CN1284074A - Novel compounds - Google Patents

Abstract

The invention provides novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.

Description

new compound

The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them, processes for the preparation of such pharmaceutical compositions, and their use in therapy.

The P2X ₇ receptor (previously called the P2Z receptor) is a ligand-gated ion channel present on a variety of cell types mostly involved in inflammatory/immune processes, notably macrophages, mast cells and lymphocytes ( T and B). Activation of _P2X7 receptors by extracellular nucleotides (specifically adenosine triphosphate) can lead to interleukin-1β (IL-1) release and giant cell formation (macrophages/microglia), degranulation (mast cell ) and L-selectin shedding (lymphocytes). _P2X7 receptors are also located on antigen presenting cells (APCs), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes.

It is desirable to prepare compounds that are effective as P2X7 receptor antagonists for the treatment of inflammatory, immune or cardiovascular diseases in which the _P2X7 receptor plays a role in the etiology of these diseases.

The present invention provides compounds of the following general formula or pharmaceutically acceptable salts and solvates thereof: Wherein X represents an oxygen or sulfur atom, or represents a group NH, CH ₂ , CH ₂ CH ₂ or OCH ₂ ; Y represents a group CH ₂ or C=O; R ¹ represents a pyridyl group (especially 3-pyridyl or 4 -pyridyl) or pyrimidyl; ^R Represents phenyl, pyridyl or pyrimidyl, each of which may optionally be substituted by one or more substituents independently selected from the following: halogen atom or amino, cyano, hydroxyl, Nitro, C ₁ -C ₆ -Alkyl, Halo-C ₁ -C ₆ -Alkyl, C ₁ -C ₆ -Alkoxy, C ₁ -C ₆ -Alkylthio, (di)C ₁ - C ₆ -Alkylamino C ₁ -C ₆ -Alkylcarbonyl, C ₁ -C ₆ -Alkoxycarbonyl, C ₁ -C ₆ -Alkylsulfinyl, C ₁ -C ₆ -Alkylsulfonyl, -NR ³ SO ₂ R ⁴ or -SO ₂ NR ⁵ R ⁶ groups, or groups -Z-(CH ₂ ) _p -Z-(CH ₂ ) _q -H, wherein Z each represents a nitrogen or oxygen atom, p is an integer of 2-5, and q is 0 or an integer of 1-5; R ³ and R ⁴ each independently represent a hydrogen atom or a C ₁ -C ₆ -alkyl group; and R ⁵ and R ⁶ each independently represent a hydrogen atom or C ₁ -C ₆ -Alkyl or, together with the nitrogen atom to which they are bound, form pyrrolidinyl or piperidinyl.

In this specification, unless otherwise stated, the alkyl substituent or the alkyl moiety in the substituent group may be linear or branched, and each alkyl moiety in the dialkylamino substituent may be the same or different. Additionally, when X represents the group _OCH2 , the oxygen atom is located in the ortho position to the carbonyl group in the ring.

The group ^R preferably represents phenyl, pyridyl or pyrimidinyl, each of which may optionally be substituted by one, two, three or four substituents independently selected from the group consisting of halogen atoms (such as fluorine, chlorine, bromine or iodine) or amino, cyano, hydroxyl, nitro, C ₁ -C ₆ -alkyl (such as methyl, ethyl, propyl, butyl, pentyl or hexyl), halo-C ₁ -C ₆ -Alkyl (such as trifluoromethyl), C ₁ -C ₆ -Alkoxy (such as methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy), C ₁ - C ₆ -Alkylthio (such as methylthio, ethylthio, propylthio, butylthio, pentylthio or hexylthio), (di)C ₁ -C ₆ -alkylamino (such as methylamino, Dimethylamino, ethylamino or diethylamino), C ₁ -C ₆ -alkylcarbonyl (such as methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylcarbonyl), C ₁ -C ₆ -alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentyloxy- or hexyloxycarbonyl), C ₁ -C ₆ -alkyl Thionyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulfinyl), C ₁ -C ₆ -alkylsulfonyl (e.g. methyl-, ethyl- , propyl-, butyl-, pentyl- or hexylsulfonyl), -NR ³ SO ₂ R ⁴ or -SO ₂ NR ⁵ R ⁶ groups, or groups -Z-(CH ₂ ) _p -Z- (CH ₂ ) _q -H, wherein Z each independently represents a nitrogen or oxygen atom, p is an integer of 2-5 and q is 0 or an integer of 1-5.

More preferably ^R Represents phenyl, pyridyl or pyrimidyl, each of which may be optionally substituted by one, two or three substituents independently selected from the group consisting of a halogen atom or an amino group, a cyano group, a hydroxyl group, a nitro group, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio(di)C ₁ -C ₄ -alk Amino, C ₁ -C ₄ -Alkylcarbonyl, C ₁ -C ₄ -Alkoxycarbonyl, C ₁ -C ₄ -Alkylsulfinyl, C ₁ -C ₄ -Alkylsulfonyl, -NR ₃ SO ₂ R ⁴ or —SO ₂ NR ⁵ R ⁶ groups.

More preferably ^R represents phenyl, pyridyl or pyrimidinyl, each of which may be optionally substituted by one or two substituents independently selected from the group consisting of halogen atom or amino, cyano, nitro, C ₁ -C ₄ -Alkyl, halo-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or -SO ₂ NR ⁵ R ⁶ radicals.

Most preferably ^R represents a phenyl or pyridyl group optionally substituted by one or two substituents independently selected from the group consisting of fluorine or chlorine atoms or amino, cyano, nitro, trifluoromethyl, methoxy or -SO ₂ NR ⁵ R ⁶ groups.

Preferably R ³ and R ⁴ each independently represent a hydrogen atom or a C ₁ -C ₄ -alkyl group (eg methyl or ethyl).

Preferably R ⁵ and R ⁶ each independently represent a hydrogen atom or a C ₁ -C ₄ -alkyl group (such as methyl or ethyl), or together with the nitrogen atom to which they are bonded form a pyrrolidinyl or piperidinyl group, especially is pyrrolidinyl.

Preferred compounds of the invention include:

(+/-)-(N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione,

(+/-)-N-[1-(3′-methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-di ketone,

(+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione,

(+/-)-N-[1-(3′-chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione,

(+/-)-N-[1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione,

(+/-)-N-[1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidine-2,5-di ketone,

(+/-)-N-[1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-di ketone,

(2R)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione,

(2R)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione,

(2R)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione ,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidine-2,5-dione ,

(+/-)-N-[1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidine-2,5-dione,

(+/-)-N-[1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione,

id="tilte4" font-size="5"> (+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]oxa Oxazolidin-2-one, (2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl] Thiazolidine-2,4-dione,

(2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5- diketone,

(2R)-N-[1-(3′,5′-dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4- diketone,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2-dione,

(2R)-N-[1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione,

(+/-)-N-[1-(3'-(trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2, 4-diketone,

(+/-)-N-[1-(2′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-di ketone,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]piperidine-2,6-dione ,

(+/-)-N-[1-(3′-aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[1,3]oxazinane -2-one,

(2S)-N-[1-(3′-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione,

(2S)-N-[1-(3'-aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione,

(2S)-N-[1-(3′-Methanesulfonylaminobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione ,

(2S,3S)-N-[1-(3′-(pyrrolidine-1-sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]pyrrolidine -2,5-diketone,

(2S,3S)-N-[1-(3′-cyano-4′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]pyrrolidine-2 , 5-diketone,

(2S)-N-[1-(3′-cyano-4′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4 - diketones,

(+/-)-N-[1-(4'-fluoro-3'-sulfamoylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine -2-one,

(+/-)-N-[1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]oxazolidine- 2-keto,

(+/-)-N-[1-(biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one,

(+/-)-N-[1-(4'-chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one,

(+/-)-N-[1-(4'-methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one,

(+/-)-N-[1-(4'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one,

(+/-)-N-[1-(3′,4′-dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- ketone,

(+/-)-N-[1-(4-(6-methoxypyridin-2-yl)-phenoxy)-4-(4-pyridinyl)-2-butyl]piperidine-2 , 6-diketone,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]imidazolidine-2,4-dione ,

(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]piperidin-2-one, and

(+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidin-2-one.

The present invention further provides a preparation method of the above-mentioned compound of formula (I), the method comprising:

(a) make general formula (II) compound:

Wherein L represents a leaving group (such as hydroxyl), and R ¹ and R ² are as defined above, and react with the compound of general formula (Ⅲ):

wherein X and Y are as defined above, but when X is an oxygen atom or _OCH2 , then Y cannot be a _CH2 group; or

(b) when X is an oxygen atom and Y is _a CH group, the compound of general formula (IV):

wherein R ^and R are as defined above, reacted with ² -chloroethyl chloroformate; or

(c) reacting the compound of formula (IV) described in (b) above with 3-chloropropanol in the presence of phosgene when X is an _OCH group and Y is a _CH group; or

(d) reacting a compound of formula (IV) as described in (b) above with 4-chlorobutyryl chloride when X is a CH _group and Y is a _CH group; or

(e) reacting a compound of formula (IV) as described in (b) above with 5-pentanoyl chloride when X is _{a CH2CH2} group and Y is a _CH2 group; or

(f) when X is an oxygen atom or _an OCH group, make the compound of general formula (Ⅴ): wherein X represents an oxygen atom or an OCH ₂ group, and Y and R ¹ are as defined above, react with a compound of the general formula (VI) R ² -B(OH) ₂ , wherein R ² is as defined above; or (g) when X Be oxygen atom or OCH ₂ when group, make general formula (VII) compound:

wherein X represents an oxygen atom or an OCH ₂ group, and Y and R ¹ are as defined above, react with a compound of general formula (Ⅷ), R ² -Br, wherein R ² is as defined above; and optionally in (a), ( After b), (c), (d), (e), (f) or (g), the compound of formula (I) is converted into other compounds of formula (I) and/or the druggable compound of formula (I) is formed Use salts or solvates.

