JP2006056830A - 2-arylaminobenzoxazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a VLA (very late antigen)-4 inhibitor which is excellent in water solubility and small intestine membrane permeability, effective by oral administration and highly stable. <P>SOLUTION: The prophylactic and/or therapeutic agent for diseases caused by cell adhesion comprises a compound represented by general formula (I), a salt thereof, or a solvate thereof. In the formula, W<SP>a</SP>is an optionally substituted aryl group or an optionally substituted heteroaryl group; W<SP>b</SP>is a divalent group comprised of an optionally substituted 1,3-benzoxazole ring or an optionally substituted 1,3-benzothiazole ring; R<SP>1</SP>is a hydrogen atom or a lower alkyl group; R<SP>2</SP>is a group of formula (II); Y is a group: -(CH<SB>2</SB>)<SB>n</SB>-O- (wherein n is an integer of 1 or 2); and Z is a cyclohexane ring. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a compound having an excellent VLA-4 inhibitory action, good oral absorption and safety, and further to a medicament containing it.

  The major pathological feature of inflammatory and autoimmune diseases is the accumulation of activated leukocytes in damaged tissues (inflamed tissues). The process of infiltration of leukocytes from the circulatory system into the inflamed site is divided into the following four stages of cascade reactions that interact with each other. That is, (1) splicing and rotation (rolling), (2) activation, (3) firm adhesion, and (4) infiltration (Non-Patent Document 1). Initially, white blood cells lightly connect to the vascular endothelium and rotate on its surface. Subsequently, cell activation mediated by soluble chemotactic stimuli is triggered and it begins to progress to a tighter connection between individual leukocytes and vascular endothelial cells. The tight bond causes sequential adhesion and infiltration of leukocytes through the vascular endothelial cell gap. These stages occur sequentially and each stage is essential for causing leukocyte infiltration. This also means that leukocyte infiltration is regulated at each stage, thus providing many interesting targets for pharmacology.

  Although many receptors are known, receptors involved in leukocyte infiltration are particularly characterized as belonging to the cell adhesion molecule family (Non-patent Document 2). The initial attachment and rotation (rolling) is mediated by an adhesion receptor called selectin. Tight adhesion is mediated by the interaction of leukocyte surface integrins with immunoglobulin superfamily molecules expressed on the surface of vascular endothelium. Both integrin and immunoglobulin type adhesion molecules are also primarily involved in leukocyte infiltration. After infiltration, whether leukocytes pass through the extracellular matrix or stop at the site of inflammation depends on the integrin.

  Integrins are a large family consisting of heterodimers of glycoproteins in which two non-equivalent α and β-subunits are associated (Non-patent Document 3). There are at least 16 different α-subunits (α1-α9, αL, αM, αD, αX, αE, αIIb, αV) and at least 9 different β-subunits (β1-β9). Integrins are divided into subfamilies based on the β-subunit. Leukocytes express many different integrins, including α4β1, α5β1, α6β1, α4β7, αLβ2, αXβ2, and αVβ3.

  α4β1 is also known as very late antigen-4 (VLA-4) or CD49d / CD29 and is expressed on monocytes, lymphocytes, eosinophils and basophils. All of these are key modifiers in various inflammatory disorders (Non-Patent Document 4). α4β1 integrin functions as a receptor for vascular cell adhesion molecule-1 (VCAM-1), and an extracellular protein fibronectin (FN) is known as another similar receptor. (Non-patent document 5). Anti-inflammatory effects and delayed development of disease have been demonstrated in in vivo experiments using monoclonal antibodies that inhibit the binding of integrin α4β1 and VCAM-1 (Non-patent Document 6). In a pulmonary inflammation model using guinea pigs, anti-α4 antibody suppressed both antigen-induced airway hypersensitivity and leukocyte accumulation in the alveolar secretions in the airway (Non-patent Document 7). Anti-α4 or anti-VCAM-1 antibody suppressed eosinophil infiltration into the mouse respiratory tract in an antigen induction model (Non-patent Document 8). In addition, it has been reported that treatment of anti-α4 or anti-VCAM-1 monoclonal antibody has delayed or suppressed the onset of delayed skin hypersensitivity reaction in mice and monkeys.

  Furthermore, graft-versus-host disease after bone marrow transplantation (non-patent document 10) in heart transplant rejection model mice (non-patent document 9) caused by specific immunosuppressive action (non-patent document 9), experiments in rats or mice Inhibition of autoimmune encephalomyelitis (Non-patent Document 11) by anti-α4 antibody or anti-VCAM-1 antibody has been reported.

  Soluble VCAM-Immunoglobulin (Ig) in which two N-terminal human immunoglobulin (Ig) -like regions (domain 1 and domain 2) are fused to the common part of human IgG1 in Rational Drug Design. ) Has also been reported. When this fusion protein was administered in an in vivo model using non-obese diabetic mice, the onset was greatly delayed (Non-patent Document 12).

  As another approach, there is a report of synthesizing a cyclic peptide antagonist using a three-dimensional crystal structure of a VCAM-1 fragment and mimicking the binding loop part of α4 integrin in domain-1 of VCAM-1. CQIDSPC, a synthetic VCAM-1 peptide, inhibited VLA-4 produced by cells expressing VLA-4 from adhering to VCAM-1 (Non-patent Document 13).

  On the other hand, it is considered that the disease is improved by inhibiting the binding of fibronectin to the connecting segment-1 (CS-1) portion, which is the junction region with VCAM-1. Yes. (Non-Patent Document 14). Synthetic CS-1 tripeptide (phenylacetic acid-Leu-Asp-Phe-Asp-Pro-amide) inhibits VLA-4 mediated leukocyte adhesion in vitro and promotes coronary artery disease in rabbit heart transplantation Has been reported to decrease (Non-patent Document 15). The results of these individual studies demonstrate that selective inhibition of adhesion mediated by the binding of integrin α4β1 to VCAM-1 is a solution for the treatment of autoimmune and allergic inflammatory diseases.

On the other hand, many low molecular weight VLA-4 inhibitors have been reported (Non-patent Document 16), but none are used clinically. The reasons include problems of pharmacokinetics such as low oral absorption and low blood retention, and problems of physical properties such as low water solubility.
Patent Documents 1 to 6 are known as VLA-4 inhibitory compounds having an arylaminobenzoxazole partial structure. In these prior arts, compounds exhibiting high in vitro VLA-4 inhibitory activity have been reported, but have problems such as low oral absorption and low blood retention. Further, the representative compound of Patent Document 7 has problems in physical properties such as low water solubility.
Springer, T., Ann. Rev. Physiol., 57: 827 (1995) Carlos and Harlan, Blood, 82: 2068 (1994) Heynes, R., Cell, 69: 11 (1992) Helmer, M. Ann. Rev. Immunol., 8: 365 (1990) Elices, et al., Cell, 60: 577 (1990) Lobb et al., J. Clin., Invest., 94: 1722-28 (1994) Pretolani, et al., J. Exp. Med., 180: 795 (1994) Nakajima et al., J. Exp. Med., 179: 1145 (1994) Isobe et al., J. Immunol., 153: 5810 (1994) Yang et al., Proc. Natl. Acad. Sci. USA, 90; 10494 (1993) Yednock, et al., Nature., 356: 63 (1992) Jakubowski et al., J. Immunol., 155: 938 (1995) Wang et al., Proc. Natl. Acad. Sci. USA, 92; 5714 (1995) EA Wayner, J. Cell. Biol., 116; 489 (1992) Molossi et al., J. Clin. Invest., 95; 2601 (1995) Jefferson W. Tilley and Achyutharao Sidduri, Drugs of the Future, 26 (1), 985-998, (2001) WO 00/05223 WO 00/05224 WO 00/15612 WO 00/49005 WO 00/68213 WO 01/58871 WO 02/053534

  Therefore, a low molecular weight non-peptide selective VLA-4 inhibitor which is effective by oral administration, has high safety, and can be administered for a long time for chronic inflammatory diseases is desired.

