsulfinyl, alkynylthio, cycloalkylthio, cycloalkynylthio, amino, mono-or di-alkanoylamino, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenyl-sulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl, wherein each substituent may be optionally further substituted by these substituents.

Examples of the benzene ring which may be optionally substituted in the present invention include benzene rings which may be optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, sulfonic group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkoxy group, cycloalkenyloxy group, cycloalkynyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl group, cycloalkynylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group; aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkoxycarbonyloxy, alkynylthio, cycloalkylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkylcarbamoyl, mono-or di-aryl, Alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylene, alkyleneoxy, alkylenedioxy, and alkenylene, wherein each substituent may be optionally further substituted by these substituents.

Further, examples of the optionally substituted benzene ring include a benzene ring substituted with an alkylene group to form a condensed carbocyclic ring together with the attached carbon atom, and a benzene ring substituted with an alkenylene group to form a condensed carbocyclic ring together with the attached carbon atom, such as a condensed benzene ring.

Preferred examples of the optionally substituted unsaturated monocyclic heterocyclic ring include unsaturated monocyclic heterocyclic rings which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, hydroxyl group, alkoxy group, alkyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, cycloalkenyl group, cycloalkoxy group, aryl group, aryloxy group, arylalkoxy group, cyano group, nitro group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, heterocyclic group, and oxo group.

Preferred examples of the optionally substituted unsaturated fused heterobicyclic ring include unsaturated fused heterobicyclic rings which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, alkoxy group, alkyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, cycloalkenyl group, cycloalkoxy group, aryl group, aryloxy group, arylalkoxy group, cyano group, nitro group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, heterocyclic group, and oxo group.

Preferred examples of the optionally substituted benzene ring include benzene rings which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, hydroxyl group, alkoxy group, alkyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkoxy group, aryl group, aryloxy group, arylalkoxy group, cyano group, nitro group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, heterocyclic group, alkylene group, alkyleneoxy group, alkylenedioxy group, and alkenylene group.

In another preferred embodiment of the present invention, the optionally substituted unsaturated monocyclic heterocycle is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, sulfamoyl group, mono-or di-alkyl-sulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group; and is

The optionally substituted benzene ring is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group, alkylene group and alkenylene group;

wherein each of the above substituents on the unsaturated monocyclic heterocycle, unsaturated fused heterobicyclic ring and benzene ring may be further substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, mono-or di-alkylamino group, carboxyl group, alkoxycarbonyl group, phenyl group, alkyleneoxy group, alkylenedioxy group, oxo group, carbamoyl group, and mono-or di-alkylcarbamoyl group.

In a preferred embodiment, the optionally substituted unsaturated monocyclic heterocycle is an unsaturated monocyclic heterocycle which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono-or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, a phenyl group, a heterocyclic group and an oxo group;

an optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring that may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono-or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, a phenyl group, a heterocyclic group and an oxo group; and is

The optionally substituted benzene ring is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, cyano group, alkyl group, alkoxy group, alkanoyl group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, phenyl group, heterocyclic group, alkylene group and alkenylene group;

wherein each of the above substituents on the unsaturated monocyclic heterocycle, unsaturated fused heterobicyclic ring and benzene ring may be further substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkanoyl group, mono-or di-alkylamino group, carboxyl group, hydroxyl group, phenyl group, alkylenedioxy group, alkyleneoxy group, alkoxycarbonyl group, carbamoyl group and mono-or di-alkylcarbamoyl group.

In a further preferred embodiment of the method,

(1) ring a is an unsaturated monocyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group, and

ring B is an unsaturated monocyclic heterocycle, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group, alkylene group, and alkenylene group;

(2) ring a is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group, alkylene group and alkenylene group, and

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono-or di-alkylamino group, a sulfamoyl group, a mono-or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkylsulfonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclic group, an alkylene group; and

(3) ring a is an unsaturated fused heterobicyclic ring that may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group, and

ring B is an unsaturated monocyclic heterocycle, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono-or di-alkylamino group, a sulfamoyl group, a mono-or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkylsulfonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclic group, an alkylene group;

wherein each of the above substituents on ring a and ring B may be further optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkanoyl group, mono-or di-alkylamino group, carboxyl group, hydroxyl group, phenyl group, alkylenedioxy group, alkyleneoxy group, alkoxycarbonyl group, carbamoyl group and mono-or di-alkylcarbamoyl group.

In a more preferred embodiment of the invention, ring a and ring B are:

(1) ring a is an unsaturated monocyclic heterocyclic ring which may be optionally substituted with a halogen atom, lower alkyl group, halogeno-lower alkyl group, lower alkoxy group or oxo group, and ring B is (a) a benzene ring which may be optionally substituted with the following substituents: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or mono-or di-lower alkylamino; or a heterocyclic group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; (b) an unsaturated monocyclic heterocycle which may be optionally substituted by a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, mono-or di-lower alkylamino group; or (c) an unsaturated fused heterobicyclic ring which may be optionally substituted with a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, mono-or di-lower alkylamino group;

(2) ring a is a benzene ring which may be optionally substituted with a halogen atom, lower alkyl, halogeno-lower alkyl, lower alkoxy, phenyl or lower alkenylene, and ring B is (a) an unsaturated monocyclic heterocycle which may be optionally substituted with: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, phenyl-lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; or a heterocyclic group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; (b) an unsaturated fused heterobicyclic ring which may be optionally substituted with a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, phenyl-lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be substituted by halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, or a mono-or di-lower alkylamino group; or

(3) Ring a is an unsaturated fused heterobicyclic ring which may be optionally substituted with a halogen atom, lower alkyl, halogeno-lower alkyl, lower alkoxy or oxo, and ring B is (a) a benzene ring which may be optionally substituted with a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, or a mono-or di-lower alkylamino group; (b) an unsaturated monocyclic heterocycle which may be optionally substituted with: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; or a heterocyclic group which may be optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; or (c) an unsaturated fused heterobicyclic ring which may be optionally substituted with a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be substituted by halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group or mono-or di-lower alkylamino group.

In another preferred embodiment, Y is-CH₂-and is attached at the 3-position of ring a, and X is at the 1-position, ring a being a benzene ring substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, halogen atom, lower alkoxy, phenyl and lower alkenylene, and ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, phenyl-lower alkyl, halogen atom, lower alkoxy, halogenated lower alkoxy, phenyl, halophenyl, cyanophenyl, lower alkylphenyl, halogenated lower alkylphenyl, lower alkoxyphenyl, halogenated lower alkoxyphenyl, lower alkylenedioxyphenyl, lower alkyleneoxyphenyl, mono-or di-lower alkylaminophenyl, carbamoylphenyl, mono-or di-lower alkylcarbamoylphenyl, heterocyclic group, halogenated heterocyclic group, cyanoheterocyclic group, lower alkylheterocyclic group, lower alkoxyheterocyclic group, mono-or di-lower alkylaminocyclic group, carbamoylheterocyclic group, and mono-or di-lower alkylcarbamoyl.

In another more preferred embodiment, Y is-CH₂-and is attached at the 3-position of ring a, and X is at the 1-position, ring a being an unsaturated monocyclic heterocycle which may be substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, a halogen atom, lower alkoxy, and oxo, and ring B is a benzene ring which may be substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, halogen atom, lower alkoxy, halogenated lower alkoxy, phenyl, halogenated phenyl, cyanophenyl, lower alkylphenyl, halogenated lower alkylphenyl, lower alkoxyphenyl, heterocyclic group, halogenated heterocyclic group, cyanoheterocyclic group, lower alkylheterocyclic group and lower alkoxyheterocyclic group.

In addition, in another preferred embodimentIn which Y is-CH₂-and is attached at the 3-position of ring a, and X is at the 1-position, ring a being an unsaturated monocyclic heterocycle which may be substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, a halogen atom, lower alkoxy, and oxo, and ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, halogen atom, lower alkoxy, halogenated lower alkoxy, phenyl, halogenated phenyl, cyanophenyl, lower alkylphenyl, halogenated lower alkylphenyl, lower alkoxyphenyl, halogenated lower alkoxyphenyl, heterocyclic group, halogenated heterocyclic group, cyanoheterocyclic group, lower alkylheterocyclic group and lower alkoxyheterocyclic group.

In a more preferred embodiment of the invention, X is a carbon atom and Y is-CH₂-。

Furthermore, in another preferred embodiment, ring a and ring B are:

(1) ring a is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, lower alkyl optionally substituted by halogen atom or lower alkoxy, lower alkoxy optionally substituted by halogen atom or lower alkoxy, cycloalkyl, cycloalkoxy, phenyl and lower alkenylene, and

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy, or carbamoyl; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group, or a carbamoyl group; and an oxo group;

(2) ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, lower alkyl optionally substituted by lower alkoxy, lower alkoxy optionally substituted by halogen atom or lower alkoxy, cycloalkyl, cycloalkoxy and oxo, and

ring B is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; lower alkylene;

(3) ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted with a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group and an oxo group,

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; and an oxo group;

(4) ring a is an unsaturated fused heterobicyclic ring that may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a lower alkyl group optionally substituted with a lower alkoxy group, a lower alkoxy group optionally substituted with a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group and an oxo group,

ring B is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; and lower alkylene; or

(5) Ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a lower alkyl group optionally substituted with a lower alkoxy group, a lower alkoxy group optionally substituted with a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group and an oxo group,

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; and an oxo group.

In another preferred embodiment of the present invention, Y is attached to the 3-position of ring A, and X is located at the 1-position, ring A being a benzene ring which may be optionally substituted with the following substituents: a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a phenyl group, and ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with a halogen atom or phenyl; lower alkoxy; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl or lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group or a lower alkoxy group; and an oxo group.

In another preferred embodiment of the invention, Y is attached at the 3-position and X is at the 1-position of ring A, which is an unsaturated monocyclic heterocycle which may optionally be substituted by substituents selected from the group consisting of: halogen atom, lower alkyl group and oxo group, and ring B is a benzene ring which may be optionally substituted with a substituent selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with a halogen atom or phenyl; lower alkoxy; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl or lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group or a lower alkoxy group; and lower alkylene.