Methods (a), (b), (c), (d), (e), (f) and (g) can be conveniently prepared in solvents such as dichloromethane, chloroform, acetonitrile, dioxane or tetrahydrofuran ) at a temperature in the range of 0-100°C, preferably at a temperature of 10-80°C, especially at ambient temperature (20°C).

Compounds of formula (II) are known from WO97/20815 and WO98/42670, or can be prepared in analogy to those described in WO97/20815 and WO98/42670.

Compounds of formula (III), (VI) and (VIII) are known or commercially available compounds, or may be prepared according to methods known in the art.

Compounds of formula (IV) can be prepared from compounds of formula (II) according to methods known in the art.

Compounds of formula (V) and (VII) can be prepared in a similar manner to (a), (b) or (c) above using the corresponding bromo- or boron-containing compound of formula (II) or (IV).

It is easy for those skilled in the art to understand that in the method of the present invention, some functional groups such as hydroxyl or amino groups in the intermediate compounds may need to be protected with protecting groups. Thus, the final stage in the preparation of compounds of formula (I) may include the removal of one or more protecting groups.

For an introduction to the protection and deprotection of functional groups see Protecting Groups in Organic Chemistry [ed. J.W.F. McOmie, Plenum Press (1973)] and Protecting Groups in Organic Synthesis [Second Edition, T.W. Greene and P.G.M. Wuts, Wiley -Interscience (1991)].

Compounds of formula (I) can be converted into other compounds of formula (I) using standard methods. For example, compounds of formula (I) wherein ^R2 is nitrophenyl can be converted to compounds of formula (I) wherein ^R2 is aminophenyl as follows: in ethanol or an ethanol/water mixture under reflux conditions iron powder and ammonium chloride for reduction.

Above-mentioned formula (I) compound can be converted into pharmaceutically acceptable salt or its solvate, preferably acid addition salt such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate , tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate, or an alkali metal salt such as sodium or potassium.

Some compounds of formula (I) can exist in stereoisomeric forms. Therefore, it should be understood that the present invention includes all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Their tautomers and mixtures thereof also form an aspect of the invention.

The compounds of the present invention are advantageous in that they possess pharmacological activity. This shows that they can be used as drugs for the treatment or prevention of the following diseases: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, airway hyperresponse, septic shock, glomerulonephritis, Allergic bowel disease, Crohn's disease, ulcerative conjunctivitis, atherosclerosis, growth and metastasis of malignant cells, myocardial ischemia, cardiac reperfusion injury, cerebral ischemia, stroke, myoblastic leukemia, diabetes, Alzheimer's disease , osteoporosis, burns, stroke, varicose veins and meningitis.

Accordingly, the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts and solvates thereof, for use in therapy.

In another aspect, the present invention provides the use of the compound of the above formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a therapeutic drug.

The present invention further provides a method of producing immunosuppression (such as in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis), which method comprises administering to a patient a therapeutically effective amount of the above formula (I ) compound, or a pharmaceutically acceptable salt or solvate thereof.

For the above therapeutic uses the dosage administered will of course vary with the compound employed, the mode of administration, the desired therapeutic effect and the condition to be treated.

The compound of formula (I) and its pharmaceutically acceptable salt and solvate can be used in its original form, but usually in the form of pharmaceutical composition, wherein the compound of formula (I)/salt/solvate (active ingredient) and pharmaceutical Adjuvants, diluents or carriers used in combination. According to the mode of administration, the pharmaceutical composition preferably comprises 0.05-99% w (percentage by weight), more preferably 0.10-70% w active ingredient, and 1-99.95% w (more preferably 30-99.90% w) of pharmaceutically acceptable auxiliary agent, diluent or carrier, all weight percentages are based on the total weight of the composition.

To this end, the present invention also provides a pharmaceutical composition, which includes the compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

The present invention further provides a preparation method of the pharmaceutical composition of the present invention, which comprises mixing the compound of formula (I) above, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the present invention can be administered locally (such as to the lungs and/or airways or to the skin) in the form of solutions, suspensions, sevoflurane aerosols, and dry powder formulations; or systemically, such as by tablet Orally in the form of elixirs, capsules, syrups, powders or granules, or parenterally in the form of solutions or suspensions, or subcutaneously or rectally in the form of suppositories or transdermally.

The present invention will be further understood with reference to the following examples. The terms MS, NMR and DMSO in each case mean mass spectrometry, nuclear magnetic resonance and dimethyl sulfoxide, respectively.

Example 1 (+/-)-(N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione

To a solution of triphenylphosphine (0.16 g) in tetrahydrofuran (2 ml) was added diethyl azodicarboxylate (0.1 ml); the reaction was observed to be slightly exothermic. The resulting orange solution was stirred for 5 minutes, then succinimide (0.062 g) was added, stirring was continued for 5 minutes, and (±)-1-(biphenyl-4-yl, prepared as described in Example 25 of WO97/20815, was added. Oxy)-4-(3-pyridyl)-2-butanol (0.10 g). After stirring for 1.5 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel, eluting with ethyl acetate, to give the title compound (0.09 g) as a colorless solid. Melting point: 150-151°C MS (APCI+ve) 401 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.42-8.40 (2H, m), 7.64-7.55 (5H, m), 7.43 ( 2H,t), 7.33-7.28(2H,m), 6.97(2H,d), 4.45-4.33(2H,m), 4.27-4.23(1H,m), 2.62-2.57(6H,m), 2.32- 2.24(1H,m), 2.11-2.02(1H,m)

Example 2 (+/-)-N-[1-(3'-methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2 , 5-diketone

Following the method of Example 1 above, using succinimide (0.30 g) and (±)-1-(3'-methoxybiphenyl-4-yloxy)-4-(3-pyridyl)- 2-Butanol (0.25g) [prepared as described in WO97/20815, Example 42] was prepared to give the title compound (0.17g) as a white solid. Melting point: 92-94°C MS(EI) 430(M+H) ^{+ 1} H NMR(DMSO-d ₆ ) δ8.42-8.40(2H,m), 7.61(1H,m), 7.59(2H,t) , 7.33-7.28(2H,m), 7.16(1H,d), 7.12(1H,t), 6.97(2H,d), 6.88(1H,dd), 4.44-4.33(2H,m), 4.26-4.24 (1H,m), 3.81(3H,s), 2.62-2.57(6H,m), 2.32-2.24(1H,m), 2.11-2.02 (1H,m)

Example 3 (+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione

Following the procedure of Example 1 above, using (±)-1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butan prepared as described in Example 25 of WO97/20815 Alcohol (0.32g) and 2,4-thiazolidinedione (0.23g) were prepared to give the title compound (0.08g) as a white solid. Melting point: 125-126°C MS (FAB) 419 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.42-8.40 (2H, m), 7.55-7.49 (5H, m), 7.41 (2H, t), 7.33-7.28(2H,m), 6.97(2H,d), 4.76(1H,m), 4.52(1H,t), 4.16(1H,dd), 3.83(2H,s), 2.73-2.60 (2H,m), 2.55-2.49(1H,m), 2.15-2.06(1H,m)

Example 4 (+/-)-N-[1-(3'-chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5 - dione

Following the procedure of Example 1 above, using (±)-1-(3'-chlorobiphenyl-4-yloxy)-4-(3-pyridyl) prepared as described in Example 33 of WO97/20815 -2-Butanol (0.42g) and succinimide (0.24g) were prepared to afford the title compound (0.21g) as a white solid. Melting point: 154°C MS (APCI+ve) 436/438 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.47-8.45 (2H, m), 7.53-7.23 (8H, m), 6.92 ( 2H,d), 4.63(1H,m), 4.50(1H,t), 4.16(1H,dd), 2.73(1H,m), 2.62-2.57(6H,m), 2.11-2.02(1H,m)

Example 5 (+/-)-N-[1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5 - dione

Following the procedure of Example 1 above, using (±)-1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl) prepared as described in Example 43 of WO97/20815 -2-Butanol (0.05g) and succinimide (0.03g) were prepared to give the title compound (0.06g) as a white solid. Melting point: 148°C MS (APCI+ve) 419 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.42-8.40 (2H, m), 7.54-7.45 (3H, m), 7.38-7.20 ( 4H,m), 7.01(1H,m), 6.91(2H,d), 4.62(1H,m), 4.50(1H,t), 4.16(1H,dd), 2.75-2.47(2H,m), 2.56 (4H,s), 2.53(1H,m), 2.11-2.02(1H,m)

a)(+/-)-4-溴苯氧基甲基环氧乙烷Example 6 (+/-)-N-[1-(3'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2 , 5-diketone

a) (+/-)-4-Bromophenoxymethyloxirane

To a solution of 4-bromophenol (17g) and chloromethoxypropane (25ml) in acetonitrile (50ml) was added cesium carbonate (24g) and the resulting suspension was heated for 4 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was partitioned between diethyl ether and water. The organic phase was separated, washed with brine, dried over magnesium sulfate ( _MgSO4 ) and concentrated under reduced pressure to give another residue. The residue was distilled under vacuum to give the subtitle compound (13 g) as a colorless oil. Boiling point: 140°C (oil pump) MS (gcms) 228/230M ⁺ .b) (+/-)-1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol

Add n-butyllithium in hexane (5.8 ml, 2.5M solution) to a solution of 4-picoline (1.2 g)/tetrahydrofuran (10 ml) cooled to -78 ° C, warm the reaction mixture to 0 ° C, and Add slowly via cannula to a solution of 4-bromophenoxymethyloxirane (3.0 g) from step a) above in tetrahydrofuran (5 ml), cooled to 0°C. After stirring at room temperature for 1.5 hours, the reaction mixture was quenched by the addition of ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over magnesium sulfate (MgSO ₄ ), and concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel (eluting with 5% methanol/dichloromethane) to give the subtitle compound as a yellow solid (1.8g). MS(APCI+ve)322/324(M+H) ⁺ .c)(+/-)-1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl )-2-butanol

1-(4-Bromophenoxy)-4-(4-pyridyl)-2-butanol (1.8 g) [prepared as described in step b) above], 3-methoxyphenylboronic acid ( A mixture of tetrakis(triphenylphosphine)palladium(0) (0.16g), aqueous sodium carbonate (3.5ml, 2M solution), ethanol (2ml) and toluene (7.5ml) was held at reflux for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated, washed with brine, dried over magnesium sulfate ( _MgSO4 ), and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluting with 5% methanol/dichloromethane) to give the subtitle compound (1.0 g) as a white solid. Melting point: 74-76°C MS(APCI+ve) 350(M+H) ⁺ .d)(+/-)-(N-[1-(3′-methoxybiphenyl-4-yloxy) -4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5-dione

According to the method of Example 1, using (±)-1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2 prepared as described in step c) above -Butanol (0.42g) and succinimide (0.30g) were prepared to give the title compound (0.15g) as a white solid. Melting point: 111-113°C MS (EI) 431 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.42 (2H, s), 7.48 (2H, d), 7.34 (1H, t), 7.15 (3H,m), 7.06(1H,m), 6.88(2H,d), 6.84(1H,m), 4.61(1H,m), 4.47(1H,t), 4.16(1H,dd), 3.83( 3H,s), 2.78(1H,m), 2.61-2.50(2H,m), 2.46(4H,s), 2.11-2.02(1H,m)

Example 7 (+/-)-N-[1-(3'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2 , 4-diketone

Following the procedure of Example 1 above, using (±)-1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-4-(4-pyridyl)- 2-Butanol (0.10g) and 2,4-thiazolidinedione (0.067g) were prepared to give the title compound as a colorless solid (0.07g). Melting point: 111-112°C MS (EI) 449 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, d), 7.58 (2H, d), 7.34 (1H, t), 7.23 (2H,d), 7.17(2H,d), 7.12(1H,d), 6.88(2H,d), 4.53(1H,m), 4.44(1H,t), 4.28(1H,dd), 4.18( 2H,s), 3.81(3H,s), 2.62(2H,t), 2.37-2.24(1H,m), 2.16-2.06(1H,m)

Example 8 (2R)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4- diketone

Following the method of Example 1 above, using (2S)-1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl) prepared as described in Example 38 of WO97/20815 )-2-butanol (0.20 g) and 2,4-thiazolidinedione (0.13 g) to give the title compound (0.14 g) as a white solid. Melting point: 110-112°C MS (EI) 444 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.43 (2H, m), 8.10 (1H, s), 7.97 (1H, d), 7.76 (1H,d), 7.70-7.60(4H,m), 7.32(1H,dd), 7.01(2H,d), 4.56(1H,m), 4.46(1H,t), 4.30(1H,dd), 4.19(2H,s), 2.65(2H,t), 2.30(1H,m), 2.09(1H,m)

Example 9 (2R)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5- diketone

Following the procedure of Example 1 above, using (2S)-1-(3'-nitrobiphenyl-4-yloxy)-4-(3-pyridyl) prepared as described in Example 41 of WO97/20815 )-2-butanol (0.10 g) and succinimide (0.054 g) to give the title compound (0.03 g) as a white solid. Melting point: 115-117°C MS (EI) 446 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.40 (3H, m), 8.14 (2H, s), 7.72 (3H, m), 7.63 (1H,d), 7.32(1H,ddd), 7.03(2H,d), 4.42(2H,m), 4.28(1H,dd), 2.61(6H,m), 2.28(1H,m), 2.07( 1H,m)

Example 10 (2R)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5- diketone

Following the procedure of Example 1 above, using (2S)-1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl) prepared as described in Example 38 of WO97/20815 )-2-butanol (0.15g) and succinimide (0.09g) gave the title compound (0.09g) as a white solid. Melting point: 136-137°C MS (EI) 426 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.41 (2H, m), 8.11 (1H, s), 7.97 (1H, d), 7.77 (1H,d), 7.69-7.60(4H,m), 7.32(1H,dd), 6.99(2H,d), 4.39(2H,m), 4.28(1H,dd), 2.60(6H,m), 2.27(1H,m), 2.02(1H,m)

a)(+/-)-1-(3′-硝基联苯-4-基氧基)-4-(4-吡啶基)-2-丁醇Example 11 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2, 4-diketone

a) (+/-)-1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol

According to the method of Example 6c) above, using 1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol (3.12g) and 3-nitrobenzene prepared in Example 6b) Boronic acid (2.59g) gave the subtitle compound as an orange oil (2.20g). MS(APCI+ve)365(M+H) ⁺ .b)(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl )-2-butyl]-thiazolidine-2,4-dione

Following the procedure of Example 1 above, using (+/-)-1-(3'nitrobiphenyl-4-yloxy)-4-(4-pyridyl)- prepared as described in step a) above 2-Butanol (0.14g) and 2,4-thiazolidinedione (0.09g) were prepared to give the title compound (0.11g) as a pale yellow solid. Melting point: 145-150°C MS (EI) 446 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.47 (2H, d), 8.38 (1H, s), 8.17 (1H, d), 8.11 (1H,d), 7.75-7.70(3H,m), 7.23(2H,dd), 7.04(2H,d), 4.60-4.44(2H,m), 4.31(1H,dd), 4.19(2H,s ), 2.65(2H,t), 2.32(1H,m), 2.09(1H,m)

Example 12 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2, 5-diketone

Following the procedure of Example 1 above, using (+/-)-1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl) prepared as described in Example 11a) -2-Butanol (0.09g) and succinimide (0.05g) were prepared to give the title compound (0.03g) as a yellow solid. Melting point: 116-118°C MS (EI) 426 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, m), 8.38 (1H, s), 8.16 (1H, d), 8.11 (1H,d), 7.75-7.70(3H,m), 7.22(2H,d), 7.03(2H,d), 4.76-4.34(2H,m), 4.28(1H,dd), 2.65-2.60(6H ,m), 2.29(1H,m), 2.08(1H,m)

a)(+/-)-1-(4′-氟联苯-4-基氧基)-4-(4-吡啶基)-2-丁醇Example 13 (+/-)-N-[1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5 - dione

a) (+/-)-1-(4′-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol

According to the method of Example 6c), using 1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol (0.40 g) prepared as described in Example 6b) and 4-fluoro Phenylboronic acid (0.28g) was prepared to give the subtitle compound (0.23g) as a colorless solid. MS(APCI+ve)338(M+H) ⁺ .b)(+/-)-N-[1-(4′-fluorobiphenyl-4-yloxy)-4-(4-pyridyl) -2-Butyl]-pyrrolidine-2,5-dione

Following the method of Example 1 above, using (+/-)-1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butan prepared in step a) Alcohol (0.10 g) and succinimide (0.06 g) were prepared to give the title compound (0.06 g) as a pale yellow solid. Melting point: 113-114°C MS (EI) 419 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, d), 7.63 (2H, dd), 7.55 (2H, d), 7.28 -7.21(4H,m), 6.87(2H,d), 4.45-4.33(2H,m), 4.26(1H,m), 2.59(6H,m), 2.28(1H,m), 2.08(1H,m )

Example 14 (+/-)-N-[1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4 - dione

Following the procedure of Example 1 above, using (+/-)-1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)- prepared as described in Example 13a) 2-Butanol (0.12g) and 2,4-thiazolidinedione (0.08g) were prepared to give the title compound as a light gray solid (0.06g). Melting point: 88-90°C MS (EI) 437 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, d), 7.23 (4H,m), 6.97(2H,d), 4.50(lH,m), 4.44(1H,t), 4.28(1H,dd), 4.18(2H,s), 2.65(2H,t), 2.30( 1H,m), 2.12(1H,m)

Example 15 (+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidin-2-one a) (+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl-isoindole-1,3-dione

According to the method described in Example 1, from (±)-1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (2.55g) (implemented in WO97/20815 prepared as described in Example 25), triphenylphosphine (3.62g), diethyl azodicarboxylate (2.52ml) and phthalimide (2.36g) were prepared in tetrahydrofuran. The resulting residue was purified by flash column chromatography eluting with hexane:ethyl acetate (3:2) to afford the subtitle compound as a colorless solid (3.9g). Melting point: 132-133°C MS (EI) 448 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.40 (1H, d), 8.25 (1H, d), 7.85 (4H, m), 7.62 -7.51(5H,m), 7.41(2H,t), 7.29(1H,t), 7.23(1H,dd); 6.93(2H,d), 4.52(2H,m), 4.38(1H,dd), 2.70(2H,t), 2.40(1H,n), 2.20(1H,m).b)(±)-1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2 -Butylamine