  Therefore, the present inventor screened compounds using not only the VLA-4 inhibitory action in vitro but also water solubility, absorbability and the like as an index. As a result, the compound represented by the general formula (I) described below was obtained in vivo. Was found to be useful as a selective VLA-4 inhibitor because of its excellent pharmacological effects, solubility in water, small intestinal membrane permeability, and absorbability by oral administration.

（式中、Ｗ^ａは置換基を有していてもよいアリール基または置換基を有していてもよいヘテロアリール基を示し；
Ｗ^ｂは置換基を有していてもよい１，３−ベンゾオキサゾール環または置換基を有していてもよい１，３−ベンゾチアゾール環からなる２価の基を示し；
Ｒ¹は水素原子または低級アルキル基を示し；
Ｒ²は下記式（II）

（式中、Ｒ³およびＲ⁴はそれぞれ独立して水素原子、水酸基、置換基を有していてもよい低級アルキル基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよい低級アルコキシ基または置換基を有していてもよいシクロアルキルオキシ基を示すか、Ｒ³、Ｒ⁴および窒素原子が一緒になって４から７員環のヘテロ環を形成していてもよく、形成する環上に、ハロゲン原子、置換基を有していてもよい低級アルキル基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよい低級アルコキシ基、置換基を有していてもよいアミノ基、アルキレン基、環状アミノ基から選ばれる１から３個の置換基を有していてもよいことを示す。）
の基を示し；
Ｙは−（ＣＨ₂）_n−Ｏ−の基を示し、ｎは１または２の整数を示し；
Ｚはシクロヘキサン環を示す。）で表される化合物、その塩またはそれらの溶媒和物を提供するものである。 That is, the present invention provides the following general formula (I)

(Wherein W ^a represents an optionally substituted aryl group or an optionally substituted heteroaryl group;
W ^b represents a divalent group consisting of an optionally substituted 1,3-benzoxazole ring or an optionally substituted 1,3-benzothiazole ring;
R ¹ represents a hydrogen atom or a lower alkyl group;
R ² represents the following formula (II)

(In the formula, R ³ and R ⁴ each independently have a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, or a substituent. An optionally substituted lower alkoxy group or an optionally substituted cycloalkyloxy group, or R ³ , R ⁴ and a nitrogen atom together form a 4- to 7-membered heterocyclic ring. And a halogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a lower alkoxy which may have a substituent on the ring to be formed. And 1 to 3 substituents selected from a group, an amino group which may have a substituent, an alkylene group and a cyclic amino group.
The group of
Y represents a group of — (CH ₂ ) _n —O—, and n represents an integer of 1 or 2;
Z represents a cyclohexane ring. ), A salt thereof, or a solvate thereof.

The present invention also provides a medicament containing the compound represented by the above general formula (I), a salt thereof or a solvate thereof.
Moreover, this invention provides use of the compound represented by the said general formula (I), its salt, or those solvates for manufacturing a pharmaceutical.
Furthermore, the present invention provides a method for preventing and / or treating a disease caused by cell culture, which comprises administering a compound represented by the above general formula (I), a salt thereof or a solvate thereof. Is.
Furthermore, the present inventor has also found that an intermediate useful for the production of the compound (I) of the present invention can be efficiently obtained according to the production methods described in Scheme 4B and Scheme 4C.

  The compound of the present invention has an excellent VLA-4 inhibitory action, is excellent in water solubility and small intestinal membrane permeability, and is excellent in oral absorption, and is caused by various cell adhesions involving VLA-4. It is useful as a therapeutic and prophylactic agent for various diseases.

The substituent which the compound represented by the formula (I) of the present invention has will be described.
The alkyl group means a linear or branched saturated hydrocarbon group having 1 to 12 carbon atoms, preferably a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. is there. Specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a heptyl group, and an octyl group.

  The lower alkyl group means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, preferably a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. It is. Specific examples thereof include methyl group, ethyl group, propyl group, isopropyl group, normal butyl group, isobutyl group, tert-butyl group and pentyl group.

  The cycloalkyl group is a cyclic alkyl group having 3 to 10 carbon atoms, preferably a cyclic alkyl group having 3 to 6 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

  The aryl group means an aromatic cyclic hydrocarbon group having 6 to 18 carbon atoms, and preferably an aromatic cyclic hydrocarbon group having 6 to 10 carbon atoms. Specific examples thereof include a phenyl group and a naphthyl group.

  The heteroaryl group means an aromatic heterocyclic group having 5 to 18 atoms constituting the ring and at least one oxygen, nitrogen or sulfur atom constituting the ring, preferably the number of atoms Are groups of 5 to 14 aromatic heterocycles. Examples of the aromatic heterocycle forming the group include pyrrole, imidazole, furan, thiophene, triazole, tetrazole, thiazole, 1,3,3-thiadiazole, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyridazine, Pyrazine, 2H-pyran, 4H-pyran, indole, indazole, benzimidazole, 2,3-benzofuran, benzo [b] thiophene, benzotriazole, benzothiazole, benzoxazole, 1,2-benzisoxazole, 1,2 Benzisothiazole, quinoline, isoquinoline, 1-benzopyran-4 (4H) -one, quinazoline, pyrido [1,2-a] pyrimidine, thiazolo [4,5-b] pyridine, thiazolo [4,5-c] Pyridine, dibenzo Run, dibenzothiophene, carbazole, xanthene, such as xanthone, and the like.

  A heterocycle is an aliphatic group having 4 to 18 atoms constituting the ring, wherein at least one nitrogen atom is a ring atom, and oxygen, nitrogen, and sulfur atoms may be ring atoms. Or an aromatic ring, preferably an aliphatic or aromatic heterocycle having 4 to 14 atoms. The same thing as the above is mentioned as an aromatic heterocyclic ring. Aliphatic heterocycles include, for example, pyrrolidine, pyrroline, imidazolidine, imidazoline, thiazolidine, thiazoline, oxazoline, oxazolidine, isoxazolidine, isoxazoline, piperidine, morpholine, thiamorpholine, piperazine, tetrahydrobenzimidazole, tetrahydrobenzothiazole, tetrahydrobenzo Examples include oxazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroquinazoline and the like.

  A halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  The lower alkoxy group is a linear or branched alkoxy group having 1 to 8 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a normal butoxy group, an isobutyloxy group, a third group. Examples include butoxy, pentyloxy and hexyloxy groups.

The cycloalkyloxy group is a cyclic alkyloxy group having 3 to 10 carbon atoms, and a cyclic alkyl group having 3 to 6 carbon atoms is preferable. Specific examples include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
The cyclic amino group is a cyclic amino group having 3 to 10 atoms, preferably 4 to 7 atoms, constituting the ring. Specifically, for example, 1-azetidinyl group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, 1-piperazinyl group, 4-thiamorpholinyl group, 2-isoxazolidinyl group, [1 , 2] oxazinan-2-yl group, [1,2] oxazepan-2-yl group, 1-homopiperidinyl group, 1-homopiperazinyl group and the like.

  Examples of the alkylene group include a linear or branched alkylene group having 2 to 6 carbon atoms, and an ethylene group, a trimethylene group, and a tetramethylene group are preferable.

W phenyl group as the aryl group represented by ^a, a naphthyl group are preferable, and phenyl group are preferred. As the heteroaryl group, an imidazolyl group, a pyridyl group, a pyrimidyl group, and the like are preferable, and a pyridyl group is particularly preferable.

The aryl group or a substituent on the heteroaryl group represented by W ^a, lower alkyl group, one to three selected from a lower alkoxy group and a halogen atom. Of these substituents, 1 to 3 groups selected from a methyl group, a methoxy group, and a halogen atom are particularly preferable.