Preferred examples of the unsaturated monocyclic heterocyclic ring include 5-or 6-membered unsaturated heterocyclic rings containing 1 or 2 hetero atoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms. More specifically, furan, thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine, and tetrazole are preferable. Preferred unsaturated fused heterobicyclic rings include 9-or 10-membered unsaturated fused heterocyclic rings containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms, and sulfur atoms. More specifically, indoline, isoindoline, benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline, benzothiophene, benzofuran, thienothiophene, and dihydroisoquinoline are preferable.

In a more preferred embodiment of the invention, ring a is a benzene ring which may be optionally substituted with a substituent selected from the group consisting of: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group and phenyl group, and ring B is a heterocyclic ring selected from the group consisting of: thiophene, furan, benzofuran, benzothiophene, and benzothiazole, wherein the heterocycle may be optionally substituted with a substituent selected from the group consisting of: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, phenyl-lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, phenyl group, halogenated phenyl group, lower alkylphenyl group, lower alkoxyphenyl group, thienyl group, halogenated thienyl group, pyridyl group, halogenated pyridyl group and thiazolyl group.

In another preferred embodiment, Y is-CH₂-ring a is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring selected from: thiophene, dihydroisoquinoline, dihydroisoxazole, triazole, pyrazole, dihydropyridine, indoline, indole, indazole, pyridine, pyrimidine, pyrazine, quinoline, and isoindoline, wherein the heterocycle may be optionally substituted with a substituent selected from the group consisting of: halogen atom, lower alkyl group and oxo group, and ring B is a benzene ring which may be optionally substituted by a substituent selected from the following group: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group and halogenated lower alkoxy group.

In another preferred embodiment of the present invention, ring a is a benzene ring substituted with a halogen atom or a lower alkyl group, and ring B is a thienyl group substituted with a phenyl group or a heterocyclic group, wherein the phenyl group and the heterocyclic group are substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkoxy group, a lower alkoxy group and a halogenated lower alkoxy group.

Furthermore, in another aspect of the present invention, preferred examples of the compound of formula (I) include compounds wherein ring A is

Wherein R is^1a、R^2a、R^3a、R^1b、R^2bAnd R^3bEach independently is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidene groupA group, cycloalkenyl, cycloalkoxy, phenyl, phenylalkoxy, cyano, nitro, amino, mono-or di-alkylamino, alkanoylamino, carboxy, alkoxycarbonyl, carbamoyl, mono-or di-alkylcarbamoyl, alkanoyl, alkylsulfonylamino, phenylsulfonylamino, alkylsulfinyl, alkylsulfonyl or phenylsulfonyl, and

ring B is

Wherein R is^4aAnd R^5aEach independently is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, a phenylalkyl group, an alkoxyalkoxy group, a hydroxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkoxy group, a phenoxy group, a phenylalkoxy group, a cyano group, a nitro group, an amino group, a mono-or di-alkylamino group, an alkanoylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinyl group; phenyl optionally substituted by a halogen atom, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylenedioxy, alkyleneoxy or mono-or di-alkylamino; or a heterocyclic group optionally substituted by a halogen atom, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, carbamoyl group or mono-or di-alkylcarbamoyl group, or R^4aAnd R^5aBonded to each other at their ends to form an alkylene group; and is

R^4b、R^5b、R^4cAnd R^5cEach independently is a hydrogen atom; a halogen atom; a hydroxyl group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; cycloalkylidenemethyl; a cycloalkenyl group; cycloalkoxy radical(ii) a A phenoxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; mono-or di-alkylamino; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; mono-or di-alkylcarbamoyl; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; phenyl optionally substituted by a halogen atom, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, methylenedioxy, ethyleneoxy or mono-or di-alkylamino; or a heterocyclic group optionally substituted with a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group.

More preferred are compounds wherein R is^1a、R^2a、R^3a、R^1b、R^2bAnd R^3bEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a phenyl group;

R^4aand R^5aEach independently is a hydrogen atom; a halogen atom; a lower alkyl group; a halogenated lower alkyl group; phenyl-lower alkyl; phenyl optionally substituted by a halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, methylenedioxy group, ethyleneoxy group, or mono-or di-lower alkylamino group, carbamoyl group, or mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a carbamoyl group, or a mono-or di-lower alkylcarbamoyl group; or R^4aAnd R^5aBonded to each other at their ends to form a lower alkylene group; and is

R^4b、R^5b、R^4cAnd R^5cEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group.

More preferred are compounds wherein ring B is

Wherein R is^4aIs phenyl optionally substituted by a halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, methylenedioxy group, ethyleneoxy group, mono-or di-lower alkylamino group, carbamoyl group or mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a carbamoyl group or a mono-or di-lower alkylcarbamoyl group, and

R^5ais a hydrogen atom, or

R^4aAnd R^5aBonded to each other at their ends to form a lower alkylene group.

More preferred are compounds wherein ring A is

Wherein R is^1aIs a halogen atom, a lower alkyl group or a lower alkoxy group, and R^2aAnd R^3aIs a hydrogen atom;

and ring B is

Wherein R is^4aIs phenyl optionally substituted with a substituent selected from the group consisting of: halogen atom, cyano group, lower alkyl group, halo-lower alkyl group, lower alkoxy group, halo-lower alkoxy group, mono-or di-lower alkylamino group, carbamoyl group and mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted by a halogen atom, cyano group, lower alkyl group, lower alkoxy group, carbamoyl group and mono-or di-lower alkylcarbamoyl group, and R^5aTo hydrogen atomsAnd Y is-CH₂-。

In a more preferred embodiment, R^4aIs phenyl optionally substituted by halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; or a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group.

In another preferred embodiment of the present invention, preferred compounds may be represented by formula IA as follows:

wherein R is^AIs a halogen atom, a lower alkyl group or a lower alkoxy group; r^BIs phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, methylenedioxy group, ethyleneoxy group, mono-or di-lower alkylamino group, carbamoyl group and mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group; r^CIs a hydrogen atom; or R^BAnd R^CTaken together are fused benzene rings which may be substituted with halogen atoms, lower alkyl groups, halogenated lower alkyl groups, lower alkoxy groups or halogenated lower alkoxy groups.

In a preferred embodiment, R^AIs a halogen atom or a lower alkyl group, R^CIs a hydrogen atom, and R^BIs a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group; or is substituted by 1 to 3 atoms selected from halogen atomsCyano, lower alkyl, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, mono-or di-lower alkylamino, carbamoyl and mono-or di-lower alkylcarbamoyl. The chemical structures of these compounds can be represented by formula (IA'):

wherein R is^AIs a halogen atom, or a lower alkyl group, and ring C is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono-or di-lower alkylamino group, a carbamoyl group, and a mono-or di-lower alkylcarbamoyl group; or a heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group.

In a more preferred embodiment, ring C is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, and a mono-or di-lower alkylamino group; or a heterocyclic group substituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group and a halogenated lower alkoxy group.

Among them, preferred are those wherein ring C is a phenyl group substituted by a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; or a heterocyclic group substituted with a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group.

Preferred heterocyclic groups include 5-or 6-membered heterocyclic groups containing 1 or 2 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, or 9-or 10-membered heterocyclic groups containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms. In particular, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, quinolinyl, tetrazolyl, and oxazolyl are preferable.

In a more preferred embodiment, ring C is phenyl substituted with a halogen atom or cyano, or pyridyl substituted with a halogen atom.

In another preferred embodiment of the present invention, preferred are compounds wherein ring a is

Wherein R is^1aIs a halogen atom, a lower alkyl group or a lower alkoxy group, and R^2aAnd R^3aIs a hydrogen atom;

and ring B is

Wherein R is^4bAnd R^5bEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group.

In another aspect of the invention, preferred examples of compounds of formula I include compounds represented by formula IB:

wherein R is⁸、R⁹And R¹⁰Each independently of the other is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group,Alkenyl, alkynyl, cycloalkyl, cycloalkylidenemethyl, cycloalkenyl, cycloalkoxy, aryloxy, arylalkoxy, cyano, nitro, amino, mono-or di-alkylamino, alkylcarbonylamino, carboxy, alkoxycarbonyl, carbamoyl, mono-or di-alkylcarbamoyl, alkanoyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfinyl, alkylsulfonyl or arylsulfonyl; and

a group represented by the formula:

is composed of

Wherein R is^6aAnd R^7aEach independently is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkoxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono-or di-alkylamino group, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group^6bAnd R^7bEach independently a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group or an alkoxy group.

Among the compounds represented by formula IB, more preferred are compounds wherein R is⁸、R⁹And R¹⁰Each independently is hydrogen atom, halogen atom, lower alkyl, cycloalkyl, hydroxy-lower alkyl, halogeno-lower alkyl, lower alkoxy, ringAlkoxy, halogeno-lower alkoxy or lower alkoxy-lower alkoxy, and

a group represented by the formula:

is composed of

Wherein R is^6a、R^7aEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halogenated lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloalkoxy group, a halogenated lower alkoxy group or a lower alkoxy-lower alkoxy group, or a group represented by the formula:

is composed of

Wherein R is^6bAnd R^7bEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group or a lower alkoxy group.

In another aspect of the present invention, preferred examples of compounds of formula (I) include compounds represented by formula IC:

wherein ring B' is an optionally substituted benzene ring, an optionally substituted unsaturated monocyclic heterocycle, or an optionally substituted unsaturated fused heterobicyclic ring.

Preferred examples of the ring B' include a benzene ring and a heterocyclic ring, both of which may have a substituent selected from the group consisting of: a halogen atom; a cyano group; lower alkyl optionally substituted by halogen atom; lower alkoxy optionally substituted by halogen atom; a lower alkanoyl group; mono-or di-lower alkylamino; a lower alkoxycarbonyl group; a carbamoyl group; mono-or di-lower alkylcarbamoyl; phenyl optionally substituted with a substituent selected from: a halogen atom, a cyano group, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group optionally substituted with a halogen atom, a lower alkanoyl group, a mono-or di-lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono-or di-lower alkylcarbamoyl group; heterocyclyl optionally substituted with a substituent selected from: a halogen atom, a cyano group, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group optionally substituted with a halogen atom, a lower alkanoyl group, a mono-or di-lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono-or di-lower alkylcarbamoyl group; an alkylene group; and an oxo group.