(+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-isoindole-1,3-dione (3.41 g) Dissolve in 30% methylamine/methanol solution (100ml). The solution was heated to reflux temperature for 3 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by chromatography on neutral alumina (eluent: 10% methanol/dichloromethane) gave the subtitle compound as a cream solid (1.08g). Melting point: 52-53°C MS(EI)318(M+H) ^{+ 1} H NMR(CDCl ₃ )δ8.51(1H,d); 8.45(1H,d); 7.56-7.51(5H,m); 7.42 (2H,t);7.32-7.31(1H,m);7.24-7.22(1H,m);6.96(2H,d);4.00-3.96(1H,m);3.82(1H,t);3.25-3.15 (1H,m); 2.89-2.82(1H,m); 2.78-2.72(1H,m); 1.92-1.88(1H,m); 1.80-1.72(3H,m).c)(+/-)- N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazolidin-2-one

2-Chloroethyl chloroformate (0.516ml) was added dropwise to (±)-1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butylamine (0.318g) in acetonitrile (30ml) solution. The resulting solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (5ml) and dimethylformamide (1ml). Sodium hydride (60% oil dispersion) (0.12 g) was added to the solution. Stirring was continued at room temperature for 1 hour, then 20 ml of water was added to the reaction mixture, the product was extracted with ethyl acetate, and the organic extract was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel eluting with 3% methanol/dichloromethane followed by recrystallization from ether gave the title compound (0.093g) as a white solid. Melting point: 58-59°C MS(FAB) 389(M+H) ^{+ 1} H NMR(CDCl ₃ ) δ8.50-8.49(2H,m); 7.58-7.52(5H,m); 7.42(2H,0; 7.31(1H,t); 7.29-7.23(1H,m); 6.95(2H,d); 4.43-4.26(3H,m); 4.15(2H,d); 3.73-3.60(2H,m); 2.74( 2H,t); 2.16-2.03(2H,m).

a)(2S)-1-(3′-氯-4′-氟联苯-4-基氧基)-4-(3-吡啶基)-2-丁醇Example 16 (2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine- 2,4-Diketone

a) (2S)-1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol

According to the method of Example 1, using (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol prepared as described in WO97/20815 Example 40a) ( 0.214g) and 3-chloro-4-fluorophenylboronic acid (0.18g) gave the subtitled compound (0.24g) as a yellow gum. MS(APCI+ve)372/374(M+H) ⁺ .b)(2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-( 3-pyridyl)-2-butyl]-thiazolidine-2,4-dione

According to the method of Example 1, using (2S)-1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2- prepared in step a) Butanol (0.14g) and 2,4-thiazolidinedione (0.088g) were prepared. After chromatography on silica gel (eluting with 80% ethyl acetate/isohexane), the title compound was obtained as a colorless gum (0.077g). MS(APCI+ve)471/473(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.43-8.40(2H,m), 7.81(1H,dd), 7.65-7.60(4H,m) , 7.46(1H,t), 7.32(1H,dd), 6.97(2H,d), 4.50(1H,m), 4.45(1H,t), 4.28(1H,dd), 4.19(2H,d), 2.64(2H,t), 2.39-2.26(1H,m), 2.18-2.03(1H,m)

Example 17 (2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine- 2,5-Diketone

According to the method of Example 7 above, using (2S)-1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)- prepared in Example 16a) 2-Butanol (0.10 g) and succinimide (0.053 g) were prepared. Purification by silica gel chromatography (eluting with 50% acetone/isohexane) gave the title compound as a light brown foam (0.05g). MS(APCl+ve)453/455(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.41(1H,s), 8.39(1H,m), 7.81(1H,dd), 7.65-7.59 (4H,m), 7.56(1H,t), 7.32(1H,dd), 6.97(2H,d), 4.45-4.32(2H,m), 4.26 (1H,m), 2.51(6H,m), 2.25(1H,m), 2.07(1H,m)

a)(2S)-1-(4-溴苯氧基)-4-(3-吡啶基)-2-(叔丁基二甲基甲硅烷氧基)丁烷Example 18 (2R)-N-[1-(3′,5′-dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine- 2,4-Diketone

a) (2S)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane

(2S)-4-(3-pyridyl)-1,2-butanediol (10g) [prepared according to the method described in Example 26c) of WO97/20815] and 1,1-carbonyldiimidazole (12g) The solution in chloroform (250ml) was stirred overnight at room temperature. The resulting mixture was half-concentrated under reduced pressure, then filtered through a pad of silica. Evaporation of the filtrate gave a residue which was further dissolved in dimethylformamide (100ml). Then 4-bromophenol (11.6 g) and cesium carbonate (16.6 g) were added and the mixture was heated at reflux temperature for 18 hours. The cooled reaction mixture was acidified with 2M hydrochloric acid, followed by extraction with ether (x3). The aqueous layer was separated and 2M sodium hydroxide was added until the pH of the mixture reached 9, then extracted with ethyl acetate (x3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a residue. Dimethylformamide (10 ml) was added to the residue, followed by imidazole (6 g) and tert-butyldimethylsilyl chloride (8.4 g), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then added to water and extracted twice with 1:1 ether/hexane. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a residue. Chromatography on silica gel eluting with 1:1 ether/hexanes gave the subtitle compound as an oil (13.27g). MS(APCI+ve)436/438(M+H)b)(2S)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy] Phenylboronic acid

-78°C under stirring, to (2S)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylformaldehyde) prepared as described in step a) To a solution of siloxy)butane (5.0g) and triisopropyl borate (4.3ml) in tetrahydrofuran (200ml) was added dropwise a solution of tert-butyllithium (1.7m solution in hexane, 15.0ml, note: will spontaneously ignite]. After the addition, the reaction mixture was stirred at -70°C for 1 hour. Then water (200ml) and ethyl acetate (200ml) were added. The organic phase was separated, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a The oil was purified by silica gel chromatography eluting with 5:1 ethyl acetate/methanol to give the subtitled compound (4.06 g) as a foam. MS (APCI+ve) 402 (M+H) ⁺ .c) (2S)-1-(3′,5′-dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol

(2S)-4-[4-(3-Pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]phenylboronic acid (0.479 g) [prepared as described in step b)] , 5-bromo-1,3-benzenedicarbonitrile (0.371g, see J.Het.Chem.(1994), 31(6), p1417-1420, registration number 160892-07-9), tetrakis(triphenyl A mixture of phosphine)palladium(0) (0.035g), aqueous sodium carbonate (0.9ml, 2M solution), toluene (10ml), and ethanol (4ml) was heated at 100°C for 2 hours. The reaction mixture was partitioned between diethyl ether and 2N hydrochloric acid, and the layers were separated. The aqueous phase was neutralized with 2N sodium hydroxide, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a residue. This residue was dissolved in tetrahydrofuran (25ml) and tetrabutylammonium fluoride (0.163g). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure and partitioned between diethyl ether and 2N hydrochloric acid, and the layers were separated. The aqueous phase was neutralized with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. Chromatography on silica gel eluting with 2:1 dichloromethane/acetone followed by recrystallization from ethyl acetate/isohexane gave the subtitle compound as a white solid. MS(APCI+ve)370(M+H) ⁺ .d)(2R)-N-[1-(3′,5′-dicyanobiphenyl-4-yloxy)-4-(3- Pyridyl)-2-butyl]-thiazolidine-2,4-dione

According to the method of Example 1, using (2S)-1-(3′,5′-dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2- prepared in step c) Butanol (0.05g) and 2,4-thiazolidinedione (0.032g) were prepared. Purification by supercritical liquid chromatography (eluting with 0%-45% methanol/liquid carbon dioxide) gave the title compound (0.015g) as a glass. MS(APCI+ve)469(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.49(2H,m), 8.41(2H,m), 8.36(1H,s), 7.80(2H,6 ), 7.63(1H,d), 7.32(1H,dd), 7.03(2H,m), 4.47(2H,m), 4.31(1H,dd), 4.19(2H,s), 2.65(2H,t) , 2.30(1H,m), 2.20(1H,m)

Example 19 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidine-2 -ketone a) (+/-)-N-2-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-1,3-dione

Following the procedure of Example 15a), using 1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol (6.02 g) (prepared as described in Example 6b)) and o-benzene Dicarboximide (5.49 g) was prepared. The subtitle compound was obtained as a golden oil (10.13g). MS(APCI)451/453(M+H) ⁺ .b)(+/-)-N-2-(4-bromophenoxy)-4-(4-pyridyl)-butylamine

According to the method of Example 15b), using (+/-)-N-2-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole- 1,3-Diketone (9.78g) was prepared to give the subtitle compound (3.04g) as a yellow solid. Melting point: 168-169°C MS(APCI) 321/323(M+H) ⁺ .c)(+/-)-N-2-(3′-nitrobiphenyl-4-yloxy)-4- (4-pyridyl)-butylamine

(+/-)-N-2-(4-Bromophenoxy)-4-(4-pyridyl)-butylamine (0.5 g), prepared as described in step b) above, 3-nitrobenzene A mixture of boronic acid (0.31 g), tetrakis(triphenylphosphine)palladium(0) (0.03 g), aqueous sodium carbonate (2M solution, 0.93 ml) and ethanol (2 ml) was heated at reflux for 4 hours. After cooling to room temperature, the solvent was removed in vacuo. Dilute hydrochloric acid was then added, and the mixture was extracted with ether. The aqueous mixture was basified with some solid sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina gel using dichloromethane:ethanol (98:2) as eluent and then ethanol to give the subtitled compound (0.28g) as a yellow oil. MS(APCI)364(M+H) ⁺ .d)(+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)- 2-Butyl]-oxazolidin-2-one

