WO2014142086A1 - Pyrrolidin-3-yl acetate derivative and piperidin-3-yl acetate derivative - Google Patents

Abstract

In the present invention, a pyrrolidin-3-yl acetate derivative or piperidin-3-yl acetate derivative, or a pharmacologically acceptable salt thereof, has an inhibiting effect in the fractalkine-CX3CR1 pathway.

Description

[Replenishment under Rule 26 01.04.2014] Pyrrolidin-3-ylacetic acid derivatives and piperidin-3-ylacetic acid derivatives

The present invention relates to pyrrolidin-3-ylacetic acid derivatives and piperidin-3-ylacetic acid derivatives. More particularly, the present invention relates to pyrrolidin-3-ylacetic acid derivatives and piperidin-3-ylacetic acid derivatives that have applicability as therapeutic agents for inflammatory bowel disease.

Chemokines are the main cell migration factors in the body, and control tissue infiltration of lymphocytes through enhancement of cell movement and activation of cell adhesion molecules. Chemokines are classified into four subfamilies, CC, CXC, C, and CX3C, based on the sequence of their first two cysteine residues.

Fractalkine is the only member of the CX3C chemokine, and its structure and function have distinctive features not found in other chemokines. By fractalkine binding to the receptor CX3CR1, it is possible to mediate strong adhesion alone without the intervention of selectins and integrins even in the presence of a physiological blood flow rate. That is, the fractalkine-CX3CR1 cell invasion system mediates a function similar to the multistage cell invasion mechanism via selectins and integrins in a single step reaction.

Fractalkine is induced when vascular endothelial cells are treated with inflammatory cytokines TNF and IL-1. On the other hand, CX3CR1 is expressed in a part of T cells in monocytes and NK cells, but not in neutrophils. Thus, the fractalkine-CX3CR1 cell invasion system appears to be a very efficient mechanism for recruiting certain immune cells on or into the endothelial cells of damaged tissues.

Regarding the relationship between the fractalkine-CX3CR1 system and the pathological condition, the fractalkine-CX3CR1 system is involved in the pathogenesis and pathology of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, lupus nephritis, and multiple sclerosis. (Non-Patent Document 1). Regarding inflammatory bowel disease in particular, it has been reported that the expression of fractalkine is enhanced at the inflammatory site of the large intestine tissue of the patient, and that CX3CR1 plays an important role in infiltration of immune cells into the intestinal tissue. (Non-Patent Document 2).

So far, as fractalkine inhibitors, antibodies described in Patent Document 1 and low molecular compounds described in Patent Documents 2 to 6 are known.

Furthermore, although the compound described in Patent Document 7 is described as being useful as an antagonist of the chemokine CCR2 receptor, the target chemokine family is different.

JP 2002-345454 A International Publication No. 2006/107257 International Publication No. 2006/107258 International Publication No. 2008/039138 International Publication No. 2008/039139 International Publication No. 2009/120140 US Patent Application Publication No. 2010/0210633

The problem to be solved by the present invention is to provide a compound having an inhibitory action in the fractalkine-CX3CR1 pathway.

As a result of diligent efforts, the present inventors have found the present invention. That is, the present invention
[1] 2- {1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetic acid,
2- (1-[(2-Chloro-6-methylphenyl) methyl] -3-{[(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} piperidin-3-yl ) Acetic acid,
2-[(3S, 4R) -3-{[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -1-[(2,6-dichloro-3-fluorophenyl ) Methyl] -4-methylpyrrolidin-3-yl] acetic acid,
2-[(3S ^* , 4S ^* )-1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidine -4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid,
2-[(3S, 4R) -1-{[2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1- Ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid,
2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-({1-[(2-methylcyclohex-1-ene-1 -Yl) methyl] piperidin-4-yl} carbamoyl) pyrrolidin-3-yl] acetic acid,
2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} pyrrolidine-3- Yl] acetic acid,
2-[(3S, 4R) -1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl ] Carbamoyl} pyrrolidin-3-yl] acetic acid, and 2- [1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-ene- 1-ylmethyl) piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetic acid or a pharmaceutically acceptable salt thereof.
[2] A medicament comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
[3] A therapeutic agent for inflammatory bowel disease comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
[4] The therapeutic agent according to [3], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
[5] An inhibitor of the fractalkine-CX3CR1 pathway comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
[6] A fractalkine inhibitor comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
[7] A CX3CR1 inhibitor comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
[8] A method for treating inflammatory bowel disease, comprising administering the compound according to [1] or a pharmacologically acceptable salt thereof to a patient.
[9] The method according to [8], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
[10] A method for inhibiting the fractalkine-CX3CR1 pathway, which comprises administering to the patient a compound according to [1] or a pharmaceutically acceptable salt thereof.
[11] A method for inhibiting fractalkine, comprising administering the compound of [1] or a pharmacologically acceptable salt thereof to a patient.
[12] A method for inhibiting CX3CR1, comprising administering the compound of [1] or a pharmacologically acceptable salt thereof to a patient.
[13] The compound according to [1] or a pharmacologically acceptable salt thereof for use in the treatment of inflammatory bowel disease.
[14] The compound or pharmacologically acceptable salt thereof according to [13], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
[15] The compound according to [1] or a pharmacologically acceptable salt thereof for use in inhibiting the fractalkine-CX3CR1 pathway.
[16] The compound according to [1] or a pharmacologically acceptable salt thereof used for inhibiting fractalkine.
[17] The compound according to [1] or a pharmacologically acceptable salt thereof for use in inhibiting CX3CR1.
[18] Use of the compound of [1] or a pharmacologically acceptable salt thereof in the manufacture of a therapeutic agent for inflammatory bowel disease.
[19] The use according to [18], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
[20] Use of the compound of [1] or a pharmaceutically acceptable salt thereof in the manufacture of a fractalkine-CX3CR1 pathway inhibitor.
[21] Use of the compound of [1] or a pharmaceutically acceptable salt thereof in the production of a fractalkine inhibitor.
[22] Use of the compound of [1] or a pharmacologically acceptable salt thereof in the manufacture of a CX3CR1 inhibitor.
About.

From the results of the tests described below, the compound according to the present invention has an inhibitory action in the fractalkine-CX3CR1 pathway. Therefore, the compound according to the present invention has applicability as a therapeutic agent for inflammatory bowel disease.

6 is a graph showing the results of Test Example 2 regarding the compound of Example 7.

Hereinafter, the contents of the present invention will be described in detail.

In the present specification, the present invention is not limited to a specific crystal form, although a crystal polymorph may exist, and a single substance of any crystal form may be a mixture. There may be. Further, the present invention includes amorphous forms, and the compounds according to the present invention include anhydrides, hydrates and solvates.

Hereinafter, the meanings of terms, symbols, and the like described in this specification will be described, and the present invention will be described in detail.

The “pharmacologically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention and is pharmacologically acceptable. Organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, and the like.

Preferable examples of inorganic acid salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and preferable examples of organic acid salts include, for example, acetate, succinate and fumarate. , Maleate, tartrate, citrate, lactate, stearate, benzoate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate Etc.

Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt and the like, and preferred examples of organic base salts Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.

Preferred examples of acidic amino acid salts include aspartate and glutamate, and preferred examples of basic amino acid salts include arginine salt, lysine salt and ornithine salt.

The compound according to the present invention or a pharmacologically acceptable salt thereof can be formulated by a conventional method. Examples of the dosage form include oral preparations (tablets, granules, powders, capsules, syrups, etc.). ), Injections (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration), external preparations (transdermal absorption preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories Etc.).

These solid preparations such as tablets, capsules, granules, and powders are usually 0.001 to 99.5% by weight, preferably 0.01 to 90% by weight of the compound according to the present invention or a pharmaceutically acceptable product thereof. Possible salts.

When producing an oral solid preparation, the compound according to the present invention or a pharmacologically acceptable salt thereof, if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, etc. Can be made into tablets, granules, powders, and capsules by conventional methods. Tablets, granules, powders, capsules and the like may be coated with a film as necessary.

Examples of the excipient include lactose, corn starch, crystalline cellulose, and the like. Examples of the binder include hydroxypropylcellulose and hydroxypropylmethylcellulose. Examples of the disintegrant include carboxymethylcellulose calcium and croscarmette. Examples include sodium loose.

Examples of the lubricant include magnesium stearate and calcium stearate, and examples of the colorant include titanium oxide.

Examples of the film coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like.

Of course, any of the above-mentioned additives is not limited to these.

When producing an injection (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration), the compound according to the present invention or a pharmacologically acceptable salt thereof is used as necessary. , PH adjusters, buffers, suspending agents, solubilizers, antioxidants, preservatives (preservatives), isotonic agents, and the like can be added, and can be produced by conventional methods. Alternatively, it may be freeze-dried to obtain a freeze-dried preparation that is dissolved at the time of use. These injections can be administered intravenously, subcutaneously, intramuscularly and the like.

Examples of pH adjusting agents and buffering agents include organic acids or inorganic acids and / or salts thereof. Examples of suspending agents include methyl cellulose, polysorbate 80, sodium carboxymethyl cellulose, and so on. For example, polysorbate 80, polyoxyethylene sorbitan monolaurate, etc., antioxidants such as α-tocopherol, etc., and preservatives such as methyl paraoxybenzoate, ethyl paraoxybenzoate etc. Examples of the agent include glucose, sodium chloride, mannitol and the like, but of course not limited thereto.

These injection solutions can usually contain 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound according to the present invention or a pharmacologically acceptable salt thereof.

When producing an external preparation, a base material is added to the compound according to the present invention or a pharmacologically acceptable salt thereof, and if necessary, the above-mentioned emulsifier, preservative, pH adjuster, coloring A transdermal absorption preparation (an ointment, a patch, etc.), an eye drop, a nasal drop, a suppository, and the like can be produced by adding conventional preparations and the like.

As the base material to be used, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used. For example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, purified water And other raw materials.

These external preparations can usually contain 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound according to the present invention or a pharmacologically acceptable salt thereof.

The dose of the pharmaceutical agent according to the present invention usually varies depending on symptoms, age, sex, weight, etc., but may be an amount sufficient for producing a desired effect. For example, in the case of an adult, about 0.1 to 5000 mg (preferably 0.5 to 1000 mg, more preferably 1 to 600 mg) per day is once per day or 2 to 6 times a day. Used in divided times.

The present invention also includes isotope-labeled compounds of the compounds of the present invention, which have an atomic mass or mass number that differs from the atomic mass or mass number in which one or more atoms are normally found in nature. It is the same as the compound according to the present invention except that it is replaced by an atom having it. The isotopes that can be incorporated into the compounds according to the present invention are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. ² H, ³ H, ¹¹ C, ¹⁴ C, ¹³ N, ¹⁵ O, ¹⁸ F, ³² P, ³⁵ S, ¹²³ I, ¹²⁵ I and the like are included.

The compounds according to the invention or their pharmaceutically acceptable derivatives (eg salts) containing the aforementioned isotopes and / or other isotopes are within the scope of the claims herein. Isotopically-labeled compounds of the present invention, for example, compounds incorporating radioactive isotopes such as ³ H and / or ¹⁴ C, are useful in pharmaceutical and / or substrate tissue distribution assays. ³ H and ¹⁴ C are considered useful because of their ease of preparation and detection. The isotopes ¹¹ C and ¹⁸ F are considered useful in PET (positron emission tomography), and the isotope ¹²⁵ I is considered useful in SPECT (single photon emission computed tomography), all useful in brain imaging. It is. Substitution with heavier isotopes such as ² H results in certain therapeutic benefits such as increased in vivo half-life or reduced dose requirements due to higher metabolic stability, and therefore under certain circumstances It is considered useful. The isotope-labeled compounds of the compounds of the present invention can be prepared by using readily available isotope-labeled reagents in place of non-isotopically-labeled reagents and the procedures disclosed in the following schemes and / or examples. It can be uniformly prepared by carrying out.