More preferred examples of the ring B' include benzene rings which may be substituted with a substituent selected from the group consisting of: a halogen atom; a cyano group; lower alkyl optionally substituted by halogen atom; lower alkoxy optionally substituted by halogen atom; mono-or di-lower alkylamino; phenyl optionally substituted with: halogen atom, cyano group, lower alkyl group optionally substituted by halogen atom, lower alkoxy group optionally substituted by halogen atom; heterocyclyl optionally substituted with: halogen atom, cyano group, lower alkyl group optionally substituted by halogen atom, lower alkoxy group optionally substituted by halogen atom.

Preferred compounds of the present invention may be selected from the following group of compounds, pharmaceutically acceptable salts thereof and prodrugs thereof:

1- (β -D-glucopyranosyl) -4-chloro-3- (6-ethylbenzo [ b ] thiophen-2-ylmethyl) benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (5-thiazolyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- (5-phenyl-2-thienyl-methyl) benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (2-pyrimidinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (2-pyrimidinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (3-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (4-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (3-difluoromethyl-phenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (3-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl ] benzene;

1- (beta-D-glucopyranosyl) -4-fluoro-3- (5- (3-cyanophenyl) -2-thienylmethyl) benzene.

Particularly preferred compounds of the invention include:

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (3-cyano-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-cyano-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluoro-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (3-cyano-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and

1- (β -D-glucopyranosyl) -4-fluoro-3- (5- (3-cyanophenyl) -2-thienylmethyl) benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Abbreviations used in this specification, particularly in the "schemes" and "examples", are as follows:

BF₃OEt₂boron trifluoride diethyl ether

DCE ═ dichloroethane

DCM ═ dichloromethane

DMAP ═ 4- (N, N-dimethylamino) pyridine

DMF ═ N, N-dimethylformamide

Et₃SiH ═ triethylsilane

IPA (isopropyl alcohol)

MeOH ═ methanol

MTBE ═ methyl-tert-butyl ether

NMM ═ N-methyl-morpholine

TEA ═ triethylamine

THF ═ tetrahydrofuran

Generally, for commercial use, it is preferred that the product exhibit good handleability properties. Furthermore, for commercial use, it is preferred to produce the product in a substantially pure and crystalline form, so that the formulation meets precise pharmaceutical requirements and specifications. Furthermore, for commercial scale preparation, it is preferred that the product be in a form that can be easily filtered and easily dried. Finally, preferred products are stable for long periods of time and do not require special storage conditions.

As used herein, unless otherwise indicated, the term "isolated form" shall mean that the compound is present in a form separate from any mixture, solvent system, or biological environment formed with the additional compound. In one embodiment, the compound of formula (I), the compound of formula (I-S), the compound of formula (I-K), the crystalline form of the compound of formula (I-S), and/or the crystalline form of the compound of formula (I-K) are present and/or prepared in isolated form.

As used herein, unless otherwise indicated, the term "substantially pure" shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In one embodiment, the compound of formula (I), the compound of formula (I-S), the compound of formula (I-K), the crystalline form of the compound of formula (I-S), and/or the crystalline form of the compound of formula (I-K) are present and/or prepared in substantially pure form.

As used herein, unless otherwise indicated, the term "substantially free of corresponding salt forms" when used to describe a compound of formula (I) shall mean that the molar percentage of any corresponding salt form in the isolated compound is less than about 5 mole%, preferably less than about 2 mole%, more preferably less than about 0.5 mole%, most preferably less than about 0.1 mole%. In one embodiment, the compound of formula (I), the compound of formula (I-S), the compound of formula (I-K), the crystalline form of the compound of formula (I-S), and/or the crystalline form of the compound of formula (I-K) are present and/or prepared in a form that is substantially free of the corresponding salt form.

In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I), wherein the compound of formula (I) is substantially pure. In another embodiment, the invention relates to a process for preparing a compound of formula (I-S), wherein the compound of formula (I-S) is substantially pure. In another embodiment, the invention relates to a process for preparing a compound of formula (I-K), wherein the compound of formula (I-K) is substantially pure.

In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I), wherein the compound of formula (I) is substantially free of the corresponding salt form. In another embodiment, the invention relates to a process for the preparation of a compound of formula (I-S), wherein the compound of formula (I-S) is substantially free of the corresponding salt form. In another embodiment, the invention relates to a process for the preparation of compounds of formula (I-K), wherein the compounds of formula (I-K) are substantially free of the corresponding salt forms.

As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compound of formula (I) of the present invention exhibits excellent sodium-dependent glucose transporter inhibitory activity, and excellent blood glucose lowering effect. Accordingly, the compounds of the present invention are useful in treating or delaying the progression or onset of: diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension. In particular, the compounds of the present invention are useful for the treatment or prevention of diabetes (type 1 and type 2 diabetes, etc.), diabetic complications (e.g., diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) or obesity, or for the treatment of postprandial hyperglycemia.

The compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention may be administered orally or parenterally and may be used in the form of suitable pharmaceutical preparations. Pharmaceutical preparations suitable for oral administration include, for example, solid preparations such as tablets, granules, capsules, powders and the like, or solution preparations, suspension preparations, emulsion preparations and the like. Pharmaceutical formulations suitable for parenteral administration include, for example, suppositories; injection preparations and intravenous drip preparations using distilled water for injection, physiological saline or aqueous glucose solution: or an inhalation formulation.

The dosage of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the route of administration, the age, body weight, condition of the patient, or the type and severity of the disease to be treated, and is generally in the range of about 0.01 to 300 mg/kg/day, or any range therein, preferably about 0.1 to 50 mg/kg/day, or any range therein, preferably about 0.1 to 30 mg/kg/day, or any range therein.

If desired, the compounds of formula I may be used in combination with one or more other antidiabetic agents, one or more agents for treating diabetic complications, and/or one or more agents for treating other diseases. The present compound and these other agents may be administered in the same dosage form, or in separate oral dosage forms or by injection.

Other antidiabetic agents include, for example, antidiabetic or antihyperglycemic agents including insulin, insulin secretagogues, or insulin sensitizers, or other antidiabetic agents having a mechanism of action other than SGLT inhibition, and preferably 1, 2, 3 or 4 of these other antidiabetic agents may be used. Specific examples thereof are biguanide compounds, sulfonylurea compounds, α -glucosidase inhibitors, PPAR γ agonists (e.g., thiazolidinediones), PPAR α/γ double agonists, dipeptidyl peptidase IV (DPP4) inhibitors, mitiglinide (mitiglinide) compounds and/or nateglinide (nateglinide) compounds, as well as insulin, glucagon-like peptide-1 (GLP-1), PTP1B inhibitors, glycogen phosphorylase inhibitors, RXR modulators and/or glucose 6-phosphatase inhibitors.

Agents useful for treating other diseases include, for example, anti-obesity agents, antihypertensive agents, antiplatelet agents, anti-atherosclerotic agents, and/or hypolipidemic agents.

If necessary, the SGLT inhibitor of formula I may be used in combination with an agent for treating diabetic complications. Such agents include, for example, PKC inhibitors and/or ACE inhibitors.

The dosage of these agents may vary depending on the age, weight and condition of the patient, as well as the administration route, dosage form, and the like.

These pharmaceutical compositions can be administered orally, for example, in the form of tablets, capsules, granules or powders, or parenterally in the form of injection preparations, or intranasally, or in the form of transdermal patches to mammals (including humans, apes, dogs, etc.).

One skilled in the art will recognize that the reaction steps, if not otherwise indicated, are carried out according to known methods under suitable conditions to provide the desired product.

Suitable solvents, bases, reaction temperatures and other reaction parameters and components are given in the detailed description below. Those skilled in the art will recognize that the list of examples is not intended to, and should not be construed as, limiting in any way the invention set forth in the claims below.

One skilled in the art will also recognize that in the description and claims presented herein, if a reagent or class/type of reagent (e.g., base, solvent, etc.) is recited in more than one step of the method, each reagent is independently selected for each reaction step and may be the same or different from each other. For example, if two steps of the process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step can be the same or different from the organic or inorganic base of the second step.

In order to provide a more concise description, certain quantitative representations given herein are not intended to be limited by the term "about". It is to be understood that each quantity given herein is intended to refer to the actual given value, and it is also intended to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such given value, whether or not the term "about" is explicitly used.

To provide a more accurate description, some numerical expressions herein are stated as being within the range of about X to about Y. It should be understood that when a range is recited, the range is not limited to the recited upper and lower limits, but includes all ranges from about X to about Y, or any range therein.

Unless otherwise indicated, the term "A nitrogen protecting group "will mean a group that can be attached to a nitrogen atom to protect the nitrogen atom from participating in a reaction and that can be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, carbamate-groups of the formula-C (O) O-R, where R is, for example, methyl, ethyl, t-butyl, benzyl, phenethyl, CH₂＝CH-CH₂-and the like; amide-a group of formula-c (o) -R ', wherein R' is, for example, methyl, phenyl, trifluoromethyl, and the like; n-sulfonyl derivatives of formula-SO₂A group of-R ', wherein R' is, for example, tolyl, phenyl, trifluoromethyl, 2, 5, 7, 8-pentamethylchroman-6-yl-, 2, 3, 6-trimethyl-4-methoxybenzene or the like. Other suitable nitrogen protecting groups may be found, for example, in t.w. greene& P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley &Sons, 1991.

One skilled in the art will recognize that if the reaction step of the present invention can be carried out in a variety of solvents or solvent systems, the reaction step can also be carried out in a mixture of suitable solvents or solvent systems.

If the process for preparing the compounds according to the invention yields mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or the individual enantiomers may be prepared by enantioselective synthesis or by resolution. The compounds may be resolved, for example, into their component enantiomers by standard techniques, for example, by salt formation with an optically active acid (e.g., (-) -di-p-toluoyl-D-tartaric acid and/or (+) -di-p-toluoyl-L-tartaric acid) to form diastereomeric pairs, followed by fractional crystallization and regeneration to give the free base. The compounds may also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

During any preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be doneBy conventional protecting groups, e.g. inProtective Groups in Organic Chemistry(protecting groups in organic chemistry), editions by j.f.w.mcomie, Plenum Press, 1973; and t.w.greene 1991&P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley &Those described in Sons, 1991. The protecting group may be removed at an appropriate subsequent step using methods known in the art.

One skilled in the art will recognize that in any of the methods described herein, reactive substituents on the compounds of formula (I), such as hydroxy, oxo, carboxy and the like, are preferably protected and subsequently deprotected according to known methods at appropriate points along the synthetic route.

The present invention relates to a process for the preparation of compounds of formula (I) as shown in scheme 1 below.