Prepared according to the method of example 15c) using 2-chloroethyl chloroformate (0.030ml). The final product was purified by NPHPLC using a 0-10% ethanol/dichloromethane gradient to afford the title compound (0.025g) as a yellow foam. Melting point: 67-69℃ MS(APCI) 434(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,dd), 8.39(1H,t), 8.18-8.09(2H,m) , 7.76-7.70(3H,m), 7.30(2H,d), 7.09(2H,d), 4.32-4.20(2H,m), 4.16(2H,d), 4.14(1H,m), 3.63-3.47 (2H,m), 2.72-2.58(2H,m), 1.95(2H,q)

a)(2S)-1-(3′-氟联苯-4-基氧基)-4-(3-吡啶基)-2-丁醇Example 20 (2R)-N-[1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-di ketone

a) (2S)-1-(3′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol

Following the procedure of Example 18c) above using (2S)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy) prepared as described in Example 18b) above Butoxy]phenylboronic acid (0.30g) and 1-bromo-3-fluorobenzene (0.15ml) were prepared to give the subtitled compound (0.21g) as a colorless oil. MS(APCI+ve)338(M+H) ⁺ .b)(2R)-N-[1-(3′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2 -Butyl]-thiazolidine-2,4-dione

According to the method of Example 1, (2S)-1-(3′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.205g ) and 2,4-thiazolidinedione (0.14 g). The title compound was obtained as a colorless solid (0.032 g) after purification by normal phase HPLC (eluting with 0%-10% ethanol/dichloromethane) and recrystallization from ethanol. Melting point: 117-118°C MS (APCI+ve) 437 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.42 (2H, m), 7.63 (3H, m), 7.44 (3H, m) , 7.33(1H,dd), 7.13(1H,m), 6.98(2H,d), 4.54(1H,m), 4.45(1H,t), 4.27(1H,dd), 4.19(2H,s), 2.62(2H,t), 2.30(1H,m), 2.10(1H,m)

a)(+/-)-1-(3′-(三氟甲基)联苯-4-基氧基)-4-(4-吡啶基)-2-丁醇Example 21 (+/-)-N-[1-(3'-(trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazole Alkane-2,4-dione

a) (+/-)-1-(3′-(trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol

According to the method of Example 6c), using 1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and 3-tri Fluoromethylphenylboronic acid (0.13g) was prepared to give the subtitle compound (0.18g) as a yellow oil. MS(APCI+ve)388(M+H) ⁺ .b)(+/-)-N-[1-(3'-(trifluoromethyl)biphenyl-4-yloxy)-4-( 4-pyridyl)-2-butyl]-thiazolidine-2,4-dione

According to the method of Example 1, using (+/-)-1-(3'-trifluoromethylbiphenyl-4-yloxy)-4-(4-pyridyl)-2- obtained in step a) Butanol (0.175g) and 2,4-thiazolidinedione (0.106g) were prepared. The resulting residue was purified by silica gel chromatography (eluting with 2% methanol/dichloromethane) and supercritical liquid chromatography (eluting with 0%-45% methanol/liquid carbon dioxide), followed by ethanol/ethyl acetate/isohexane The alkane mixture was crystallized to give the title compound (0.10 g) as a colorless solid. Melting point: 95-96°C MS (APCI+ve) 487 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, m), 7.92 (2H, m), 7.67 (4H, m) , 7.23(2H,d), 7.01(2H,m), 4.56(1H,m), 4.46(1H,t), 4.30(1H,dd), 4.18(2H,s), 2.65(2H,t), 2.32(1H,m), 2.10(1H,m)

a)(+/-)-1-(2′-甲氧基联苯-4-基氧基)-4-(4-吡啶基)-2-丁醇Example 22 (+/-)-N-[1-(2'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2 , 4-diketone

a) (+/-)-1-(2′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol

According to the method of Example 6c), using 1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and 2-methyl Oxyphenylboronic acid (0.104g) was prepared to give the subtitle compound as a colorless solid (0.18g). MS(APCI+ve)350(M+H) ⁺ .b)(+/-)-N-[1-(2′-methoxybiphenyl-4-yloxy)-4-(4-pyridine base)-2-butyl]-thiazolidine-2,4-dione

According to the method of Example 1 above, using (+/-)-1-(3'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2 prepared in step a) above -Butanol (0.17g) and 2,4-thiazolidinedione (0.114g) were prepared. The resulting residue was purified by silica gel chromatography (eluting with 2% methanol/dichloromethane) and supercritical liquid chromatography (eluting with 0%-45% methanol/liquid carbon dioxide), followed by ethanol/ethyl acetate/isohexane The mixture of alkanes crystallized to give the title compound as a colorless solid (0.055g). Melting point: 128-130℃ MS(APCI+ve) 487(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,d), 7.38(2H,d), 7.33-7.22(4H, m), 7.08(1H,d), 6.99(1H,m), 6.91(2H,d), 4.55(1H,m), 4.44(1H,t), 4.26(1H,dd), 4.18(2H,s ), 3.75(3H,s), 2.65(2H,t), 2.31(1H,m), 2.10(1H,m)

Example 23 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidine-2, 6-diketone

Following the procedure of Example 1 above, using (+/-)-1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl) prepared as described in Example 11a) -2-Butanol (0.25g) and glutarimide (0.16g) were prepared to give the title compound (0.11g) as a pale yellow foam. Melting point: 53-55℃ MS(APCI) 460(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.45(2H,d), 8.38(1H,s), 8.17-8.09(2H,m) , 7.75-7.70(3H,m), 7.21(2H,d), 7.02(2H,d), 5.10-5.00(1H,m), 4.43-4.29(2H,m), 2.57(6H,t), 2.36 -2.21(1H,m), 2.16-2.01(1H,m), 1.74(2H,t)

Example 24 (+/-)-N-[1-(3'-aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4 - dione

(+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]- A yellow suspension of thiazolidine-2,4-dione (0.377g), ammonium chloride (0.17g) and iron powder (0.18g) in a 1:1 ethanol/water mixture was heated at reflux for 1.5 hours. The cooled reaction mixture was filtered. The colorless filtrate was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulfate ( _{Na2SO4 )} , and concentrated under reduced pressure to give a residue. Purification by normal phase HPLC (0%-10% ethanol/dichloromethane) and precipitation with ethanol/ethyl acetate/isohexane mixtures gave the title compound as a colorless solid (0.34g). Melting point: 147-148°C MS(APCI+ve) 434(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,d), 7.46(2H,d), 7.23(2H,d) , 7.05(1H,t), 6.94(2H,d), 6.77(1H,s), 6.71(1H,d), 6.50(1H,d), 5.10(2H,s), 4.54(1H,m), 4.43(1H,t), 4.26(1H,dd), 4.17(2H,s), 2.62(2H,t), 2.31(1H,m), 2.12(1H,m)

Example 25 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[1,3] -Oxazinan-2-one

To a solution of phosgene (1.93M in toluene, 0.31ml) in toluene (10ml) was added the (+/-)-N-2-(3'-nitrobiphenyl-4-yloxygen) obtained in step 19c). yl)-4-(4-pyridyl)-butylamine (0.20 g), and the reaction mixture was stirred at room temperature for 2 hours. 3-Chloropropanol (0.09ml) was then added to the mixture and stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was redissolved in dimethylformamide (10ml). This solution was added slowly to a suspension of sodium hydride (60% dispersion in oil, 0.09g) in dimethylformamide (1ml). The mixture was heated at 70°C for 9 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was made basic with sodium hydroxide (2M) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC using a 0-10% ethanol/dichloromethane gradient to give the title compound (0.009g) as a yellow oil. MS(APCI)448(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,dd),8.39(1H,t),8.18-8.09(2H,m),7.75-7.70(3H , m); 7.29(2H,dd), 7.09(2H,dd), 4.48-4.33(1H,m), 4.20-4.12(4H,m), 3.31-3.21(2H,m), 2.65(2H,t ), 2.07-1.86(4H,m)

Example 26 (2S)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4- diketone

To (2R)-1-(3′-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5 μmol) [as described in Example 37 of WO97/20815 Method Preparation] was added triphenylphosphine (50 μl, 0.2M solution in tetrahydrofuran), followed by 2,4-thiazolidinedione (50 μl, 0.2M solution in tetrahydrofuran). Diethyl azodicarboxylate (2 [mu]l) was then added and the reaction mixture was sealed and stirred overnight at room temperature. The mixture was concentrated under reduced pressure to obtain a residue. The resulting residue was then dissolved in dimethyl sulfoxide to give the title compound as a 10 mM dimethyl sulfoxide solution, which was subjected to HPLC analysis on a 50 mm x 3.9 mm, 5 μm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate. MS(APCI+ve)444(M+H) ⁺ .