The compound according to the present invention can be used as a chemical probe for capturing a target protein of a physiologically active low-molecular compound. That is, the compound according to the present invention is different from the structural portion essential for the expression of the activity of the compound in a portion different from J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5 2003, p492-498 or WO2007 / 139149 can be converted into affinity chromatography, photoaffinity probe, etc. by introducing a labeling group, a linker, etc. by the method described in WO2007 / 139149.

Examples of the labeling group and linker used for the chemical probe include groups shown in the following groups (1) to (5).
(1) Photoaffinity labeling groups (for example, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group and nitro group) and chemical affinity groups (for example, alpha carbon atom is halogen) A protein labeling group such as a ketone group substituted with an atom, a carbamoyl group, an ester group, an alkylthio group, a Michael acceptor such as an α, β-unsaturated ketone, an ester, and an oxirane group);
(2) a cleavable linker such as —SS—, —O—Si—O—, monosaccharide (glucose group, galactose group, etc.) or disaccharide (lactose etc.), and oligopeptide cleavable by enzymatic reaction Linker,
(3) a fishing tag group such as biotin, 3- (4,4-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora-s-indasen-3-yl) propionyl group,
(4) Radiolabeling groups such as ¹²⁵ I, ³² P, ³ H, ¹⁴ C; fluorescein, rhodamine, dansyl, umbelliferone, 7-nitrofurazanyl, 3- (4,4-difluoro-5,7-dimethyl-4H -3a, 4a-diaza-4-bora-s-indacene-3-yl) propionyl group and other fluorescent labeling groups; chemiluminescent groups such as lumiferin and luminol; heavy metal ions such as lanthanoid metal ions and radium ions can be detected Or (5) a group to be bound to a solid phase carrier such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, nylon beds, etc.
A probe prepared by introducing a labeling group selected from the group consisting of the above (1) to (5) into the compound according to the present invention according to the method described in the above document is a new drug discovery target. It can be used as a chemical probe for the identification of a labeled protein that is useful for searching for a protein.

The compounds according to the present invention can be produced, for example, by the methods described in the following examples, and the effects of the compounds according to the present invention can be confirmed by the methods described in the following test examples. However, these are illustrative, and the present invention is not limited to the following specific examples in any case.

In ¹ H-NMR for confirming the structure of a compound, when heavy water is used as a measurement solvent, the chemical shift of the spectrum of each compound is a value corrected by assuming that the chemical shift of a solvent residual peak in heavy water is 4.79. .

(Example 1) Optically active substance of 2- {1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetic acid

Example 1a tert-butyl N- (1-pentylpiperidin-4-yl) carbamate tert-butyl N- (piperidin-4-yl) carbamate (61 g, 304.6 mmol), acetic acid (6.1 mL), and A mixture of tetrahydrofuran (dehydrated) (700 mL) was cooled in an ice bath. To the mixture was added a solution of valeraldehyde (38.4 mL, 365.5 mmol) in tetrahydrofuran (dehydrated) (100 mL). After 20 minutes, sodium triacetoxyborohydride (84 g, 396.0 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 14 hours and 40 minutes. The reaction mixture was cooled in an ice bath, and water (700 mL) was added to stop the reaction. The resulting mixture was made alkaline by adding 5N aqueous sodium hydroxide solution (240 mL), and the resulting solution was extracted twice with ethyl acetate (600 mL). The organic layer was washed with saturated brine, dried over magnesium sulfate, the desiccant was filtered, and concentrated under reduced pressure to give the title compound as a crude product (86.43 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 8 Hz), 1.20-1.68 (8H, m), 1.44 (9H, s), 1.88-1.97 (2H, m), 1.98-2.07 (2H, m), 2.26-2.32 (2H, m), 2.80-2.88 (2H, m) ), 3.40-3.50 (1H, m), 4.38-4.45 (1H, m).

(Example 1b) 1-pentylpiperidin-4-amine A mixture of tert-butyl N- (1-pentylpiperidin-4-yl) carbamate (86.43 g, 319.6 mmol) obtained in Example 1a and methanol (300 mL). The mixture was cooled in an ice bath, to which 5N hydrochloric acid (300 mL, 1500 mmol) was added. The reaction solution was stirred at room temperature for 15 hours and 45 minutes. Further, 5N hydrochloric acid (130 mL, 650 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed twice with tert-butyl methyl ether (500 mL). The aqueous layer was basified with 5N aqueous sodium hydroxide solution (495 mL) to pH 12-13, and the resulting solution was extracted three times with ethyl acetate (500 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to obtain the title compound (42.08 g, yield: 77%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 8 Hz), 1.20-1.54 (10H, m), 1.76-1.85 (2H M), 1.91-2.00 (2H, m), 2.26-2.32 (2H, m), 2.60-2.69 (1H, m), 2.84-2.90. (2H, m).

(Example 1c) 1-benzyl 3-ethyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarbosichelate Similar to the method described in WO2008 / 090944 A1 By the method, the title compound (25.7 g, yield: 92.4%) was obtained from 1-benzyl 3-ethylpiperidine-1,3-dicarboxylate (20 g, 68.6 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.10-1.30 (3H, m), 1.30-1.50 (9H, m), 1.55-1.76 (3H, m) 1.90-2.05 (1H, m), 2.42-2.76 (2H, m), 3.25-3.38 (1H, m), 3.45-3.80 (3H, m), 4.07-4.20 (2H, m), 5.02-5.20 (2H, m), 7.27-7.40 (5H, m).
(Analysis conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 90/10 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) When the obtained title compound was analyzed under the above analysis conditions, a peak with a retention time of 6.24 minutes and a peak of 8.12 minutes were observed.

Example 1d (3RS) -1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-3-carboxylic acid 1-benzyl 3 obtained in Example 1c 5N water for a solution of ethyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarboxylate (100.7 g, 248.3 mmol) in ethanol (700 mL) An aqueous alkali solution prepared from an aqueous sodium oxide solution (400 mL, 2000 mmol) and water (600 mL) was added, and the mixture was stirred at room temperature for 118 hours 30 minutes. The reaction mixture was extracted 3 times with tert-butyl methyl ether, and the extracted layers were combined and concentrated. Water and ethyl acetate (1 L) were added to the residue, and 2N hydrochloric acid (250 mL) was further added under ice cooling. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate (1 L). First, the aqueous layer produced upon extraction with tert-butyl methyl ether was acidified with 5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were combined and dried over magnesium sulfate, and the desiccant was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (62 g, yield: 66.1%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.32-1.43 (9H, m), 1.60-1.78 (3H, m), 1.92-2.03 (1H M), 2.53 (1H, d, J = 16 Hz), 2.63 (1H, d, J = 16 Hz), 3.20-3.30 (1H, m), 3.63-3.78 (3H, m), 5.02-5.20 (2H, m), 7.27-7.40 (5H, m).

Example 1e Benzyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidine-1-carboxylate Example 1d (3RS) -1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-3-carboxylic acid (10.0 g, 26.5 mmol) obtained in Example To a mixture of 1-pentylpiperidin-4-amine, triethylamine (11 mL, 78.9 mmol) and dimethylformamide (100 mL) obtained in 1b, benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (hereinafter, (Referred to as PyBOP) (20.7 g, 39.8 mmol) Stir at room temperature for 13 hours. Ethyl acetate (200 mL) and water (300 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate (300 mL). The organic layers were combined, washed with a saturated aqueous ammonium chloride solution (300 mL), dried over magnesium sulfate, the desiccant was filtered, and concentrated under reduced pressure to obtain a crude product of the title compound (24 g). The same reaction and operation as above were repeated, and (3RS) -1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-3-carboxylic acid (52.1 g, The crude product of the title compound (121 g) was obtained separately from 26.5 mmol). The resulting crude product of the title compound was combined and purified three times by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (77.8 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 8 Hz), 1.20-1.60 (13H, m), 1.42 (9H, s), 1.84-1.93 (1H, m), 1.95-2.08 (2H, m), 2.20-2.30 (4H, m), 2.64 (1H, d, J = 16 Hz) ), 2.70-2.85 (2H, m), 2.86-3.08 (1H, m), 3.68-3.78 (1H, m), 3.85-4.06 (1H) M), 4.40-4.62 (1H, m), 5.16 (2H, s), 6.70-6.95 (1H, m), 7.30-7.40 (5H, m). ).

Example 1f tert-Butyl 2-{(3RS) -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetate benzyl (3RS) -3- obtained in Example 1e [2- (tert-Butoxy) -2-oxoethyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidine-1-carboxylate (71.8 g, 135.6 mmol) and methanol (350 mL) To the mixture, 10% Pd / C (7.2 g) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. 10% Pd / C was removed by filtration, and the solvent was distilled off to obtain the title compound (54.7 g, yield: quantitative).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 8 Hz), 1.20-1.74 (11H, m), 1.41 (9H, s), 1.85-2.05 (5H, m), 2.15-2.22 (2H, m), 2.30-2.38 (2H, m), 2.50-2.60 (2H, m) ), 2.80-2.95 (3H, m), 3.00-3.05 (1H, m), 3.60-3.65 (1H, m), 3.80-3.93 (1H) , M), 9.10-9.15 (1H, m).

Example 1g tert-butyl 2-{(3RS) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetate Tert-butyl 2-{(3RS) -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetate (54.7 g, 138.4 mmol) obtained in Example 1f was ice-cooled. Under mixing with potassium carbonate (38.2 g, 276.7 mmol) in dimethylformamide (200 mL). To the mixture was added 2,6-dichlorobenzyl bromide (34.9 g, 145.3 mmol). The ice bath was removed and the mixture was stirred at room temperature for 4 hours. Ethyl acetate (600 mL) and water (600 mL) were added to the reaction mixture under ice cooling, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted with ethyl acetate (600 mL). The organic layers were combined, washed with a saturated aqueous ammonium chloride solution (600 mL), dried over magnesium sulfate, the desiccant was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (63.7 g, yield: 83%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.90 (3H, t, J = 8 Hz), 1.10-1.20 (2H, m), 1.25-1.40 (4H) , M), 1.33 (9H, s), 1.42-1.55 (5H, m), 1.60-1.70 (1H, m), 1.85-2.02 (5H, m) ), 2.10-2.18 (2H, m), 2.26-2.31 (2H, m), 2.85-2.90 (2H, m), 2.95-3.06 (2H) , M), 3.43-3.48 (1H, m), 3.68-3.78 (1H, m), 3.72 (2H, s), 7.17-7.21 (1H, m ), 7.34 (2H, d, J = 8 Hz), 8.10-8.15 (1H, m).
Analysis conditions (analysis conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 90/10 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) When the obtained title compound was analyzed under the above analysis conditions, a peak having a retention time of 2.70 minutes and a peak of 3.76 minutes were observed.

(Example 1h) Optically active substance of tert-butyl 2- {1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetate Tert-Butyl 2-{(3RS) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} obtained in Example 1g Acetate (31 g) was optically resolved repeatedly under the following conditions, and the peak with a short retention time was collected to obtain the title compound (13.16 g).
(Preparation conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (3 cmφ × 25 cm), eluent: hexane / ethanol = 9/1 (v / v), flow rate: 30 mL / min. Detection: UV (210 nm)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.90 (3H, t, J = 8 Hz), 1.10-1.20 (2H, m), 1.25-1.40 (4H) , M), 1.33 (9H, s), 1.42-1.55 (5H, m), 1.60-1.70 (1H, m), 1.85-2.02 (5H, m) ), 2.10-2.18 (2H, m), 2.26-2.31 (2H, m), 2.85-2.90 (2H, m), 2.95-3.06 (2H) , M), 3.43-3.48 (1H, m), 3.68-3.78 (1H, m), 3.72 (2H, s), 7.17-7.21 (1H, m ), 7.34 (2H, d, J = 8 Hz), 8.10-8.15 (1H, m).
Analysis by HPLC;
(Analysis conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 90/10 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) The purified optically active substance was analyzed under the above analysis conditions. As a result, the retention time was 2.71 minutes and the enantiomeric excess was> 99% ee.

(Example 1i) Optically active substance of 2- {1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetic acid Example 1h Tert-butyl 2- {1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetate optically active substance (13 .16 g, 23.7 mmol) and dichloromethane (22.5 mL) were added with trifluoroacetic acid (90 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours 30 minutes. The reaction mixture was concentrated azeotropically with dichloromethane, and the resulting residue was purified twice by column chromatography (ODS silica gel, elution solvent: water / methanol), and the title compound was prepared in lot A (4.71 g), lot B. (5.83 g). The NMR data of lot A is described below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.90 (3H, t, 8 Hz), 1.25-1.40 (4H, m), 1.41-1.74 (7H, m ), 1.80-1.90 (1H, m), 1.95-2.50 (8H, m), 2.60-2.70 (2H, m), 2.90-3.15 (4H) M), 3.65-3.80 (3H, m), 7.19-7.23 (1H, m), 7.37 (2H, d, J = 4 Hz), 9.00-9.07. (1H, m).
¹ H-NMR of lot B: Consistent with ¹ H-NMR of lot A.

Example 2 2- (1-[(2-Chloro-6-methylphenyl) methyl] -3-{[(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} Piperidin-3-yl) acetic acid optically active substance

Example 2a 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine By a method similar to that described in Examples 1a and 1b, tert-butyl N- (piperidin-4-yl) was obtained. ) The title compound (57.0 g) was obtained from carbamate (65 g, 325 mmol) and 1-cyclohexene-1-carboxaldehyde (42.9 g, 389 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.30-1.50 (4H, m), 1.51-1.70 (4H, m), 1.75-2.08 (8H M), 2.59-2.68 (1H, m), 2.72-2.88 (4H, m), 5.55 (1H, s).

(Example 2b) 1-benzyl 3-ethyl 3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarbochelate optically active substance The same method as described in Example 1c 1-benzyl 3-ethyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarboxylate (5 g) obtained in 1 above was repeatedly optically resolved under the following conditions: The title compound (1.59 g) was obtained by fractionating a peak having a long retention time.
(Preparation conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries) (2 cmφ × 25 cm), eluent: hexane / ethanol = 9/1 (v / v), flow rate: 20 mL / min. Detection: UV (210 nm)
Analysis by HPLC;
(Analysis conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 90/10 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) The purified optically active substance was analyzed under the above analysis conditions. As a result, the retention time was 7.9 minutes and the enantiomeric excess was> 99% ee.

(Example 2c) 1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy)]-2-oxoethyl] piperidine-3-carboxylic acid optically active substance 1-benzyl obtained in Example 2b 3-ethyl 3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarbosichelate optically active substance (1.59 g, 3.92 mmol) was dissolved in ethanol (12 mL) and iced. Under cooling, 2N aqueous sodium hydroxide solution (16 mL, 32 mmol) was added, and the mixture was stirred at room temperature for 92 hours 30 minutes. To the reaction mixture was added 2N hydrochloric acid (16 mL) and concentrated. The obtained mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the desiccant was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (1.11 g, yield: 75%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.32-1.43 (9H, m), 1.60-1.78 (3H, m), 1.92-2.03 (1H M), 2.53 (1H, d, J = 16 Hz), 2.63 (1H, d, J = 16 Hz), 3.20-3.30 (1H, m), 3.63-3.78 (3H, m), 5.02-5.20 (2H, m), 7.27-7.40 (5H, m).

Example 2d benzyl 3- [2- (tert-butoxy) -2-oxoethyl] -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} piperidine- Optically active form of 1-carboxylate Optically active form of 1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy)]-2-oxoethyl] piperidine-3-carboxylic acid obtained in Example 2c (40 mg, 0.106 mmol), 1- (cyclohex-1-en-1-ylmethyl) piperidin-4-amine (33 mg, 0.17 mmol), triethylamine (0.045 mL, 0.323 mmol) obtained in Example 2a ), Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (51 mg, 0.2 mmol), and tetra A mixture of hydrofuran (1.5 mL) was stirred at room temperature for 19 hours 50 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the desiccant was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (49 mg, yield: 83.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.22-1.71 (10H, m), 1.41 (9H, s), 1.80-2.05 (8H, m), 2.08-2.40 (2H, m), 2.58-2.80 (5H, m), 2.85-3.15 (1H, m), 3.66-3.76 (1H, m ), 3.85-4.10 (1H, m), 4.40-4.65 (1H, m), 5.13 (1H, d, J = 12.2 Hz), 5.18 (1H, d) , J = 12.2 Hz), 5.53 (1 H, s), 6.70-6.92 (1 H, m), 7.28-7.40 (5 H, m).

Example 2e tert-butyl 2- {1-[(2-chloro-6-methylphenyl) methyl] -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl ] Carbamoyl] piperidin-3-yl} acetate optically active benzyl 3- [2- (tert-butoxy) -2-oxoethyl] -3-{[1- (cyclohex-1-ene] obtained in Example 2d -1-ylmethyl) piperidin-4-yl] carbamoyl} piperidine-1-carboxylate optically active substance (49 mg, 0.089 mmol) was mixed with 10% Pd / C (6.5 mg) in methanol under a hydrogen atmosphere. For 2 hours 30 minutes at room temperature. 10% Pd / C was removed by filtration, and the solvent was distilled off. The residue was mixed with 2-chloro-6-methylbenzaldehyde (55 mg, 0.36 mmol), acetic acid (0.020 mL), and sodium triacetoxyborohydride (75 mg, 0.35 mmol) in tetrahydrofuran and mixed at 50 ° C. with 4 Stir for 30 minutes. The mixture was further stirred at room temperature for 15 hours. Water and aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (7 mg, yield: 14.2%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.21-1.39 (3H, m), 1.31 (9H, s), 1.42-1.70 (4H, m), 1.81 -2.28 (14H, m), 2.44 (3H, s), 2.78-2.88 (4H, m), 2.92-3.06 (2H, m), 3.37 (1H , D, J = 11.6 Hz), 3.57 (1H, d, J = 12.8 Hz), 3.61 (1H, d, J = 12.8 Hz), 3.68-3.78 (1H, m), 5.58 (1H, s), 7.08-7.17 (2H, m), 7.23-7.27 (1H, m), 7.90-8.01 (1H, m) .

Example 2f 2- (1-[(2-chloro-6-methylphenyl) methyl] -3-{[(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} Optically active form of piperidin-3-yl) acetic acid In a similar manner as described in Example 1i, tert-butyl 2- {1-[(2-chloro-6-methylphenyl) methyl obtained in Example 2e ] From the optically active substance (7 mg, 0.013 mmol) of 3-{[1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl] piperidin-3-yl} acetate, the title compound (4.5 mg, yield: 71.7%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.21-1.35 (2H, m), 1.39-1.70 (5H, m), 1.72-2.10 (10H M), 2.15-2.33 (3H, m), 2.43 (3H, s), 2.70-2.90 (6H, m), 2.96-3.10 (2H, m ), 3.55-3.75 (3H, m), 5.57 (1H, s), 7.08-7.19 (2H, m), 7.23-7.29 (1H, m), 8.90-9.05 (1H, m).

Example 3 2-[(3S, 4R) -3-{[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -1-[(2,6-dichloro -3-Fluorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetic acid

Example 3a (2,6-Dichloro-3-fluorophenyl) methanol 10M borane-dimethylsulfide with respect to a solution of 2,6-dichloro-3-fluorobenzoic acid (1 g, 4.78 mmol) in tetrahydrofuran (10 mL) Complex (0.718 mL, 7.18 mmol) was added at room temperature. The mixture was stirred for 10 hours under heating to reflux. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N aqueous sodium hydroxide solution, water, and saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to give the title compound (873 mg, yield: 93.6%). )
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.08-2.15 (1H, m), 4.97 (2H, d, J = 7 Hz), 7.09 (1H, dd, J = 8,9 Hz), 7.32 (1H, dd, J = 5, 9 Hz).

Example 3b (4-Methoxyphenyl) methyl (2E) -but-2-enoate Crotonic acid (17.2 g, 200 mmol) was cooled to N, N-dimethylformamide (100 mL) in an ice bath under nitrogen. Dissolve and add powdered potassium carbonate (15.2 g, 110 mmol). The mixture was stirred for 30 minutes before 4-methoxybenzyl chloride (29.8 g, 190 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature for 4 hours and at 45 ° C. for 14 hours. Ethyl acetate (500 mL) and water (200 mL) were added to the reaction solution. The separated organic layer was washed with water (100 mL × 2) and saturated brine (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, the desiccant was filtered, and then concentrated under reduced pressure to obtain a crude product of the title compound (40.51 g, yield: 98.2%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.87 (3H, dd, J = 2, 7 Hz), 3.81 (3H, s), 5.10 (2H, s), 5.87 (1H , Dq, J = 2, 16 Hz), 6.86-6.92 (2H, m), 7.00 (1H, dq, J = 7, 16 Hz), 7.28-7.34 (2H, m) .

(Example 3c) (4-Methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate (4-Methoxyphenyl) methyl (2E) -but-- obtained in Example 3b 2-Enoate (40.6 g, 197 mmol) was dissolved in dichloromethane (250 mL) under nitrogen and the mixture was cooled in an ice / water bath with stirring. Trifluoroacetic acid (0.758 mL, 9.84 mmol) was added, and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (51.4 g, 216 mmol) was added dropwise while washing with dichloromethane (5 mL). The reaction was allowed to reach room temperature and stirred for 14 hours. The reaction solution was concentrated and purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane). The fraction containing the desired compound was concentrated to obtain the title compound (57.86 g, yield: 86.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.12 (3H, d, J = 7 Hz), 2.17-2.24 (1H, m), 2.46-2.62 (2H , M), 2.73-2.86 (2H, m), 2.87-2.93 (1H, m), 3.55 (1H, d, J = 13 Hz), 3.63 (1H, d , J = 13 Hz), 3.81 (3H, s), 5.03-5.10 (2H, m), 6.86-6.92 (2H, m), 7.21-7.35 (7H , M).

Example 3d (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate Example 3c (4-Methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate (56.7 g, 166 mmol) obtained in 1 above was equipped with two 200 mL dropping funnels and a thermometer. It was poured into a 3 L 4-neck flask that had been dried in an oven in advance while washing with tetrahydrofuran (dehydrated) (total 800 mL). The solution was cooled to −74.5 ° C. with stirring under a nitrogen atmosphere. 1.11M Lithium diisopropylamide / tetrahydrofuran solution (172 mL, 191 mmol) was transferred to the dropping funnel with a cannula and added dropwise to the reaction solution at such a rate that the internal temperature did not exceed −73 ° C. The dripping took 65 minutes. The mixture was stirred at −75 ° C. for 30 minutes, and then tetrahydrofuran (30 mL) and tert-butyl bromoacetate (30.4 mL, 208 mmol) were transferred to the dropping funnel. The reaction solution was then added dropwise. The dripping took 40 minutes. The mixture was stirred at −75 ° C. for an additional 15 minutes, and then an aqueous ammonium chloride solution (800 mL) was added. Immediately thereafter, ethyl acetate (2 L) was added. The separated organic layer was washed with saturated brine (200 mL), dried over magnesium sulfate, the desiccant was filtered and concentrated under reduced pressure. The residue was immediately purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane). The fraction containing the desired compound was concentrated to obtain the title compound (60.3 g, yield: 80.1%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.83 (3H, d, J = 7 Hz), 1.35 (9H, s), 2.05-2.14 (2H, m), 2.51 (1H, d, J = 17Hz), 2.90-2.98 (2H, m), 3.60 (1H, d, J = 13Hz), 3.70 (1H, d, J = 13Hz) ), 3.81 (3H, s), 5.04 (1H, d, J = 12 Hz), 5.07 (1H, d, J = 12 Hz), 6.85-6.91 (2H, m), 7.19-7.34 (7H, m).

(Example 3e) (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (4-methoxyphenyl) methyl (Example 3d) 3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (20 g, 44.1 mmol) was dissolved in methanol (316 mL), 10% Pd / C (3.93 g) was added and replaced with hydrogen gas. After the mixture was stirred at room temperature overnight, warm water (36 ° C., 160 mL) was added and stirred for 30 minutes to dissolve the precipitated solid. After filtering Pd / C, the solution was concentrated so that 20-40 mL of water remained, and methanol (80 mL) was added to the cloudy residue containing water, followed by stirring for 30 minutes. The precipitated solid was filtered (Lot A). The ¹ H-NMR of lot A is shown below.
(4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (21 g, 46.3 mmol) Used to obtain (Lot B) in a similar manner. ^{After 1} H-NMR of the lot B was confirmed to be identical to ¹ H-NMR of the lot A, dried the combined lot A and lot B, to give the title compound (9.91 g).
¹ H-NMR (400 MHz, D ₂ O) δ (ppm): 0.97 (3H, d, J = 6 Hz), 1.42 (9H, s), 2.12-2.24 (1H, m) 2.29 (1 H, d, J = 17 Hz), 2.93 (1 H, d, J = 17 Hz), 3.04 (1 H, t, J = 12 Hz), 3.18 (1 H, d, J = 12 Hz), 3.49 (1H, dd, J = 8, 12 Hz), 4.03 (1H, d, J = 12 Hz).

Example 3f (3RS, 4SR) -1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid In Example 3e The obtained (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (9.84 g, 40.5 mmol), acetone (39 mL) and water ( (49 mL), 2N aqueous sodium hydroxide solution (20.2 mL) was added under ice-cooling and stirring (0-1 ° C.), and the mixture was stirred for 45 minutes to obtain a reaction mixture. To the reaction mixture, benzyl chloroformate (6.35 mL, 44.5 mmol) and 2N aqueous sodium hydroxide solution (22.3 mL) were simultaneously added with ice-cooling and stirring (0-1 ° C.) at an internal temperature of 3.5 ° C. or less. It was added dropwise over 20 minutes. The reaction solution was stirred in an ice bath and gradually returned to room temperature. The mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH 12 by adding 1N aqueous sodium hydroxide solution (10 mL) under ice-cooling and stirring (internal temperature around 15 ° C.). The reaction solution was returned to room temperature and washed three times by adding ethyl ether. The aqueous layer was adjusted to pH 2-3 by sequentially adding ice-cold stirring (internal temperature of 5 ° C. or lower), 2N hydrochloric acid (20.2 mL), and 1N hydrochloric acid (13 mL). The aqueous layer was returned to room temperature and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed 4 times with water and then with saturated brine. The organic layer was dried over sodium sulfate, the desiccant was filtered and then concentrated under reduced pressure to obtain the title compound (14.53 g, yield: 95.1%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.02 (3H, t, J = 8 Hz), 1.42 (9H, s), 2.14-2.22 (1H, m), 2.27 (1H, d, J = 17 Hz), 3.04 (1 H, d, J = 5, 17 Hz), 3.12-3.19 (1 H, m), 3.35 (1 H, dd, J = 7,12 Hz), 3.65-3.72 (1H, m), 4.29 (1H, dd, J = 7,12 Hz), 5.09-5.19 (2H, m), 7.26. -7.38 (5H, m).

Example 3g 1,3-dibenzyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 3f (3RS, 4SR) -1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (14.5 g, 38.5 mmol) Benzyl bromide (4.48 mL, 37.7 mmol) was added to a mixture of potassium carbonate (10.6 g, 77 mmol) and N, N-dimethylformamide (50 mL) under ice-cooling and stirring (internal temperature: 3-7 ° C.). The mixture was stirred for 1 hour, returned to room temperature, and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous ammonium chloride solution (5 times), water (2 times), and saturated brine, dried over sodium sulfate, filtered with a drying agent, and concentrated under reduced pressure to give the title compound ( 17.67 g, yield: 98.2%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.84-0.89 (3H, m), 1.36-1.39 (9H, m), 2.09-2.18 (1H M), 2.24 (1H, dd, J = 3, 17 Hz), 3.04-3.13 (2H, m), 3.35 (1H, dd, J = 8, 12 Hz), 3.59 -3.68 (1H, m), 4.32 (1H, t, J = 12 Hz), 5.06-5.20 (4H, m), 7.29-7.36 (10H, m).
Analysis by HPLC;
(Analysis conditions 1) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 95/5 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) When the obtained title compound was analyzed under the above analysis condition 1, a peak with a retention time of 8.56 minutes and a peak of 10.85 minutes were observed.
(Analysis condition 2) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 95/5 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) When the obtained title compound was analyzed under the above analysis condition 2, a peak having a retention time of 6.78 minutes and a peak of 8.20 minutes were observed.

Example 3h (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 1,3-dibenzyl (3RS, obtained in Example 3g) 4SR) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate (9.1 g) is optically repeated under the following two preparative conditions A or B: Divided.
Optical resolution by HPLC;
(Preparation condition A) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries) (2 cmφ × 25 cm), eluent: hexane / ethanol = 85/15 (v / v), flow rate: 8-10 mL / min.
(Preparation condition B) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (3 cmφ × 25 cm), eluent: hexane / ethanol = 95/5 (v / v), flow rate: 22 mL / min.
After separating a peak having a short retention time, the obtained 3 lots were analyzed under the following analysis conditions.
Analysis by HPLC;
(Analysis conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 95/5 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) Retention time was 9.0 minutes to 9.3 minutes, and the enantiomeric excess was> 99% ee in all lots.
Three lots were collected, and the obtained optically active substance (4.04 g) was dissolved in methanol (121 mL), 10% Pd / C (0.77 g) was added, and the gas was replaced with hydrogen gas. After the mixture was stirred at room temperature for 13 hours, warm water (30-40 ° C., 122 mL) was added and stirred to dissolve the precipitated solid. After filtering Pd / C, the solvent was concentrated and dried to obtain the title compound (2.1 g).
¹ H-NMR (400 MHz, D ₂ O) δ (ppm): 0.97 (3H, d, J = 7 Hz), 1.42 (9H, s), 2.15 to 2.22 (1H, m) , 2.30 (1H, d, J = 17 Hz), 2.93 (1H, d, J = 17 Hz), 3.04 (1H, t, J = 12 Hz), 3.18 (1H, d, J = 12 Hz), 3.49 (1H, dd, J = 8, 12 Hz), 4.03 (1H, d, J = 12 Hz).

Example 3i tert-Butyl 2-[(3S, 4R) -3-{[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -1-[(2, 6-Dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetate (2,6-Dichloro-3-fluorophenyl) methanol obtained in Example 3a (150 mg, 0.77 mmol) in dichloromethane (5 mL), triphenylphosphine (303 mg, 1.16 mmol), and carbon tetrabromide (383 mg, 1.16 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was passed through a silica gel pad, and the eluate was concentrated to give 2- (bromomethyl) -1,3-dichloro-4-fluorobenzene (250 mg). Separately, the (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (150 mg, 0.617 mmol) obtained in Example 3h 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine (180 mg, 0.926 mmol), dimethylformamide (2.86 mL), triethylamine (0.259 mL, 1.86 mmol) obtained in 2a, And PyBOP (643 g, 1.23 mmol) were added and stirred at 45 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the desiccant was filtered and concentrated under reduced pressure. To this was added 2- (bromomethyl) -1,3-dichloro-4-fluorobenzene (250 mg) obtained above, potassium carbonate (128 mg, 0.926 mmol), and N, N-dimethylformamide (3 mL). And stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified twice by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane and silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (83 mg, yield: 22.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.91 (3H, d, J = 7 Hz), 1.32-1.44 (2H, m), 1.41 (9H, s), 1.54-1.72 (4H, m), 1.82-2.12 (10H, m), 2.56-2.76 (6H, m), 2.92 (1H, t, J = 10 Hz) ), 3.12 (1H, d, J = 16 Hz), 3.60-3.72 (2H, m), 3.97 (2H, s), 5.53 (1H, s), 7.08 ( 1H, t, J = 9 Hz), 7.32 (1H, dd, J = 5, 9 Hz), 8.00 (1H, d, J = 8 Hz).

Example 3j 2-[(3S, 4R) -3-{[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -1-[(2,6-dichloro -3-Fluorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetic acid In a manner similar to that described in Example 1i, tert-butyl 2-[(3S, 4R)- 3-{[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidine- The title compound (35 mg, yield: 46.6%) was obtained from 3-yl] acetate (83 mg, 0.139 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.97 (3H, d, J = 6 Hz), 1.40-1.71 (7H, m), 1.80-1.89 (1H , M), 1.95-2.12 (6H, m), 2.5-2.40 (1H, m), 2.42-2.68 (3H, m), 2.72-3.07 (6H, m), 3.32-3.42 (1H, m), 3.68-3.78 (1H, m), 3.94 (1H, d, J = 13 Hz), 3.98 (1H , D, J = 13 Hz), 5.58 (1H, s), 7.10 (1H, t, J = 8 Hz), 7.34 (1H, dd, J = 5, 8 Hz), 8.52-8 .62 (1H, m).

Example 4 2-[(3S ^* , 4S ^* )-1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-ene- 1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid As in the IUPAC nomenclature, the absolute configuration is unknown, but if the relative configuration is known, * Used to indicate. In this example, 2-[(3S, 4S) -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-ene-1 -Ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid, or 2-[(3R, 4R) -1-{[2-chloro-6- (trifluoromethyl) phenyl] Methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid.

Example 4a 2- (Bromomethyl) -1-chloro-3- (trifluoromethyl) benzene [2-Chloro-6- (trifluoromethyl) phenyl] methanol (150 g, 713 mmol) in tetrahydrofuran (1.5 L) The solution was stirred under ice cooling, and triethylamine (199 mL, 1.43 mol) was added thereto. Further, methanesulfonyl chloride (82.8 mL, 1.07 mol) was added dropwise over 1 hour and 10 minutes in a nitrogen stream. After 10 minutes, water (1.5 L) and ethyl acetate (1.5 L) were added, and the aqueous layer was removed. The organic layer was dried over magnesium sulfate and the desiccant was filtered. To the resulting mixture, lithium bromide (186 g, 2.15 mol) was added in small portions with stirring under ice cooling. After 20 minutes, the mixture was returned to room temperature and further stirred for 2 hours and 45 minutes. Water (1.5 L) was added and washed. The organic layer was washed with saturated brine (1.5 L), dried over magnesium sulfate, the desiccant was filtered and concentrated under reduced pressure to give the title compound (181.1 g, yield: 92.9%). Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.73 (2H, s), 7.39 (1H, t, J = 8 Hz), 7.62 (2H, t, 8 Hz).

Example 4b 1-benzyl 4-tert-butyl 2- (dimethoxyphosphoryl) butanedioate To a solution of sodium hydride (5.41 g, 135 mmol) in tetrahydrofuran (200 mL) under ice-cooling, benzyl 2- (dimethoxyphosphoryl) Acetate (27 g, 104 mmol) was added and stirred at room temperature for 6 hours. Tert-butyl bromoacetate (20.4 g, 104 mmol) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (18.8 g, yield: 48.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.40 (9H, s), 2.71-2.79 (1H, m), 2.97-3.06 (1H, m), 3.46-3.55 (1H, m), 3.70-3.74 (6H, m), 5.16 (1H, d, J = 12 Hz), 5.28 (1H, d, J = 12 Hz) ), 7.31-7.41 (5H, m).

(Example 4c) 1-benzyl 4-tert-butyl 2-ethylidenebutanedioate 1-benzyl 4-tert-butyl 2- (dimethoxyphosphoryl) butanedioate (3.4 g, 9.15 mmol) obtained in Example 4b Tetrohydrofuran (34 mL) was added to the solution, and potassium tert-butoxide (1.13 g, 10.1 mmol) was added under ice cooling, followed by stirring for 15 minutes. Acetaldehyde (1.03 mL, 18.4 mmol) was then added dropwise. After returning to room temperature and stirring for 30 minutes, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, the desiccant was filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (2.03 g, geometric isomer mixture, yield: 76.4%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.37 (2.7 H, s), 1.40 (6.3 H, s), 1.83 (2.1 H, d, J = 7 Hz) ), 2.09 (0.9 H, td, J = 0.8, 7 Hz), 3.19-3.20 (0.6 H, m), 3.29-3.30 (1.4 H, m) , 5.19 (2H, s), 6.14-6.20 (0.3H, m), 7.06-7.12 (0.7H, m), 7.28-7.39 (5H, m).

Example 4d Benzyl (3RS, 4RS) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate 1-Benzyl obtained in Example 4c 4-tert-butyl 2-ethylidenebutanedioate (2,03 g, 6.99 mmol) versus N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (2.49 g, 10.5 mmol), dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (1.51 g, yield: 50.9%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.98 (3H, d, J = 7 Hz), 1.36 (9 H, s), 2.18 (1 H, t, J = 9 Hz), 2.44 (1H, d, J = 10 Hz), 2.50-2.60 (2H, m), 2.82-2.94 (2H, m), 3.46 (1H, d, J = 10 Hz) ), 3.59 (1H, d, J = 14 Hz), 3.64 (1H, d, J = 14 Hz), 5.15 (2H, s), 7.19-7.36 (10H, m).

Example 4e (3RS, 4RS) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid benzyl (3RS, 4RS) -1 obtained in Example 4d -Benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (1 g, 2.36 mmol) in methanol (20 mL) and 20% palladium hydroxide (300 mg) And stirred overnight at room temperature under a hydrogen atmosphere. The reaction vessel was purged with nitrogen, water was added, and the mixture was stirred for 5 minutes. 20% Palladium hydroxide was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (530 mg, yield: 92.3%).
¹ H-NMR (400 MHz, D ₂ O) δ (ppm): 0.89 (3H, d, J = 7 Hz), 1.29 (9 H, s), 2.28 (1 H, d, J = 17 Hz) , 2.34-2.43 (1H, m), 2.71 (1H, d, J = 17 Hz), 2.84 (1H, dd, J = 8, 12 Hz), 3.24 (1H, d, J = 12 Hz), 3.42 (1H, dd, J = 8, 12 Hz), 3.82 (1H, d, J = 12 Hz).

Example 4f tert-butyl 2-[(3RS, 4RS) -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-ene -1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetate (3RS, 4RS) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 4e ] -4-methylpyrrolidine-3-carboxylic acid (280 mg, 1.15 mmol) was added to 1- (cyclohex-1-en-1-ylmethyl) piperidin-4-amine (290 mg, 1.5 mmol) obtained in Example 2a. 49 mmol), dimethylformamide (3 mL), triethylamine (0.48 mL, 3.44 mmol), and PyBOP (1.02 g, 1.95 mmol). And the mixture was stirred for 2 hours at 50 ° C.. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Thereto 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene (409 mg, 1.5 mmol), potassium carbonate (238 mg, 1.73 mmol) obtained in Example 4a, and N, N-dimethyl Formamide (1 mL) was added and stirred at 50 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The desiccant was filtered and concentrated under reduced pressure. The residue was purified twice by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane and silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (302 mg, yield: 42.9%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.93 (3H, d, J = 7 Hz), 1.24 to 1.42 (2H, m), 1.40 (9H, s), 1.54-1.72 (5H, m), 1.76-1.82 (1H, m), 1.85-1.94 (2H, m), 1.95-2.12 (6H, m) ), 2.22-2.35 (2H, m), 2.68-2.78 (4H, m), 3.02 (1H, d, J = 8 Hz), 3.17 (1H, t, J = 8 Hz), 3.57-3.68 (2 H, m), 3.84 (1 H, d, J = 13 Hz), 3.89 (1 H, d, J = 13 Hz), 5.54 (1 H, s) ), 7.02 (1H, d, J = 8 Hz), 7.37 (1H, dt, J = 0.4, 8 Hz), 7.61-7.65 (2H, m).
(Analysis conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 95/5 (v / v), flow rate: 1 mL / min. Detection: UV (210 nm)
(Analysis result) When the obtained title compound was analyzed under the above analysis conditions, a peak with a retention time of 4.34 minutes and a peak of 6.82 minutes were observed.

Example 4g tert-butyl 2-[(3S ^* , 4S ^* )-1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1 -En-1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetate tert-Butyl obtained in Example 4f 2-[(3RS, 4RS) -1-{[2- Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] Acetate (302 mg) was optically resolved repeatedly under the following preparative conditions, and a peak with a short retention time was collected to obtain the title compound (132 mg).
(Preparation conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (2 cmφ × 25 cm), eluent: hexane / ethanol, flow rate: 15 mL / min. Detection: UV (210 nm)
Analysis by HPLC;
(Analysis conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), eluent: hexane / ethanol = 95/5 (v / v), flow rate: 1 mL / min. , Detection: UV (210 nm)
(Analysis result) The purified optically active substance was analyzed under the above analysis conditions. As a result, the retention time was 4.35 minutes and the enantiomeric excess was> 99% ee.

Example 4h 2-[(3S ^* , 4S ^* )-1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-ene- 1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid In a manner similar to that described in Example 1i, tert-butyl 2-[(3S ^* , 4S ^* )-1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] The title compound (80 mg, yield: 66.6%) was obtained from carbamoyl} -4-methylpyrrolidin-3-yl] acetate (132 mg, 0.216 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.00 (3H, d, J = 7 Hz), 1.30-1.41 (2H, m), 1.44-1.70 (6H) M), 1.75-1.82 (1H, m), 1.90-2.07 (5H, m), 2.10 (1H, t, J = 9 Hz), 2.33-2.50. (3H, m), 2.75-2.96 (5H, m), 3.20-3.32 (2H, m), 3.60-3.70 (1H, m), 3.90 (2H , S), 5.58 (1H, s), 7.38 (1H, t, J = 8 Hz), 7.62-7.74 (3H, m).

Example 5 2-[(3S, 4R) -1-{[2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl} -3-{[1- (cyclohex-1 -En-1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid

(Example 5a) (2-Bromo-6-chlorophenyl) methanol From 2-bromo-6-chlorobenzoic acid (4 g, 17 mmol) in the same manner as described in Example 3a, the title compound (3.3 g) was obtained. Yield: 87.6%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.11 (1H, t, J = 6.9 Hz), 4.99 (2H, d, J = 6.9 Hz), 7.12 (1H , T, J = 8.1 Hz), 7.37 (1H, dd, J = 1, 8.1 Hz), 7.51 (1H, dd, J = 1, 8.1 Hz).

Example 5b [2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methanol 1 of (2-bromo-6-chlorophenyl) methanol (2.2 g, 10 mmol) obtained in Example 5a , 2-dimethoxyethane (44 mL) and water (15.5 mL) were mixed with 2-methoxypyridine-4-boronic acid (1.68 g, 10.8 mmol), sodium carbonate (1.6 g, 14.8 mmol). And 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) (363 mg, 0.498 mmol) were added at room temperature. The mixture was heated and stirred at an external temperature of 100 degrees for 4.5 hours. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane and silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (1.6 g, yield: 64.1%). It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.12 (1H, t, J = 6.3 Hz), 3.99 (3H, s), 4.65 (2H, d, J = 6) .3 Hz), 6.83 (1 H, s), 6.98 (1 H, dd, J = 1.6, 5.2 Hz), 7.21 (1 H, dd, J = 1.2, 7.8 Hz) , 7.33 (1H, t, J = 7.8 Hz), 7.47 (1H, dd, J = 1.2, 7.8 Hz), 8.2-8.24 (1H, m).

Example 5c 4- [3-Chloro-2- (chloromethyl) phenyl] -2-methoxypyridine [2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] obtained in Example 5b To a solution of methanol (0.5 g, 1.99 mmol) in dichloromethane (dehydrated) (10 mL) was added thionyl chloride (0.73 mL, 10 mmol) under ice cooling, and then stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to give the title compound (0.49 g, yield: 91.8%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.00 (3H, s), 4.58 (2H, s), 6.81-6.84 (1H, m), 6.98 ( 1H, dd, J = 1.6, 5.6 Hz), 7.17 (1H, dd, J = 1.1, 7.9 Hz), 7.34 (1H, t, J = 7.9 Hz), 7 .49 (1H, dd, J = 1.1, 7.9 Hz), 8.23-8.26 (1H, m).

Example 5d tert-butyl 2-[(3S, 4R) -1-{[2-chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl} -3-{[1- (cyclohex Su-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetate obtained in Example 3h by a method similar to that described in Example 4f (3S , 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (105 mg, 0.432 mmol), 1- (cyclohex-1) obtained in Example 2a -En-1-ylmethyl) piperidin-4-amine (126 mg, 0.648 mmol) and 4- [3-chloro-2- (chloromethyl) obtained in a manner similar to that described in Example 5c. ) Phenyl] -2-methoxy pyridine (174 mg, 0.648 mmol), the title compound (157 mg, yield: 55.8%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.81-0.90 (3H, m), 1.32-1.49 (2H, m), 1.39 (9H, s), 1.52-1.72 (4H, m), 1.80-2.06 (11H, m), 2.35-2.49 (2H, m), 2.65-2.79 (4H, m ), 3.06 (1H, d, J = 16.4 Hz), 3.47 (1H, d, J = 9.6 Hz), 3.60-3.80 (3H, m), 3.98 (3H) , S), 5.55 (1H, s), 6.64-6.67 (1H, m), 6.79 (1H, dd, J = 1.4, 5.1 Hz), 7.10 (1H , Dd, J = 1.2, 7.9 Hz), 7.28 (1H, t, J = 7.9 Hz), 7.48 (1H, dd, J = 1.2, 7.9 Hz), 7. 93 (1H, d, J = 8 0Hz), 8.19 (1H, d, J = 5.1Hz).

Example 5e 2-[(3S, 4R) -1-{[2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl} -3-{[1- (cyclohex-1 -En-1-ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid In a manner similar to that described in Example 1i, tert-butyl 2- [(3S, 4R) -1-{[2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) The title compound (100 mg, yield: 69.7%) was obtained from piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetate (157 mg, 0.241 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.91 (3H, d, J = 7.2 Hz), 1.42-1.72 (6H, m), 1.76-1.86 (1H, m), 1.92-2.24 (9H, m), 2.42-2.61 (4H, m), 2.76-2.92 (4H, m), 3.09-3 .18 (1H, m), 3.75-3.82 (3H, m), 4.00 (3H, s), 5.59 (1H, s), 6.64 (1H, s), 6. 77 (1H, d, J = 5.2 Hz), 7.12 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 7.5 Hz), 7.49 (1H, d , J = 7.5 Hz), 8.22 (1H, d, J = 5.2 Hz), 8.64 (1H, d, J = 7.6 Hz).

Example 6 2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-({1-[(2-methylcyclohex- 1-en-1-yl) methyl] piperidin-4-yl} carbamoyl) pyrrolidin-3-yl] acetic acid

Example 6a (2-Methylcyclohex-1-en-1-yl) methanol ethyl 2-oxocyclohexane-1-carboxylate (10 g, 58.75 mmol) in a similar manner to that described in WO02068384 A2. The title compound (1.49 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.26 (1H, t, J = 8.0 Hz), 1.50-1.65 (4H, m), 1.70 (3H, s ), 1.90-1.98 (2H, m), 2.06-2.15 (2H, m), 4.06-4.15 (2H, m).

Example 6b 2-Methylcyclohex-1-ene-1-carbaldehyde (2-Methylcyclohex-1-en-1-yl) methanol (1.49 g, 11.81 mmol) obtained in Example 6a , Triethylamine (8.23 mL, 59.04 mmol), dimethyl sulfoxide (3.69 mL, 51.95 mmol) in dichloromethane (60 mL), sulfatrioxide pyridine complex (8.27 g, 51.95 mmol) at 0 ° C. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure until the solvent amount was reduced to about half. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (8.59 g, content: 9.55%, yield: 55.9%) containing heptane.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.55-1.68 (4H, m), 2.13 (3H, s), 2.15-2.25 (4H, m), 10.15 (1H, s).

Example 6c tert-Butyl N- {1-[(2-methylcyclohex-1-en-1-yl) methyl] piperidin-4-yl} carbamate By a method similar to that described in Example 1a 2-methylcyclohex-1-ene-1-carbaldehyde (8.59 g, content: 9.55%, 6.60 mmol) and heptane obtained in Example 6b and tert-butyl N- (piperidine- The title compound (1.63 g, yield: 80%) was obtained from 4-yl) carbamate (1.59 g, 7.92 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.20-2.05 (17H, m), 1.44 (9H, s), 2.65-2.77 (2H, m), 2.86 (2H, s), 3.34-3.50 (1H, m), 4.33-4.50 (1H, m).

Example 6d 1-[(2-Methylcyclohex-1-en-1-yl) methyl] piperidin-4-amine tert-butyl N- {1-[(2-methylcyclohexyl) obtained in Example 6c 5N hydrochloric acid (10 mL, 50 mmol) was added to ethanol (10 mL) of (S-1-en-1-yl) methyl] piperidin-4-yl} carbamate (1.63 g, 5.28 mmol) and stirred at room temperature for 17 hours. did. The reaction mixture was ice-cooled, 5N aqueous sodium hydroxide solution (10 mL, 50 mmol) was added, and the solvent was evaporated. Ethanol was added to the residue and insolubles were filtered off. The filtrate was concentrated to obtain the title compound (1.03 g, yield: 94.0%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.12 (2H, brs), 1.32-1.39 (2H, m), 1.54-1.60 (4H, m), 1.64 (3H, s), 1.72-1.80 (2H, m), 1.85-2.05 (6H, m), 2.57-2.68 (1H, m), 2. 71-2.79 (2H, m), 2.87 (2H, s).

Example 6e 2,6-Dichloro-3-fluorobenzaldehyde (2,6-Dichloro-3-fluorophenyl) methanol (1.93 g, 9.90 mmol) obtained in the same manner as described in Example 3a ) In dimethyl sulfoxide (30 mL) was added triethylamine (11.0 mL, 78.9 mmol) and sulfatrioxide pyridine complex (7.88 g, 49.48 mmol) under water cooling, and the mixture was stirred for 110 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous ammonium chloride solution, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (0.984 g, yield: 51.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.26-7.34 (1H, m), 7.37-7.40 (1H, m), 10.45 (1H, s).

Example 6f (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidine- 3-Carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (200 mg, 0.822 mmol) obtained in Example 3h, acetic acid To a mixture of (0.047 mL, 0.822 mmol) and methanol (4 mL) was added 2,6-dichloro-3-fluorobenzaldehyde (159 mg, 0.820 mmol) obtained in Example 6e and sodium triacetoxyborohydride (180 mg, 0.85 mmol) was added, and the mixture was stirred at an external temperature of 45 ° C. for 2.5 hours. Further, 2,6-dichloro-3-fluorobenzaldehyde (158 mg, 0.820 mmol) and sodium triacetoxyborohydride (180 mg, 0.85 mmol) were added, and the mixture was stirred at an external temperature of 45 ° C. for 4.5 hours. Further, 2,6-dichloro-3-fluorobenzaldehyde (158 mg, 0.820 mmol) and sodium triacetoxyborohydride (180 mg, 0.85 mmol) were added, and the mixture was stirred at an external temperature of 45 ° C. for 19 hours and 50 minutes. Water was added to the reaction mixture, and the mixture was extracted 4 times with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (NAM silica gel, elution solvent: heptane / ethyl acetate / methanol) to obtain the title compound (180 mg, yield: 52.1%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.01 (3H, d, J = 4 Hz), 1.42 (9H, s), 2.05-2.11 (1H, m), 2.15-2.26 (1H, m), 2.65-2.69 (2H, m), 2.96-3.05 (2H, m), 3.72 (1H, d, J = 12 Hz) ), 4.07-4.15 (2H, m), 7.13 (1H, t, J = 8 Hz), 7.35 (1H, dd, J = 4, 8 Hz).

Example 6g tert-butyl 2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-({1-[(2-methyl Cyclohex-1-en-1-yl) methyl] piperidin-4-yl} carbamoyl) pyrrolidin-3-yl] acetate obtained in Example 6f by a method similar to that described in Example 1e (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (60 mg, 0 From the 1-[(2-methylcyclohex-1-en-1-yl) methyl] piperidin-4-amine (38.7 mg, 0.186 mmol) obtained in Example 6d. Objects (63 mg, yield: 72%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.80-0.93 (3H, m), 1.26-2.10 (19H, m), 1.41 (9H, s), 2.55-2.74 (4H, m), 2.84 (2H, s), 2.91 (1H, t, J = 12 Hz), 3.12 (1H, d, J = 16 Hz), 3. 55-3.70 (2H, m), 3.97 (2H, s), 7.08 (1H, t, J = 8 Hz), 7.32 (1H, dd, J = 4, 8 Hz), 7. 97 (1H, d, J = 8 Hz).

Example 6h 2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-({1-[(2-methylcyclohex- 1-en-1-yl) methyl] piperidin-4-yl} carbamoyl) pyrrolidin-3-yl] acetic acid In a manner similar to that described in Example 1i, the tert-butyl 2- [ (3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-({1-[(2-methylcyclohex-1-en-1-yl) The title compound (47 mg, yield: 82.5%) was obtained from (methyl) piperidin-4-yl} carbamoyl) pyrrolidin-3-yl] acetate (63 mg, 0.103 mmol).
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.89 (3H, d, J = 8 Hz), 1.20-1.35 (2H, m), 1.57-1.68 ( 5H, m), 1.72 (3H, s), 1.85-2.25 (8H, m), 2.50-2.68 (4H, m), 2.99-3.15 (4H, m), 3.26-3.37 (1H, m), 3.61 (1H, d, J = 12 Hz), 3.70-3.80 (1H, m), 3.99-4.06 ( 2H, m), 7.25 (1H, t, J = 10 Hz), 7.46 (1H, dd, J = 8, 8 Hz).

Example 7 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl } Pyrrolidin-3-yl] acetic acid

Example 7a tert-Butyl N- [1- (3-phenylpropyl) piperidin-4-yl] carbamate By a method similar to that described in Example 1a, tert-butyl N- (piperidin-4-yl) ) The title compound (2.1 g, yield: 66.0%) was obtained from carbamate (2 g, 9.99 mmol) and 3-phenylpropanal (1.47 g, 10.99 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.38-1.49 (2H, m), 1.44 (9H, s), 1.77-1.85 (2H, m), 1.87-1.95 (2H, m), 1.97-2.08 (2H, m), 2.31-2.36 (2H, m), 2.62 (2H, t, J = 8 Hz) ), 2.74-2.89 (2H, m), 3.35-3.50 (1H, m), 4.33-4.45 (1H, m), 7.16-7.32 (5H) , M).

Example 7b 1- (3-Phenylpropyl) piperidin-4-amine By a method similar to that described in Example 6d, tert-butyl N- [1- (3-phenylpropyl) obtained in Example 7a was used. ) Piperidin-4-yl] carbamate (2.1 g, 6.594 mmol) gave the title compound (1.5 g, yield: quantitative).
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.35 to 1.43 (2H, m), 1.75 to 1.88 (4H, m), 1.98 to 2.04 ( 2H, m), 2.34-2.40 (2H, m), 2.57-2.65 (3H, m), 2.87-2.92 (2H, m), 7.04-7. 27 (5H, m).

Example 7c (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid obtained in Example 3h by a method similar to that described in Example 6f ( The title compound (10.27 g, yield: 89%) was obtained from 7 g, 28.77 mmol) and 2,6-dichlorobenzaldehyde (12.59 g, 71.93 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.01 (3H, d, J = 8 Hz), 1.42 (9H, s), 2.05-2.24 (2H, m), 2.64-2.69 (2H, m), 2.96-3.04 (2H, m), 3.71 (1H, d, J = 12 Hz), 4.07-4.15 (2H, m ), 7.13 (1H, dd, J = 8, 8 Hz), 7.35 (2H, d, J = 8 Hz).

Example 7d tert-butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3-{[1- (3-phenylpropyl) piperidine-4- Yl] carbamoyl} pyrrolidin-3-yl] acetate (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl obtained in Example 7c by a method similar to that described in Example 1e ] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (70 mg, 0.174 mmol) and 1- (3-phenylpropyl) piperidine-4 obtained in Example 7b -The title compound (94 mg, yield: 90%) was obtained from the amine (45.6 mg, 0.209 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.86-0.91 (3H, m), 1.23-2.10 (10H, m), 1.40 (9H, s), 2.29-2.33 (2H, m), 2.57-2.64 (4H, m), 2.74-2.83 (2H, m), 2.92 (1H, t, J = 10 Hz ), 3.12 (1H, d, J = 16 Hz), 3.55-3.70 (2H, m), 3.95 (2H, s), 7.13-7.37 (8H, m), 8.12 (1H, d, J = 8 Hz).

Example 7e 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl } Pyrrolidin-3-yl] acetic acid In a manner similar to that described in Example 1i, tert-butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl obtained in Example 7d ] -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetate (94 mg, 0.157 mmol) from the title compound (47.5 mg, yield) Rate: 56.0%).
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.80-0.91 (3H, m), 1.54-1.65 (2H, m), 1.75-1.95 ( 4H, m), 2.11-2.25 (2H, m), 2.40-2.69 (8H, m), 2.99-3.10 (4H, m), 3.62 (1H, d, J = 12 Hz), 3.70-3.80 (1H, m), 3.98-4.05 (2H, m), 7.16-7.30 (6H, m), 7.41 ( 2H, d, J = 8 Hz).

Example 8 2-[(3S, 4R) -1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -4-methyl-3-{[1- (3-phenylpropyl) Piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetic acid

Example 8a (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -4-methyl Pyrrolidine-3-carboxylic acid (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methyl obtained in Example 3h by a method similar to that described in Example 6f From the pyrrolidine-3-carboxylic acid (0.2 g, 0.822 mmol) and 2-chloro-6- (trifluoromethyl) benzaldehyde (0.857 g, 4.11 mmol), the title compound (0.252 g, yield: 70 .3%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.03 (3H, d, J = 8 Hz), 1.40 (9H, s), 2.05-2.24 (2H, m), 2.60 (1H, d, J = 12 Hz), 2.74-2.78 (1 H, m), 2.94-3.03 (2 H, m), 3.62 (1 H, d, J = 12 Hz) ), 4.08 (2H, q, J = 12 Hz), 7.42 (1H, t, J = 8 Hz), 7.64-7.67 (2H, m).

Example 8b 2-[(3S, 4R) -1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -4-methyl-3-{[1- (3-phenylpropyl) Piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetic acid (3S, 4R) -3- [2- (tert-butoxy) obtained in Example 8a by a method similar to that described in Example 1e -2-Oxoethyl] -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -4-methylpyrrolidine-3-carboxylic acid (50 mg, 0.115 mmol) and 1 obtained in Example 7b From-(3-phenylpropyl) piperidin-4-amine (30.1 mg, 0.138 mmol), tert-butyl 2-[(3S, 4R) -1-{[2-chloro-6- (trifluoro (Chyl) phenyl] methyl} -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetate (73 mg, yield: quantitative) was obtained. . In a manner similar to that described in Example 1i, the above tert-butyl 2-[(3S, 4R) -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -4-methyl The title compound (40 mg, yield: 60.1%) was obtained from -3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetate (73 mg).
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 0.89 (3H, d, J = 8 Hz), 1.25-1.35 (1H, m), 1.54-1.85 ( 3H, m), 1.87-1.97 (3H, m), 2.12-2.25 (2H, m), 2.40-2.70 (7H, m), 2.95-3. 15 (4H, m), 3.54 (1H, d, J = 8 Hz), 3.65-3.80 (1H, m), 3.93-4.06 (2H, m), 7.16- 7.30 (5H, m), 7.45-7.52 (1H, m), 7.69-7.77 (2H, m).

Example 9 2- [1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidine-4 -Il] carbamoyl} pyrrolidin-3-yl] acetic acid optically active substance

Example 9a 1-Benzyl 3-ethyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance 1-benzyl 3-ethyl (3RS) -pyrrolidine A solution of 1,3-dicarboxylate (16 g, 57.7 mmol) in tetrahydrofuran (dehydrated) (250 mL) was cooled with dry ice-acetone and 1.14 M lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (55.7 mL, 63 0.5 mmol) was added dropwise at -78 ° C. After 1 hour, tert-butyl bromoacetate (12.6 g, 70.7 mmol) was added dropwise over 40 minutes. Stirring was continued at −78 ° C. for 3 hours, and then the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the desiccant was filtered and concentrated. The residue was purified twice by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane and silica gel, elution solvent: ethyl acetate / heptane), and the racemate of the title compound (15.6 g, yield: 69.1%). )
Optical resolution by HPLC;
(Analysis conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (0.46 cmφ × 15 cm), 40 ° C., eluent: hexane / ethanol = 9/1 (v / v), flow rate: 1 mL / min. , Detection: UV (210 nm)
(Analysis result) When the racemate of the obtained title compound was analyzed under the above analysis conditions, a peak with a retention time of 4.06 minutes and a peak of 6.74 minutes were observed.
The racemate of the title compound (5 g, 12.8 mmol) obtained above was optically resolved repeatedly under the following preparative conditions, and the isomer with a short retention time was collected to give the title compound (2.04 g, yield). Rate: 40.8%).
(Preparation conditions) Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries) (2 cmφ × 25 cm), eluent: hexane / ethanol = 91/9 (v / v), flow rate: 15 mL / min. , Detection: UV (220 nm)
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.24 (3H, t, J = 7 Hz), 1.42 (9H, s), 1.84-1.92 (1H, m), 2.30-2.44 (1H, m), 2.57-2.76 (2H, m), 3.34-3.38 (1H, m), 3.48-3.55 (2H, m ), 3.97 (1H, d, J = 11.2 Hz), 4.17 (2H, q, 7 Hz), 5.14 (2H, s), 7.28-7.38 (5H, m).
(Analysis result) When the obtained title compound was analyzed under the above analysis conditions, the retention time was 4.02 minutes and the enantiomeric excess was> 99% ee.

Example 9b 1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-3-carboxylic acid optically active substance 1-benzyl 3 obtained in Example 9a -Ethyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance (4.2 g, 10.7 mmol), tetrahydrofuran (5 mL), methanol (20 mL), A mixture of 2N aqueous sodium hydroxide (10 mL) was stirred at room temperature for 3 hours. The mixture was concentrated, 2N hydrochloric acid (10 mL) and ethanol were added and concentrated. Ethanol was added to the residue and filtered, and the filtrate was concentrated. Ethanol / ethyl acetate (1/1) was added to the residue and filtered, and the filtrate was concentrated to obtain the title compound (3.8 g, yield: 97.7%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.42 (9H, s), 1.91 (1H, dt, J = 16, 7 Hz), 2.34-2.47 (1H, m ), 2.60-2.80 (2H, m), 3.38 (1H, dd, J = 17, 6 Hz), 3.50-3.60 (2H, m), 4.02 (1H, dd) , J = 3, 11 Hz), 5.10-5.18 (2H, m), 7.30-7.39 (5H, m).

(Example 9c) 1-benzyl 3-methyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance 1-[(benzyl) obtained in Example 9b Oxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-3-carboxylic acid optically active substance (1 g, 2.75 mmol), tetrahydrofuran (5 mL) and methanol (10 mL) in a mixture. Trimethylsilyldiazomethane (4.13 mL, 8.25 mmol) was added at room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (835 mg, yield: 80.4%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.42 (9H, s), 1.84-1.93 (1H, m), 2.39-2.45 (1H, m), 2.67 (1H, dd, J = 52, 16 Hz), 2.68 (1H, s), 3.37 (1H, dd, J = 12, 3 Hz), 3.48-3.55 (2H, m ), 3.72 (3H, s), 3.96 (1H, d, J = 12 Hz), 5.12 (1H, d, J = 12 Hz), 5.15 (1H, d, J = 12 Hz), 7.28-7.38 (5H, m).

Example 9d Optically Active Methyl 3- [2- (tert-Butoxy) -2-oxoethyl] pyrrolidine-3-carboxylate 1-Benzyl 3-methyl 3- [2- (tert -Butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance (834 mg) and methanol (20 mL) were added with 10% Pd / C (200 mg) and stirred at room temperature for 4 hours under hydrogen atmosphere. did. The reaction solution was filtered, and the filtrate was concentrated to obtain the title compound (544 mg, yield: quantitative).
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.42 (9H, s), 1.69-1.77 (1H, m), 2.21-2.28 (1H, m) , 2.64-2.75 (3H, m), 2.88-3.01 (2H, m), 3.31-3.34 (1H, m), 3.69 (3H, s).

Example 9e Optical activity of methyl 3- [2- (tert-butoxy) -2-oxoethyl] -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} pyrrolidine-3-carboxylate The optically active form (545 mg, 2.24 mmol) of methyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-3-carboxylate obtained in Example 9d and N, N-dimethylformamide (4 mL) Was stirred at room temperature, potassium carbonate (619 mg, 4.48 mmol), 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene (796 mg, 2.91 mmol) and N, N-dimethylformamide ( 3 mL) of the mixture was added. The mixture was stirred for 11 hours and 20 minutes. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over sodium sulfate. After filtering the desiccant, the filtrate was concentrated under reduced pressure and purified by NH silica gel column chromatography to obtain the title compound (897 mg, yield: 91.9%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.39 (9H, s), 1.64-1.72 (1H, m), 2.34-2.40 (1H, m), 2.56-2.81 (5H, m), 2.92 (1H, d, J = 9 Hz), 3.69 (3H, s), 3.88 (2H, s), 7.30 (1H, t = 8 Hz), 7.57 (2H, d, J = 8 Hz).

Example 9f Optically active substance of 3- [2- (tert-butoxy) -2-oxoethyl] -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} pyrrolidine-3-carboxylic acid Optical of methyl 3- [2- (tert-butoxy) -2-oxoethyl] -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} pyrrolidine-3-carboxylate obtained in Example 9e 2N aqueous sodium hydroxide solution (2.05 mL, 4.11 mmol) was added to a mixture of the active form (897 mg, 2.05 mmol), methanol (6 mL), and tetrahydrofuran (1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was stirred under ice-cooling, 2N hydrochloric acid (2.11 mL) was added, and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (837 mg, yield: 96.8%).
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.38 (9H, s), 1.84-1.93 (1H, m), 2.20-2.28 (1H, m) , 2.53 (1H, d, J = 16 Hz), 2.80 (1H, d, J = 16 Hz), 2.93 (1H, d, J = 10 Hz), 3.10-3.19 (2H, m), 3.45 (1H, d, J = 10 Hz), 4.31 (1H, d, J = 14 Hz), 4.36 (1H, d, J = 14 Hz), 7.57 (1H, t, J = 8 Hz), 7.77 (1H, d, J = 8 Hz), 7.81 (1H, d, J = 8 Hz).

Example 9g tert-butyl 2- [1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) Optically active form of piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetate 3- [2- (tert-butoxy) -2 obtained in Example 9f by a method similar to that described in Example 1e -Oxoethyl] -1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} pyrrolidine-3-carboxylic acid optically active substance (59 mg, 0.14 mmol) and 1- (obtained in Example 2a) The title compound (74 mg, yield: 88%) was obtained from cyclohex-1-en-1-ylmethyl) piperidin-4-amine (32.6 mg, 0.168 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.17-1.69 (7H, m), 1.42 (9H, s), 1.72-2.08 (9H, m), 2.27 (1 H, d, J = 16 Hz), 2.34 (1 H, d, J = 1 Hz), 2.39-2.50 (1 H, m), 2.62-2.78 (4 H, m ), 2.93 (1H, d, J = 16 Hz), 3.00-3.08 (1H, m), 3.40 (1H, d, J = 10 Hz), 3.57-3.69 (1H , M), 3.85-3.94 (2H, m), 5.55 (1H, brs), 7.15 (1H, d, J = 8 Hz), 7.37 (1H, d, J = 8 Hz) ), 7.63 (1H, d, J = 8 Hz), 7.64 (1H, d, J = 8 Hz).

Example 9h 2- [1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidine-4 -Il] carbamoyl} pyrrolidin-3-yl] acetic acid optically active substance tert-butyl 2- [1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-] obtained in Example 9g {[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetate optically active substance (70 mg, 0.117 mmol) in toluene (2 mL, 18. 776 mmol) solution was stirred at room temperature and trifluoroacetic acid (2 mL, 25.96 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours and concentrated. The residue was purified by column chromatography (ODS silica gel, elution solvent: water / methanol) to obtain the title compound (49 mg, yield: 77%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.20-1.33 (2H, m), 1.40-1.52 (1H, m), 1.57-1.69 (5H) M), 1.72-2.14 (10H, m), 2.36 (1H, d, J = 10 Hz), 2.58-2.83 (6H, m), 3.14 (1H, d) , J = 10 Hz), 3.57-3.69 (1H, m), 3.90 (1H, d, J = 13 Hz), 4.01 (1H, d, J = 13 Hz), 5.56 (1H , Brs), 7.40 (1 H, d, J = 8 Hz), 7.65 (1 H, d, J = 8 Hz), 7.66 (1 H, d, J = 8 Hz), 7.93 (1 H, d , J = 8 Hz).

(Reference Example 1) (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid

(Reference Example 1a) (4-Methoxyphenyl) methyl (3R, 4R) -1-benzyl-4-methylpyrrolidine-3-carboxylate (-)-Dibenzoyl-L-tartrate The method described in Example 3c (4-Methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate (1000 mg, 2.946 mmol) obtained in a similar manner was dissolved in methyl isobutyl ketone (4 mL), (−)-Dibenzoyl-L-tartaric acid (1055 mg) was added and dissolved. To the obtained solution, (4-methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate and (−)-dibenzoyl-L obtained in the same manner as in Example 3c were added. -Crystals obtained from tartaric acid were added as seed crystals, and the resulting precipitate was filtered to obtain the title compound (757 mg, yield: 36.8%). Ethanol (3.02 mL) was added to 755 mg of the obtained solid, and after dissolution with heating, tert-butyl methyl ether (6.04 mL) was further added. The resulting precipitate was filtered to obtain the title compound (658 mg, yield: 87.2%) as crystals.
Separately obtained (4-methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate (150.0 g, 441 mmol) in the same manner as described in Example 3c It was dissolved in isobutyl ketone (600 mL), and (−)-dibenzoyl-L-tartaric acid (157.0 g) was added and dissolved under stirring. The title compound obtained by the above method was added as seed crystals (7.5 mg) to the resulting solution, and the mixture was stirred for 18 hours and 18 minutes. The precipitated solid was filtered and washed with methyl isobutyl ketone (150 mL). The obtained solid was dried under reduced pressure at 50 ° C. to obtain the title compound (152.07 g, yield: 49.4%). Ethanol (600 mL) was added to 150.00 g of the obtained solid and heated to 80 ° C. with stirring. After confirming dissolution of the solid, heating was stopped. 59 minutes after stopping the heating, tert-butyl methyl ether (300 mL) was added over 9 minutes, and seed crystals (5 mg) were added after another 6 minutes. After 12 minutes, tert-butyl methyl ether (900 mL) was added over 2 hours and 38 minutes, and the mixture was further stirred for 10 hours and 43 minutes. The precipitated solid was filtered and washed with a mixed solution of ethanol and tert-butyl methyl ether (75 mL + 150 mL). The obtained solid was dried at 50 ° C. under reduced pressure to obtain the title compound (106.40 g, yield: 70.9%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.05 (3H, d, J = 6 Hz), 2.32-2.45 (2H, m), 2.64-2.78 (1H, m), 2.92-3.12 (3H, m), 3.75 (3H, s), 3.80-3.94 (2H, m), 5.04 (2H, dd, J = 12, 16 Hz), 5.77 (2H, s), 6.90-6.96 (2H, m), 7.26-7.38 (7H, m), 7.52-7.58 (4H) M), 7.66-7.72 (2H, m), 7.95-8.05 (2H, m).
Analysis by HPLC;
(Analysis conditions) Column: CHIRALCEL OJ-H (manufactured by Daicel Chemical Industries) (0.46 cmφX25 cm), eluent: hexane / ethanol / diethylamine = 850/150/1 (v / v / v), flow rate: 1 mL / min . Detection: UV (226 nm)
(Analysis result) When the obtained title compound was analyzed under the above analysis conditions, a peak having a retention time of 8.62 minutes (enantiomeric excess: 98.0% ee) and a peak of 10.9 minutes were observed.

(Reference Example 1b) (4-Methoxyphenyl) methyl (3R, 4R) -1-benzyl-4-methylpyrrolidine-3-carboxylate (4-Methoxyphenyl) methyl (3R, 4R)-obtained in Reference Example 1a To 1-benzyl-4-methylpyrrolidine-3-carboxylate (-)-dibenzoyl-L-tartrate (104.0 g), ethyl acetate (900 mL) was added, and 1N aqueous sodium hydroxide solution (600 mL) was added with stirring. It was. The aqueous layer was discarded and the organic layer was washed twice with water (100 mL, 50 mL). The obtained organic layer was concentrated under reduced pressure at 50 ° C. to obtain the title compound (49.8 g, yield: 98.5%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.12 (3H, d, J = 7 Hz), 2.19 (1H, dd, J = 6, 9 Hz), 2.44-2.62 (2H, m), 2.73-2.84 (2H, m), 2.85-2.92 (1H, m), 3.55 (1H, d, J = 13 Hz), 3.63 (1H , D, J = 13 Hz), 3.81 (3H, s), 5.02-5.10 (2H, m), 6.85-6.90 (2H, m), 7.21-7.33 (7H, m).

(Reference Example 1c) (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (4-methoxyphenyl) methyl obtained in Reference Example 1b Tetrahydrofuran (200 mL) was added to 3R, 4R) -1-benzyl-4-methylpyrrolidine-3-carboxylate (29.50 g, 87 mmol), followed by azeotropic dehydration. Further, tetrahydrofuran (200 mL) was added to perform azeotropic dehydration. To this was added tetrahydrofuran (400 mL), cooled in a dry ice-ethanol bath, and 1.11 M lithium diisopropylamide / n-hexane-tetrahydrofuran solution (129 mL, 144 mmol) was added over 27 minutes. After 30 minutes, a solution of tert-butyl bromoacetate (21.20 g, 144 mmol) in tetrahydrofuran (30 mL) was added over 7 minutes. After 39 minutes, 20% aqueous ammonium chloride solution (440 mL) was added, and ethyl acetate (440 mL) was further added for extraction. The obtained organic layer was washed twice with water (60 mL, 60 mL) and concentrated at 30 ° C. under reduced pressure. Methanol (150 mL) and palladium hydroxide (885 mg) were added to the obtained concentrate, and the mixture was stirred under hydrogen pressure (0.35 MPa) for 7 hours and 20 minutes. Water (200 mL) and tetrahydrofuran (100 mL) were added to the reaction solution and filtered, and the catalyst was washed successively with methanol (50 mL) and water (50 mL × 2). The filtrate was concentrated at 50 ° C. under reduced pressure, the obtained aqueous layer was washed with tert-butyl methyl ether (100 mL), and the washed aqueous layer was concentrated at 50 ° C. under reduced pressure. Methanol (150 mL) was added to the resulting residue and treated with ultrasound, followed by filtration. The obtained solid was dried at 50 ° C. under reduced pressure to obtain the title compound (8.16 g, yield: 38.5%).
¹ H-NMR (400 MHz, D ₂ O) δ (ppm): 1.00 (3H, d, J = 7 Hz), 1.45 (9H, s), 2.16-2.28 (1H, m) 2.33 (1 H, d, J = 17 Hz), 2.97 (1 H, d, J = 17 Hz), 3.08 (1 H, t, J = 12 Hz), 3.22 (1 H, d, J = 12 Hz), 3.50-3.58 (1 H, m), 4.07 (1 H, d, J = 12 Hz).

Reference Example 2 (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid Hydrogen phosphate (R)-(−)-1,1 '-Binaphthyl-2,2'-diyl salt Ethanolate (3RS, 4SR) -3- [2- (tert-Butoxy) -2-] obtained in the same manner as in Example 3e in a 50 mL eggplant flask. Oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (500 mg), hydrogen phosphate (R)-(−)-1,1′-binaphthyl-2,2′-diyl (359 mg), ethanol (10.0 mL) And water (10.0 mL) were sequentially added, and the mixture was stirred at room temperature for about 22 hours. The precipitated solid was collected by filtration and washed with a 1: 1 ethanol-water mixture (2 mL). The wet substance was dried under reduced pressure at 40 ° C. for about 1 hour to obtain the title compound (269 mg, yield: 20.5%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.88 (3H, d, J = 7 Hz), 1.06 (3H, t, J = 7 Hz), 1.38 (9H, s ), 2.09-2.16 (1H, m), 2.44 (1H, d, J = 18 Hz), 2.74 (1H, t, J = 12 Hz), 2.87 (1H, d, J = 18 Hz), 3.11 (1H, d, J = 12 Hz), 3.41-3.47 (2H, m), 3.81 (1H, d, J = 12 Hz), 4.36 (1H, t , J = 5 Hz), 7.21 (2H, d, J = 9 Hz), 7.29 (2H, t, J = 8 Hz), 7.38-7.45 (4H, m), 8.02 (4H) , T, J = 8 Hz).
The white solid (8.85 mg) was weighed into a screw glass container. To this was added MilliQ water (0.2 mL) and 99.5% ethanol (0.8 mL). This was then aliquoted into 1.5 mL LCMS vials, loosely capped and left at room temperature. After 9 days, it was observed that crystals were deposited in the vial. Using the obtained single crystal (0.40 × 0.40 × 0.06 mm), an X-ray diffraction experiment was conducted with R-AXIS RAPID II (Rigaku Corporation). Crystallographic data and structural analysis results are shown in Table 1, and atomic coordinate data are shown in Tables 2 to 4. From these results, the absolute structure of the title compound was identified.

Among the compounds of Examples 1 to 9, those for which absolute stereochemistry was specified were named based on the information obtained in Reference Example 2 above.

The chemical formulas of the compounds of Examples 1 to 9 are as follows.

(Test Example 1) Cell migration inhibitory effect in fractalkine-induced cell migration model (1) Method B300 cells in which CX3CR1 was forcibly expressed were used to examine the inhibitory effect of the implemented compounds on fractalkine-induced cell migration.
After Transwell (24 well clusters, pore size: 5 μm, Corning) was equilibrated, a fractalkine solution (0.3 nM, RandD) was added to the lower layer. Subsequently, CX3CR1-expressing B300 cells preincubated with the compound of the example (final concentration: 0.001, 0.003, 0.01, 0.03 μM) for 30 minutes are added to the upper layer of Transwell, 5% CO ₂ , 37 ° C. Incubated at conditions for 3.5 hours. The number of cells that migrated to the lower layer was evaluated using CellTiter (manufactured by Promega).
For the calculation of the inhibition rate of the Example compounds against fractalkine-induced cell migration, the amount of cell migration in the presence of fractalkine / test compound [A], and the amount of cell migration in the presence of fractalkine / no test compound [B], the amount of cell migration in the absence of both fractalkine and the test compound was determined as [C] by the following formula, and the 50% inhibitory concentration (IC ₅₀ ) was calculated based on this.
Inhibition rate (%) = [1-{(AC) / (BC)}] × 100

(2) Results Table 5 shows the results of this test example. The compounds of Examples 1-9 all showed an IC ₅₀ of 15 nM or less.

(Test Example 2) Body weight reduction inhibitory effect in T cell transfer colitis model (1) Method Using a colitis model induced by transferring CD4 positive CD45RB high positive cells collected from Balb / c mice into scid mice, The body weight reduction inhibitory effect of the example compounds was examined. The experiment was carried out over 28 days. On the first day, CD4 positive CD45RB high positive cells (5 × 10 ⁵ cells / mouse) collected from the spleen of Balb / c mice were intravenously administered. From the 14th day to the 28th day, the Example compounds were orally administered once a day, and body weights were measured on the 14th, 17th, 19th, 21st, 23rd, 25th and 28th days.
The body weight reduction inhibitory effect was evaluated by the body weight change rate (BW gain,%) on the 14th, 17, 19, 21, 23, 25, and 28th days. The body weight on the 14th day is [A], the body weight on each body weight measurement day (the 17th, 19, 21, 23, 25, 28th day) is [B], and the body weight changes from the following formula The rate (%) was determined.
Body weight change rate (%) = B / A × 100

(2) Results The results of this test example are shown in FIG.

Claims (7)

1. 2- {1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl} acetic acid,
   2- (1-[(2-Chloro-6-methylphenyl) methyl] -3-{[(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} piperidin-3-yl ) Acetic acid,
   2-[(3S, 4R) -3-{[1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl} -1-[(2,6-dichloro-3-fluorophenyl ) Methyl] -4-methylpyrrolidin-3-yl] acetic acid,
   2-[(3S ^* , 4S ^* )-1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1-ylmethyl) piperidine -4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid,
   2-[(3S, 4R) -1-{[2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl} -3-{[1- (cyclohex-1-en-1- Ylmethyl) piperidin-4-yl] carbamoyl} -4-methylpyrrolidin-3-yl] acetic acid,
   2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-({1-[(2-methylcyclohex-1-ene-1 -Yl) methyl] piperidin-4-yl} carbamoyl) pyrrolidin-3-yl] acetic acid,
   2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl] carbamoyl} pyrrolidine-3- Yl] acetic acid,
   2-[(3S, 4R) -1-{[2-Chloro-6- (trifluoromethyl) phenyl] methyl} -4-methyl-3-{[1- (3-phenylpropyl) piperidin-4-yl ] Carbamoyl} pyrrolidin-3-yl] acetic acid, and 2- [1-{[2-chloro-6- (trifluoromethyl) phenyl] methyl} -3-{[1- (cyclohex-1-ene- 1-ylmethyl) piperidin-4-yl] carbamoyl} pyrrolidin-3-yl] acetic acid or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
3. A therapeutic agent for inflammatory bowel disease comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
4. The therapeutic agent according to claim 3, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
5. An inhibitor of the fractalkine-CX3CR1 pathway comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
6. A fractalkine inhibitor comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
7. A CX3CR1 inhibitor comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.

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