Scheme 1

Accordingly, an appropriately substituted compound of formula (V), being a known compound or a compound prepared by known methods, is reacted with a compound of formula (VI-S), being a known compound or a compound prepared by known methods; wherein the compound of formula (VI-S) is preferably present in an amount in the range of from about 1.0 to about 2.0 molar equivalents, or in any range therein, more preferably in the range of from about 1.0 to about 1.25 molar equivalents, or in any range therein, more preferably in about 1.2 molar equivalents;

the reaction is in the presence of alkyllithium (e.g., trimethylsilylmethyl lithium, trimethylphenyl lithium (i.e., 2, 4, 6-trimethylphenyl lithium), triethylsilylmethyl lithium, preferably trimethylsilylmethyl lithium, etc.), wherein the alkyllithium is preferably present in an amount in the range of from about 2.0 to about 3.0 molar equivalents, or any range therein, more preferably in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents;

in an organic solvent such as THF, hexane, pentane, MTBE, dioxane, etc., preferably THF; at a temperature in the range of from about 0 ℃ to about-78 ℃, or any range therein, preferably at about-40 ℃; to give the corresponding compound of formula (VII).

Preferably, the alkyllithium is added to a mixture of the compound of formula (V) and the compound of formula (VI-S).

Those skilled in the art will recognize that the compound of formula (V) may alternatively be reacted with a compound of formula (VI-S) (as described above) wherein the Trimethylsilyl (TMS) substituent is substituted with one or more appropriately selected alternative silyl groups such as triethylsilyl, phenyldimethylsilyl and the like.

Reacting a compound of formula (VII) with BF₃OEt₂In the presence of a suitably selected trialkylsilane such as Et₃SiH, etc.; wherein BF₃OEt₂Is preferably present in an amount in the range of from about 2.0 to about 10.0 molar equivalents, or any range therein, more preferably in the range of from about 2.0 to about 6.0 molar equivalents, and most preferably about 3.0 molar equivalents; and wherein the trialkylsilane is preferably present in an amount in the range of about 2.0 to about 10.0 molar equivalents, or any range therein, more preferably in the range of about 2.0 to about 6.0 molar equivalents, or any range therein, most preferably about 3.0 molar equivalents; preferably, wherein BF₃OEt₂The ratio to trialkylsilane is about 1: 1;

the reaction is carried out in an organic solvent such as DCM, DCE, acetonitrile, toluene, etc., or in a mixture of said organic solvents, preferably DCM; preferably at a temperature in the range of from about 0 ℃ to about-40 ℃, or any range therein, more preferably at about-30 ℃; to give the corresponding compound of formula (VIII).

Those skilled in the art will recognize that alternatively the compound of formula (VII) may be deprotected according to known methods (e.g. by reaction with an appropriately selected acid such as HCl or the like) to yield the corresponding compound of formula (X),

then it is reacted with BF₃OEt₂In the presence of a suitably selected trialkylsilane such as Et₃SiH, etc.; wherein BF₃OEt₂Is preferably present in an amount in the range of from about 2.0 to about 10.0 molar equivalents, or any range therein, more preferably in the range of from about 2.0 to about 6.0 molar equivalents, and most preferably about 3.0 molar equivalents; and wherein the trialkylsilane is preferably present in an amount in the range of about 2.0 to about 10.0 molar equivalents, or any range therein, more preferably in the range of about 2.0 to about 6.0 molar equivalents, or any range therein, most preferably about 3.0 molar equivalents; preferably, wherein BF₃OEt₂The ratio to trialkylsilane is about 1: 1;

the reaction is carried out in an organic solvent such as DCM, DCE, acetonitrile, toluene, etc., or in a mixture of said organic solvents, preferably DCM; preferably at a temperature in the range of from about 0 ℃ to about-40 ℃, or any range therein, more preferably at about-30 ℃; to give the corresponding compound of formula (VIII).

Reacting a compound of formula (VIII) with acetic anhydride or acetyl chloride, preferably acetic anhydride of a known compound; wherein the acetic anhydride is preferably present in an amount in the range of from about 4.0 to about 6.0 molar equivalents, or any range therein, more preferably in the range of from about 4.5 to about 5.0 molar equivalents, or any range therein, most preferably about 5.0 molar equivalents;

the reaction is carried out in the presence of an organic base such as N-methylmorpholine (NMM), TEA, pyridine, etc., preferably in the presence of NMM; wherein the organic base is preferably present in an amount in the range of from about 3.0 to about 6.0 molar equivalents, or any range therein, more preferably about 5.0 molar equivalents; optionally in the presence of a catalyst such as DAMP or the like, preferably in the presence of a catalytic amount of DMAP;

without addition of a solvent or in an organic solvent such as THF, acetonitrile, etc., preferably in THF; preferably, at a temperature in the range of from-10 ℃ to about room temperature, or any range therein, preferably at a temperature in the range of from about 0 ℃ to about room temperature; to give the corresponding compound of formula (IX).

Preferably the compound of formula (IX) is slurried or dissolved in a solvent, more preferably slurried; followed by filtration, preferably at elevated temperature, to remove impurities and/or by-products.

The compound of formula (IX) is deprotected according to known methods. For example, the compound of formula (IX) is reacted with a suitably selected base, such as LiOH, NaOH, and the like (preferably LiOH), wherein the base is preferably present in an amount in the range of from about 0.1 to about 1.0 molar equivalents, or any range therein, more preferably in the range of from about 0.25 to about 0.5 molar equivalents, or any range therein, and most preferably about 0.5 molar equivalents (e.g., a catalytic amount); in a mixture of water, THF and methanol, wherein the ratio of water to THF to methanol is preferably about 1: 2: 3; preferably at room temperature; to give the corresponding compound of formula (I).

The compounds of formula (I) are preferably isolated and/or recrystallized according to known methods.

In one embodiment, the present invention relates to a method for preparing compounds of formula (I-S), as shown in scheme 2 below.

Scheme 2

Thus, an appropriately substituted compound of formula (V-S), being a known compound or a compound prepared by known methods, is reacted with a compound of formula (VI-S), being a known compound or a compound prepared by known methods; wherein the compound of formula (VI-S) is preferably present in an amount in the range of from about 1.0 to about 2.0 molar equivalents, or any range therein, more preferably in the range of from about 1.0 to about 1.25 molar equivalents, or any range therein, most preferably about 1.2 molar equivalents;

the reaction is in the presence of an alkyllithium such as trimethylsilylmethyl lithium, tritolyl lithium (i.e., 2, 4, 6-trimethylphenyl lithium), triethylsilylmethyl lithium, preferably trimethylsilylmethyl lithium and the like, wherein the alkyllithium is preferably present in an amount in the range of from about 2.0 to about 3.0 molar equivalents, or any range therein, more preferably in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents;

in an organic solvent such as THF, hexane, pentane, MTBE, dioxane, etc., preferably in THF; at a temperature in the range of from about 0 ℃ to about-78 ℃, or any range therein, preferably at about-40 ℃; to give the corresponding compound of formula (VII-S).

Preferably, the alkyllithium is added to a mixture of the compound of formula (V-S) and the compound of formula (VI-S).

Those skilled in the art will recognize that the compound of formula (V-S) may alternatively be reacted with a compound of formula (VI-S) (as described above) wherein the Trimethylsilyl (TMS) substituent is substituted with one or more appropriately selected alternative silyl groups such as triethylsilyl, phenyldimethylsilyl and the like.

Reacting a compound of formula (VII-S) with BF₃OEt₂In the presence of a suitably selected trialkylsilane such as Et₃In the case of SiH or the likeThe preparation method comprises the following steps of; wherein BF₃OEt₂Is preferably present in an amount in the range of from about 2.0 to about 10.0 molar equivalents, or any range therein, more preferably in the range of from about 2.0 to about 6.0 molar equivalents, and most preferably about 3.0 molar equivalents; and wherein the trialkylsilane is preferably present in an amount in the range of about 2.0 to about 10.0 molar equivalents, or any range therein, more preferably in the range of about 2.0 to about 6.0 molar equivalents, or any range therein, most preferably about 3.0 molar equivalents; preferably, wherein BF₃OEt₂The ratio to trialkylsilane is about 1: 1;

the reaction is carried out in an organic solvent such as DCM, DCE, acetonitrile, toluene, etc., or in a mixture of said organic solvents, preferably DCM; preferably at a temperature in the range of from about 0 ℃ to about-40 ℃ or any range therein, most preferably at about-30 ℃; to give the corresponding compound of formula (VIII-S).

Reacting a compound of formula (VIII-S) with acetic anhydride or acetyl chloride, preferably acetic anhydride of a known compound; wherein the acetic anhydride is preferably present in an amount in the range of from about 4.0 to about 6.0 molar equivalents, or any range therein, more preferably in the range of from about 4.5 to about 5.0 molar equivalents, or any range therein, most preferably about 5.0 molar equivalents;

the reaction is carried out in the presence of an organic base such as N-methylmorpholine (NMM), TEA, pyridine, etc., preferably NMM; wherein the organic base is preferably present in an amount in the range of from about 3.0 to about 6.0 molar equivalents, or any range therein, more preferably about 5.0 molar equivalents; optionally in the presence of a catalyst such as DAMP or the like; preferably in the presence of a catalytic amount of DMAP;

without addition of a solvent or in an organic solvent such as THF, acetonitrile, etc., preferably in THF; preferably, at a temperature in the range of from about-10 ℃ to about room temperature, or any range therein, preferably at a temperature in the range of from about 0 ℃ to about room temperature; to give the corresponding compound of formula (IX-S).

Preferably, the compound of formula (IX-S) is slurried or dissolved in a solvent, more preferably slurried in a solvent; and then filtered, preferably at elevated temperatures, to remove impurities and/or by-products. Preferably, a mixture of the compound of formula (IX-S) in an organic solvent such as methanol, ethanol and the like (preferably methanol) is slurried or dissolved, preferably slurried, and then filtered, preferably at elevated temperature, to remove impurities and/or by-products.

The compound of formula (IX-S) is deprotected according to known methods. For example, the compound of formula (IX-S) is reacted with an appropriately selected base such as LiOH, NaOH, etc. (preferably LiOH); wherein the base is preferably present in an amount in the range of from about 0.1 to about 1.0 molar equivalents, or any range therein, more preferably in the range of from about 0.25 to about 0.5 molar equivalents, or any range therein, most preferably about 0.5 molar equivalents (e.g., a catalytic amount); the reaction is carried out in a mixture of water, THF and methanol, preferably in a ratio of water to THF to methanol of about 1: 2: 3; preferably at room temperature; to give the corresponding compounds of formula (I-S).