Example 27 (2S)-N-[1-(3'-aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-di ketone

According to the method of Example 26 above, using (2R)-1-(3′-aminobiphenyl-4-yloxy)-4-(3-pyridine prepared according to the method described in Example 50 of WO97/20815 base)-2-butanol (5 μmol), triphenylphosphine (50 μl, 0.2M tetrahydrofuran solution), 2,4-thiazolidinedione (50 μl, 0.2M tetrahydrofuran solution) and diethyl azodicarboxylate (2 μl ) to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a 50 mm x 3.9 mm, 5 μm particle size Waters Symmetry C8 column, eluting with 0.1% ammonium acetate in water. MS(APCI+ve)434(M+H) ⁺

Example 28 (2S)-N-[1-(3'-methylsulfonylaminobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2, 4-diketone

According to the above Example 26), from (2R)-1-(3'-methanesulfonylaminobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5 μmol) [prepared according to the method described in Example 98 of WO97/20815], triphenylphosphine (50 μl, 0.2M tetrahydrofuran solution), 2,4-thiazolidinedione (50 μl, 0.2M tetrahydrofuran solution) and azodicarboxylate The ethyl ester (2 μl) was prepared to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a 50 mm x 3.9 mm, 5 μm particle size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate. MS(APCI+ve)512(M+H) ⁺

Example 29 (2S, 3S)-N-[1-(3'-(pyrrolidin-1-sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl ]-pyrrolidine-2,5-dione

According to the method of Example 26) above, using (3R, 4S)-1-pyridin-3-yl-4-[3′-(pyrrolidine-1-sulfonic acid) prepared according to the method described in Example 72 of WO98/42670 Acyl)biphenyl-4-yloxy]pentan-3-ol (6.67 μmol), triphenylphosphine (50 μl, 0.27M solution in tetrahydrofuran), succinimide (50 μl, 0.27M solution in tetrahydrofuran) and azobis Diethyl carboxylate (3 μl) was prepared to give the title compound as a 10 mM solution in dimethylsulfoxide and analyzed by HPLC on a 50 mm x 3.9 mm, 5 μm particle size Waters Symmetry C8 column, eluting with 0.1% ammonium acetate in water . MS (APCI+ve) 548 (M+H) ⁺ Example 30 (2S, 3S)-N-[1-(3'-cyano-4'-fluorobiphenyl-4-yloxy)-4- (3-pyridyl)-3-pentyl]-pyrrolidine-2,5-dione

According to the method of Example 26), using (1S, 2R)-4-fluoro-4'-(2-hydroxyl-1-methyl-4-pyridine-3 prepared according to the method described in WO98/42670 in Example 36) -ylbutoxy)biphenyl-3-carbonitrile (6.67 μmol), triphenylphosphine (50 μl, 0.27M solution in tetrahydrofuran), succinimide (50 μl, 0.27M solution in tetrahydrofuran) and diethyl azodicarboxylate Esters (3 μl) were prepared to give the title compound as a 10 mM solution in DMSO and analyzed by HPLC on a 50 mm x 3.9 mm, 5 μm particle size Waters Symmetry C8 column eluting with 5%-95% acetonitrile/ammonium acetate. MS(APCI+ve)458(M+H) ⁺

Example 31 (2S)-N-[1-(3'-cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine -2,4-dione

According to the method of Example 26), use (2R)-1-(3'-cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol ( 6.67 μmol), triphenylphosphine (50 μl, 0.27M tetrahydrofuran solution), 2,4-thiazolidinedione (50 μl, 0.27M tetrahydrofuran solution) and diethyl azodicarboxylate (3 μl) were prepared to obtain The title compound was as a 10 mM solution in DMSO and analyzed by HPLC on a 50 mm x 3.9 mm, 5 μm particle size WatersSymmetry C8 column, eluting with 5%-95% acetonitrile/ammonium acetate. MS(APCI+ve)462(M+H) ⁺

a)(+/-)-N-[1-(4-溴苯氧基)-4-(4-吡啶基)-2-丁基]-噁唑烷-2-酮Example 32 (+/-)-N-[1-(4'-fluoro-3'-sulfamoylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl] Oxazolidin-2-one

a) (+/-)-N-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one

According to the method described in Example 15c), using (+/-)-N-2-(4-bromophenoxy)-4-(4-pyridyl)-butylamine (Example 19b), 1.08g), 2-Chloroethyl chloroformate (0.521ml) and sodium hydride (60% dispersion in mineral oil) (0.408g) were prepared. After reacting at 70°C for 10 hours, water (100ml) was added, and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using dichloromethane:ethanol (95:5) as eluent to give the subtitle compound (0.651 g) as an oil. MS(APCI+ve)391/393(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,dd), 7.44(2H,dd), 7.28(2H,dd), 6.92(2H ,dd), 4.29-4.19(2H,m), 4.07(2H,d), 4.04-3.96(1H,m), 3.59-3.41(2H,m), 2.70-2.56(2H,m), 1.90(2H ,q).b)(+/-)-[4-(4-pyridyl)-2-(oxazolidin-2-one-1-yl)butoxy]phenylboronic acid

According to the method described in Example 18b), using (+/-)-N-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl] prepared in step a) -Oxazolidin-2-one (0.20g), tert-butyllithium (1.7M in hexane, 0.60ml) and triisopropyl borate (0.17ml) were prepared to give the subtitled compound (0.09g) as a foam . MS (APCI+ve) 313 (MB (OH) ₂ ) ⁺ . ¹ H NMR (DMSO-d ₆ ) δ8.56 (2H, d), 7.82 (2H, d), 7.39 (2H, d), 6.91 ( 2H,d), 4.25-4.15(2H,m), 4.07(2H,d), 4.05-3.94(1H,m), 3.60-3.46(2H,m), 2.74-2.62(2H,m), 1.92( 2H,q).c)(+/-)-N-[1-(4′-fluoro-3′-sulfamoylbiphenyl-4-yloxy)-4-(4-pyridyl)-2 -Butyl]oxazolidin-2-one

According to the method described in Example 6c), using the (+/-)-[4-(4-pyridyl)-2-(oxazolidin-2-one-1-yl)butoxy] obtained in step b) Phenylboronic acid (0.090g), 5-bromo-2-fluorophenylsulfonamide (0.097g) [prepared as described in Example 35a of WO98/42760], ethanol (1ml), aqueous sodium bicarbonate (2M, 0.2ml ) and tetrakis(triphenylphosphine)palladium(0) (0.010g).

After work-up, the residue was purified by column chromatography on silica gel, eluting successively with dichloromethane:ethanol (95:5) and then dichloromethane:ethanol (90:10) to give the title compound (0.034g) as a solid. Melting point: 89-91℃ MS(APCI+ve) 486(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,d), 7.95(1H,dd), 7.91-7.86(1H, m), 7.72(2H,s), 7.60(2H,d), 7.48(1H,t), 7.29(2H,d), 7.07(2H,d), 4.29-4.19(2H,m), 4.14(2H ,d), 4.08-4.00(1H,m), 3.63-3.47(2H,m), 2.72-2.60(2H,m), 1.99-1.90(2H,m).

Example 33 (+/-)-N-[1-(4-(6-methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]oxa oxazolidin-2-one

According to the method described in Example 6c), using (+/-)-[4-(4-pyridyl)-2-(oxazolidin-2-one-1-yl)butoxy]phenylboronic acid (Example 32b, 0.100g), 2-bromo-6-methoxypyridine (J.Org.Chem_55, (1990), 69-73, 0.079g), ethanol (3ml), aqueous sodium bicarbonate (2M, 0.2ml) Prepared with tetrakis(triphenylphosphine)palladium(0) (0.010 g).

After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol/dichloromethane to give the title compound as an oil (0.082g). MS(APCI+ve) 420(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,dd), 8.04(2H,d), 7.73(1H,t), 7.48(1H,d ), 7.30(2H,dd), 7.04(2H,d), 6.70(1H,d), 4.29-4.22(2H,m), 4.15(2H,d), 4.09-4.02(1H,m), 3.94( 3H,s), 3.60-3.50(2H,m), 2.73-2.59(2H,m), 1.94(2H,q).

Example 34 (+/-)-N-[1-(biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one

According to the method described in Example 6c), using (+/-)-N-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- Ketone (Example 32a), 0.100 g), phenylboronic acid (0.047 g), ethanol (3 ml), aqueous sodium bicarbonate (2M, 0.2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.010 g) preparation.

After work-up, the residue was purified by NPHPLC eluting with a 0-10% ethanol/dichloromethane gradient to afford the title compound as a solid (0.012g). Melting point: 116-117°C MS (APCI+ve) 389 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, d), 7.60 (4H, t), 7.43 (2H, t) , 7.30(3H,d), 7.03(2H,d), 4.31-4.20(2H,m), 4.13(2H,d), 4.07-4.00(1H,m), 3.62-3.48(2H,m), 2.72 -2.59(2H,m), 1.94(2H,q)

Example 35 (+/-)-N-[1-(4'-chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one

According to the method described in Example 6c), using (+/-)-N-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- Ketone (Example 32a), 0.100 g), 4-chlorophenylboronic acid (0.060 g), ethanol (3 ml), aqueous sodium bicarbonate (2M, 0.2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.010 g) Preparation.

After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol/dichloromethane to give the title compound as a solid (0.038g). Melting point: 103-105°C MS (APCI+ve) 423 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, d), 7.62 (4H, q), 7.47 (2H, d) , 7.29(2H,d), 7.03(2H,d), 4.30-4.20(2H,m), 4.13(2H,d), 4.07-4.00(1H,m), 3.62-3.48(2H,m), 2.70 -2.58(2H,m), 1.94(2H,q).

Example 36 (+/-)-N-[1-(4'-methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- ketone

According to the method described in Example 6c), using (+/-)-N-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- Ketone (Example 32a), 0.100 g), 4-methylphenylboronic acid (0.052 g), ethanol (3 ml), aqueous sodium bicarbonate (2M, 0.2 ml) and tetrakis(triphenylphosphine)palladium(0) ( 0.010g) for preparation.