Of the 1,3-benzoxazole ring and 1,3-benzothiazole ring represented by W ^b , a 1,3-benzoxazole ring is more preferable. The 1,3-benzoxazole ring or the 1,3-benzothiazole ring is preferably bonded to W ^a —NH— at the 2-position and bonded to —CH ₂ CO— at the 6-position.

Examples of the substituent on the 1,3-benzothiazole ring and 1,3-benzoxazole ring represented by W ^b include 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group and a halogen atom. Of these substituents, one or two selected from a methyl group, a methoxy group and a halogen atom are preferred.

The lower alkyl group represented by R ¹ is preferably a C _1-8 alkyl group. R ¹ is preferably a hydrogen atom.

Examples of the lower alkyl group which may have a substituent represented by R ³ or R ⁴ or the cycloalkyl group which may have a substituent include a C _1-8 alkyl group and a C _3-6 cycloalkyl group. It is done. More preferably, a methyl group, an ethyl group, an isopropyl group, an n-propyl group, a cyclopropyl group, a cyclobutyl group, etc. are mentioned. Preferred groups that can be substituted with a lower alkyl group or a cycloalkyl group include a hydroxyl group, a lower alkoxy group, a halogen atom, and the like.

The lower alkoxy group which may have a substituent represented by R ³ or R ⁴ or the cycloalkyloxy group which may have a substituent includes a C _1-8 alkoxy group or a C _3-6 cycloalkyloxy group Is mentioned. More preferably, a methoxy group, an ethoxy group, an n-propyloxy group, etc. are mentioned. Preferred groups that can be substituted with a lower alkoxy group or a cycloalkyloxy group include a hydroxyl group, a lower alkoxy group, a halogen atom, and the like.

The 4- to 7-membered heterocyclic ring formed by R ³ and R ⁴ together with the nitrogen atom is preferably an aliphatic heterocyclic ring (saturated heterocyclic ring), such as an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group. , Piperazinyl group, thiamorpholinyl group, homopiperidinyl group, homopiperazinyl group, isoxazolidinyl group, [1,2] oxadinanyl group, [1,2] oxazepanyl group and the like. Of these, azetidinyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, piperazinyl group, thiamorpholinyl group, and homopiperidinyl group are more preferable.

Among the substituents on the heterocycle, the lower alkyl group which may have a substituent includes a halogen atom, a C _1-8 alkoxy group, an amino group, a mono C _1-8 alkylamino group, a di C _{1- Examples} thereof include C _1-8 alkyl groups which may be substituted by ₈ alkylamino groups, N—C _3-6 cycloalkyl-N—C _1-8 alkylamino groups, and the like. Specifically, methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, fluoromethyl, fluoroethyl, aminomethyl, dimethylaminomethyl, N-cyclo And a propyl-N-aminomethyl group.

Examples of the cycloalkyl group that may have a substituent on the heterocycle include a C _3-6 cycloalkyl group, and specific examples include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group. Examples of the lower alkoxy group that may have a substituent on the heterocycle include a C _1-8 alkoxy group, and specific examples include a methoxy group, an ethoxy group, and an isopropyloxy group. Examples of the cycloalkyl group which may have a substituent on the heterocycle include a C _3-6 cycloalkyl group such as a cyclopropyloxy group, a cyclobutyloxy group, and a cyclopentyloxy group.

As the amino group which may have a substituent on the heterocyclic ring, one or two selected from a hydroxy group, a C _1-8 alkoxy group, a C _1-8 alkyl group, and a C _3-6 cycloalkyl group are substituted. The amino group which may be mentioned is mentioned. Specifically, methylamino group, dimethylamino group, cyclopropylamino group, N-cyclopropyl-N-methylamino group, di (cyclopropyl) amino group, N-methoxy-N-methylamino group, N-hydroxy -N-methylamino group etc. are mentioned.

  Examples of the cyclic amino group on the heterocycle include an abitidinyl group and a pyrrolidinyl group.

The alkylene group in the heterocyclic ring, include C ₂ -C ₄ alkylene group, more particularly an ethylene, trimethylene, if tetramethylene etc. combine to form a spiro ring on one carbon atom on the heterocyclic ring Is mentioned.

  One to three of these substituents on the heterocycle may be present.

Y is —CH ₂ O— or —CH ₂ CH ₂ O—, and —CH ₂ O— is particularly preferred.

Examples of the group (W ^a —NH—W ^b —CH ₂ —C (O) — in the formula (I) include the following groups.
[7-fluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [7-fluoro-2- (5-fluoro-2-methylphenylamino) -1, 3-benzoxazol-6-yl] acetyl group, [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [7-fluoro- 2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-pyridinylamino) -7-fluoro-1,3-benzoxazole-6- Yl] acetyl group, [7-fluoro-2- (2-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (3-fluoro-4 Methoxyphenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methoxyphenylamino) -7-fluoro-1,3-benzoxazole-6 -Yl] acetyl group, [7-fluoro-2- (2,5-dimethylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methyl)- 7-fluorophenylamino] -1,3-benzoxazol-6-yl] acetyl group, [7-fluoro-2- (2,5-difluorophenylamino) -1,3-benzoxazol-6-yl] acetyl Group, [2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (3,4-dichlorophenyl) Nylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (3,4-dichlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl group, [ 2- (4-Chlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (4-chlorophenylamino) -1,3-benzoxazol-6-yl] Acetyl group, [4,7-difluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, (2-phenylamino-1,3-benzoxazol-6-yl) ) Acetyl group, [2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl group, (7-fluoro-2-phenylamido) No-1,3-benzoxazol-6-yl) acetyl group, [2- (4-fluorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (4 -Fluorophenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [ 2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [4-fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] Acetyl group, [4-chloro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro 2-methoxyphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl group, [4-fluoro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazole -6-yl] acetyl group, [2- (4-chloro-2-methoxyphenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (5-fluoro-2 -Methoxyphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methoxyphenylamino) -4-methoxy-1,3-benzoxazole- 6-yl] acetyl group, [7-chloro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, 7-chloro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methylphenylamino) -4-fluoro-1,3 -Benzoxazol-6-yl] acetyl group, [2- (4-chlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (3,4-difluorophenylamino) ) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (2,4,5-trifluorophenylamino) -1,3-benzoxazol-6-yl] acetyl Group, [2- (2,3,4-trifluorophenylamino) -1,3-benzoxazol-6-yl] acetyl group.

  Specific examples of the group of the formula (II) include groups of the following formulas (ia) to (i-dt).

  Among the compounds (I) of the present invention, a more preferable compound is a compound represented by the following formula (Ic).

Wherein R ^a , R ^b , R ^c , R ^d and R ^e are the same or different and each represents a group selected from a hydrogen atom, a C _1-8 alkyl group, a C _1-8 alkoxy group and a halogen atom. R ¹ , R ³ and R ⁴ are as defined above.

  Since the compound (I) of the present invention has a plurality of asymmetric carbon atoms, there are many stereoisomers, but the present invention includes each of these stereoisomers and a mixture of these stereoisomers in all ratios. It is.

  Preferred stereoisomers are represented by the following general formula (Ia)

(Wherein W ^a , W ^b , R ¹ and R ² have the same meanings as described above).

  More preferred stereoisomers are represented by the following general formula (Ib)

(Wherein W ^a , W ^b , R ¹ and R ² have the same meanings as described above).