The compound of the formula (I-S) is preferably recrystallized. In one embodiment, the compound of formula (I-S) is recrystallized according to the following method:

step A: dissolving the compound of formula (I-S) in an organic solvent such as ethyl acetate, methanol, ethanol, etc., preferably ethyl acetate; then optionally filtering;

and B: heating the mixture of step a to a temperature in the range of about 25 ℃ to about 45 ℃, preferably to a temperature in the range of about 30 to about 35 ℃; then optionally filtering;

and C: water is added to the mixture prepared in step B, preferably from about 1.0 to about 2.0 molar equivalents, more preferably about 1.5 molar equivalents.

Step D: to the mixture prepared in step C, heptane is slowly added (to initiate precipitation-i.e., heptane acts as an anti-solvent), preferably in an amount such that the final volume to volume ratio of ethyl acetate to heptane is in the range of from about 1: 1 to about 1.5: 1, more preferably about 1.2: 1;

to produce a precipitate of the compound of formula (I-S); the precipitate is preferably isolated by filtration and then dried according to known methods.

Preferably, in the recrystallization of the compound of formula (I-S), after addition of heptane, the resulting mixture is seeded with the desired polymorph of formula (I-S).

The invention also relates to novel crystalline forms of the compounds of formula (I-S). The invention also relates to novel crystalline forms of the compounds of formula (I-K).

One skilled in the art will recognize that there are several methods for characterizing crystalline forms, and it is not intended that the present invention be limited by the selected method or the equipment used in characterizing the compounds of the present invention. For example, for powder X-ray diffraction patterns, as known in the art, the intensity of diffraction peaks in the experimental pattern can vary, primarily due to preferred orientation (non-random orientation of crystals) in the prepared sample. Therefore, the scope of the present invention must be considered in terms of the variability of the characterization as understood by those skilled in the art.

The invention also relates to crystalline forms of the compounds of formula (I-S)

In one embodiment, the present invention relates to a crystalline form of the compound of formula (I-S) prepared according to the recrystallization process described herein. In another embodiment, the invention relates to a crystalline form of the compound of formula (I-S) prepared according to the following recrystallization method:

step A: dissolving a compound of formula (I-S) in ethyl acetate to produce mixture a; then optionally filtering the mixture A;

and B: heating mixture a to a temperature in the range of about 30 ℃ to about 35 ℃ to produce mixture B; optionally filtering the mixture B;

and C: adding about 1.5 molar equivalents of water to mixture B to produce mixture C;

step D: slowly adding heptane to mixture C to produce a crystalline form of the compound of formula (I-S);

step E: the crystalline form of the compound of formula (I-S) is isolated by filtration and drying.

The invention also relates to novel crystalline forms of the compounds of formula (I-K)

Using a powder X-ray diffractometer RINT-ULTIMA3(Rigaku, Tokyo, Japan) using a CuK_αMeasuring the X-ray powder diffraction spectrum of a representative sample of the crystalline form of the compound of formula (I-K) by irradiation and setting: (a) scanning rate: 1.00 degree/min; (b) target: CuK_α(ii) a (c) Voltage: 40 kV; (d) current: 40 mA; (e) scanning range: from 3 to 40.0 degrees; and (f) a sampling width: 0.0200 degrees; as shown in fig. 2.

Philips X' Pert Pro MPD powder X-ray diffractometer using CuK_αThe X-ray powder diffraction pattern of a representative sample of the crystalline form of the compound of formula (I-K) was measured by irradiation and set up as follows: (a) scanning rate: 0.207 degrees/min; (b) target: CuK_α(ii) a (c) Voltage: 45 kV; (d) current: 40mA, mixing: (e) a detector: x' celerator; (f) scanning range: from 3 to 35 degrees; (g) step length: 0.0165 degrees; and (h) time per step: 10.16 seconds; as shown in fig. 3.

The IR spectra of representative samples of the crystalline form of the compound of formula (I-K) were measured in mineral oil (as shown in FIG. 4), and in K-Br tablets (as shown in FIG. 5). In the IR spectra of the compounds of formula (I-K) as shown in FIGS. 4 and 5 below, the ordinate is the percent transmittanceNumber and abscissa is wavenumber in cm^-1。

With a resolution of 4cm^-1Fourier transform infrared (FT-IR) spectra of crystalline forms of the compounds of formula (I-K) were measured in mineral oil. The IR spectrum shown in FIG. 4 is the sum of 4 scans. The IR spectra are shown at 1492, 1463, 1377, 1268, 1065 and 1023cm^-1The main characteristic absorption band of (A) corresponds to the functional group present in the compounds (I-K).

With a resolution of 4cm^-1Fourier transform IR spectra of the crystalline forms of the compounds of formula (I-K) were measured in KBr pellets. As shown in fig. 5, the IR spectrum is the sum of 64 scans. IR spectra show 3431, 3321, 1493, 1269, 1065 and 1024cm^-1The main characteristic absorption band of (c).

Thermogravimetric analysis of the crystalline form of the compound of formula (I-K). The thermogravimetric analysis method was performed as follows: 7.35mg of the crystalline form of the compound of the formula (I-K) are weighed out and transferred to an aluminum pan of TG-8120(RIGAKU, Japan). The Thermogravimetric (TG) curve of the crystalline form of the compound of formula (I-K) is then measured at a heating rate of 5 ℃/min, using a typical measurement range, i.e. ambient temperature to 200 ℃. No crystalline form of the compound of formula (I-K) was observed to exist as a hydrate or solvate in the thermogravimetric analysis.

The invention also relates to a process for the preparation of a crystalline form of a compound of formula (I-K), which process comprises forming a solution of a compound of formula (I-K) and precipitating the crystalline form from the solution. Crystalline forms of the compound of formula (I-K) may be obtained from a solution of the compound of formula (I-K) in a suitable solvent. Sometimes certain impurities may act as crystallization inhibitors and it is desirable to remove such impurities using conventional methods, such as silica gel column chromatography, as will be readily appreciated by those skilled in the art. However, crystals of the compound of formula (I-K) may be obtained from the compound of formula (I-K) containing certain impurities.

Crystalline forms of the compounds of formula (I-K) may be prepared from solutions of the compounds of formula (I-K) in a suitably selected solvent. Examples of suitable solvents include, but are not limited to, ketones (e.g., acetone, 2-butanone), esters (e.g., ethyl acetate, methyl acetate), alcohols (e.g., methanol, ethanol, isopropanol), and mixtures of these solvents. Particularly preferred solvents include esters such as ethyl acetate. In some cases, an antisolvent may be added to the solution of the compound of formula (I-K). Examples of the antisolvent include alkanes (e.g., hexane, heptane), aromatic hydrocarbons (e.g., benzene, toluene), ethers (e.g., diethyl ether, dimethyl ether, diisopropyl ether) and mixtures of these solvents.

A preferred method of preparing a crystalline form of the compound of formula (I-K) comprises dissolving a crude or amorphous compound of formula (I-K) (for example prepared according to the procedure described in PCT publication WO 2005/012326) in a warm suitable solvent (such as an ester), followed by adding an anti-solvent to the resulting solution if necessary, then cooling the resulting solution and filtering. The precise conditions under which crystals of the compounds of formula (I-K) can be formed can be determined empirically.

Those skilled in the art will recognize that the crystalline form of the compound of formula (I-K) is easier to isolate than the corresponding amorphous form of the compound of formula (I-K), and may also be filtered off from the crystallization medium after cooling, and washed and dried.

The invention also relates to pharmaceutical compositions comprising a crystalline form of a compound of formula (I-S) or a crystalline form of a compound of formula (I-K) and a pharmaceutically acceptable carrier.

The crystalline forms of the compounds of formula (I-S) and (I-K) of the present invention are also useful as sodium-dependent glucose transporters (SGLT)₂) Inhibitors, and exhibits excellent blood glucose lowering action. In one embodiment, the crystalline forms of the compound of formula (I-S) and the crystalline forms of the compound of formula (I-K) are useful in the treatment, prevention, or delay of progression or onset of: diabetes (type 1 and type 2 diabetes, etc.), diabetic complications (e.g., diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), postprandial hyperglycemia, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, diabetes mellitus, diabetic neuropathy, diabetic nephropathy, diabetic neuropathy,obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension.

The invention also includes pharmaceutical compositions comprising a compound prepared according to any of the methods described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds described herein as the active ingredient can be prepared by intimately mixing the compound with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral formulations may also be coated with substances such as sugars or with an enteric coating to regulate the primary site of absorption. For parenteral administration, the carrier will usually consist of sterile water, and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared using aqueous carriers along with suitable additives.

To prepare the pharmaceutical compositions of the present invention, one or more of the compositions of the present invention as the active ingredient are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of administration of the preparation desired, e.g. oral or parenteral such as intramuscular injection. In preparing the compositions for oral dosage form, any of the pharmaceutically acceptable media that can be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral formulations such as powders, capsules, caplets, soft capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated with sugar or with an enteric coating by standard techniques. For parenteral dosage forms, the carrier will typically comprise sterile water, but may also comprise other ingredients, for example for purposes such as to aid solubility or preservation. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain an amount of the active ingredient per unit of measure (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.) sufficient to deliver an effective dosage as described above. The pharmaceutical compositions herein may contain about 0.01-1000mg per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoonful, etc.) or any range therein, and may be administered in a dosage of about 0.01-300 mg/kg/day, or any range therein, preferably about 0.1-50 mg/kg/day, or any range therein. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound employed. Daily administration or post-periodic (post-periodic) administration may be employed.

Preferably, these compositions are in unit dosage forms, such as tablets, pills, capsules, powders, granules, parenteral sterile solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for parenteral oral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be in a form suitable for once weekly or once monthly administration; for example, insoluble salts of the active ingredient, such as the decanoate salt, may be suitable to provide depot formulations for intramuscular injection. For the preparation of solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums), and other pharmaceutically acceptable diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. When a preformulated composition is referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. Such preformulation compositions are then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1000mg of the active ingredient of the present invention. Tablets or pills of the new composition may be coated or compounded to provide a dosage form that provides long-lasting benefits. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating on the outside of the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, thereby allowing the inner component to pass intact into the duodenum or to delay drug release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acid materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid formulations which may be incorporated into the novel compositions of the present invention for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils (cottonseed, sesame, coconut or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for use in aqueous suspensions include synthetic or natural gums (e.g. tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating a disease described herein can also be performed with a pharmaceutical composition comprising any of the compositions defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01mg to 1000mg, or any range therein, of the compound; preferably, it contains about 10-500mg of the compound and may be formulated in any form suitable for the chosen mode of administration. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coating materials. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release), granules and powders; and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, the compositions of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, the compounds of the present invention may be administered by topical intranasal administration using suitable intranasal vehicles, or via transdermal patches well known to those skilled in the art. When administered in the form of a transdermal delivery system, administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, and the like). In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture, as desired or necessary. Suitable disintegrants include, but are not limited to, starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth) or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The liquid forms may include suspending or dispersing agents, such as natural and synthetic gums, suitably flavored, such as tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desired. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

To prepare the pharmaceutical compositions of the present invention, the compound prepared according to any of the methods described herein as the active ingredient is combined with a pharmaceutical agent according to conventional pharmaceutical compounding techniquesThe carrier is intimately admixed with it, which may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. A description of certain such pharmaceutically acceptable carriers is published by the American pharmaceutical Association and the British society for pharmacyThe Handbook of Pharmaceutical ExcipientsIs found in (1).

Methods of formulating pharmaceutical compositions have been described in a number of publications, for example, edited by Lieberman et al, published by Marcel DekkerPharmaceutical Dosage Form: tablets, second edition, revised and extended editionVolumes 1-3; edited by Avisl et alPharmaceutical Dosage Forms：Parenteral MedicationsVolumes 1-2; and edited by Lieberman et alPharmaceutical Dosage Forms：Disperse SystemsVolumes 1-2.

The compounds of the invention may be administered in any of the compositions described above and according to art-established dosing regimens, as long as the treatment of the diseases described in the methods of the invention is desired.

The daily dose may vary within a wide range of 0.01-1,000mg, or any range therein. For oral administration, the compositions are preferably provided to the patient to be treated in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage. The effective amount of the drug is generally provided at a dosage level of about 0.01mg to about 300mg, or any range therein, preferably about 0.01mg/kg to about 100mg/kg, or any range therein, per kilogram of body weight per day. More preferably, the range is from about 0.01 to about 50.0mg per kilogram body weight per day, or any range therein, more preferably from about 0.01 to about 30.0mg per kilogram body weight per day, or any range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the formulation specifications, the mode of administration and the severity of the disease symptoms. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust the dosage.

One skilled in the art will recognize that both in vivo and in vitro assays are predictive of the ability of a test compound to treat or prevent a given disorder using appropriate, known and generally accepted cellular and/or animal models.

Those skilled in the art will also recognize that human clinical trials (including human first use, dose discovery, and efficacy trials in healthy patients and/or patients suffering from a given condition) can be accomplished according to methods well known in the clinical and medical arts.

The following examples are presented to aid in the understanding of the invention, but are not intended to, and should not be construed to, limit the claims which follow the examples in any way.

In the examples that follow, some of the synthetic products that have been isolated as residues are listed. It will be understood by those skilled in the art that "residue" does not limit the physical state of the product as it is isolated and may include, for example, solids, oils, foams, gums, slurries, and the like.

Example 1

(5-bromo-2-methyl-phenyl) - [5- (4-fluoro-phenyl) -thiophen-2-yl]-methanones

Step A：

To a 250mL three-necked round bottom flask was added 5-bromo-2-methylbenzoic acid (22.5g, 0.10mol), CH at ambient temperature (20 deg.C)₂Cl₂(100mL) and DMF (0.25 mL). Oxalyl chloride (12mL, 0.13mol) was added so that the internal temperature remained below 25 ℃. Vigorous gas evolution was observed. The reaction mixture was stirred under argon at ambient temperature overnight, and then the volatiles were removed under reduced pressure. The resulting residue (acid chloride compound) was dissolved in DCM (50mL) and placed under a nitrogen atmosphere.

Step B：

To a separate 500mL three-necked round bottom flask was added AlCl₃(15.0g, 0.11mol) and 100mL CH₂Cl₂. The suspension was cooled to-10 ℃ in an ice bath, then 2- (4-fluorophenyl) thiophene (18.2g, 0.10mol) was added, followed by the mixture prepared in step A above. After 30 minutes the ice bath was removed and the resulting mixture was stirred at ambient temperature for 2-3 hours. The resulting mixture was cooled to-12 ℃ and quenched by the slow addition of water (20mL), followed by the addition of 2N HCl (20mL) and heptane (100 mL). A precipitate formed. The resulting mixture was stirred for 1-2 hours and then filtered to give the title compound as a yellow solid.

Example 2

2- (5-bromo-2-methyl-benzyl) -5- (4-fluoro-phenyl) -thiophene

To a 3.0L four-necked round bottom flask was added the compound prepared as described in example 1 above (119g, 0.317mol), triethylsilane (148mL, 0.926mol), dichloromethane (700mL), and acetonitrile (700 mL). The resulting mixture was cooled to-8 ℃ with stirring in an ice bath, and then boron trifluoride diethyl etherate (115mL, 0.915mol) was added dropwise so that the temperature did not exceed 0 ℃. The resulting mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure, diluted with IPA (1.0L), filtered and washed with water to give a solid. The solid was recrystallized from IPA to give the title compound as a yellow solid.

Example 3

2- (4-fluoro-phenyl) -5- (5-iodo-2-methyl-benzyl) -thiophene

To a 1.0L four-necked reaction flask were added the compound prepared as in example 2 above (100g, 276.80mmol), sodium iodide (82g, 553.59mmol) and cuprous iodide (2.6g, 13.84 mmol). The resulting mixture was evacuated and purged with argon, then treated with toluene (261mL), diglyme (56mL) and N, N' -dimethyl-ethane-1, 2-diamine (2.7mL, 27.68mmol) and the resulting mixture was warmed to 110 ℃ overnight. After consumption of the starting material, the mixture is cooled to room temperature and then filteredWashed with EtOAc and with NH₄And (5) OH extraction. The organic phase was dried (Na)₂SO₄) Filtered and concentrated to give a solid. The solid was filtered and recrystallized from heptane to give the title compound as an off-white solid (melting point 107 ℃).

(see also Klaper, A., Buchwald, S.L., "coater-catalysis halogen Exchange in Aryl Halides: An Aromatic Finkelstein Reaction", J.Am.chem.Soc., 2002, 124, 14844-

Example 4

2, 3, 4, 6-tetra-O-trimethylsilyl-beta-D-gluconolactone

To a 5.0L three-necked round bottom flask was added gluconolactone (155.2g, 0.871mol) and 4-methylmorpholine (766mL, 6.96mol) in THF (1.55L). To the cooled (-10 ℃) mixture was added chlorotrimethylsilane (660mL, 5.21mol) at such a rate that the temperature did not exceed 5 ℃. After 1 hour the reaction mixture was heated to about 35-40 ℃ for 5 hours and then stirred under argon at ambient temperature overnight. The resulting mixture was cooled to-10 ℃ and water (500-. The resulting mixture was diluted with 4.0L of water and 2.5L of heptane. The layers were separated and the organic phase was washed with aqueous sodium dihydrogen phosphate (1.5L), water (1.0L) and brine (1.0L). The organic layer was dried over magnesium sulfate and then concentrated under vacuum to give the title compound as a pale yellow liquid.

Example 5

To a 2.0L three neck round bottom flask was added the compound prepared as described in example 3 above (100g, 232.68mmol), the compound prepared as described in example 4 above (141g, 302.49mmol), and tetrahydrofuran (750 mL). After cooling the resulting mixture to about-40 ℃, 1.0M (trimethylsilyl) methyllithium in hexane (489mL, 489mmol) was added to the mixture with an addition funnel to maintain the internal temperature at less than or equal to about-40 ℃. After the addition was complete, standard NaHCO was used₃(200mL) the reaction was quenched and allowed to warm to room temperature. The phases were separated and dried (Na)₂SO₄) Filtered and concentrated to give the title compound as a viscous oil.

Example 6

1- (beta-D-glucopyranosyl) -4-methyl-3- (5- (4-fluorophenyl) -2-thienylmethyl) benzene

To a 2.0L three-necked round bottom flask was added the compound prepared as in example 5 above (232g, 310mmol) and dichloroethane (700 mL). The resulting yellow solution was cooled to-30 ℃ in an ice bath with stirring. Triethylsilane (132mL, 826mmol) was added followed by slow addition (1.75 h) of boron trifluoride etherate (95.0mL, 756mmol) so that the temperature did not exceed-20 ℃. The ice bath was removed approximately 30 minutes after the addition was complete and the resulting yellow mixture was stirred at room temperature under argon for 1.0-1.5 hours. After completion of the reaction, the resulting mixture was poured into cold water (800 mL). Ethyl acetate (300mL) was added and the layers were separated. The organic layer was washed with saturated bicarbonate solution, dried over sodium sulfate and concentrated to give the title compound as a green foam.

Example 7

A2.0L three neck round bottom flask was charged with the compound prepared as in example 6 above (119g, 0.25mol), 4-methylmorpholine (145mL, 1.30mol), DMAP (3.25g, 0.026mol) and 1.0L THF. The resulting pale green mixture was cooled to-10 ℃ in an ice bath with stirring, and acetic anhydride (125mL, 1.30mol) was then added dropwise so that the temperature did not exceed 0 ℃. The ice bath was removed 15 minutes after the addition was complete. The resulting mixture was stirred at ambient temperature for 1.0 hour, then concentrated at 30-35 ℃ under reduced pressure to remove most of the solvent. The resulting mixture was diluted with 10% phosphoric acid (ca 300mL) so that a cream-colored precipitate formed. The resulting mixture was dissolved in a mixture of ethyl acetate (600-800mL), THF (200-300mL) and toluene (200-300 mL). Once a complete solution was obtained, the layers were separated and the organic layer was washed with saturated bicarbonate solution and brine, then dried and concentrated to give a viscous residue. Methanol was added to the residue to precipitate the solution as an off-white solid. The slurry was stirred for 30 minutes and then filtered to give the title compound as an off-white solid.