After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol/dichloromethane to give the title compound as a solid (0.033g). Melting point: 109-110°C MS(APCI+ve) 403(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,d), 7.56(2H,d), 7.50(2H,d) , 7.29(2H,d), 7.23(2H,d), 7.01(2H,d), 4.30-4.20(2H,m), 4.12(2H,d), 4.07-4.01(1H,m), 3.62-3.48 (2H,m), 2.72-2.59(2H,m), 1.94(2H,q).

Example 37 (+/-)-N-[1-(4'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2 -ketone

According to the method described in Example 6c), using (+/-)-N-[1-(4-bromophenoxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- Ketone (Example 32a), 0.100 g), 4-methoxyphenylboronic acid (0.059 g), ethanol (3 ml), aqueous sodium bicarbonate (2M, 0.2 ml) and tetrakis(triphenylphosphine)palladium (0) (0.010 g) was prepared.

After work-up, the residue was purified by NPHPLC, eluting with a 0-10% ethanol/dichloromethane gradient, to give the title compound as a solid (0.026g). Melting point: 114-115°C MS(APCI+ve) 419(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.46(2H,d), 7.53(4H,dd), 7.29(2H,d) , 6.99(4H,dd), 4.30-4.20(2H,m), 4.11(2H,d), 4.06-4.01(1H,m), 3.32(3H,s), 3.61-3.48(2H,m), 2.70 -2.59(2H,m), 1.94(2H,q).

Example 38 (+/-)-N-[1-(3′,4′-dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine -2-one

According to the method described in Example 6c), using (+/-)-[4-(4-pyridyl)-2-(oxazolidin-2-one-1-yl)butoxy]phenylboronic acid (Example 32b), 0.050g), 1-bromo-3,4-dichlorobenzene (0.048g), ethanol (2ml), aqueous sodium bicarbonate (2M, 0.1ml) and tetrakis(triphenylphosphine)palladium(0) (0.006 g) was prepared.

After work-up, the residue was purified by NPHPLC eluting with a 0-10% ethanol/dichloromethane gradient to afford the title compound as a solid (0.010 g). Melting point: 92-93°C MS (APCI+ve) 4.57/459/461 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.46 (2H, d), 7.89 (1H, d), 7.68- 7.62(4H,m), 7.29(2H,d), 7.04(2H,d), 4.30-4.20(2H,m), 4.13(2H,d), 4.07-4.01(1H,m), 3.62-3.48( 2H,m), 2.72-2.59(2H,m), 1.94(2H,q).

Example 39 (+/-)-N-[1-(4-(6-methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]piper Pyridine-2,6-dione a) (+/-)-1-(4-bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane

Solution in (+/-)-1-(4-bromophenoxy)-4-(4-pyridyl)-2-butanol (Example 6b), 14.60 g) in dry dichloromethane (500 ml) Tert-butyldimethylsilyl chloride (20.53 g) and imidazole (9.25 g) were added therein. The solution was stirred overnight at room temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure.

The residue was chromatographed on silica gel, eluting with dichloromethane:ethyl acetate (5:1 ), to give the subtitle compound as a solid (19.34g). Melting point: 73-75°C MS (APCI+ve) 436/438 (M+H) ^{+ 1} H NMR (DMSO-d ₆ ) δ8.50 (2H, dd), 7.49 (2H, dd), 7.27 (2H, d), 6.94(2H,dd), 4.13-4.02(2H,m), 3.93-3.86(1H,m), 2.82-2.68(2H,m), 1.97-1.79(2H,m), 0.91(9H, s), 0.12(3H,s), 0.09(3H,s).b)(+/-)-4-[4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy )butoxy]phenylboronic acid

According to the method described in Example 18b), using the (+/-)-1-(4-bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethyl) obtained in step a) Silyloxy)butane (10.0 g), tert-butyllithium (1.7M in hexane, 27ml) and triisopropyl borate (6ml) were prepared in anhydrous tetrahydrofuran (200ml).

After work-up, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: hexane (2: 1 ) followed by ethyl acetate, to afford the subtitle compound as a foam (4.38 g). MS(APCI+ve)402(M+H) ^{+ 1} H NMR(DMSO-d ₆ +D ₂ O) δ8.45(2H,dd), 7.71(2H,d), 7.24(2H,q), 6.87 (2H,d), 4.04-3.82(3H,m), 2.79-2.66(2H,m), 1.97-1.75(2H,m), 0.87(9H,s), 0.14(3H,s), 0.08(3H ,s).c)(+/-)-4-[4-(4-pyridyl)-2-butoxy]phenylboronic acid

(+/-)-1-(4-bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane ( 4.38g) in methanol (200ml) was added dilute hydrochloric acid (2M, 65ml). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue was partitioned between ether and water. The aqueous layer was basified with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the subtitle compound as a powder. MS(APCI+ve) 288(M+H) ^{+ 1} H NMR(DMSO-d ₆ +D ₂ O) δ8.43(2H,d), 7.71(2H,d), 7.31(2H,d), 6.92 (2H,d), 3.92(2H,d), 3.84-3.78(1H,m), 2.87-2.64(2H,m), 1.89-1.74(2H,m).d)(+/-)-1- [4-(6-Methoxypyridin-2-yl)phenoxy]-4-(4-pyridyl)-2-butanol

According to the method described in Example 6c), using (+/-)-4-[4-(4-pyridyl)-2-butoxy]phenylboronic acid (0.20 g) prepared in step c), 2-bromo -6-methoxypyridine (J.Org.Chem_55, (1990), 69-73, 0.26g), ethanol (3ml), aqueous sodium bicarbonate (2M, 0.7ml) and tetrakis(triphenylphosphine)palladium (O) (0.020 g) was prepared.

After work-up, the residue was purified by NPHPLC eluting with a 0-10% ethanol/dichloromethane gradient to afford the subtitle compound as an oil (0.15 g). MS(APCI+ve)351(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.45(2H,d), 8.03(2H,dd), 7.73(1H,t), 7.47(1H,d ), 7.26(2H,dd), 7.03(2H,dd), 6.70(1H,d), 5.08(1H,d), 3.95(2H,d), 3.83-3.78(1H,m), 3.32(3H, s), 2.85-2.77(1H,m), 2.72-2.64(1H,m), 1.91-1.83(1H,m), 1.78-1.70(1H,m)e)(+/-)-N-[1 -(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]piperidine-2,6-dione

According to the method of Example 1, using the (+/-)-1-[4-(6-methoxypyridin-2-yl)phenoxy]-4-(4-pyridyl)- obtained in step d) 2-Butanol (0.15g), glutarimide (0.1g), triphenylphosphine (0.22g) and diethyl azodicarboxylate (0.14ml) were prepared.

After work-up, the residue was purified by NPHPLC eluting with a 0-10% ethanol/dichloromethane gradient to afford the title compound as an oil (0.10 g). MS(APCI+ve) 446(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.44(2H,dd), 8.01(2H,dd), 7.73(1H,t), 7.47(1H,d ), 7.21(2H,dd), 6.97(2H,d), 6.70(1H,d), 5, 07-5.02(1H,m), 4.42-4.28(2H,m), 3.94(3H,s), 2.62-2.51(6H,m), 2.35-2.24(1H,m), 2.12-2.01(1H,m), 1.78-1.70(2H,m).

Example 40 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]imidazolidine-2,4 - dione

According to the method of Example 1, use (+/-)-N-1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (Example 15a), 0.20g), hydantoin (0.11g), triphenylphosphine (0.29g) and diethyl azodicarboxylate (0.17ml) in anhydrous tetrahydrofuran (10ml) and dimethylformamide ( 2ml) for preparation.

After work-up, the residue was purified by NPHPLC eluting with a 0-10% ethanol/dichloromethane gradient to afford the title compound as a solid (0.03g). Melting point: 143-145°C MS(APCI+ve) 447(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.45(2H,d), 8.38(1H,s), 8.17-8.07(3H, m), 7.74-7.70(3H,m), 7.24(2H,d), 7.03(2H,d), 4.51-4.45(1H,m), 4.38-4.23(2H,m), 3.87(2H,s) , 2.69-2.60(2H,m), 2.38-2.22(1H,m), 2.16-2.00(1H,m).

在三乙胺(1ml)存在下，向(+/-)-N-2-(3′-硝基联苯-4-基氧基)-4-(4-吡啶基)-丁胺(实施例19c)，0.20g)的无水二氯甲烷(10ml)溶液内缓慢加入5-氯戊酰氯(0.07ml)。室温下搅拌混合物15分钟，然后减压浓缩。Example 41 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]piperidin-2-one

In the presence of triethylamine (1ml), to (+/-)-N-2-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine (executed Example 19c) To a solution of 0.20 g) in anhydrous dichloromethane (10 ml) was slowly added 5-chlorovaleryl chloride (0.07 ml). The mixture was stirred at room temperature for 15 minutes, then concentrated under reduced pressure.

To the solution of the residue redissolved in anhydrous THF (10 mL) was added potassium tert-butoxide (1M in THF, 1.5 mL). After reacting at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

The residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol/dichloromethane to give the title compound as an oil (0.03g). MS(APCI+ve)446(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.45(2H,d), 8.38(1H,t), 8.18-8.09(2H,m), 7.75-7.69 (3H,m), 7.26(2H,d), 7.07(2H,d), 4.86-4.76(1H,m), 4.19-4.07(2H,m), 3.25-3.14(2H,m), 2.73(2H ,t), 2.28-2.22(2H,m), 2.00-1.87(2H,m), 1.64(4H,bd).

Example 42 (+/-)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2- ketone

Following the procedure of Example 41 above, using (+/-)-N-2-(3'-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-butylamine (Example 19c ), 0.20 g), triethylamine (1 ml), 4-chlorobutyryl chloride (0.06 ml) and potassium tert-butoxide solution (1M solution in tetrahydrofuran, 1.5 ml).