  The salt of the compound (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, since the compound (I) of the present invention has an acidic carboxyl group, it is generally possible to form a base addition salt. The physiologically acceptable salt may be either an organic salt or an inorganic salt. Suitable examples thereof include, for example, alkali metal salts such as lithium salt, sodium salt, or potassium salt, such as magnesium salt or calcium salt. Alkaline earth metal salts are mentioned. Furthermore, preferred examples include organic amine salts such as triethylamine salt, N-methylglucamine salt, N-benzylaminoethanolamine salt, aminoethanolamine salt, tert-butylamine salt or tris (hydroxymethyl) aminomethane salt. Can be mentioned. On the other hand, since the compound (I) of the present invention has a basic group, it is generally possible to form an acid addition salt. The physiologically acceptable salt may be either an inorganic acid salt or an organic acid salt, and suitable examples of the inorganic acid salt include inorganic acid salts such as hydrochloride, sulfate, and acetate. Furthermore, as preferable examples of the organic acid salts, for example, organic substances such as L-lactate, L-tartrate, oxalate, maleate, citrate, p-toluenesulfonate, and methanesulfonate are used. There may be mentioned acid salts.

  Furthermore, this invention compound (I) or its salt may be in the form of a hydrate or various organic solvates.

  The compound of the present invention can be synthesized, for example, according to the following [Scheme 1] to [Scheme 4b].

The compound represented by the general formula (I) or the carboxylic acid derivative (Ic) in which R ¹ is a hydrogen atom in the stereoisomers (Ia) and (Ib) is as shown in [Scheme 1]. Further, it can be produced by a deprotection step such as a condensation reaction between the carboxylic acid derivative (1) and the cyclic amine derivative (2) or a salt of (2), followed by hydrolysis of the ester moiety (in the scheme, W ^a , W ^b , R ² , Y and Z are as defined above, and R ⁵ is an ester residue which can be eliminated by hydrolysis or hydrogenation, preferably an alkyl group which may have a substituent or A benzyl group which may have a substituent is shown.).

When the ester derivative of the condensate represented by the formula (3) is an alkyl group, R ⁵ is an alkali hydrolysis and neutralization, and R ⁵ is a benzyl group which may have a substituent. It can be converted to the general formula (Ic) which is a free carboxylic acid type compound by debenzylation by catalytic hydrogenation or the like.

  The carboxylic acid derivative represented by the general formula (Ic) shown in [Scheme 1] can be produced by a known synthesis method. An inert halogenated hydrocarbon system such as methylene chloride is prepared by reacting the carboxylic acid derivative (1) and the cyclic amine (2) or (2) with a salt such as hydrochloride or trifluoroacetate according to a known condensation method. 1-ethyl-3- (3-dimethylaminopropyl) in a solvent, an inert hydrocarbon solvent such as toluene, an inert ether solvent such as tetrahydrofuran, or an inert polar solvent such as N, N-dimethylformamide Using a condensing agent such as carbodiimide hydrochloride, N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like, the range of −20 ° C. to the boiling point of the solvent, preferably 0 ° C. to room temperature. The compound of the ester derivative (3) which is a condensation product can be manufactured by making it react under the temperature of this. The reaction time is usually 30 minutes to 24 hours. In this condensation reaction, it is preferable to use an organic amine base such as triethylamine or N, N-dimethylaminopyridine in the range of 1 equivalent to 30 equivalents, and when the salt of the amine body (2) is used in the reaction. Use in excess of the stoichiometric amount required for salt neutralization. Alternatively, it is preferable to use 0.2 to 1.2 equivalents of 1-hydroxybenzotriazole simultaneously with the organic amine base.

In the following [Scheme 2A], the carboxylic acid derivative (1) used for deriving the compound represented by the general formula (I), W ^b is in the 2-position, W ^a -NH-, and the 6-position In the scheme, W ^a and R ⁵ are as defined above, and R ⁶ and R ⁷ are each independently a hydrogen atom, A halogen atom, a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, etc. X ^a represents ^a halogen atom.

  The compound represented by the formula (2A-6) in [Scheme 2A] can be produced by a known method. For example, it is known per se or, for example, Journal of Medicinal Chemistry, 20 (6), 797-801 (1977), European Journal of Medicinal Chemistry, 22 (2), 161-3 (1987), and WO 02 Aminophenol derivative (2A-1) that can be produced according to a known method described in Japanese Patent No. 053534, and commercially available potassium ethylxanthate, in an organic amine solvent such as pyridine, having a boiling point of 0 ° C. to the boiling point of the solvent. The benzoxazole 2-thiol compound (2A-2) can be derived by a known method of treatment in the range, preferably room temperature to the boiling point of the solvent. In this reaction, the aminophenol derivative (2A-1) is mixed with carbon disulfide in an organic amine solvent such as pyridine, an inert ether solvent such as tetrahydrofuran, or an inert polar solvent such as N, N-dimethylamide. And 1 equivalent to 5 equivalents, preferably 1 equivalent to 3 equivalents of sodium methoxide in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of room temperature to 100 ° C. boiling point for 10 minutes to 13 hours, preferably Can be synthesized by treating for 10 to 30 minutes.

At this time, a carboxylic acid form in which the ester moiety is hydrolyzed by excess sodium methoxide may be produced as a by-product, but after treating the reaction mixture, the resulting crude product is converted into a catalytic amount of concentrated sulfuric acid, hydrochloric acid, etc. It can be converted to the target product (2A-2) by heating under reflux in an alcohol corresponding to R ⁵ alkyl such as methanol in the presence of a mineral acid or an organic sulfonic acid such as p-toluenesulfonic acid. Next, the benzoxazole 2-thiol compound (2A-2) is converted into an inert halogenated hydrocarbon solvent such as methylene chloride or 1,2-dichloroethane, an inert hydrocarbon solvent such as toluene, or an inert ether such as tetrahydrofuran. Oxalyl chloride, thionyl chloride, phosphorus trichloride, preferably thionyl chloride and a catalytic amount of N, N-dimethylformamide in a system solvent in the range of −20 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent. Can be converted into a 2-chlorobenzoxazole (2A-3). The 2-chlorobenzoxazole (2A-3) is an inert halogenated hydrocarbon solvent such as 1,2-dichloroethane, an inert hydrocarbon solvent such as toluene, or an inert ether solvent such as tetrahydrofuran, preferably By treating with 1 equivalent to 3 equivalents of aniline (2A-4) in an inert ether solvent such as tetrahydrofuran in the range of −20 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent. To the arylaminobenzoxazole derivative (2A-5). Under the present circumstances, it is possible to reduce the usage-amount of the aniline body (2A-4) to be used to 1 equivalent-1.2 equivalent by making organic amines, such as a triethylamine, exist as a dehydrochlorination agent. The benzoxazole acetic acid ester derivative (2A-5) is obtained by neutralizing the ester moiety after performing known alkali hydrolysis, or, in the case of benzyl ester, deprotection under catalytic hydrogen to form a free carboxylic acid (2A-5). -6).

  Here, the compounds (2A-2) and (2A-3) are novel compounds and are useful as synthetic intermediates for the compounds of the present invention.

The carboxylic acid derivative represented by the formula (2B-5) can also be synthesized using the production method shown in [Scheme 2B] (in the scheme, W ^a and R ⁵ are the same as defined above, R ⁶ and R ⁷ each independently represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group or the like. Known per se or described in, for example, Journal of Medicinal Chemistry 20 (6), 797-801 (1977), European Journal of Medicinal Chemistry 22 (2), 161-3 (1987), and WO 02/053534. An aminophenol derivative (2B-2) that can be produced in accordance with the known method and an isothiocyanate compound (2B-1) that is commercially available or can be prepared by a known method, and an inert halogenated hydrocarbon solvent such as methylene chloride In an inert hydrocarbon solvent such as toluene, an inert ether solvent such as tetrahydrofuran, or an alcohol solvent such as ethanol, a temperature in the range of −20 ° C. to the boiling point of the solvent, preferably 0 ° C. to room temperature. The thiourea derivative (2B-3) can be produced by processing under the following conditions, and then according to a known method, for example, an inert hydrocarbon solvent such as toluene, tetrahydrofuran In the range of −20 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent, in an inert ether solvent such as N, N-dimethylformamide or in an alcohol solvent such as ethanol. The benzoxazole acetate derivative (2B-4) can be obtained by treatment with commercially available KO ₂ or Ni ₂ O ₃ , preferably mercuric oxide (yellow) at a range of temperatures. The benzoxazole acetic acid ester derivative (2B-4) is obtained by neutralizing the ester moiety after performing known alkali hydrolysis, or, in the case of benzyl ester, deprotection under catalytic hydrogen to form a free carboxylic acid (2B-4). -5).