Example 8

1- (beta-D-glucopyranosyl) -4-methyl-3- (5- (4-fluorophenyl) -2-thienylmethyl) benzene

The flask was charged with the compound prepared as described in example 7 above (185g, 302mmol) in THF (820mL) and MeOH (1.23L). To the stirred suspension was added a solution of lithium hydroxide monohydrate (6.33g, 147mmol) in water (410 mL). After stirring overnight at ambient temperature the volatiles were removed and the resulting residue was diluted with ethyl acetate (500-600 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with brine (250mL), dried over sodium sulfate and concentrated under reduced pressure to give a friable foam of the title compound.

Example 9

1- (beta-D-glucopyranosyl) -4-methyl-3- (5- (4-fluorophenyl) -2-thienylmethyl) benzene Crystals of (2)

To a 1.0L three-necked round bottom flask was added the compound prepared as in example 8 above (96.9g, 217mmol), water (6.0mL, 333mmol) and ethyl acetate (275 mL). The resulting solution was heated to 35 ℃ with stirring under argon. Heptane was added dropwise until the solution became cloudy (155mL heptane), followed by 14.2g seed crystals. After stirring at 35 ℃ for 1.5-2.0 hours, additional heptane (30mL, 185mL total) was added. The resulting mixture was stirred for 30 more minutes and then filtered. The filter cake was washed with about 56% ethyl acetate/heptane (50mL) and dried to give the title compound as a loose off-white crystalline solid.

The procedure described in examples 1 to 9 was carried out several times to obtain batches of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- (5- (4-fluorophenyl) -2-thienylmethyl) benzene, i.e. the compound of formula (I-S). Melting points, mass spectra and mass spectra of representative samples of the compounds of formula (I-S) (prepared according to the procedures of examples 1 to 9) were determined¹The HNMR spectra are as follows:

melting point: 106 ℃ and 107 ℃;

mass spectrum: m/z (LCMS API-ES)467 (M)⁺Na)；

¹H NMR(CD₃OD)：δ＝2.32(s，3H)，3.35-3.53(m，4H)，3.71(d，1H，J＝11.9Hz)，3.90(d，1H，J＝11.9Hz)，4.13(d，1H，J＝9.3Hz)，4.17(s，2H)，4.9(s，4H)，6.70(d，1H，J＝3.7Hz)，7.04-7.14(m，3H)，7.18(d，1H，J＝7.8Hz)，7.26(d，1H，J＝7.8Hz)，7.33(s，1H)，7.52-7.60(m，2H)。

A representative sample of the crystalline form of the compound of formula (I-S) isolated as described in example 9 above was characterized for its X-ray powder diffraction using a diffractometer using CuKa radiation 30mA, 40 KV; 1/12 ° anti-scatter slit, 0.2 receiving slit; scanning from 4 to 35 ° 2 θ at a scan rate of 0.016 ° 2 θ/sec; and an aluminum sample holder was used.

The crystalline form of the compound of formula (I-S) may be characterized by its powder XRD peaks, (preferably by its powder XRD peaks with a relative intensity greater than about 10%, more preferably by its powder XRD peaks with a relative intensity greater than about 25%, still more preferably by its powder XRD peaks with a relative intensity greater than about 35%, still more preferably by its powder XRD peaks with a relative intensity greater than about 50%), as set forth in table 1 below.

TABLE 1

Powder XRD peaks for crystalline forms of the compound of formula (I-S)

Example 10

(2-chloro-5-iodo-phenyl) - [5- (6-fluoro-pyridin-3-yl) -thiophen-2-yl]-methanones

Step A:

to a 5.0L four-necked round bottom flask was added 2-chloro-5-iodobenzoic acid (470.8g, 1.66mol), CH at ambient temperature (20 deg.C)₂Cl₂(1.6L) and DMF (5.0mL, 0.03 mol). Oxalyl chloride (170mL, 1.94mol) was added so that the internal temperature remained below 25 ℃. The addition was slightly exothermic; a vigorous gas evolution occurred. The resulting mixture was stirred under argon at ambient temperature overnight, and then the volatiles were removed under reduced pressure. The resulting residue (acid chloride compound) was diluted with dichloromethane (500mL) and placed under a nitrogen atmosphere.

Step B：

To a separate 5.0L three-necked round bottom flask was added AlCl₃(487.0g, 3.65mol) and 1.5LCH₂Cl₂To the cooled (-12 ℃) mixture was added 2-fluoro-5- (2-thienyl) pyridine (299.0g, 1.66mol), followed by the mixture prepared as in step A above. After 20 minutes the ice bath was removed and the reaction mixture was stirred at ambient temperature for 2-3 hours. After completion of the reaction, the resulting mixture was cooled to-12 ℃ and quenched by slow addition of water (400-500mL), followed by addition of 2N HCl (100mL) and heptane (100 mL). The reaction temperature must not exceed 32 ℃ during quenching with the addition of water. The resulting mixture was stirred at ambient temperature overnight so that a precipitate formed. The resulting mixture was filtered, washed with water and dried to give a solid. Recrystallizing the solid from ethyl acetate to obtainThe title compound was a gold colored solid.

Example 11

5- [5- (2-chloro-5-iodo-benzyl) -thiophen-2-yl]-2-fluoro-pyridine

To a 5.0L four-necked round bottom flask was added the compound prepared as in example 10 above (350g, 0.787mol), triethylsilane (650mL, 4.07mol), and acetonitrile (1.75L). The resulting mixture was heated to 30 ℃ and boron trifluoride diethyl etherate (500mL, 3.98mol) was added dropwise so that the temperature did not exceed 58 ℃. Stirring was continued at ambient temperature. Once complete, the resulting mixture is added to a cooled (5 ℃) aqueous solution of sodium bicarbonate (400g in 2.0L of water). The aqueous mixture was stirred at ambient temperature for one hour and then diluted with ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2X 400 mL). The combined organic phases were washed with brine, dried and concentrated to give a light brown solid. The solid was dissolved in hot toluene (about 1.5-1.75L), treated with silica gel (250g), diluted with heptane (1.0L), stirred for 30-40 minutes and then filtered while hot. The volume was reduced and heptane was additionally added. Upon cooling to room temperature the solution precipitated a solid. The resulting mixture was filtered to give the title compound as a yellow solid.

Example 12

To a 1L Erlenmeyer flask were added the compound prepared as in example 11 above (94.4g, 219.70mmol), the compound prepared as in example 4 above (102g, 219.70mmol), and tetrahydrofuran (585 mL). The obtained mixture is filtered and filled withAnd molecular sieve 4AE (10g) into a 2.0L three neck round bottom flask fitted with an overhead stirrer, nitrogen outlet, thermocouple, and addition funnel with vacuum connection. The resulting compound was then cooled to-70 ℃ by a dry ice/acetone bath. A1.0M solution of (trimethylsilyl) methyllithium in hexane (450 mL; 450mmol) was added to the addition funnel, maintaining the internal temperature below about-60 ℃. After the addition was complete, the resulting mixture was allowed to warm to-30 ℃ and then stirred NaHCO in a 2L separatory funnel₃(400 mL; 50% saturation) of the mixture, dilution with heptane (200mL) and separation of the phases. The organic phase was washed with water (20mL), brine (50mL), then the phases were separated and dried (Na)₂SO₄) Filtered and concentrated to give the title compound as a viscous oil.

Example 13

To a 2L three neck round bottom flask fitted with a cold water bath, addition funnel, temperature sensor, nitrogen outlet and overhead stirrer were added the product prepared as in example 11 above (100g, 232.73mmol) and the compound prepared as in example 4 above (130.4g, 325.8mmol), followed by THF (660 mL). The resulting mixture was then cooled to-70 ℃ by a dry ice bath in acetone. Trimethylsilylmethyllithium (210 mL; 413.70mmol) was added to the addition funnel and slowly added to the reaction mixture to maintain the internal temperature below about-70 ℃. After addition, the resulting mixture was stirred for an additional 20 minutes. The resulting mixture was worked up by addition of 2M HCl (250 mL; 500.00mmol) via an addition funnel. The resulting mixture was then allowed to warm to room temperature, then transferred to a separatory funnel and extracted with ethyl acetate (2X 200 mL). The organic phase was separated and dried (MgSO)₄) The resulting mixture was filtered and concentrated to give the title compound as a viscous oil.

Example 14

To a 3.0L four-necked round bottom flask was added the compound prepared as in example 13 above (112g, 0.23mol) and acetonitrile (1.0L). The resulting mixture was cooled to-20 ℃ in an ice bath with stirring. Triethylsilane (185mL, 1.16mol) was added followed by slow addition of boron trifluoride etherate (150mL, 1.20mol) to maintain the temperature at-20 ℃. After the addition was complete the resulting dark orange mixture was slowly warmed to 0 ℃. Once complete, an aqueous sodium bicarbonate solution (200g in 500mL of distilled water) was added to the resulting mixture and the layers were separated. The organic layer was concentrated to remove the majority of the acetonitrile and then diluted with ethyl acetate (350 mL). The aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated sodium chloride solution (100mL), dried over magnesium sulfate (135g) and concentrated to give the title compound as a yellow foam.

Example 15

A500 mL three-neck round bottom flask was charged with a solution of the compound prepared as in example 14 above (23.56g, 50.0mmol), 4-methylmorpholine (27.5mL, 250mmol) and DMAP (0.60g, 4.86mmol) in THF (160 mL). The resulting yellow mixture was cooled to-10 ℃ with stirring in an ice bath, and acetic anhydride (23.6mL, 250mmol) was then added dropwise so that the temperature did not exceed 0 ℃. The ice bath was removed 15 minutes after the addition was complete. The resulting mixture was stirred at ambient temperature for 1.5 hours and then concentrated under reduced pressure at about 30-35 ℃ to remove most of the solvent. The resulting residue was dissolved in ethyl acetate (100-150mL) and diluted with 1N HCl (100-150 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2X 30 mL). The combined organic layers were washed with 100mL each of water, saturated bicarbonate solution and brine, then dried and concentrated to give a moist solid. The solid was recrystallized from hot methanol (300-425mL) to give the title compound as a pale yellow solid.

Example 16

1- (beta-D-glucopyranosyl) -4-methyl-3- (5- (6-fluoro-pyridin-3-yl) -2-thienylmethyl Phenyl radical)

To a 250mL single neck round bottom flask was added THF (50mL) and the compound prepared as in example 15 above (8.52g, 13.4mmol) in methanol (50 mL). To the stirred suspension was added 3N sodium hydroxide (1.2mL, 3.60 mmol). The resulting mixture was stirred at ambient temperature for 1 hour. The volatiles were removed and the resulting residue was diluted with ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to half volume to give a solid precipitate. The title compound was isolated by filtration as a cream colored solid.

Melting points, mass spectra and mass spectra of representative samples of compounds of formula (I-K) (prepared according to the procedure as described in the examples above) were measured¹The HNMR spectra are as follows:

melting point: 130 ℃ to 132 ℃;

mass spectrum: m/z (LCMS API-ES)466 (M)⁺H)；

¹H NMR(DMSO-d6)：δ＝3.05-3.31(m，4H)，3.45(dt，1H，J＝5.3Hz，J＝12.2Hz)，3.70(dd，1H，J＝5.3Hz，J＝11.4Hz)，4.02(d，1H，J＝9.7Hz)，4.28(d，2H，J＝3.5Hz)，4.46(t，1H，J＝6.2Hz)，4.89(d，1H，J＝6.2Hz)，4.99(d，2H，J＝5.3Hz)，6.93(d，1H，J＝3.5Hz)，7.21(dd，1H，J＝3.5Hz，J＝8.3Hz)，7.28(dd，1H，J＝2.0Hz，J＝8.3Hz)，7.39-7.48(m，3H)，8.17(ddd，1H，J＝16.2Hz，J＝8.3Hz，J＝2.6Hz)，8.46(s，1H)。

For example, a compound of formula (I-K) prepared according to example 16 above can be characterized by its powder XRD peaks (preferably by its powder XRD peaks with a relative intensity greater than about 10%, more preferably by its powder XRD peaks with a relative intensity greater than about 25%, still more preferably by its powder XRD peaks with a relative intensity greater than about 35%, still more preferably by its powder XRD peaks with a relative intensity greater than about 50%), as set forth in table 2 below.

TABLE 2

Powder XRD peaks for crystalline forms of the compound of formula (I-K)

Example 17

1- (beta-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl] Crystallization of benzene

1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene (foamy, 23.1 g; prepared as described in PCT publication WO 2005/012326) was dissolved in ethyl acetate (345ml) and seed crystals of 1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene were added thereto. The mixture was refluxed for 30 minutes and then stirred at 50 ℃ for 14 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with ethyl acetate (100ml) and dried to give crystalline 1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene as colorless crystals (20.34 g).

The melting point is 131-134 DEG C

Calculating C₂₂H₂₁ClFNO₅Elemental analysis of S: c, 56.71; h, 4.54; n, 3.01; f, 4.08; cl, 7.61; s, 6.88; the calculation is as follows: c, 56.59; h, 4.55; n, 3.01; f, 4.00; cl, 7.60; and S, 6.94.

Example 18

1- (beta-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl] Benzene and its derivatives

To a solution of 1- (2, 3, 4, 6-tetra-O-acetyl-1- β -D-glucopyranosyl) -4-chloro-3- (5- (6-fluoro-3-pyridinyl) -2-thienylmethyl) benzene (9.64 g; prepared as described in PCT publication WO 2005/012326) in a mixture of methanol-tetrahydrofuran (75ml-75ml) was added a solution of sodium methoxide in methanol (28%, 0.09ml), and the resulting mixture was stirred at room temperature under an argon atmosphere for 1.5 hours. The organic solvent was evaporated under reduced pressure, and brine (200ml) was added thereto. The mixture was extracted with ethyl acetate (500ml), and the organic layer was dried over magnesium sulfate. After treatment with activated carbon, insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (60ml) and seed crystals of 1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene were added thereto. The mixture was stirred at 50 ℃ for 2.5 h, refluxed for 45 min and stirred at room temperature overnight. The precipitated crystals were triturated and the mixture was again stirred at 50 ℃ for 30 minutes, refluxed for 45 minutes and stirred at room temperature overnight. The precipitated crystals were collected, washed twice with ethyl acetate (40ml) and dried to give colorless crystals of 1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene (5.59 g).

The melting point was 131-.

Example 19: reference example A

Step (1): 1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -4-chloro-3- (5- (6-) Preparation of fluoro-3-pyridyl) -2-thienylmethyl) benzene

A suspension of 1- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyl) -4-chloro-3- (5-bromo-2-thienylmethyl) benzene (13.5 g; prepared as described in PCT publication WO 2005/012326), 2-chloropyridine-5-boronic acid (Frontier Scientific, 4.63g), cesium fluoride (19.96g) and tetrakis (triphenylphosphine) palladium (0) (2.53g) in 1, 2-dimethoxyethane (200ml) was refluxed for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was treated with activated carbon and filtered through a pad of aminosilane-treated silica gel (27 ml). The filtrate was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (heptane: ethyl acetate: dichloromethane 2: 1) and recrystallized from methanol to give 1- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyl) -4-chloro-3- (5- (6-fluoro-3-pyridyl) -2-thienylmethyl) benzene (8.33g) as colorless crystals.

The melting point is 161-162 DEG C

IR(Nujol)1736，1493，1463，1379，1229，1215cm^-1

APCI-Mass m/Z 634/636(M+H)，651/653(M+NH₄)

¹H-NMR(DMSO-d₆)δ1.72(s，3H)，1.93(s，3H)，1.99(s，3H)，2.01(s，3H)，4.07-4.14(m，3H)，4.28(s，1H)，4.71(d，J＝9.8Hz，1H)，4.96(t，J＝9.5Hz，1H)，5.08(t，J＝9.5Hz，1H)，5.36(t，J＝9.5Hz，1H)，6.90(d，J＝3.7Hz，1H)，7.22(dd，J＝8.7，2.5Hz，1H)，7.31-7.32(m，1H)，7.39(d，J＝2Hz，1H)，7.44-7.48(m，2H)，8.14-8.18(m，1H)，8.45(d，J＝2.0Hz，1H).C₃₀H₂₉ClFNO₉Analytical calculation of S: c, 56.83; h, 4.61; cl, 5.59; f, 3.0; n, 2.21; and S, 5.06. Experimental values: c, 56.8; h, 4.47; cl, 5.6; f, 2.91; n, 2.29; and S, 4.93.

Step (2): 1- (beta-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thiophene Radical methyl]Preparation of benzene

The compound (8.33g) prepared as in the above step (1) was dissolved in methanol (200ml) -tetrahydrofuran (100ml), and sodium methoxide (28% methanol solution, 5 drops) was added thereto, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol 100: 0-88: 12) and triturated with isopropyl ether-2-propanol to give 1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) -2-thienylmethyl ] benzene (4.61g) as a colorless powder.

APCI-Mass m/Z 466/468(M+H)，483/485(M+NH₄)

¹H-NMR(DMSO-d₆)δ3.07-3.27(m，4H)，3.38-3.49(m，1H)，3.67-3.80(m，1H)，4.02(d，J＝9.4Hz，1H)，4.27(app d，J＝3.1Hz，2H)，4.33(d，J＝4.2Hz，1H)，4.85(d，J＝5.7Hz，1H)，4.95(dd，J＝5.0，3.8Hz，2H)，6.92(d，J＝3.7Hz，1H)，7.18-7.22(m，1H)，7.26-7.29(m，1H)，7.40-7.44(m，3H)，8.13-8.19(m，1H)，8.44-8.45(m，1H)。

Example 20

As a specific example of an oral composition, 100mg of a compound prepared as in example 9 is formulated together with lactose finely divided enough to give a total amount of 580 to 590mg to fill a size O hard capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims (11)

1. A process for the preparation of a compound of formula (I-S)

Or a pharmaceutically acceptable salt thereof or a prodrug thereof;

the method comprises the following steps:

reacting a compound of formula (V-S) with a compound of formula (VI-S) in an organic solvent in the presence of an alkyl lithium at a temperature in the range of from 0 ℃ to-78 ℃, wherein the alkyl lithium is selected from the group consisting of trimethylsilylmethyl lithium, 2, 4, 6-trimethylphenyl lithium and triethylsilylmethyl lithium; to produce the corresponding compound of formula (VII-S);

and wherein the alkyl lithium is added to the mixture of the compound of formula (V-S) and the compound of formula (VI-S);

reacting said compound of formula (VII-S) with BF₃OEt₂In the presence of a trialkylsilane in an organic solvent to give the corresponding compound of formula (VIII-S);

reacting the compound of formula (VIII-S) with acetic anhydride or acetyl chloride in the presence of an organic base, either without addition of a solvent or in an organic solvent, to yield the corresponding compound of formula (IX-S); and

deprotecting the compound of formula (IX-S) to give the corresponding compound of formula (I-S).

2. The process of claim 1, wherein the compound of formula (VI-S) is present in an amount ranging from 1.0 to 1.25 molar equivalents relative to moles of compound of formula (V-S).

3. The process of claim 1, wherein the alkyl lithium is (trimethylsilyl) methyllithium, and wherein the alkyl lithium is present in an amount ranging from 2.0 to 2.5 molar equivalents relative to moles of the compound of formula (V-S).

4. The process of claim 1, wherein the alkyl lithium is added to a mixture of the compound of formula (V-S) and the compound of formula (VI-S) in the organic solvent.

5. The method of claim 1, wherein the BF is₃OEt₂Is present in a range of 2.0 to 6.0 molar equivalents relative to moles of compound of formula (VII-S), and wherein the trialkylsilane is Et₃SiH and present in an amount ranging from 2.0 to 6.0 molar equivalents relative to moles of the compound of formula (VII-S).

6. The method of claim 5, wherein BF₃OEt₂∶Et₃The molar ratio of SiH was 1: 1.

7. The process of claim 1, wherein the compound of formula (VIII-S) is reacted with acetic anhydride, and wherein the acetic anhydride is present in an amount ranging from 4.5 to 5.0 molar equivalents relative to moles of compound of formula (VIII-S).

8. The method of claim 1, wherein the organic base is NMM.

9. The process of claim 1, wherein the compound of formula (VIII-S) is reacted with acetic anhydride in the presence of a catalytic amount of DMAP.

10. The process of claim 1, wherein the compound of formula (IX-S) is further slurried in methanol and filtered.

11. The process of claim 1, wherein the compound of formula (IX-S) is deprotected by reaction with a base.