After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol/dichloromethane to afford the title compound as an oil (0.035g). MS(APCI+ve)432(M+H) ^{+ 1} H NMR(DMSO-d ₆ )δ8.45(2H,dd), 8.38(1H,t), 8.18-8.09(2H,m), 7.75-7.69 (3H,m), 7.28(2H,dd), 7.07(2H,dd), 4.34-4.27(1H,m), 4.11(2H,d), 3.38-3.26(2H,m), 2.61-2.55(2H ,m), 2.24(2H,t), 1.97-1.85(4H,m).

Embodiment 43 pharmacological research

It is known that certain compounds such as benzoylbenzoyladenosine triphosphate (bbATP) are agonists of P2X7 receptors, which can form pores in the plasma membrane (Drug Development Research (1996), 37(3), p. 126). Thus, when the receptor is activated with bbATP in the presence of 3,8-diamino-5-ethyl-6-phenylphenanthridinium bromide, a fluorescent DNA probe, intracellular DNA-bound bromide can be observed Fluorescence enhancement of ethidium. This fluorescence increase can be used as a measure of P2X7 receptor activation and thus to demonstrate the effect of compounds on P2X7 receptors.

The antagonistic activity of each of the title compounds of Examples 1-42 at the P2X ₇ receptor was tested in this manner. For example, the test is carried out in a 96-well flat-bottomed microtiter plate, and 200 μl of THP-1 cell suspension containing 10 ^-4 M 3,8-diamino-5-ethyl-6-phenylphenanthridinium bromide is added to each well. solution (2.5×10 ⁶ cells/ml), 25 μl high potassium buffer containing 10 ⁻⁵ M bbATP, and 25 μl high potassium buffer containing 3×10 ⁻⁵ M test compound in 250 μl. The titer plate was covered with a plastic plate and incubated at 37°C for 1 hour. Then the titer plate was read on a Perkin-Elmer fluorescence plate reader, excitation 520nm, emission 595nm, slit width: Ex15nm, Em20nm. For comparison, bbATP (a P2X ₇ agonist) and pyridoxal 5-phosphate (a P2X ₇ antagonist) were used as controls in the assay, respectively. From the readings obtained, the _IC50 value for each compound was calculated as the negative log concentration of the test compound required to reduce 50% of bbATP agonistic activity. Each of the compounds of Examples 1-42 demonstrated antagonistic activity with _IC50 values > 4.50.

Claims (13)

1. The compound of general formula (I) or its pharmaceutically acceptable salt or solvate:

Wherein X represents an oxygen or sulfur atom, or represents a group NH, CH ₂ , CH ₂ CH ₂ or OCH ₂ ; Y represents the group CH ₂ or C=O; R ¹ represents pyridyl or pyrimidyl; R ² represents phenyl, pyridyl or pyrimidinyl, each of which may be optionally substituted by one or more substituents independently selected from the following: halogen atom or amino, cyano, hydroxyl, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylthio, (di)C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -Alkylcarbonyl, C ₁ -C ₆ -Alkoxycarbonyl, C ₁ -C ₆ -Alkylsulfinyl, C ₁ -C ₆ -Alkylsulfonyl, -NR ³ SO ₂ R ⁴ Or -SO ₂ NR ⁵ R ⁶ groups, or groups -Z-(CH ₂ ) _p -Z-(CH ₂ ) _q -H, wherein Z each represents a nitrogen or oxygen atom, p is an integer of 2-5, and q is 0 or an integer 1-5; R ³ and R ⁴ each independently represent a hydrogen atom or a C ₁ -C ₆ -alkyl group; and R ⁵ and R ⁶ each independently represent a hydrogen atom or a C ₁ -C ₆ -alkyl group or together with the nitrogen atom to which they are bonded form a pyrrolidinyl or piperidinyl group. 2. A compound according to claim 1, wherein X represents a sulfur atom or a group _CH2 . 3. A compound according to claim 1 or 2, wherein Y represents the group C=O. 4. A compound according to any one of claims 1-3, wherein ^R represents pyridyl. 5. A compound according to any one of claims 1-4, wherein R represents phenyl, pyridyl or pyrimidinyl, ^each of which may optionally be substituted by one, two or three substituents independently selected from the group consisting of halogen atom or amino, cyano, hydroxyl, nitro, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alk Thio, (di)C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkylsulfinyl, C ₁ -C ₄ -Alkylsulfonyl, -NR ³ SO ₂ R ⁴ or -SO ₂ NR ⁵ R ⁶ radicals. 6. The compound according to any one of claims 1-5, wherein R represents phenyl, pyridyl or pyrimidinyl, ^each of which may optionally be substituted by one or two substituents independently selected from the group consisting of a halogen atom or an amino group , cyano, nitro, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or -SO ₂ NR ⁵ R ⁶ groups. 7. A compound according to claim 1, which is: (+/-)-(N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione, (+/-)-N-[1-(3′-methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-di ketone, (+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione, (+/-)-N-[1-(3′-chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione, (+/-)-N-[1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione, (+/-)-N-[1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidine-2,5-di ketone, (+/-)-N-[1-(3′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-di ketone, (2R)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione, (2R)-N-[1-(3'-nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione, (2R)-N-[1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5-dione, (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione , (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidine-2,5-dione , (+/-)-N-[1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidine-2,5-dione, (+/-)-N-[1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione, (+/-)-N-[1-(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]oxazolidin-2-one, (2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4- diketone, (2R)-N-[1-(3'-chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]pyrrolidine-2,5- diketone, (2R)-N-[1-(3′,5′-dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4- diketone, (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one, (2R)-N-[1-(3'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione, (+/-)-N-[1-(3'-(trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2, 4-diketone, (+/-)-N-[1-(2′-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-di ketone, (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]piperidine-2,6-dione , (+/-)-N-[1-(3′-aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione, (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-[1,3]oxazinane -2-one, (2S)-N-[1-(3′-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione, (2S)-N-[1-(3'-aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]thiazolidine-2,4-dione, (2S)-N-[1-(3′-Methanesulfonylaminobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4-dione , (2S,3S)-N-[1-(3′-(pyrrolidine-1-sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]pyrrolidine -2,5-diketone, (2S,3S)-N-[1-(3′-cyano-4′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]pyrrolidine-2 , 5-diketone, (2S)-N-[1-(3′-cyano-4′-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]thiazolidine-2,4 - diketones, (+/-)-N-[1-(4'-fluoro-3'-sulfamoylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine -2-one, (+/-)-N-[1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]oxazolidine- 2-keto, (+/-)-N-[1-(biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one, (+/-)-N-[1-(4'-chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one, (+/-)-N-[1-(4'-methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one, (+/-)-N-[1-(4'-methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidin-2-one, (+/-)-N-[1-(3′,4′-dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]oxazolidine-2- ketone, (+/-)-N-[1-(4-(6-methoxypyridin-2-yl)-phenoxy)-4-(4-pyridinyl)-2-butyl]piperidine-2 , 6-diketone, (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]imidazolidine-2,4-dione , (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]piperidin-2-one, or (+/-)-N-[1-(3′-nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]pyrrolidin-2-one. 8. A method for preparing the compound of formula (I) according to claim 1, the method comprising: (a) make general formula (II) compound: Wherein L represents a leaving group, and R ¹ and R ² are as defined in formula (I), and react with the compound of general formula (III):

Wherein X and Y are as defined in formula (I), except that when X is an oxygen atom or OCH ₂ , then Y cannot be a CH ₂ group; or (b) when X is an oxygen atom and Y is _a CH group, the compound of general formula (IV):

Wherein R ¹ and R ² are as defined in formula (I), with 2-chloroethyl chloroformate; or (c) when X is an _OCH group and Y is _a CH group, reacting a compound of formula (IV) as defined in (b) above with 3-chloropropanol in the presence of phosgene; or (d) reacting a compound of formula (IV) as defined in (b) above with 4-chlorobutyryl chloride when X is a _CH group and Y is a _CH group; or (e) reacting a compound of formula (IV) as defined in (b) above with 5-pentanoyl chloride when X is _{a CH2CH2} group and Y is a _CH2 group; or (f) when X is an oxygen atom or _an OCH group, make the compound of general formula (Ⅴ): Wherein X represents an oxygen atom or _{an OCH} group, and Y and R are as defined in ^formula (I), Reaction with the compound of general formula (VI) R ² -B (OH) ₂ , wherein R ² is defined as formula (I); or (g) when X is an oxygen atom or OCH ₂ group, make general formula (VII) Compound:

Wherein X represents an oxygen atom or _{an OCH} group, and Y and R are as defined in ^formula (I), Reaction with the compound of general formula (Ⅷ), R ² -Br, wherein R ² is as defined in formula (I); and optionally after (a), (b), (c), (d), (e), (f) or (g), the compound of formula (I) is converted into another compound of formula (I) and/ Or form a pharmaceutically acceptable salt or solvate of a compound of formula (I). 9. A pharmaceutical composition, which comprises the compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. 10. The preparation method of the pharmaceutical composition described in claim 9, the method comprises the compound of formula (I) described in any one of claims 1-7, or its pharmaceutically acceptable salt or solvate and pharmaceutically acceptable Adjuvant, diluent or carrier mixture. 11. The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, for therapeutic use. 12. Use of the compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a drug for treatment. 13. A method of producing immunosuppression, the method comprising administering to a patient a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof.