HK1170241B - Process for the preparation of compounds useful as inhibitors of sglt2 - Google Patents

Description

Process for the preparation of compounds useful as inhibitors of SGLT2

Cross reference to related patent applications

This application claims the benefit of U.S. provisional patent application 61/251,378 filed on 14.10.2009, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to a novel method for producing a compound having an inhibitory activity against sodium-dependent glucose transporter (SGLT) present in the intestine or kidney.

Background

Diet therapy and exercise therapy are the basic means of treating diabetes. When these therapies fail to adequately control the patient's condition, insulin or oral antidiabetic agents may additionally be used to treat diabetes. Currently, used as antidiabetic agents are: biguanide compounds, sulfonylurea compounds, agents for improving insulin resistance, and alpha-glucosidase inhibitors. However, these antidiabetic agents have various side effects. For example, biguanides can cause lactic acidosis, sulfonylureas can cause significant hypoglycemia, agents that improve insulin resistance can cause edema and heart failure, and α -glucosidase inhibitors can cause abdominal bloating and diarrhea. In view of such circumstances, it is desired to develop a new drug for treating diabetes without such side effects.

Recently, hyperglycemia has been reported to be involved in the onset and progressive damage of diabetes, the glucose toxicity theory. That is, chronic hyperglycemia causes increased insulin secretion and further causes decreased insulin sensitivity, leading to increased blood glucose concentration, so diabetes is self-worsening (Unger, r.h. et al, "hyperglycemic asian insulin sensitivity of Impatiention and Isletcellfunctional research: immunity for diabetes mellitus",Diabetologiavol.28, No. 3, p.119-121 (1985); rossetti, L. et al, "GlucoseToxicity",DiabetesCarevol.13, No. 6, p.610-630 (1990)). Therefore, by treating hyperglycemia, the self-worsening cycle is disrupted, and prevention or treatment of diabetes is possible.

As one of the methods for treating hyperglycemia, it is considered to directly excrete an excessive amount of glucose into urine so that the blood glucose concentration is normalized. For example, by inhibiting the sodium-dependent glucose transporter present in the renal proximal convoluted tubule,can inhibit the reabsorption of glucose by kidney, thereby promoting the excretion of glucose into urine and lowering blood sugar level. In fact, it was determined that by continuous subcutaneous administration of phlorizin having SGLT inhibitory activity to diabetic animal models, hyperglycemia is normalized and its blood glucose level can be maintained normal for a long period of time, whereby insulin secretion and insulin resistance are improved (Rossetti, l. et al, "corectionhyperglycemic with hyperlipidemia transmitting insulin resistance diabetes mellitus rates",JournalofClinicalInvestigation(1987), Vol.79, No. 5, p.1510-1515; rossetti, L. et al, "Effect of Chronic hyperglycemic ioninvivo acquisition in partial Pancreatized rates",JournalofClinical Investigation(1987), Vol.80, No. 4, p.1037-1044; kahn, B.B. et al, "Normalizanoto fbloodglucoscopic discovery recovery analysis-Resistantion-Resistantiglucoscopic transmission prediction glucoscopic-" Kahn, B.B. et al,J.Clin.Invest.，1991, Vol 87, pp 561-.

In addition, 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 incurring any adverse effect on the kidney or imbalance in electrolyte blood concentration, and therefore, the onset and development of diabetic nephropathy and diabetic neuropathy are prevented (kenjit et al, "Na)⁺-GlucoseCo-transporter(SGLT)InhibitorsasAntidiabeticAgents.4.SynthesisandPharmacologicalPropertiesof4‘-DehydroxyphlorizinDerivativesSubstitutedontheBRing”，J.Med.Chem.(1999), volume 42, page 5311-5324); kenjia et al, "improved design beta synthesis loop C57BL/KsJ-db/db micro ball apparatus and administration and HeNa⁺-glucosecotransporterinhibitorT-1095”，BritishJournalofPharmacology(2001), volume 132, phase 2, page 578-; ueta, K. et al, "Long term treatment with the Na + Glucosec-transporters inhibitor T-1095cause SustaineedImprocementin hyperglycemic neuron and Prevents diabetes neuro-goto-KakizakiRats",LifeSci.(2005), volume 76, 23, page 2655-2668)

In light of the above, SGLT inhibitors are expected to improve insulin secretion and insulin resistance and further prevent the occurrence and development of diabetes and diabetic complications by lowering blood glucose levels in diabetic patients.

Disclosure of Invention

The present invention relates to processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts and solvates 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 sugar moieties X- (sugar) and-Y- (ring B) moieties are located on the same heterocyclic ring of the fused heterobicyclic ring, and ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, 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

Reacting a compound of formula (VIII) (wherein each Z is an independently selected oxygen protecting group, LG)²Is a leaving group) with a compound of formula (X), wherein the compound of formula (X) is selected from

(a) Organic zinc derivatives of which Q¹Is composed ofQ²Is halogen and Q³Is absent;

(b) disubstituted zinc derivatives, wherein Q¹And Q²Are identical and each isQ³Is absent;

(c) organozincate-type complex (organozincate) derivatives wherein Q¹Is composed ofAnd Q²And Q³Each independently selected non-transferable group (wherein the zinc carries a negative charge and wherein the compound of formula (X) is present together with a counterion); and

(d) organic zincate-type complex derivative, wherein Q¹、Q²And Q³Are identical and each is(wherein the zinc carries a negative charge and wherein the compound of formula (X) is present along with a counterion);

reacting in an organic solvent or a mixture of organic solvents; to yield the corresponding compound of formula (IX); and

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

The invention also relates to processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts and solvates 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 sugar moieties X- (sugar) and-Y- (ring B) moieties are located on the same heterocyclic ring of the fused heterobicyclic ring, and ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, 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

Reacting a compound of formula (VII) (wherein M²Is a zinc species) with a compound of formula (VIII) (wherein each Z is an independently selected oxygen protecting group, and wherein LG is²Is a leaving group); reacting in a mixture of an ether solvent and a hydrocarbon solvent; to yield the corresponding compound of formula (IX);

deprotecting a 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 a compound of formula (I-S) (also known as 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) or a solvate thereof

The method comprises

Reacting a compound of formula (VII-S) (wherein M is²Is a zinc species) with a compound of formula (VIII-S) (wherein each Z is an independently selected oxygen protecting group, and wherein LG²Is a leaving group); reacting in a mixture of an ether solvent and a hydrocarbon solvent; to form the corresponding compound of formula (IX-S);

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

In another embodiment, the present invention relates to a process for the preparation of a compound of formula (I-K) (also known as 1- (. beta. -D-glucopyranosyl) -4-chloro-3- [5- (4-fluoro-3-pyridinyl) -2-thienylmethyl ] benzene) or a pharmaceutically acceptable salt or solvate thereof

The method comprises

Reacting a compound of formula (VII-K) (wherein M is²Is a zinc species) with a compound of formula (VIII-S) (wherein each Z is an independently selected oxygen protecting group, and wherein LG²Is a leaving group); reacting in a mixture of an ether solvent and a hydrocarbon solvent; to form the corresponding compound of formula (IX-K);

deprotecting a compound of formula (IX-K); to give the corresponding compounds of formula (I-K). The invention also relates to a process for the preparation of disubstituted zinc derivative compounds of formula (X-P)

Two of Q¹The radicals are identical and areAs defined herein; the method comprises

Reacting a compound of formula (Z1) (wherein Ha²Is halogen) with a lithium trialkyl magnesium (compound of formula (Z2); in a suitably selected anhydrous organic solvent or mixture of anhydrous organic solvents; to produce the corresponding compound of formula (Z3);

reacting a compound of formula (Z3) with a zinc halide-lithium halide complex (compound of formula (Z4), wherein Ha¹Is halogen); in a suitably selected anhydrous organic solvent or mixture of anhydrous organic solvents; to give the corresponding compound of formula (X-P).

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

The present invention features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a product made according to any of the methods described herein. The present invention illustrates a pharmaceutical composition made by mixing a product prepared according to any of the methods described herein with a pharmaceutically acceptable carrier. The present invention features a process for preparing a pharmaceutical composition comprising admixing a product prepared according to any of the methods described herein and a pharmaceutically acceptable carrier.

The present invention illustrates a method of treating an SGLT-mediated disorder (including treating or delaying the development 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 above compounds or pharmaceutical compositions.

The present invention also illustrates a method of treating type 1 and type 2 diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of any of the above compounds or pharmaceutical compositions, alone or in combination with at least one of the following: antidiabetic agents, agents for treating diabetic complications, anti-obesity agents, antihypertensive agents, antiplatelet agents, anti-atherosclerotic agents and/or hypolipidemic agents.

Detailed Description

The present invention relates to processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof

Wherein X, Y, ring a and ring B are as defined herein; as described in more detail below.

The compounds of formula (I) exhibit inhibitory activity against sodium-dependent glucose transporters present in the intestine and kidney of mammals and are useful for the treatment of diabetes or diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and delayed wound healing. In one embodiment, the present invention relates to a process for preparing a compound of formula (I-S), as described in more detail below. In another embodiment, the present invention relates to a process for preparing the compounds of formula (I-K), as described in more detail below.

The term "halogen" shall include chlorine, bromine, fluorine and iodine. The term "halogen atom" or "halo" when referring to a substituent on a compound of formula (I) shall mean chlorine, bromine and fluorine, with chlorine and fluorine being preferred.

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

The term "alkylene group" or "alkylene" means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms. Preferred are linear or branched alkylene groups having 1 to 6 carbon atoms, and more preferred are linear or branched alkylene groups 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 alkylene groups as defined above are attached to two different carbon atoms of the phenyl ring, they form, together with the carbon atoms to which they are attached, a fused five-, six-or seven-membered carbocyclic ring, and may optionally be substituted by one or more substituents as defined below.

The term "alkenyl group" means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and at least one double bond. Preferred alkenyl groups are linear or branched alkenyl groups having 2 to 6 carbon atoms, 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 described below, if necessary.

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

The term "alkynyl group" 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, 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-undecenyl, 4-dodecenyl and the like. The alkynyl group may be optionally and independently substituted with 1 to 4 substituents described 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 described below, if necessary. The cycloalkyl group may be optionally substituted 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) The fused, fused saturated hydrocarbon ring and the fused unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described 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 bicycloalkylene such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like. These groups may be optionally and independently substituted with 1 to 4 substituents described below, if necessary. Further, the cycloalkylene group may be optionally substituted with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, all ofThe 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) The fused, and fused saturated hydrocarbon ring and unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "cycloalkenyl" means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and at least one double bond. 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 described below, if necessary. Further, the cycloalkenyl group may be optionally combined 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) The fused, and fused saturated hydrocarbon ring and unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "cycloalkynyl" means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms and at least one triple bond. Preferred cycloalkynyl groups are monocyclic unsaturated hydrocarbon groups having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl groups such as cyclooctynyl, cyclodecynyl. These groups may be optionally substituted with 1 to 4 substituents described below, if necessary. Further, the cycloalkynyl group may be optionally and independently bonded to 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) The fused, and fused saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described 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 described below, if necessary. Further, the aryl group may be optionally substituted with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally substituted with a ringContaining oxygen, nitrogen, sulfur, SO or SO atoms₂) The fused, and fused saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "unsaturated monocyclic heterocyclic ring" means an unsaturated hydrocarbon ring containing 1 to 4 hetero atoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferred unsaturated monocyclic heterocyclic ring is a 4-to 7-membered saturated or unsaturated hydrocarbon ring containing 1 to 4 hetero atoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom. 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 can be preferably used. The "unsaturated monocyclic heterocycle" may be optionally and independently substituted with 1 to 4 substituents described below, if necessary.

The term "unsaturated fused heterobicyclic ring" means a hydrocarbon ring composed of a saturated or unsaturated hydrocarbon ring fused with the above-mentioned unsaturated monocyclic heterocyclic ring, wherein 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. "unsaturated fused heterobicyclic ring" includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydroisoquinoline, and the like. In addition, "heterocycle" also includes their possible N-or S-oxides.

The term "heterocyclyl" means a monovalent radical of an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring as mentioned above, and a monovalent radical of a saturated form of an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring as mentioned above. The heterocyclic group may be optionally and independently substituted with 1 to 4 substituents described 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 each of the above groups include, for example, halogen atoms (fluorine, chlorine, bromine), nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylidenemethyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloalkynylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkoxy-carbonyl, alkenyloxy-carbonyl, alkynyloxy-carbonyl, cycloalkoxy-carbonyl, cycloalkenyl-oxy-carbonyl, cycloalkynyl-oxy-carbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenyl-carbonyloxy, cycloalkynyl-oxy-carbonyl, heterocyclyloxycarbonyl, alkoxycarbonyloxy, cycloalkynyl-oxy-carbonyl, heterocyclyloxycarbonyl, alkoxycarbonyloxy, alkynyl-carbonyloxy, cycloalkyl-carbonyloxy, cycloalkenyl-carbonyloxy, cycloalkynyl-carbonyloxy, 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, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkynyl-carbonyloxy, alkoxycarbonylamino, alkylsulfanyl, alkenylthio, alkynylthio, alkoxycarbonylamino, mono-or di-alkoxycarbonylamino, mono-or, Cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl. Each of the above 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) are respectively substituted with one or more halogen atoms. 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 with 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. Further, 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 refer to alkyl groups 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 alkyl and alkoxy groups described above having an aryl substituent.

Unless otherwise defined, the term "lower" used in the definition of chemical formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms. More preferably, the term 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 of the hydroxyl groups of a compound of formula I with an acylating agent substituted with an alkyl, alkoxy, or aryl group using conventional methods to produce an acetate, pivalate, methoformate, benzoate, and the like. In addition, prodrugs also include esters or amides which are similarly formed by reacting one or more of the hydroxy groups of a compound of formula I with an α -amino acid or β -amino acid, and the like, using a condensing agent in a conventional manner.

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 at the carbon atom containing 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.

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

Examples of the optionally substituted unsaturated monocyclic heterocyclic ring of 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, sulfo group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl 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 group, carbonyl group, carboxyl group, 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, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkoxycarbonylamino, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl groups, wherein each substituent may be further optionally substituted by these substituents.

Examples of the optionally substituted unsaturated fused heterobicyclic ring of the present invention include unsaturated fused heterobicyclic 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, sulfo group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl 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 group, carbonyl group, carboxyl group, 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, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkoxycarbonylamino, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl groups, wherein each substituent may be further optionally substituted by these substituents.

Examples of the optionally substituted benzene ring of the present invention include benzene rings optionally substituted with 1 to 5 substituents selected from: halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, sulfo group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy 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 group, heterocyclic oxycarbonyl group, alkanoyloxy group, alkenylcarbonyloxy group, alkynyl carbonyloxy group, cycloalkylcarbonyloxy group, cycloalkynylcarbonyloxy group, arylcarbonyloxy group, heterocyclic carbonyloxy group, alkylthio group, alkenylthio group, cycloalkylcarbonyloxy group, 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, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heterocyclylsulfonyl, alkoxycarbonylamino, alkoxycarbonyla, Cycloalkynylsulphonyl, arylsulphonyl, heterocyclosulphonyl, alkylene, alkyleneoxy, alkylenedioxy and alkenylene, each of which substituents may also be optionally substituted by such 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: 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 1-3 substituents independently selected from: 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;

an optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring that 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

An optionally substituted phenyl ring is a phenyl 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 may be optionally substituted with 1-3 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

An optionally substituted phenyl ring is a phenyl 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 which may be optionally substituted with 1-3 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 1-3 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 phenyl 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; or

(3) Ring a is an unsaturated fused heterobicyclic ring that can be optionally substituted with 1-3 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 1-3 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 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 heterocycle which may be optionally substituted with: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group or oxo group, and ring B is (a) a benzene ring which may be optionally substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; 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 which may be optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; (b) an unsaturated monocyclic heterocycle which may optionally be substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; and a heterocyclic group 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 (c) an unsaturated fused heterobicyclic ring which may be optionally substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl which may be substituted by halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; and a heterocyclic group 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;

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

In another, Y is-CH₂-and is attached to ring a at the 3-position and X is at the 1-position, ring a being a phenyl 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, halogenated phenyl, 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 to ring a at the 3-position 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: lower alkyl, halogen atom, lower alkoxy and oxo, and ring B is optionally substituted by 1 to 3 substituents selected from the group consisting ofBenzene ring of the generation: 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.

Furthermore, in another preferred embodiment, Y is-CH₂-and is attached to ring a at the 3-position 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: 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 phenyl 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 a 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 a 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 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; 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 by a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted by 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 a 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 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; and an oxo group;

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

In another preferred embodiment of the invention, Y is attached to the 3-position of ring A and X is at the 1-position, ring A being a phenyl ring which may optionally be substituted with the following substituents: halogen atom, lower alkyl optionally substituted by halogen atom, lower alkoxy or phenyl, and ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring which may be optionally substituted by 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 to ring A at the 3-position and X is at the 1-position, ring A being an unsaturated monocyclic heterocycle which may optionally be 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 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 with 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 cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkoxy group, a phenyl 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, an alkylsulfonyl group

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; a cycloalkoxy group; 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, halogeno-lower alkyl group, lower alkoxy group, halogeno-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 being a hydrogen atomHalogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group or halogenated 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, halogeno-lower alkyl group, lower alkoxy group, halogeno-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, cyano group, lower alkyl group, lower alkoxy group, carbamoyl group or 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, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino groupCarbamoyl and mono-or di-lower alkylcarbamoyl; 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^5aIs a hydrogen atom, and 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 below:

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 which is optionally substituted by 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 substituted by 1-3 substituents selected from halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxyPhenyl substituted with a substituent of yl, halogeno-lower alkoxy, methylenedioxy, ethyleneoxy, mono-or di-lower alkylamino, carbamoyl and mono-or di-lower alkylcarbamoyl; 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. 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 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 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 preferred.

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 below:

wherein R is⁸、R⁹And R¹⁰Each independently is hydrogen atom, halogen atom, hydroxyl, alkoxy, alkyl, halogenated alkyl, halogenAlkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy, 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 alkoxyAlkyl, cycloalkoxy, halo-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 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 the group consisting of: 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: 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; heterocyclyl optionally substituted with: halogen atom, cyano group, lower alkyl group optionally substituted with halogen atom, lower alkoxy group optionally substituted with 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 "schemes" and "examples", are as follows:

AcOEt ═ ethyl acetate

CPME ═ cyclopentyl methyl ether

DI (water) ═ deionization (water)

DMAP ═ 4-dimethylaminopyridine

HPLC ═ high pressure liquid chromatography

IPA (isopropyl alcohol)

2-Me-THF ═ 2-methyl-tetrahydrofuran

MPLC-Medium pressure liquid chromatography

MTBE ═ methyl tert-butyl ether

n-BuLi ═ n-butyllithium

Pd/C ═ palladium on carbon

Pd(OAc)₂/Et₃SiH palladium acetate and triethylsilane

RaNi＝Nickel (aluminum nickel alloy)

RBF round-bottom flask

TEA ═ triethylamine

THF ═ tetrahydrofuran

TMEDA ═ tetramethylethylenediamine

TMS ═ trimethylsilyl

TMSBr ═ trimethyl bromosilane

TMSCH₂trimethylsilyl-CH₂-

As used herein, unless otherwise indicated, the term "isolated form" shall mean that the compound is present in a form separate from any solid mixture, solvent system, or biological environment formed with another compound. In one embodiment, the product prepared according to the methods described herein (more specifically, a compound of formula (I), preferably a compound of formula (I-S), or a compound of formula (I-K)) is prepared in isolated form.

As used herein, unless otherwise specified, the term "substantially pure" shall mean that the mole percentage of impurities 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 present invention relates to a process for preparing a compound of formula (I), wherein the compound of formula (I) is substantially pure. In another embodiment, the present 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.

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 the corresponding salt forms in the isolated base of formula (I) 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 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 present invention relates to a process for preparing 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 present invention relates to a process for preparing a compound of formula (I-K), wherein the compound of formula (I-K) is substantially free of the corresponding salt form.

As used herein, unless otherwise indicated, the terms "treating", "treating" and the like shall include treating and caring for a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, disorder or abnormality, and includes administering a compound of the present invention to prevent the onset of symptoms or complications, to alleviate symptoms or complications, or to eliminate the disease, disorder or abnormality.

As used herein, unless otherwise indicated, the term "preventing" shall include (a) reducing the frequency of occurrence of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delay or avoidance of development of additional symptoms; and/or (d) delaying or avoiding the development of the abnormality or disorder.

One skilled in the art will recognize that, in the context in which the present invention relates to a method of prevention, the subject in need thereof (i.e., the subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the abnormality, disease or disorder to be prevented. Furthermore, a subject in need thereof may also be a subject (preferably a mammal, more preferably a human) that does not exhibit any symptoms of the abnormality, disease or condition to be prevented, but is deemed by a physician, clinician or other medical professional to be at risk of developing the abnormality, disease or condition. For example, the subject may be considered at risk of developing an abnormality, disease or disorder (and thus in need of prophylactic or preventative treatment) due to the subject's medical history, including but not limited to family history, predisposition to the disease, co-existing abnormalities or disorders (with concurrent morbidity), genetic testing, and the like.

The term "subject" as used herein 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.

The term "therapeutically effective amount" as used herein, 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.

The term "composition" as used herein 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 shows excellent inhibitory activity against sodium-dependent glucose transporters, and excellent blood glucose-lowering action. Accordingly, the compounds of the present invention may be 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 according to the 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, or the like, or solution preparations, suspension preparations, emulsion preparations, or 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 solution or aqueous glucose solution: or an inhalation formulation.

The dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention may vary depending on the route of administration, the age, 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 amount or range therein, preferably in the range of about 0.1 to 50 mg/kg/day, or any amount or range therein, preferably in the range of about 0.1 to 30 mg/kg/day, or any amount or range therein. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof at a dose in the range of about 0.01 mg/kg/day to about 15 mg/kg/day, or any amount or 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 different from 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 route of administration, 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.

One skilled in the art will also recognize that in the description and claims presented herein, if a reagent or class of reagents (e.g., base, solvent, etc.) is mentioned in more than one step of the process, each reagent should be independently selected for each reaction step, and each reagent may be the same as or different from each other. For example, if two steps of the method 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 addition, one skilled in the art will recognize that if the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, the reaction steps can also be carried out in a mixture of suitable solvents or solvent systems.

Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are given in the detailed description below. Those skilled in the art will appreciate 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 appended below.

To provide a more accurate description, some quantitative representations herein are in the range of about X to about Y. It should be understood that if a range is referred to, the range is not limited to the recited upper and lower limits, but includes all ranges from about X to about Y, or any amount or range therein.

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.

The term "leaving group" as used herein, unless otherwise indicated, shall mean a charged or uncharged atom or group that is liberated during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

In any of the processes for preparing the compounds of the present invention, it may be necessary and/or desirableProtecting any sensitive or reactive groups on the molecule concerned. This can be achieved by conventional protecting groups, such as those described in the following monographs:ProtectiveGroupsinOrganic ChemistryMcOmie (eds.), plenum Press, 1973 and T.W.Greene&P.G.M.Wuts，ProtectiveGroupsinOrganicSynthesis，JohnWiley&Sons, 1991. The protecting group may be removed at a convenient subsequent stage using methods known in the art.

The term "nitrogen protecting group" as used herein, unless otherwise indicated, shall 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, carbamates-containing groups of the formula-C (O) O-R, wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenethyl, CH₂＝CH-CH₂-and so on; amide-containing groups of the formula-c (o) -R ', wherein R' is, for example, methyl, phenyl, trifluoromethyl, and the like; n-sulfonyl derivatives-containing-SO₂A group of-R ', wherein R' is, for example, tolyl, phenyl, trifluoromethyl, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-yl-, 2, 3, 6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found, for example, in t.w. greene&P.G.M.Wuts，ProtectiveGroupsinOrganicSynthesis，JohnWiley&Sons, 1991 and the like.

The term "oxygen protecting group" as used herein, unless otherwise indicated, shall mean a group that can be attached to an oxygen atom to protect the oxygen atom from participating in a reaction and that can be easily removed after the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, pivaloyl, t-butyl-dimethylsilyl, Trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups may be found, for example, in t.w. greene&P.G.M.Wuts，ProtectiveGroupsinOrganicSynthesis，JohnWiley&Sons, 1991 and the like.

If the process for the preparation of the compounds according to the invention gives rise to a mixture 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 enantiospecific synthesis or by resolution. For example, the compounds may be resolved into their component enantiomers by standard techniques, such as by salt formation with optically active acids (e.g., (-) -di-p-methylbenzoyl-D-tartaric acid and/or (+) -di-p-methylbenzoyl-L-tartaric acid) to form diastereomeric pairs, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of 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.

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 a below.

Scheme A

Accordingly, an appropriately substituted compound of formula (VIII) (wherein LG²A suitably selected leaving group such as bromo, chloro, iodo, and the like, preferably bromo, and wherein each Z is an independently selected oxygen protecting group, e.g., Z may be selected from benzyl, benzoyl, pivaloyl, isobutyryl, p-methoxy-benzyl, and the like; preferably each Z protecting group is the same, more preferably each Z is pivaloyl, which is a known compound or a compound prepared by known methods) with an appropriately substituted compound of formula (X) (a known compound or a compound prepared by known methods); wherein the compound of formula (X) is selected from

(a) Appropriately substituted organic halogensZinc compound, wherein Q¹Is composed ofQ²A suitably selected halogen such as Br, I, etc., and Q³Is absent;

(b) appropriately substituted disubstituted zinc derivatives wherein Q¹And Q²Are identical and each isAnd Q³Is absent;

(c) appropriately substituted organozincate-type complex derivatives, wherein Q¹Is composed ofAnd Q²And Q³Each independently selected non-transferable group, e.g. alkyl, cycloalkyl, TMSCH₂And the like; and

(d) an appropriately selected organic zincate-type complex derivative, wherein Q¹、Q²And Q³Are identical and each is

To yield the corresponding compound of formula (IX); the compound of formula (IX) is then deprotected according to known methods to give the corresponding compound of formula (I).

One skilled in the art will recognize that when the compound of formula (X) is an organozincate-type complex derivative as defined in (c) and (d) above, the Zn of the organozincate-type complex derivative carries a negative charge and the organozincate-type complex derivative is therefore present with a suitable counterion, such as lithium or magnesium.

An organozinc derivative of formula (X) (wherein Q)¹Is composed ofQ²A suitably selected halogen such as Br, I, etc., and Q³Absent) can be prepared, for example, according to scheme B shown below:

scheme B

More specifically, an appropriately substituted organolithium or organomagnesium compound (wherein Q is⁴A suitably selected halogen such as bromine, chlorine, iodine, etc.) with a suitably selected zinc halide. One skilled in the art will recognize that alternatively, the zinc halide can be replaced with a suitably selected zinc sulfonate and reacted as shown in scheme B above to produce the desired organic halide of formula (X).

Alternatively, an organozinc derivative of formula (X) (wherein Q¹Is composed ofQ²A suitably selected halogen such as Br, I, etc., and Q³Absent) can be prepared, for example, according to scheme C shown below:

Q¹-Q²+Zn→Q¹-Zn-Q²

scheme C

More specifically, by direct insertion of activated zinc into an appropriately substituted halogenated aromatic hydrocarbon.

Disubstituted zinc derivatives of formula (X) (wherein Q)¹And Q²Are identical and each isQ³Absent) can be prepared, for example, according to scheme D shown below:

scheme D

More specifically, 2 equivalents of an appropriately substituted organolithium or organomagnesium compound (wherein Q is⁴For a suitably selected halogen such as bromine, chlorine, iodine, etc.) with a suitably selected zinc halide (of the formula Zn (Ha)¹)₂Compounds of formula (I), wherein each Ha¹Halogen as suitably selected, such as Br, I, etc., and among them, two Ha are preferable¹The halogens are the same; or formula Zn (Ha)¹)₂·Li(Ha¹) Of zinc halide-lithium halide complexes, e.g. ZnB₂LiBr, etc.). One skilled in the art will recognize that alternatively, the zinc halide can be replaced with an appropriately selected zinc sulfonate and reacted as shown in scheme D above to produce the desired disubstituted zinc derivative of formula (X).

An organic zincate-type complex derivative of the formula (X) (wherein Q¹、Q²And Q³Are identical and each is) Can be prepared analogously, for example, according to scheme E shown below:

scheme E

More specifically, 3 equivalents of an appropriately substituted organolithium or organomagnesium compound (wherein Q is Q) are reacted by transmetallation⁴For a suitably selected halogen such as bromine, chlorine, iodine, etc.) with a suitably selected zinc halide (of the formula Zn (Ha)¹)₂Compounds of formula (I), wherein each Ha¹Halogen as suitably selected, such as Br, I, etc., and among them, two Ha are preferable¹The halogens are all the same, or of the formula Zn (Ha)¹)₂·Li(Ha¹) Of zinc halide-lithium halide complexes, e.g. ZnB₂LiBr, etc.). Those skilled in the art will recognize that, as an alternativeAlternatively, the zinc halide can be replaced by a suitably selected zinc sulfonate and reacted as shown in scheme E above to produce the desired organozincate-type complex derivative of formula (X). Those skilled in the art will also recognize that for organozincate-type complex derivatives prepared as in scheme E above, Zn may carry a negative charge, and that the organozincate-type complex derivatives may therefore be reacted with an appropriate counter ion, such as lithium or magnesium (e.g., as defined by the variable Q. C⁵Represented) are present together.

Mixed organic zincate-type complex derivatives of formula (X) (wherein Q)¹Is composed ofQ²And Q³Each independently selected non-transferable group, e.g. alkyl, cycloalkyl, TMSCH₂Etc.) can be prepared, for example, according to scheme F shown below:

scheme F

More specifically, by reacting an organolithium or organomagnesium compound (wherein Q is⁴Suitably selected halogens such as bromine, chlorine, iodine, etc.) with a disubstituted zinc derivative. Those skilled in the art will recognize that for organozincate-type complex derivatives prepared as in scheme F above, Zn can carry a negative charge, and thus the organozincate-type complex derivative is combined with an appropriate counter ion, such as lithium or magnesium (e.g., as defined by the variable Q. C⁵Represented) are present together.

Organolithium (Q) reacted in schemes B through F above¹-Li) and organomagnesium (Q)¹-Mg-Q⁴) The compounds are known compounds or compounds which can be prepared according to known methods. For example, Q can be lithiated by a solution of an alkyllithium such as n-butyllithium or the like in a suitably selected solvent¹Substituted halides (e.g. Br, I), sulfides, selenides, tellurides, stannanes or mixtures thereofHis precursor to the preparation of formula Q¹-a Li organolithium compound.

Formula Q¹-Mg-Q⁴Can be prepared by reacting Q with an organic magnesium compound¹A halogen (e.g. Br) compound with an alkylmagnesium halide, such as primary, secondary, tertiary cyclic or acyclic alkyl magnesium bromide or chloride, in a suitably selected organic solvent. Alternatively, formula Q¹-Mg-Q⁴The organomagnesium compound can be prepared by reacting Q¹A halide (e.g. Br) compound with activated magnesium.

One skilled in the art will recognize that the formula Mg (Q) can be used in the reactions described in schemes B through F above¹)₂Diorganomagnesium compound of the formula Q¹-Mg-Q⁴To produce the desired compound of formula (X). According to the Schlenk equilibrium shown below in scheme G, formula Mg (Q)¹)₂The diorganomagnesium compound being present in an ether solution of a Grignard reagent

Scheme G

Wherein Q⁶Suitably selected halogens such as bromine, chlorine, iodine, and the like; those skilled in the art will readily recognize this.

Those skilled in the art will also recognize that formula (Q) may alternatively be used¹)₃The MgLi arylmagnestoate-type complex derivatives are used in the methods described in schemes B to F above, and can be prepared from appropriately substituted magnestoate-type complex derivatives as shown in scheme H below

Scheme H

More particularly, by appropriately substituted Q¹-Q⁴Aryl halide (wherein Q⁴For transmetallation of a suitably selected halogen such as bromine, chlorine, iodine, etc.), the compound is reacted with 1/3 equivalents of an appropriately substituted magnesium carboxylate-type complex in which Q is⁷、Q⁸And Q⁹Each independently selected alkyl or cycloalkyl group).

In another example, disubstituted zinc derivatives of formula (X)

Wherein Q¹And Q²Are identical and each isAnd Q³Absent, it can be prepared according to scheme J shown below.

Scheme J

Accordingly, the formula Q is appropriately substituted¹-Ha²Organic halide compound (wherein Ha²Suitably selected halogens such as Br, I, and the like, preferably I) with suitably selected trialkylghtium lithium (such as dibutylhexylmagnesium lithium (lihtiuundibutylhexylmagnesium silicate), tributylmagnesium lithium, trihexylmagnesium lithium (lithiumtrihexylamagenate), hexyldi-t-butylmagnesium lithium, and the like, preferably dibutylhexylmagnesium lithium, which is a known compound or a compound prepared by a known method); in an appropriately selected anhydrous organic solvent or a mixture of anhydrous organic solvents (e.g., anhydrous toluene, anhydrous n-dibutyl ether, fluorobenzene, chlorobenzene, trifluorotoluene, cyclopentyl methyl ether, etc.); to form the corresponding tri-substituted magnesium lithium; preferably, the compound is not isolated.

The tri-substituted magnesium lithium is then reacted with an appropriately selected halideZinc (formula Zn (Ha)¹)₂Compounds of formula (I), wherein each Ha¹Suitably selected halogens such as Br, I, etc.) or zinc halide-lithium halide complexes such as ZnBr₂LiBr and the like or zinc halide diamine complexes such as zinc bromide bipyridine complex and the like; preferred are zinc halide-lithium halide complexes, more preferred are ZnBr₂LiBr; in a suitably selected anhydrous organic solvent or mixture of anhydrous organic solvents, such as anhydrous toluene, anhydrous n-dibutyl ether, anhydrous cyclopentyl methyl ether, and the like; preferably in the same solvent or solvent mixture as used in the previous reaction step; to give the corresponding disubstituted zinc derivative.

In one embodiment of the invention, the disubstituted zinc derivative of formula (X), preferably prepared according to the process shown in scheme J above, is a compound of formula (X-P)

In another embodiment of the present invention, the disubstituted zinc derivative of formula (X), preferably prepared according to the process shown in scheme J above, is a compound of formula (X-P) selected from the group consisting of compounds of formula (X-S) and compounds of formula (X-K) as follows:

further processes for the preparation of organozinc derivatives, such as compounds of formula (X), are known in the art, for example as described in the organic chemistry literature such as: "organic reactions", volume 58, LarryE.Overman et al (eds.), 2001, John Wiley&Sons, Inc. publication (see Chapter 2: preparation and application of functional and organic Compounds, Knochel, P. et al, page 417-) (ii) a The group of MONGIN, F, et al,TetrahedronLett.2005, page 7989-7992, volume 46; and KITAGAWA, k, et al,Angew.Chem.Int.Ed.2000, 2481, page 2493, volume 39.

In one embodiment, the present invention relates to a process for preparing a compound of formula (I), as shown in scheme 1 below.

Scheme 1

Accordingly, appropriately substituted compounds of formula (V) wherein LG¹LG is preferred for a suitably selected leaving group such as bromo, iodo and the like¹Is a bromo group or an iodo group, which is a known compound or a compound prepared by a known method) with an appropriately selected organolithium reagent such as trimethylsilylmethyllithium, n-hexyllithium, sec-butyllithium, n-butyllithium, tert-butyllithium, methyllithium, etc., preferably n-hexyllithium; wherein the organolithium reagent is preferably present in an amount in the range of about 0.5 to about 2.0 molar equivalents, preferably in an amount in the range of about 1.0 to about 1.2 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, diisopropyl ether, di-n-butyl ether, MTBE, 2-methyl-THF, cyclopentyl methyl ether, and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, trifluorotoluene, etc., preferably toluene; preferably at a temperature below about room temperature, more preferably at a temperature in the range of from about-78 ℃ to about room temperature; to give the corresponding compound of the formula (VI) in which M¹Is lithium. Preferably, the compound of formula (VI) is not isolated.

By reacting a compound of formula (VI) with a suitably selected zinc salt, such as zinc dibromide (ZnBr)₂) Zinc diiodide (ZnI)₂) Zinc bistrifluoromethanesulfonate, etc., preferably ZnBr₂(ii) a Or amine complexes with zinc halides such as zinc pyridinium bromide complex, zinc N-methylmorpholine bromide complex, and the like; wherein the amine complex of the zinc salt or zinc halide is preferably present in an amount in the range of from about 0.33 to about 3.0 molar equivalents, more preferably in an amount in the range of from about 0.33 to about 1.0 molar equivalents, most preferably in an amount of about 0.5 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, diisopropyl ether, di-n-butyl ether, MTBE, cyclopentyl methyl ether and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, etc., preferably toluene; the reaction is preferably carried out in the same solvent mixture as used in the preceding reaction step; to give the corresponding compound of the formula (VII) in which M²As the corresponding zinc species, e.g. when the zinc salt is ZnBr₂Then, in the compound of the formula (VII), M²Is ZnBr; if the zinc salt is ZnI₂In the compound of the formula (VII), M²Is ZnI; if the zinc salt is zinc bistrifluoromethane sulfonate, then in the compound of formula (VII), M²Is zinc trifluoromethanesulfonate. Preferably, the compound of formula (VII) is not isolated.

Preferably, the compound of formula (VI) is reacted with a zinc salt in the presence of a suitably selected amine or lithium salt such as lithium bromide, lithium iodide, pyridine, N-methylmorpholine, 2, 6-dimethylpyridine, TMEDA and the like; wherein the amine or lithium salt is preferably present in an amount in the range of from about 1.0 to about 2.0 molar equivalents.

Reacting a compound of formula (VII) with an appropriately substituted compound of formula (VIII) (wherein LG²As suitably selected leaving groups such as bromo, chloro, iodo and the like, bromo is preferred; and wherein each Z is independently a suitably selected oxygen protecting group, e.g. Z may be selected from benzyl, benzoyl, pivaloyl, isobutyrylP-methoxy-benzyl, etc., preferably each Z protecting group is the same, more preferably each Z is pivaloyl, which is a known compound or a compound prepared by a known method); wherein the compound of formula (VIII) is preferably present in an amount in the range of from about 0.5 to about 3.0 molar equivalents, or any amount or range therein, more preferably in an amount in the range of from about 0.8 to about 1.25 molar equivalents, or any amount or range therein, more preferably in an amount in the range of from about 1.0 to about 1.1 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, di-n-butyl ether, MTBE, 2-methyl-THF, diisopropyl ether, cyclopentyl methyl ether and the like, preferably di-n-butyl ether or cyclopentyl methyl ether, and a suitably selected hydrocarbon solvent, such as toluene, fluorobenzene, chlorobenzene, trifluorotoluene and the like, preferably toluene, preferably in the same solvent mixture as used in the previous reaction step, at a temperature in the range of from about room temperature to about reflux temperature, more preferably in the range of from about 60 ℃ to about 95 ℃; to give the corresponding compound of formula (IX).

Preferably, the compound of formula (VIII) is added as a solution in a suitably selected hydrocarbon solvent, more preferably a suitably selected aromatic hydrocarbon such as toluene, xylene, fluorobenzene, chlorobenzene, trifluorotoluene and the like, to a solution of the compound of formula (VII) in a suitably selected ether solvent other than THF such as diisopropyl ether, 1, 4-dioxane, 2-methyl-THF, MTBE, cyclopentyl methyl ether (CPME), di-n-butyl ether and the like, more preferably CPME or di-n-butyl ether. Preferably, the final solvent mixture is mixed in an ether solvent ratio of about 1: to about 1: 3: the hydrocarbon solvent is present in a volume ratio.

Alternatively, an appropriately substituted disubstituted zinc derivative, i.e. a compound of formula (X)

Wherein Q¹And Q²Are identical and each isQ³Absent (e.g., prepared according to the procedures shown in scheme J above) and appropriately substituted compounds of formula (VIII) (wherein LG is²As suitably selected leaving groups such as bromo, chloro, iodo and the like, bromo is preferred; and wherein each Z is independently a suitably selected oxygen protecting group, e.g. Z may be selected from benzyl, benzoyl, pivaloyl, isobutyryl, p-methoxy-benzyl and the like, preferably each Z protecting group is the same, more preferably each Z is pivaloyl, a compound known or prepared by known methods); wherein the compound of formula (VIII) is preferably present in an amount in the range of about 0.5 to about 3.0 molar equivalents, or any amount or range therein, more preferably in an amount in the range of about 0.8 to about 1.25 molar equivalents, or any amount or range therein;

in a suitably selected solvent such as toluene, or a mixture of a suitably selected ether solvent such as diethyl ether, di-n-butyl ether, MTBE, 2-methyl-THF, diisopropyl ether, cyclopentyl methyl ether and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, trifluorotoluene, etc., preferably toluene; preferably in the same solvent mixture as used in the previous reaction step; at a temperature in the range of about room temperature to about reflux temperature, more preferably in the range of about 60 ℃ to about 100 ℃; to give the corresponding compound of formula (IX).

In one embodiment of the invention, the disubstituted zinc derivative of formula (X) is a compound of formula (X-P)

Wherein Q¹Formula (la) is as defined herein, and wherein two Q's are¹The groups are all the same. In thatIn another embodiment of the present invention, the disubstituted zinc derivative of formula (X) is selected from the group consisting of compounds of formula (X-S) and compounds of formula (X-K) as follows:

the compound of formula (IX) is deprotected according to known methods to give the corresponding compound of formula (I). For example, if each Z is pivaloyl, the compound of formula (IX) may be deprotected by reaction with an appropriately selected alkoxide or hydroxide base, such as sodium methoxide, sodium ethoxide, lithium hydroxide and the like, in an appropriately selected solvent, such as methanol, ethanol and the like, to yield the corresponding compound of formula (I).

One skilled in the art will recognize that depending on the particular protecting group Z, other reagents may be used for this deprotection step, such other reagents including, but not limited to, Pd/C, Pd (OH)₂、PdCl₂、Pd(OAc)₂/Et₃SiH, RaNi, a suitably selected acid, a suitably selected base, fluoride, and the like.

The compounds of formula (I) are preferably isolated according to known methods, for example by extraction, filtration or column chromatography. It is further preferred to purify the compound of formula (I) according to known methods, for example by recrystallization.

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

Scheme 2

Accordingly, an appropriately substituted compound of the formula (V-S) in which LG is present¹LG is preferred for a suitably selected leaving group such as bromo, iodo and the like¹Is bromo or iodo, which is a known compound or a compound prepared by a known method) With a suitably selected organolithium reagent such as trimethylsilylmethyllithium, n-hexyllithium, sec-butyllithium, n-butyllithium, tert-butyllithium, methyllithium, and the like, preferably n-hexyllithium; wherein the organolithium reagent is preferably present in an amount in the range of about 0.5 to about 2.0 molar equivalents, preferably in an amount in the range of about 1.0 to about 1.2 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, diisopropyl ether, di-n-butyl ether, MTBE, cyclopentyl methyl ether and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, trifluorotoluene, etc., preferably toluene; preferably at a temperature below about room temperature, more preferably at a temperature in the range of from about-78 ℃ to about room temperature; to give the corresponding compound of the formula (VI-S), in which M¹Is lithium. Preferably, the compound of formula (VI-S) is not isolated.

By reacting a compound of formula (VI-S) with a suitably selected zinc salt such as zinc dibromide (ZnBr)₂) Zinc diiodide (ZnI)₂) Zinc bistrifluoromethanesulfonate, etc., preferably ZnBr₂(ii) a Or amine complexes with zinc halides such as zinc pyridinium bromide complex, zinc N-methylmorpholine bromide complex, and the like; wherein the amine complex of the zinc salt or zinc halide is preferably present in an amount in the range of from about 0.33 to about 3.0 molar equivalents, more preferably in an amount in the range of from about 0.33 to about 1.0 molar equivalents, most preferably in an amount of about 0.5 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, diisopropyl ether, di-n-butyl ether, MTBE, cyclopentyl methyl ether and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, etc., preferably toluene; preferably in the same solvent mixture as used in the previous reaction step; to give the corresponding compound of the formula (VII) in which M²As the corresponding zinc species, e.g. when the zinc salt is ZnBr₂In the compounds of the formula (VII-S),M²is ZnBr; if the zinc salt is ZnI₂In the compound of the formula (VII-S), M²Is ZnI; if the zinc salt is zinc bistrifluoromethane sulfonate, then in the compound of formula (VII-S), M²Is zinc trifluoromethanesulfonate. Preferably, the compound of formula (VII-S) is not isolated.

Preferably, the compound of formula (VI-S) is reacted with a zinc salt in the presence of a suitably selected amine or lithium salt such as lithium bromide, lithium iodide, pyridine, N-methylmorpholine, 2, 6-dimethylpyridine, TMEDA and the like; wherein the amine or lithium salt is preferably present in an amount in the range of from about 1.0 to about 2.0 molar equivalents.

Reacting a compound of formula (VII-S) with an appropriately substituted compound of formula (VIII-S) (wherein LG²As suitably selected leaving groups such as bromo, chloro, iodo and the like, bromo is preferred; and wherein each Z is independently a suitably selected oxygen protecting group, e.g. Z may be selected from benzyl, benzoyl, pivaloyl, isobutyryl, p-methoxy-benzyl and the like; preferably, each Z protecting group is the same, more preferably each Z is pivaloyl, a compound that is a known compound or a compound prepared by a known method); wherein the compound of formula (VIII-S) is preferably present in an amount in the range of from about 0.5 to about 3.0 molar equivalents, or any amount or range therein, more preferably in an amount in the range of from about 0.8 to about 1.25 molar equivalents, or any amount or range therein, more preferably in an amount in the range of from about 1.0 to about 1.1 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, di-n-butyl ether, MTBE, 2-Me-THF, cyclopentyl methyl ether, diisopropyl ether, and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, trifluorotoluene, etc., preferably toluene; preferably in the same solvent mixture as used in the previous reaction step; at a temperature in the range of about room temperature to about reflux temperature, more preferably in the range of about 60 ℃ to about 95 ℃; to give the corresponding compound of formula (IX-S).

Preferably, the compound of formula (VIII-S) is added as a solution in a suitably selected hydrocarbon solvent, more preferably a suitably selected aromatic hydrocarbon such as toluene, xylene, fluorobenzene, chlorobenzene, trifluorotoluene and the like, to a solution of the compound of formula (VII) in a suitably selected ether solvent other than THF such as diisopropyl ether, 1, 4-dioxane, 2-methyl-THF, MTBE, cyclopentyl methyl ether (CPME), di-n-butyl ether and the like, more preferably CPME or di-n-butyl ether. Preferably, the final solvent mixture is mixed in an ether solvent ratio of about 1: 1 to about 1: 3: the hydrocarbon solvent is present in a volume ratio.

The compound of formula (IX-S) is deprotected according to known methods to give the corresponding compound of formula (I-S). For example, if each Z is pivaloyl, the compound of formula (IX-S) may be deprotected by reaction with an appropriately selected alkoxide or hydroxide base, such as sodium methoxide, sodium ethoxide, lithium hydroxide and the like, in an appropriately selected solvent, such as methanol, ethanol and the like, to yield the corresponding compound of formula (I-S).

One skilled in the art will recognize that other reagents may be used for this deprotection step, depending on the particular protecting group Z, including but not limited to Pd/C, Pd (OH)₂、PdCl₂、Pd(OAc)₂/Et₃SiH, RaNi, a suitably selected acid, a suitably selected base, fluoride, and the like.

The compounds of formula (I-S) are preferably isolated according to known methods, for example by extraction, filtration or column chromatography. It is further preferred to purify the compound of formula (I) according to known methods, for example by recrystallization.

In another embodiment, the invention relates to a process for preparing compounds of formula (I-K), as shown in scheme 3 below.

Scheme 3

Accordingly, an appropriately substituted compound of the formula (V-K) in which LG is present¹LG is preferred for a suitably selected leaving group such as bromo, iodo and the like¹Is a bromo group or an iodo group, which is a known compound or a compound prepared by a known method) with an appropriately selected organolithium reagent such as trimethylsilylmethyllithium, n-hexyllithium, sec-butyllithium, n-butyllithium, tert-butyllithium, methyllithium, etc., preferably n-hexyllithium; wherein the organolithium reagent is preferably present in an amount in the range of about 0.5 to about 2.0 molar equivalents, preferably in an amount in the range of about 1.0 to about 1.2 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, diisopropyl ether, di-n-butyl ether, MTBE, cyclopentyl methyl ether and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, trifluorotoluene, etc., preferably toluene; preferably at a temperature below about room temperature, more preferably at a temperature in the range of from about-78 ℃ to about room temperature; to give the corresponding compound of the formula (VI-K), in which M¹Is lithium. Preferably, the compound of formula (VI) is not isolated.

By reacting a compound of formula (VI-K) with a suitably selected zinc salt, such as zinc dibromide (ZnBr)₂) Zinc diiodide (ZnI)₂) Zinc bistrifluoromethanesulfonate, etc., preferably ZnBr₂(ii) a Or amine complexes with zinc halides such as zinc pyridinium bromide complex, zinc N-methylmorpholine bromide complex, and the like; wherein the amine complex of the zinc salt or zinc halide is preferably present in an amount in the range of from about 0.33 to about 3.0 molar equivalents, more preferably in an amount in the range of from about 0.33 to about 1.0 molar equivalents, most preferably in an amount of about 0.5 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, diisopropyl ether, and a suitably selected hydrocarbon solventPropyl ether, di-n-butyl ether, MTBE, cyclopentyl methyl ether, etc., preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, etc., preferably toluene; preferably in the same solvent mixture as used in the previous reaction step; to give the corresponding compound of the formula (VII-K), in which M²As the corresponding zinc species, e.g. when the zinc salt is ZnBr₂When, in the compound of formula (VII-K), M²Is ZnBr; if the zinc salt is ZnI₂In the compound of the formula (VII-K), M²Is ZnI; if the zinc salt is zinc bistrifluoromethane sulfonate, then in the compound of formula (VII-K), M²Is zinc trifluoromethanesulfonate. Preferably, the compound of formula (VII-K) is not isolated.

Preferably, the compound of formula (VI-K) is reacted with a zinc salt in the presence of a suitably selected amine or lithium salt such as lithium bromide, lithium iodide, pyridine, N-methylmorpholine, 2, 6-dimethylpyridine, TMEDA and the like; wherein the amine or lithium salt is preferably present in an amount in the range of from about 1.0 to about 2.0 molar equivalents.

Reacting a compound of formula (VII-K) with an appropriately substituted compound of formula (VIII-S) (wherein LG²As suitably selected leaving groups such as bromo, chloro, iodo and the like, bromo is preferred; and wherein each Z is independently a suitably selected oxygen protecting group, e.g. Z may be selected from benzyl, benzoyl, pivaloyl, isobutyryl, p-methoxy-benzyl and the like; preferably, each Z protecting group is the same, more preferably each Z is pivaloyl, a compound that is a known compound or a compound prepared by a known method); wherein the compound of formula (VIII) is preferably present in an amount in the range of from about 0.5 to about 3.0 molar equivalents, or any amount or range therein, more preferably in an amount in the range of from about 0.8 to about 1.25 molar equivalents, or any amount or range therein, more preferably in an amount in the range of from about 1.0 to about 1.1 molar equivalents;

in a mixture of a suitably selected ether solvent, such as diethyl ether, di-n-butyl ether, MTBE, 2-Me-THF, cyclopentyl methyl ether, and the like, and a suitably selected hydrocarbon solvent, preferably di-n-butyl ether or cyclopentyl methyl ether; and wherein the hydrocarbon solvent is, for example, toluene, fluorobenzene, chlorobenzene, trifluorotoluene, etc., preferably toluene; preferably in the same solvent mixture as used in the previous reaction step; at a temperature in the range of about room temperature to about reflux temperature, more preferably in the range of about 60 ℃ to about 95 ℃; to give the corresponding compound of formula (IX-K).

Preferably, the compound of formula (VIII-K) is added as a solution in a suitably selected hydrocarbon solvent, more preferably a suitably selected aromatic hydrocarbon such as toluene, xylene, fluorobenzene, chlorobenzene, trifluorotoluene and the like, to a solution of the compound of formula (VII-S) in a suitably selected ether solvent other than THF such as diisopropyl ether, 1, 4-dioxane, 2-methyl-THF, MTBE, cyclopentylmethyl ether (CPME), di-n-butyl ether and the like, more preferably CPME or di-n-butyl ether. Preferably, the final solvent mixture is mixed in an ether solvent ratio of about 1: 1 to about 1: 3: the hydrocarbon solvent is present in a volume ratio.

Deprotection of the compound of formula (IX-K) according to known methods yields the corresponding compound of formula (I-K). For example, if each Z is pivaloyl, the compound of formula (IX-K) may be deprotected by reaction with an appropriately selected alkoxide or hydroxide base, such as sodium methoxide, sodium ethoxide, lithium hydroxide and the like, in an appropriately selected solvent, such as methanol, ethanol and the like, to yield the corresponding compound of formula (I-K).

One skilled in the art will recognize that other reagents may be used for this deprotection step, depending on the particular protecting group Z, including but not limited to Pd/C, Pd (OH)₂、PdCl₂、Pd(OAc)₂/Et₃SiH, RaNi, a suitably selected acid, a suitably selected base, fluoride, and the like.

The compounds of formula (I-K) are preferably isolated according to known methods, for example by extraction, filtration or column chromatography. It is further preferred to purify the compounds of formula (I-K) according to known methods, for example by recrystallization.

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 of the invention described herein as the active ingredient can be prepared by intimately mixing the compounds 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 formulations, such as powders, capsules and tablets, suitable carriers and additives 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 is typically composed of sterile water and other ingredients may be added to increase solubility or preserve. 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 pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral such as intramuscular. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, fats and 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. Tablets may be sugar-coated or enteric-coated, if desired, 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. Suspensions for injection may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.) the amount of active ingredient required to deliver the effective dose as described above. The pharmaceutical compositions herein may contain from about 0.01 to about 1000mg, or any amount or range therein, per unit dosage unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoonful, etc.), and may be administered in a dosage amount of from about 0.01 to about 300 mg/kg/day, or any amount or range therein, preferably from about 0.1 to about 50 mg/kg/day, or any amount or 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-cycle administration (post-periodicosylation) may be employed.

Preferably, these compositions are in unit dosage forms, such as tablets, pills, capsules, powders, granules, sterile parenteral 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 compounds, such as the decanoate, may be suitable to provide depot formulations for intramuscular injection. To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable carrier, such as conventional tableting ingredients, for example corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutically acceptable diluents, such as 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 referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. The solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1000mg, or any amount or range therein, of the active ingredient of the present invention. Tablets or pills of the novel composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. 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 covering the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, thereby leaving the inner component intact in the duodenum or delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acid materials along with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid preparations which may be incorporated into the novel compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils (e.g., cottonseed, sesame, coconut or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, for example tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The methods of treating the diseases 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 from about 0.01mg to about 1000mg of the compound or any amount or range therein; preferably about 10 to about 500mg of the compound or any amount or range therein, and may be configured in any form suitable for the selected 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 in intranasal form by topical use of suitable intranasal vehicles, or via transdermal drug patches well known to those of ordinary skill in the art. Administration is in the form of a transdermal delivery system, and dosing will, of course, be continuous rather than intermittent throughout the dosing 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 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 are suitably flavored suspending or dispersing agents, such as synthetic and natural gums, e.g., tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desirable. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

To prepare the pharmaceutical compositions of the present invention, a compound prepared according to any of the methods described herein as the active ingredient is intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques, depending upon the desired administration (e.g., oral or parenteral)Administration), the carrier can take a wide variety of forms. Suitable pharmaceutical carriers are well known in the art. Some of these pharmaceutical carriers are described in the American society for pharmacy and the British society for pharmacyThe HandbookofPharmaceuticalExcipientsIs 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 DosageForms: tablets, second edition, revised and extended editionVolumes 1-3; edited by Avisl et alPharmaceuticalDosageForms：ParenteralMedicationsVolumes 1-2; and edited by Lieberman et alPharmaceuticalDosageForms： DisperseSystemsVolumes 1-2.

The compounds of the present 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 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 strength of the formulation, the mode of administration and the advancement of the disease condition. 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 experiments using appropriate, known and generally accepted cell and/or animal models can predict the ability of a test compound to treat or prevent a given disease.

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

The following examples are given to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims that follow thereafter. In the examples that follow, some of the synthesis products that have been isolated as residues are listed. It will be understood by those of ordinary skill in the art that the term "residue" does not limit the physical state of the product as it is isolated and can include, for example, solids, oils, foams, gums, slurries, and the like.

Examples 12 to 16 below describe the formulations/procedures used to synthesize the title compound. One or more batches of the compound were prepared according to the recipe/procedure described in these examples.

Example 1

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a dry and argon atmosphere 250mL round-bottomed flask with mechanical stirrer, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (22.20 mmol; 9.06g) was dissolved at room temperature in a dry and degassed mixture of toluene (37.00 mL; 32.23 g)/diethyl ether (37.00 mL; 26.24g) after cooling to-50 deg.C with vigorous stirring (isopropanol + dry ice bath), (trimethylsilyl) methyllithium (1M pentane solution, 37.00mL) was added dropwise to the heterogeneous mixture 30 minutes after the end of the addition, the conversion was checked by sampling and additional (trimethylsilyl) methyllithium was added as required 15 minutes, zinc dibromide (22.20 mmol; 5.00g) (Aldrich, ultra-dry solid) was added in one portion and the resulting mixture was allowed to warm to 25 deg.C for 1 hour with stirring at room temperature after 15 minutes, reduced pressure (400) at 15 deg.C and diethyl ether were evaporated, finally dissolved in 10.3 minutes (2-4 mL) of dimethylpentan (2-4-4.3-4 g) acetone, 3.72 g) was added dropwise to the resulting mixture was stirred in one portion and the resulting mixture was stirred for 1 hour at room temperature18.50mmol) and the resulting mixture was heated at 75 ℃ for 21 hours. After cooling to room temperature, an aqueous solution of ammonium chloride (1M, 100mL) and ethyl acetate (150mL) was added. After stirring for 10 min, the two phases were separated and the organic layer was washed twice with water (100mL) and once with brine (100 mL). The organic layer was then dried over sodium sulfate and the solvent evaporated under reduced pressure to give a clear brown oil. Through MPLC (tubular column: 330 gSiO)₂And (3) a solvent system: 95/5 to 85/15 heptane/AcOEt) to yield the title compound tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester as a single isomer.¹HNMR spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 2

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a dry 25mL Schlenk reactor under argon atmosphere, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (1.99 mmol; 813.71mg) was dissolved in dry cyclopentyl methyl ether (CPME) (7.2mL) at room temperature after cooling to-50 deg.C (acetonitrile + dry ice) with vigorous stirring, n-hexyllithium (2.3M hexane solution, 966.31. mu.L) was added dropwise to the mixture, after 15 minutes, zinc dibromide (996.50. mu.L; 2MCPME solution) was added and the resulting mixture was allowed to warm to 15 deg.C over 1.5 hours, then 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-glucopyranose bromide (1.05g, 1.81mmol) dissolved in CPdegassed ME (1.81mL) was added dropwise over 10 minutes, the resulting mixture was heated at 85 deg.C after cooling to room temperature, ammonium chloride (1M) and ethyl acetate (15mL) were added with stirring overnightAfter 0 min, the two phases were separated and the organic layer was washed twice with water (10mL) and once with brine (10 mL). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure to give a clear brown oil which contained the title compound tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester as a single isomer by quantitative HPLC.¹HNMR spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 3

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a dry 25mL Schlenk reactor under argon atmosphere, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (1.90 mmol; 775mg) is dissolved in toluene (3.45 mL)/diethyl ether (3.45mL) at room temperature after cooling to-50 ℃ under vigorous stirring (acetonitrile + dry ice), n-hexyllithium (2.3M hexane solution, 920.29 μ L) is added dropwise to the mixture, after 15 minutes, zinc dibromide (2.07 mmol; 466mg) is added in one portion and the mixture obtained is allowed to warm to 15 ℃ over 1.5 hours, the mixture obtained is then cooled to 0 ℃, dropwise (trimethylsilyl) methyllithium (1M pentane solution, 1.9mL) is added after 1 hour, diethyl ether and hexane are evaporated off under reduced pressure (400) at 15 ℃ after 1 hour, 2, 3, 4, 6-O- (2, 2-O) -propionyl-2, 2-dimethyl-propionic acid (1.73mL) dissolved in toluene (1.73mL) are added dropwise, after 10 minutes, the mixture is degassed twice, and the aqueous solution of ethyl bromide and the resulting mixture is heated to 10mL, after 10mL of ethyl bromide is removed overnight and the mixture is stirredBrine (10mL) was washed once. The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure to give a clear brown oil which contained the title compound tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester as a single isomer by quantitative HPLC.¹HNMR spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 4

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a dry 25mL Schlenk reactor under argon atmosphere, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (1.58 mmol; 643mg) is dissolved in toluene (2.86 mL)/2-methyltetrahydrofuran (2.86mL) at room temperature after cooling to-50 ℃ under vigorous stirring (acetonitrile + dry ice), n-hexyllithium (2.3M hexane solution; 764 μ L) is added dropwise to the mixture after 15 minutes, zinc dibromide (1.72 mmol; 387mg) dissolved in 2-methyltetrahydrofuran (859 μ L) is added in one portion and the resulting mixture is allowed to warm to 15 ℃ over 1.5 hours, then 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-bromoglucopyranose (1.43 mmol; 830mg) dissolved in degassed toluene (1.43mL) is added dropwise over 10 minutes and the resulting mixture is washed twice under reduced pressure with degassed toluene (1.43mL), the aqueous solution of the title compound is separated off by evaporation of ethyl acetate, the aqueous solution is washed twice under reduced pressure (85 mL), the aqueous solution of the title compound is separated by evaporation to give a clear aqueous solution (10mL), and the title compound is separated by evaporation, washed under reduced pressure, and the concentration of ethyl acetate is measuredA single isomer of 2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester.¹HNMR spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 5

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a dry 25mL schlenk reactor under argon atmosphere, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (1.90 mmol; 775mg) is dissolved in toluene (3.45 mL)/diethyl ether (3.45mL) at room temperature after cooling to-50 ℃ (acetonitrile + dry ice) under vigorous stirring, n-hexyllithium (2.3M hexane solution, 920 μ L) is added dropwise to the mixture, after 15 minutes, zinc dibromide (2.07 mmol; 466mg) is added in one portion and the resulting mixture is allowed to warm to 15 ℃ over 1.5 hours, after which diethyl ether and hexane are evaporated at 15 ℃ under reduced pressure (400mm hg) and then 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-bromoglucopyranose (1.73 mmol; 1.00g) dissolved in degassed toluene (1.73mL) is added dropwise over 10 minutes, the 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-bromoglucopyranose (1.73mL) is degassed twice after heating the resulting mixture at 50 ℃ under reduced pressure (400 mL) to give a clear aqueous solution of ethyl propionate, after cooling to give a brownish oil, the title compound, which is washed with 5mL, washed with 5mL of sodium hydroxide, and the title compound is removed by heating with 5-methyl acetate, washed with 5-methyl-5 mL, after 5mL of water, 5mL of ethyl acetate, 10 min, 5mL of tetrahydrofuran, 5mL of ethyl acetate, 5mL of a clear aqueous solution, 5-methyl-5-methyl-phenyl-ethyl acetate, 10 min, 5-ethyl acetate, and after cooling to give a crude mixture, 5-.¹HNMROf spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 6

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a dry 25mL schlenk reactor under argon atmosphere, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (2.60 mmol; 1.06g) is dissolved in toluene (4.73 mL)/methoxy-cyclopentane (4.73mL) at room temperature after cooling to-50 ℃ (acetonitrile + dry ice) under vigorous stirring, n-hexyllithium (2.3M hexane solution, 1.26mL) is added dropwise to the mixture after 15 minutes, zinc dibromide (2.84 mmol; 639mg) dissolved in dry methoxy-cyclopentane (1.40mL) is added dropwise and the resulting mixture is allowed to warm to 15 ℃ for 1 hour, then 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-bromoglucopyranose (2.36 mmol; 1.37g) dissolved in degassed toluene (2.36mL) is added dropwise over 10 minutes and the resulting mixture is heated to 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-bromoglucopyranose (2.36 mmol; 1.37g) and the resulting mixture is heated under reduced pressure to 2.5 mL, washed twice with aqueous solution of the title compound, dried, washed, dried, and the title compound is separated off as a brown oil by evaporation, washed with 3-methyl-phenyl-ethyl acetate, and the title compound is added to yield a clear aqueous solution after 5 mL.¹HNMR spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 7

III (2)2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2- Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

In a 50mL schlenk reactor, dry and under argon atmosphere at room temperature, 2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (2.45 mmol; 1.00g) is dissolved in n-butyl ether (980 μ L)/toluene (8.8mL), the temperature is then lowered to-60 ℃ and, after 2 hours of addition of n-hexyllithium (2.3M hexane solution, 1.20mL), zinc dibromide (607mg) is added in one portion at-60 ℃, the resulting mixture is slowly warmed to 10 ℃ over 2 hours, at 10 ℃ 2, 1 minute is added 2, 3, 4, 6-O- (2, 2-dimethylpropionyl) - α -D-bromoglucopyranose (2.69 mmol; 1.56g) dissolved in toluene (2.69mL) and the temperature is raised to 50 ℃ the mixture is raised to 60 ℃ for 1 hour, finally, after 2 days at 70 ℃ to cooling to room temperature, after 2 days, 2-D-bromoglucopyranose (2.69 mmol; 1.56g) is cooled, the aqueous phase of the title compound is washed off by evaporation of the organic solvent containing the methylo-phenyl-ethyl-5-phenyl-5- (5-iodo-methyl) thiophene, the resulting in a brownish-2-ethyl acetate, washed twice with 5-methyl-5-methyl-phenyl-ethyl-5-phenyl-4-ethyl-5-phenyl-ethyl-5-ethyl-5-ethyl-phenyl-4-ethyl-acetate, 10-ethyl-5-10-methyl-ethyl-10-phenyl-ethyl-5-ethyl-4-phenyl-ethyl-acetate, 10-5-ethyl-4-phenyl-ethyl-4-.¹HNMR spectra with previously measured title compound¹The HNMR spectra are consistent.

Example 8

Tetrakis (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -6- (pivaloyloxymethyl) tetrahydro 2H-pyran-2, 3, 4, 5-tetrayl ester

D-glucose (25.0g, 0.139mol) was suspended in anhydrous dichloromethane (416mL) under nitrogen and the resulting mixture was stirred at room temperature for 5 minutes, then cooled to 0 ℃ and stirred for 10 minutes. TEA (154.7mL) was then added dropwise to the resulting mixture over about 10-15 minutes with stirring; DMAP (1.25g, 0.0102mol) was then added in one portion. Pivaloyl chloride (136mL) diluted with dichloromethane (83mL) was added to the resulting mixture over 30 minutes at 0 ℃. The ice bath was removed and the resulting mixture was stirred at room temperature for 20 hours. The resulting mixture was then poured into dichloromethane (500mL) and hydrochloric acid (1.5M, 375mL) and the resulting phases were separated. The organic layer was washed with sodium bicarbonate solution (500ml di water, 550g, 1N) and then evaporated to a small volume. Ethanol (95%, 240mL) was added to the resulting residue and the mixture was heated to reflux temperature to give a homogeneous mixture. The resulting mixture was cooled to 0 ℃ resulting in the formation of white crystals which were filtered and dried under vacuum at room temperature overnight to yield the title compound.

Example 9

Tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl esters

Tetrakis (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-2, 3, 4, 5-tetrayl ester (10.0g, 16.65mmol) was dissolved in anhydrous dichloromethane (100mL) under nitrogen and stirred at room temperature for 5 minutes. Zinc bromide (0.76g, 3.33mmol) was then added to the mixture and the resulting yellow solution was stirred at room temperature for 5 minutes. Tribromosilane (10.2g, 66.58mmol) diluted with dichloromethane (10mL) was then added to the mixture over 15-20 minutes, and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was filtered to remove solids and the filtrate was cooled to 0 ℃. A sodium bicarbonate solution (132g in 120mL water) was then added to the cooled filtrate to a final pH in the range of 7-8. The resulting two phases were separated, the organic layer was washed with water (120mL), and the combined aqueous layers were evaporated to a small volume. To the resulting residue was added IPA (39.3g) and the mixture was heated to dissolution. The resulting mixture was cooled to 0 ℃ resulting in the formation of white crystals which were filtered and dried under vacuum at room temperature overnight to yield the title compound.

Example 10

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophene-2-) Yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

Step A: preparation of aryl lithium mixtures

2- (4-fluorophenyl) -5- (5-iodo-2-methylbenzyl) thiophene (12.81g, 31.37mmol) was placed in a dry Schlenk tube under argon atmosphere. Anhydrous toluene (15.7mL) and anhydrous CPME (9.4mL) were added by syringe without stirring, and the resulting mixture was cooled to-45 ℃ and then stirred. Then n-hexyllithium (14.3g, 32.94mmol) was added to the resulting cold mixture as a 2.5M solution in hexane (14.3mL) over about 5-10 minutes; and the mixture was allowed to warm to-25 ℃ over 1 hour.

And B: preparation of the title Compound

Zinc bromide (3.88g, 17.25mmol) and lithium bromide (2.72g, 34.50mmol) were dried in a Schlenk tube in anhydrous CPME (18.6mL) under vacuum at 200 ℃. The mixture was then added to the aryl lithium mixture (prepared as described in step a above) via cannula at-25 ℃ and the resulting mixture was allowed to warm to 0 ℃ over 1 hour. To the resulting mixture was then added tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (20.0g, 34.50mmol) in dry toluene (31.4 mL). The ice bath was removed and the resulting mixture was stirred at room temperature for 30 minutes; then heated to 65 ℃ for 48 hours. The resulting suspension was filtered through a frit filter, rinsed with toluene (20mL) and the filtrate washed with 1N ammonium chloride solution (100mL) and water (100 mL). The toluene was evaporated to a small volume. Methanol (157mL) was added to the resulting residue, the mixture was cooled to 0 ℃ resulting in the formation of crystals which were filtered and dried under vacuum at 40 ℃ overnight to yield the title compound.

Example 11

(2S, 3R, 4R, 5S, 6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylbenzene 6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (39.0g, 50.0mmol) was suspended in methanol (150mL) at room temperature. Sodium methoxide solution (9.3mL) was added and the resulting suspension was stirred at room temperature, heated to 60 ℃ for 16 hours, and then cooled. Water (50mL) was then added to the resulting yellow solution and the title compound was seeded. An additional portion of water (50mL) was added and the mixture was stirred at 0 ℃ for 1 hour resulting in the formation of a precipitate which was collected by filtration to give the title compound.

Example 12

Tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4R, 5S, 6S) -2- (pivaloyloxymethyl) -6-p-tert Trimethyltetrahydro-2H-pyran-3, 4, 5-triyl ester

A solution of lithium dibutylhexylmagnesium (0.4 equiv., 0.35mmol) was added dropwise to a mixture of 4-iodotoluene (230mg, 1.04mmol) dissolved in anhydrous toluene (0.43mL) and anhydrous di-n-butyl ether (0.26mL) at 0 deg.C in a 10mL Schlenk tube under argon atmosphere. After completion of the halogen-metal exchange (determined by GC or HPLC), ZnBr is added dropwise₂A solution of LiBr in dibutyl ether (34 w/w%, 0.6 eq, 0.52 mmol). After 1 hour, tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (1 eq, 500mg, 0.86mmol) dissolved in dry toluene (0.86mL) was added to the organozinc mixture. The resulting mixture was heated to 100 ℃ until conversion was complete (as determined by GC). After cooling to room temperature, the resulting mixture was quenched with aqueous HCl1M (10 mL). The two layers are then separated. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with water (10mL) and then brine solution (10 mL). The organic layer was dried through a pre-packed column and concentrated under reduced pressure in a rotary evaporator (rotavapor). The resulting mixture was purified by chromatography on silica gel to give the title compound as a residue.

Example 13

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (4-methoxyphenyl) -6- (neopentyl) and its use Acyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl esters

A solution of lithium dibutylhexylmagnesium (0.4 equiv., 0.35mmol) was added dropwise to a mixture of 4-iodoanisole (250mg, 1.04mmol) dissolved in anhydrous toluene (0.43mL) and anhydrous di-n-butyl ether (0.26mL) at 0 deg.C in a 10mL Schlenk tube under argon atmosphere.After completion of the halogen-metal exchange, ZnBr is added dropwise₂A solution of LiBr in dibutyl ether (34 w/w%, 0.6 eq, 0.52 mmol). After 1 hour, tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (1 eq, 500mg, 0.86mmol) dissolved in dry toluene (0.86mL) was added to the organozinc mixture. The resulting mixture was heated to 100 ℃ until conversion was complete (as determined by GC). After cooling to room temperature, the resulting mixture was quenched with aqueous HCl1M (10 mL). The two layers are then separated. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with water (10mL) and then brine solution (10 mL). The organic layer was dried through a pre-packed column and concentrated in a rotary evaporator under reduced pressure. The resulting mixture was purified by crystallization to give the title compound as a residue.

Example 14

Tris (2, 2-dimethylpropionic acid) - (2S, 3S, 4R, 5R, 6R) -2- (2, 6-dimethoxyphenyl) -6- (New) Valeryloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

A solution of sec-butyllithium (1.2 eq, 4.14mmol) was added dropwise to a mixture of 1, 3-dimethoxybenzene (0.54mL, 4.14mmol) dissolved in anhydrous toluene (1.72mL) and anhydrous n-dibutyl ether (1.04mL) in a 10mL Schlenk tube under argon atmosphere at 0 ℃. After completion of the halogen-metal exchange, ZnBr is added dropwise₂A solution of LiBr in dibutyl ether (34 w/w%, 0.6 eq, 2.07 mmol). After 1 hour, tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (1 eq, 2000mg, 3.45mmol) dissolved in dry toluene (3.44mL) was added to the organozinc mixture. The resulting mixture was heated to 100 ℃ until conversion was complete (as determined by GC). After cooling to room temperature, the mixture was quenched with aqueous HCl1M (40mL)The resulting mixture was quenched. The two layers are then separated. The aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with water (40mL) and then brine solution (40 mL). The organic layer was dried through a pre-packed column and concentrated in a rotary evaporator under reduced pressure. The resulting mixture was purified by chromatography on silica gel to give the title compound as a residue.

Example 15

Tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4R, 5S, 6S) -2- (pivaloyloxymethyl) amide 6- (4- (trifluoromethyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester

Dibutylhexylmagnesiumlithium (0.4 equiv., 0.35mmol) was added dropwise to a mixture of 4-iodotrifluorotoluene (0.15mL, 1.04mmol) dissolved in anhydrous toluene (0.43mL) and anhydrous n-dibutyl ether (0.26mL) in a 10mL Schlenk tube under argon atmosphere at-50 ℃. After completion of the halogen-metal exchange, ZnBr is added dropwise₂A solution of LiBr in dibutyl ether (34 w/w%, 0.6 eq, 0.52 mmol). After 1 hour, tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (1 eq, 500mg, 0.86mmol) dissolved in dry toluene (0.86mL) was added to the organozinc mixture. The resulting mixture was heated to 100 ℃ until conversion was complete (as determined by GC). After cooling to room temperature, the resulting mixture was quenched with aqueous HCl1M (10 mL). The two layers are then separated. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with water (10mL) and then brine solution (10 mL). The organic layer was dried through a pre-packed column and concentrated in a rotary evaporator under reduced pressure. The resulting mixture was purified by reverse phase (kromasil c18) to yield the title compound as a residue.

Example 16

Tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2- (pivaloyloxymethyl) -6- (thia-zo Phen-2-yl) tetrahydro-2H-pyran-3, 4, 5-triyl esters

A solution of dibutylhexylmagnesiumlithium (0.4 equiv., 0.35mmol) was added dropwise to a mixture of 2-iodothiophene (0.115mL, 1.04mmol) dissolved in anhydrous toluene (0.43mL) and anhydrous di-n-butyl ether (0.26mL) at 0 deg.C in a 10mL Schlenk tube under an argon atmosphere. After completion of the halogen-metal exchange, ZnBr is added dropwise₂A solution of LiBr in dibutyl ether (34 w/w%, 0.6 eq, 0.52 mmol). After 1 hour, tris (2, 2-dimethylpropionic acid) - (2R, 3R, 4S, 5R, 6R) -2-bromo-6- (pivaloyloxymethyl) tetrahydro-2H-pyran-3, 4, 5-triyl ester (1 eq, 500mg, 0.86mmol) dissolved in dry toluene (0.86mL) was added to the organozinc mixture. The resulting mixture was heated to 100 ℃ until conversion was complete (controlled by GC). After cooling to room temperature, the resulting mixture was quenched with aqueous HCl1M (10 mL). The two layers are then separated. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with water (10mL) and then brine solution (10 mL). The organic layer was dried through a pre-packed column and concentrated in a rotary evaporator under reduced pressure. The resulting mixture was purified by reverse phase (kromasil c18) to yield the title compound as a residue.

Example 17

Solid oral preparation-prophetic example

As a specific example of an oral composition, 100mg of the compound prepared as in example 11 above was 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 appended claims and their equivalents.

Claims (18)

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

(I-S)

The method comprises the following steps

In which M is²Is a zinc-containing fractionAnd the zinc-containing moiety is ZnBr and a compound of formula (VII-S) wherein each Z is pivaloyl and wherein LG²Reacting a compound of formula (VIII-S) which is bromine in a mixture of an ether solvent and a hydrocarbon solvent to form the corresponding compound of formula (IX-S); wherein the ether solvent is selected from di-n-butyl ether or cyclopentyl methyl ether and wherein the hydrocarbon solvent is toluene;

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

2. The process of claim 1, wherein the compound of formula (VIII-S) is present in an amount in the range of 0.8 to 1.25 molar equivalents.

3. The process of claim 2, wherein the compound of formula (VIII-S) is present in an amount in the range of 1.0 to 1.1 molar equivalents.

4. The process of claim 1, wherein a solution of a compound of formula (VIII-S) in the hydrocarbon solvent is added to a solution of a compound of formula (VII-S) in the ether solvent.

5. The process of claim 1, wherein the compound of formula (VII-S) is reacted with the compound of formula (VIII-S) at a temperature in the range of 60 ℃ to 95 ℃.

6. The method of claim 1, further comprising:

in which LG is¹Reacting a compound of formula (V-S) as a leaving group with an organolithium reagent in a mixture of an ether solvent and a hydrocarbon solvent;to give the corresponding compound of the formula (VI-S), in which M¹Is lithium;

reacting a compound of formula (VI-S) with a zinc salt in a mixture of an ether solvent and a hydrocarbon solvent to form the corresponding compound of formula (VII-S),

wherein the LG¹The leaving group is selected from bromine and iodine; the organolithium reagent is selected from the group consisting of trimethylsilylmethyl lithium, n-hexyl lithium, sec-butyl lithium, n-butyl lithium, tert-butyl lithium, methyl lithium; the ether solvent is selected from diethyl ether, diisopropyl ether, di-n-butyl ether, MTBE, cyclopentyl methyl ether; the hydrocarbon solvent is selected from toluene, fluorobenzene, chlorobenzene and trifluorotoluene; the zinc salt is selected from zinc dibromide, zinc diiodide and zinc bistrifluoromethane sulfonate.

7. The process of claim 6, wherein the organolithium reagent is n-hexyllithium.

8. The process of claim 6, wherein the organolithium reagent is present in an amount in the range of 0.5 to 2.0 molar equivalents.

9. The process of claim 8, wherein the organolithium reagent is present in an amount in the range of 1.0 to 1.2 molar equivalents.

10. The process of claim 6, wherein the ether solvent is di-n-butyl ether or cyclopentyl methyl ether and wherein the hydrocarbon solvent is toluene.

11. The process of claim 6, wherein the compound of formula (V-S) is reacted with an organolithium reagent at a temperature in the range of-78 ℃ to room temperature.

12. The method of claim 6, wherein the zinc salt is selected from the group consisting of zinc dibromide, zinc diiodide, and zinc bistrifluoromethane sulfonate.

13. The method of claim 6, wherein the compound of formula (VI-S) is reacted with a zinc salt; and wherein the zinc salt is zinc dibromide.

14. The method of claim 13, wherein the zinc dibromide is present in an amount in the range of 0.33 to 1.0 molar equivalents.

15. The method of claim 14, wherein the zinc dibromide is present in an amount of 0.5 molar equivalents.

16. The process of claim 6, wherein the compound of formula (VI-S) is reacted with a zinc salt in the presence of a lithium salt.

17. The method of claim 16, wherein the lithium salt is selected from lithium bromide, lithium iodide.

18. The method of claim 17, wherein the lithium salt is present in an amount in the range of 1.0 to 2.0 molar equivalents.