Next, in the following [Scheme 3A], the 2,5-disubstituted cyclic amine derivative (2) or the 2,5-disubstituted cyclic amine derivative (2) used for producing the compound of the general formula (I) For example, a general production method of hydrochloride or trifluoroacetate was shown (in the scheme, R ³ , R ⁴ , R ⁵ , Y and Z are as defined above, and P is an amino group protecting group) Is preferably described in Protective Groups in Organic Synthesis, eds.by TWGreene and PGWuts, John Wiley & Sons, Inc., New York, (1991). Preferable examples include a tert-butoxycarbonyl group (Boc group) and a benzyloxycarbonyl group.

  As shown in [Scheme 3A], the 2,5-disubstituted cyclic amine derivative (3A-5) is converted into an aldehyde derivative (3A-2) by using a known oxidation method for the hydroxyl group of the pyrrolidinemethanol derivative (3A-1). Then, the aldehyde derivative (3A-2) and the amine body (3A-3) are subjected to a reductive condensation reaction to obtain an aminomethylpyrrolidine derivative (3A-4), and then free base is obtained by a known deprotection step. The step of leading to the cyclic amine derivative (3A-5) or the cyclic amine derivative (3A-5), for example, hydrochloride or trifluoroacetate was shown. As a method of deriving the hydroxyl group of the pyrrolidinemethanol derivative (3A-1) shown as [Step-1] in [Scheme 3A] to the aldehyde derivative (3A-2), a known oxidation for converting a primary hydroxyl group to an aldehyde Although the reaction is adaptable, a mild oxidation reaction that prevents isomerization of the alpha carbon atom of the formyl group is preferred.

  For example, Swern oxidation (Giordano, C .; Cavicchioli, S .; Levi, S .; Villa, M .; J Org. Chem. 56 (21), 6114-6118 (1991), Konradi, AW; Pedersen, SF; J Org. Chem. 57 (1), 28-32 (1992)., Etc.), hypochlorous acid-tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, free Radical reaction using radicals (Jurczak, J .; Prokopowicz, p .; Golebiowski, A .; Tetrahedron Letters, 34 (44), 7107-7110 (1993), etc.), oxidation method using DMSO-cyanuric chloride (De Luca, L .; Giacomelli, G .; Porcheddu, A .; J Org. Chem., 66 (23), 7907-7909, (2001), De Luca, L .; Giacomelli, G .; Porcheddu, A .; Org Letters, 3 (19), 3041-3043 (2001)), oxidation method using sulfur trioxide pyridine complex (Konradi, AW; Pedersen, SF; J Org. Chem., 55 (15), 4506-4508, (1990 ), Takemoto, Y .; Matsumoto, t .; ITO, Y .; Terashima, S .; Chem. Pharm. Bull., 39 (9), 242-2428, (1991)) It can be implemented by applying conditions.

The aldehyde derivative (3A-2) and amine compound (3A-3) shown in [Step-2] in [Scheme 3A] are introduced into the aminomethylpyrrolidine derivative ( The reaction conditions and reducing agent for conversion to 3A-4) are preferably sodium triacetoxyborohydride or sodium cyanoborohydride. Examples of similar reactions using sodium triacetoxyborohydride include Gordon, DW Steele, J .; Bioorg. Med. Chem. Letters, 5 (1), 47-50 (1995), and examples using sodium cyanoborohydride include Kelley, JL; Mclean, EW; Ferris, RM; Howard, JL; J Med. Chem., 33 (7), 1910-1914 (1990). These similar conditions can be used to convert to the aminomethylpyrrolidine derivative (3A-4). Moreover, the amine body (3A-3) used for [Step-2] in [Scheme 3A] is commercially available or can be prepared by a production method known in the literature.

  Next, a 2,5-disubstituted cyclic amine derivative (3A-5) or a cyclic amine derivative corresponding to the cyclic amine (2) shown in [Scheme 1] from the aminomethylpyrrolidine derivative (3A-4) To convert (3A-5) to, for example, hydrochloride or trifluoroacetate salt, the deprotection conditions of the protecting groups listed above (Protective Groups in Organic Synthesis, eds. By TWGreene and PGWuts, John Wiley & Sons, Inc., New York, 1991). For example, when P is tert-butoxycarbonyl (Boc group), a stoichiometric to 50-fold amount of 4N hydrochloric acid / dioxane solution (commercially available) ) Or trifluoroacetic acid, and the protecting group can be removed under the conditions of treatment in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of 0 ° C. to room temperature. The reaction time is about 30 minutes to 2 days, usually 60 minutes to 2 hours. After completion of the reaction, the reaction mixture is concentrated to dryness under reduced pressure to give hydrochloride or trifluoroacetate salt depending on the acid used. When this is neutralized with a saturated aqueous sodium bicarbonate solution or, for example, a 1N aqueous sodium hydroxide solution, a free cyclic amine derivative (3A-5) can be obtained. Moreover, when P is a benzyloxycarbonyl group, deprotection is possible by catalytic reduction according to the literature cited above. At this time, when hydrochloric acid or trifluoroacetic acid is added to the reaction solution, it can be isolated as the hydrochloride or trifluoroacetate salt of the cyclic amine derivative (3A-5). If these acids are not added, the free cyclic amine derivative (3A-5) is isolated. ) Is obtained.

  Next, in [Scheme 4A] and [Scheme 4B] below, a method for producing the pyrrolidine derivative (3A-1) of [Scheme 3A] will be described.

  A known method for producing a 2,5-disubstituted pyrrolidine derivative can be applied to the production of the pyrrolidine derivative (3A-1). That is, Y. Yamamoto et al. (Y. Yamamoto, J. Hoshino, Y. Fujimoto, J. Ohmoto, S. Sawada, Synthesis 1993; 298-302, or T. Kyohei, M. Satoshi, F. Tomomi, H. Yasuo, Y. Yukio, Tetrahedron Asymmetry, 8 (1), 101-107 (1997), etc.) or the method of Nakayama et al. (Japanese Patent Application No. 2004-166523, filing date: 2004) improved from the method of Y. Yamamoto et al. In accordance with (June 4, 2014), adipic acid dichloride was converted into a known 2,5-dibromoadipic acid methyl ester from the starting material, and as shown in [Step-2] above, (R) -phenyl A cyclization reaction is performed using ethylamine ((R) -PEA) to synthesize the pyrrolidine derivative as a mixture of three stereoisomers, and the 2S, 5S-coordinate pyrrolidine derivative (4A-3) preferred in the present invention. ) Can be obtained by optical resolution recrystallization from among three stereoisomers. Next, a 2S, 5S-bis (hydroxymethyl) pyrrolidine derivative (4A-) preferable as a key intermediate through the reduction step of [Step-3] and [Step-4] and the protection step of [Step-5]. 6). In addition, as P which is a protecting group of a compound (4A-6), a tert-butoxycarbonyl group (Boc group) and a benzyloxycarbonyl group are mentioned. Although a multi-step process is required, a method for producing 2S, 5S-bis (hydroxymethyl) pyrrolidine derivative (4A-6) stereospecifically is described in S. Takano, K .; The method of Ogasawara et al. (Tetrahedron Letters, 30 (29), 3805-6 (1989)) is also known.

In the next [Scheme 4B], a hydroxymethylpyrrolidine derivative (from which the above-mentioned 2S, 5S-bis (hydroxymethyl) pyrrolidine derivative (4A-6) is synthesized as a raw material for the cyclic amine (2) shown in [Scheme 3A] ( 4B-6-trans) will be described. In [Scheme 4B], R ⁵ has the same meaning as above, R ⁸ represents a lower alkyl group which may have a substituent or a benzyl group which may have a substituent, and R ⁹ has a substituent. A lower alkylsulfonyl group which may be substituted, and a benzenesulfonyl group which may have a substituent; P is an amino-protecting group and represents —COOR ⁸ .

[Step-1] of [Scheme 4B] is a generally known method for converting the hydroxyl group of the 2S, 5S-bis (hydroxymethyl) pyrrolidine derivative (4B-1) to a leaving group, and sulfonyl of R ⁹ As the group, a p-toluenesulfonyl group, a methanesulfonyl group, and the like are preferable. From the alcohol form (4B-1) to the corresponding 2,5-bis (substituted or unsubstituted arylsulfonyloxy)-or 2,5-bis (substituted or unsubstituted lower alkylsulfonyloxy) -form (4B-2) Examples of the conversion method include the following known methods. The alcohol (4B-1) is converted into an organic base such as 1 to 10 equivalents of triethylamine, pyridine, imidazole, 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate (anhydrous) or sodium carbonate (anhydrous), preferably In the presence of an organic base such as 1 to 2.5 equivalents of triethylamine, 4-dimethylaminopyridine, hydrocarbon solvents such as toluene, inert ether solvents such as diethyl ether and tetrahydrofuran, methylene chloride, 1,2-dichloroethane In an inert chlorine-based solvent such as the above, between -78 ° C and the boiling point of the solvent, preferably in the range of 0 ° C to room temperature, 2 to 5 equivalents, preferably 2-3 equivalents of p-toluenesulfonyl chloride, methanesulfonyl chloride, etc. By treatment with a sulfonyl chloride or bromide derivative of Can be converted to Oniruokishi body (4B-2). The reaction time usually proceeds from 1 hour to 24 hours. The sulfonyloxy compound (4B-2) can be sufficiently used for the next substitution reaction after confirmation of purification by instrument data without going through a purification step using silica gel.

  The next [Step-2] is a coupling of a sulfonyloxy form (4B-2) with a sodium, potassium or lithium phenolate derivative prepared from a commercially available 4-hydroxybenzoic acid ester (4B-3). This reaction is generally known as a reaction for forming an arylalkyl ether bond by reaction of a phenolate anion. Furthermore, in [Step-2], the phenolate anion formed in the reaction system acts as a base, and the intramolecular cyclization reaction with the carbonyl group of the acyloxy unit at the 1-position of the pyrrolidine ring proceeds to newly produce 2-oxo. This is a step of forming a -1,3-oxazolidine ring. Accordingly, the required phenolate anion is stoichiometrically required in an amount equivalent to twice that of the substrate sulfonyloxy form (4B-2). Preferred bases used to form the phenolate anion from 4-hydroxybenzoate ester (4B-3) are alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium ethoxide, sodium methoxide, potassium tert- Examples include alkali metal alkoxides such as butoxide and sodium tert-butoxide, organolithium reagents such as phenyl lithium and n-butyl lithium, and bases such as sodium hydride. Solvents used include hydrocarbon solvents such as toluene, inert ether solvents such as diethyl ether and tetrahydrofuran, or aprotic such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide. Among them, tetrahydrofuran, N, N-dimethylformamide and the like are preferable, and phenols formed in the reaction system by treating commercially available 4-hydroxybenzoic acid ester with the above-mentioned bases and the like in these solvents. Oxazolidinone derivatives in which the cyclization reaction and the substitution of the phenoxy unit proceeded simultaneously by treating the lation anion with the sulfonyloxy compound (4B-2) in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of 20 ° C. to 120 ° C. (4B-4) can be obtained. This reaction is preferably carried out under a nitrogen stream in order to avoid hydrolysis of the ester group and decomposition of the sulfonyloxy compound (4B-2), and the bases and solvents used are anhydrous in the generally used range. Those are preferred. While the reaction time varies depending on the reaction temperature, it is completed in 30 minutes to 48 hours, usually from 1 hour to 10 hours.

  The next [Step-3] is a step in which the benzene ring of the oxazolidinone derivative (4B-4) is hydrogenated under mild conditions to convert it to a cyclohexane ring. As a similar reaction example, for example, the method of WMPearlman et al. (Organic Synthesis, Collective volume 5, p670-672, John Wiley and Sons, Inc.). Examples of the catalyst that can be used in the catalytic hydrogenation step include a commercially available palladium-carbon catalyst, platinum dioxide catalyst, strontium carbonate catalyst, and rhodium-alumina catalyst. Preferably, the rhodium-alumina catalyst is reduced. 1% to 50% (w / w), preferably 3% to 20% (w / w) based on the substrate, the reaction solvent is an alcoholic solvent such as ethanol or methanol, or an inert ether such as tetrahydrofuran or dioxane. Organic solvents such as acetic acid and acetic acid, preferably methanol or ethanol and a combination of the above preferred solvents. The reaction is carried out in the above solvent in the range of normal pressure to 15 MPa, preferably in the range of normal pressure to 3 MPa hydrogen pressure, the reaction temperature in the range of 0 ° C. to 100 ° C., preferably in the range of room temperature to 60 ° C. The time is usually in the range of 1 hour to 48 hours, and catalytic hydrogenation can be carried out with stirring to produce the cyclohexanecarboxylic acid ester derivative (4B-5).

The next [Step-4] is an isomerization via enolate of the α carbon of the ester group of the cyclohexanecarboxylic acid ester derivative (4B-5) predominantly obtained in the catalytic reduction step with high cis selectivity. This is a step of improving the trans isomer ratio, which is a preferred relative coordination of the inventive compound, and further separating and purifying these two isomers. In addition, the carboxylic acid product by-produced during the isomerization can be easily re-esterified, and then the trans-cyclohexanecarboxylic acid ester derivative (4B-5-trans) is separated and purified from both isomers by column chromatography. Is possible. The isomerization reaction can be carried out by the method described in WO 02/053534, but in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base, preferably in the range of 0 ° C. to the boiling point of the solvent. Is in the range of 0 ° C. to 50 ° C. The solvent used is an aprotic polar solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, preferably N, N-dimethylformamide may be mentioned. Examples of the base to be used include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like, and a metal alkoxide composed of the same alcohol as the ester of R ⁵ is preferable. Is preferably sodium methoxide, and in the case of ethyl ester, sodium ethoxide is preferred. The reaction time is usually in the range of 10 minutes to 12 hours. On the other hand, as an example of converting the by-product carboxylic acid to an ester form (4B-5), aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone Preferably, N, N-dimethylformamide is used, and it can be converted to the corresponding ester by treatment with an alkyl halide corresponding to the ester group (R ⁵ ) such as R ⁵ -bromide. In addition, the trans form (4B-5-trans) can be separated and purified by column chromatography using ordinary silica gel, and higher separation efficiency can be obtained by using a commercially available medium pressure column separator. It is done. Separation can also be performed using other methods such as preparative HPLC.

[Step-5] is a step for producing a hydroxymethylpyrrolidine derivative (4B-6-trans) by opening the oxazolidinone ring of the oxazolidinone derivative (4B-5-trans). The oxazolidinone derivative (4B-5-trans) is subjected to a ring-opening reaction and hydrolysis simultaneously under basic conditions, and the resulting carboxylic acid is regenerated to a lower alkyl ester corresponding to R ⁵ under a catalytic amount of an acid catalyst. The nitrogen atom at the 1-position of the pyrrolidine ring can be converted to a hydroxymethylpyrrolidine derivative (4B-6-trans) protected with a tert-butoxycarbonyl group or a benzyloxycarbonyl group. At this time, isomerization of 1,4-trans-coordinated cyclohexane does not proceed. In the first ring-opening reaction under basic conditions, a lower alcohol solvent such as methanol or ethanol or an inert ether solvent such as tetrahydrofuran can be used as a solvent. Among these solvents, a lower alcohol solvent such as methanol or ethanol is used. The base used is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in the range of 0.25 N to 10 N, or an aqueous solution of an alkali metal carbonate such as sodium carbonate or potassium carbonate as a substrate. The range of 2 equivalents to 10 equivalents with respect to oxazolidinone (4B-5-trans) is used, the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent, and the reaction time is usually 30 minutes. It can be carried out in 24 hours. The next esterification can be obtained by cooling the reaction mixture, adding a commercially available hydrochloric acid / ethanol mixture, hydrochloric acid / dioxane, etc. to neutralize the excess base, and then concentrating the reaction mixture to dryness under reduced pressure. In the carboxylic acid crude product, a non-polar hydrocarbon solvent such as toluene or xylene may be used as an auxiliary solvent in a lower alcohol solvent corresponding to the alkyl group of R ⁵ such as methanol or ethanol, or as a high boiling point solvent. Often, the acid catalyst added is preferably a mineral acid such as concentrated sulfuric acid. The esterification reaction temperature is preferably in the range of room temperature to the boiling point of the solvent, and the reaction time is usually completed in the range of 10 minutes to 10 hours. After completion of the esterification reaction, the reaction mixture is neutralized with an acid used for the catalyst using a saturated aqueous sodium bicarbonate solution, and then an ester can be obtained from the organic layer by an extraction operation. Next, a protective group is introduced into the 1-position nitrogen atom of the pyrrolidine ring portion of the ester obtained here, and then purified by silica gel column chromatography to produce the desired hydroxymethylpyrrolidine derivative (4B-6-trans). it can. The method for introducing a protecting group for the 1-position nitrogen atom of the pyrrolidine ring moiety is a known method (Protective Groups in Organic Synthesis, eds. By tWGreene and pGWuts, John Wiley and Sons, Inc., New York, 1991), for example, water. In an inert polar solvent such as acetonitrile, in an inert ether solvent such as tetrahydrofuran, acid anhydrides such as di-tert-butyl dicarbonate, or acyl-halides such as benzyloxycarbonyl chloride and The desired hydroxymethylpyrrolidine derivative (4B-6-trans) can be produced by treatment in the presence of an organic amine base such as triethylamine or an inorganic base such as potassium carbonate.

In addition, another scheme for synthesizing a hydroxymethylpyrrolidine derivative (4C-7-trans), which is a raw material for producing the cyclic amine (2), will be described in [Scheme 4C]. In the following scheme, R ⁵ , R ⁸ and R ⁹ are as defined above, P is as defined in Scheme 4B, R ¹¹ represents a phenyl group or lower alkyl group which may have a substituent, R ^12a , R ^12b and R ^12c each independently represent a lower alkyl group or a phenyl group, and n represents an integer of 1 or 2. M means an alkali metal atom or an alkaline earth metal atom.

  [Step-1] in [Scheme 4C] is represented by the 2,5-bis (sulfonyloxymethyl) pyrrolidine derivative (4B-2) described in [Scheme 4B] and the compound (4C-1). For example, by treatment with commercially available sodium benzoate, potassium benzoate, sodium acetate or potassium acetate, the substitution reaction and the cyclization reaction proceed simultaneously as in [Step-2] of [Scheme 4B] above. This is a step for producing the acyloxymethylpyrrolidine derivative (4C-2). Therefore, the required sodium salt or potassium salt as in the previous case requires a stoichiometric equivalent of 2 times equivalent. In addition, sodium salt or potassium salt can be prepared in advance in the reaction system using, for example, benzoic acid or acetic acid, and preferred bases used for salt formation are alkali metal carbonates such as sodium carbonate and potassium carbonate. Salts, sodium hydride and the like. Solvents used include hydrocarbon solvents such as toluene, inert ether solvents such as diethyl ether and tetrahydrofuran, or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfate. Examples include aprotic polar solvents such as foxides, among which tetrahydrofuran, N, N-dimethylformamide and the like are preferable, and these solvents are commercially available or formed in a reaction system, for example, sodium benzoate, potassium benzoate, By treating sodium acetate or potassium acetate with the sulfonyloxy compound (4B-2) in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of 20 ° C. to 120 ° C., the cyclization reaction and substitution of the acyloxy unit proceed simultaneously. Of the obtained oxazolidinone derivative (4C-2) It is possible. In order to avoid side reactions, this reaction is preferably carried out under a nitrogen stream, and the bases and solvents used are preferably anhydrous in the generally used range. Although the reaction time varies depending on the reaction temperature, the reaction is completed in 30 minutes to 48 hours, usually 1 hour to 10 hours. Subsequent [Step-2] is a method in which the acyloxy group is hydrolyzed and converted to the alcohol form (4C-3). Acyloxymethyl derivative (4C-2) is preferably 0.1 N to 4 N, preferably 0.25 N to 1 N sodium hydroxide or potassium hydroxide in an inert ether solvent such as diethyl ether or tetrahydrofuran. And the target alcohol body (4C-3) can be obtained by processing in the range of 0 degreeC-50 degreeC, Preferably 0 degreeC-room temperature. The reaction time is usually completed in the range of 5 minutes to 2 hours. The next [Step-3] is a step of converting the hydroxymethyl group of the alcohol form (4C-3) into a substituted silyloxymethyl group, and is a step of converting a hydroxyl group into a substituted silylether group for the substitution reaction. . This reaction, which is also widely used as a method for protecting hydroxyl groups, is described in many ways in the above method (Protective Groups in Organic Synthesis, eds. By tWGreene and pGWuts, John Wiley and Sons, Inc., New York, 1991). However, the reaction may be carried out by reacting trialkylsilyl halide or alkyldiphenylsilyl halide, preferably trialkylsilyl chloride or alkyldiphenylsilyl chloride in the presence of a base. The alkyl group may be methyl, ethyl, isopropyl. Group, t-butyl group is preferred.

  As the substituted silyl halide, those corresponding to the substituted silyl employed are used, and examples thereof include trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, and t-butyldiphenylsilyl chloride. It is preferable to use these in the range of 1 equivalent to 2.5 equivalents, particularly 1 equivalent to 1.5 equivalents, relative to the alcohol form (4C-3).

  As the base to be used, an organic base such as alkylamines such as triethylamine, diisopropylethylamine, imidazole, 4-dimethylaminopyridine, aromatic amines, or nitrogen-containing heterocyclic compounds may be used. Preferably, organic bases such as triethylamine, diisopropylethylamine, and imidazole are used. The amount of these used may be in the range of 1 equivalent to 10 equivalents, preferably 1 equivalent to 2.5 equivalents, with respect to the alcohol (4C-3), if the substituted silyl halide to be used and an equimolar amount are used. Good.

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but a hydrocarbon solvent such as toluene, an ether solvent such as diethyl ether and tetrahydrofuran, a chlorine solvent such as methylene chloride and 1,2-dichloroethane, Examples thereof include nitrile solvents such as acetonitrile. Preferable solvents include ether solvents such as diethyl ether and tetrahydrofuran, hydrocarbon solvents such as toluene, and nitrile solvents such as acetonitrile.
The reaction temperature may be in the range of -78 ° C to the boiling point of the solvent, but it is preferably carried out in the range of 0 ° C to room temperature.
The reaction time may be between 5 minutes and 24 hours, but is usually completed in about 30 minutes to 6 hours.

  The next [Step-4] is a step of reductively introducing the cyclohexanecarboxylic acid ester unit (4C-5) into the silyloxymethyl derivative (4C-4) to newly construct an ether bond. For the introduction as the cyclohexanecarboxylic acid ester unit, 4-oxocyclohexanecarboxylic acid ester may be used. For example, methyl esters and ethyl esters can be obtained as commercial products.

  Examples of the reductive etherification reaction of a substituted silyl ether of alcohol and an aldehyde or ketone derivative include, for example, Mark B. Sassaman, Kirtivan D. Kotian, GKSurya Prakash, and George A. Olah, J. Org. Chem. 1987, 52, 4314-4319, Joginder S. Bajwa, Xinglong Jiang, Joel Slade, Kapa Prasad, Oljan Repic and Thomas J. Blacklock, Teterahedron Letters 43 (2002) 6709-6713, S. Hatakeyama, H. Mori, K. Kitano, H. Yamada and M. Nishizawa, Teterahedron Letters 35 (1994) 4367-4370, J. Kato, N. Iwasaki, and T. Mukaiyama, Chemistry Letters, 734-746 (1985).

  This step is a step showing that it is also useful for the synthesis of nitrogen-containing heterocyclic derivatives. As the catalyst, trialkylsilyl halide is useful, and trimethylsilyl iodide and trimethylsilyl bromide are preferable. Trimethylsilyl iodide may be a commercially available product, or may be generated from iodine and trimethylsilyl chloride, or iodine and hexamethyldisilane and used in the reaction system. Trimethylsilyl bromide can be prepared and used from bismuth (III) bromide and triethylsilane in the reaction system as described in the above-mentioned literature. As the reducing agent, trialkylsilane is used, and preferred examples include trimethylsilane, triethylsilane, triiisopropylsilane, and the like.

The solvent used for the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include chlorinated solvents such as methylene chloride and 1,2-dichloroethane, and nitrile solvents such as acetonitrile. Preferable solvents include chlorinated solvents such as methylene chloride and 1,2-dichloroethane, and nitrile solvents such as acetonitrile, and those which are anhydrous within a generally used range are preferable.
The reaction temperature is in the range of −78 ° C. to the boiling point of the solvent, preferably in the range of −20 ° C. to room temperature.
The reaction time may be between 30 minutes and 72 hours, but is usually completed in about 10 hours to 48 hours.

  In addition, this reaction is preferably carried out under anhydrous conditions in order to avoid hydrolysis of the ester group.

  As shown in [Scheme 4C], compound [4C-6] can be converted to a hydroxymethyl derivative (4C-7-trans) in the same manner as in Step 5 of [Scheme 4B].

The compound of the present invention, a salt thereof or a solvate thereof thus obtained selectively inhibits cell adhesion molecules from binding to VLA-4 in vitro and in vivo as shown in the test examples described later. In addition, it is excellent in water solubility, small intestinal membrane permeability and oral absorption. Therefore, the compound of the present invention is a disease caused by cell adhesion involving VLA-4, that is, various diseases mediated by leukocyte drift and adhesion, such as inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal congestion, It is useful as a preventive and / or therapeutic agent for diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and transplant rejection.
The medicament of the present invention can be administered by various methods including oral administration.
Moreover, when it is set as an injection, it can administer by any methods, such as intravenous injection, intramuscular injection, and subcutaneous injection.
About the preparation method of such a formulation, a suitable formulation can be selected according to the administration method, and it can prepare by the adjustment method of the various formulation normally used.
Examples of oral preparations include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. As injections, stabilizers, preservatives, and solubilizing agents may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it may be used as a solid preparation by lyophilization if desired. It may be a preparation prepared at the time. Examples of liquid preparations include solutions, suspensions, emulsions, and the like. When these preparations are prepared, suspending agents, emulsifiers, and the like can be used as additives.
The medicament containing the compound of the present invention is desirably administered as a compound once a day per adult and repeated at appropriate intervals. The dosage is in the range of 0.01 mg to 2000 mg, preferably in the range of 0.1 mg to 1000 mg.
Furthermore, the medicament of the present invention includes anti-inflammatory agents, anti-arthritic agents, corticosteroids (corticosteroids), immunosuppressive agents, anti-psoriatic agents, bronchodilators as necessary, as long as the effects of the present invention are not impaired. A drug, an anti-bronchial asthma drug or an anti-diabetic drug can be used in combination.

EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this.
Melting points were measured using a Yanagimoto micro melting point instrument, and all values are uncorrected. Infrared spectrum (IR) was measured by KBr tableting method or ATR method using Hitachi 270-30 spectrometer or Horiba FT-720 (ST Japan Durascope (Diamond / KRS-5) .Perkin-Elmer CHNS / O 2400II The mass spectrometer was a JEOL JMS-AX505W (EI, CI), JEOL JMS-HX110 (FD, FAB) spectrometer, Thermoquest Finning AQA (ESI) or Agilent Thechnologies Agilent 1100 series LC / MSD. Nuclear magnetic resonance spectrum (NMR) was measured using JEOL JNM-EX400, and unless otherwise indicated, means proton ¹ H-NMR, and tetramethylsilane was used as an internal standard. Multiplicity means s = singlet, d = doublet, t = triplet, q = quintet, and m = multiplet The silica gel used for column chromatography is Kiesel-gel 60 (particle size 0.060 from E-Merck). -0.200mm or 0.040-0.063mm) and thin layer chromatography (TLC) The plate used was Kieselgel 60 F ₂₅₄ manufactured by E-Merck, Inc. HPLC was measured under the following conditions using Shimadzu LC-6AD, 10Avp.

Column: (WATERS Symmetry ^TM C18 4.6 x 250mm)
Mobile phase: 10mM-KH ₂ PO ₄ Buffer (pH = 2.5): MeCN = 1: 1
Flow rate: 1.0 mL / min (1.5 mL / min)
Column temp.:room temperature
Detection: UV 254nm and radioactivity (flow cell)
Run length: 40min

  Moreover, the following abbreviations were used in the specification.

BH ₃・ DMS: Borane dimethyl sulfide complex
Boc: tert-butoxycarbonyl
Boc ₂ O: Di-tert-butyl dicarbonate
BOM: Benzyloxymethyl
Bn: benzyl
Cbz: benzyloxycarbonyl
CDCl ₃ : Deuterated chloroform
DIAD: Diisopropyl azodicarboxylate
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
HOBt: 1-hydroxybenzotriazole
Ms: Methanesulfonyl
TBDMS: tert-butyldimethylsilyl
TBDMS-Cl: tert-butyldimethylsilyl chloride
TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical
THF: Tetrahydrofuran
TLC: Thin layer chromatography

Example 1
Trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrole Dinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of 4-[(5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] benzoic acid methyl ester hydrochloride
4- [1-tert-Butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] benzoic acid methyl ester (7.21 g, 19.7 mmol) was dissolved in dioxane (50 ml) and 4 N HCl. / Dioxane solution (200 ml) was added. The reaction solution was stirred for 9 hours and then concentrated under reduced pressure. The residue was recrystallized from THF / ether to give the title product (5.31 g, 89%) as a colorless solid.
¹ H NMR (DMSO) δ: 1.69-1.85 (2H, m), 2.02-2.21 (2H, m), 3.55 (1H, m), 3.67 (2H, d, J = 9.0 Hz), 3.81 (3H, s ), 3.96 (1H, br), 4.23 (1H, dd, J = 10.5, 2.2 Hz), 4.30 (1H, dd, J = 7.3, 2.7 Hz), 5.38 (1H, br), 7.08 (2H, dd, J = 8.4, 2.4 Hz), 7.93 (2H, dd, J = 8.8, 2.4 Hz), 9.18 (1H, br), 9.34 (br, 1H); δ
MS (LC-ESI) m / z: 266 (M ⁺ +1).

(Process 2)
Synthesis of 4-[(5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester hydrochloride
4-[(5S) -Hydroxymethyl- (2S) -pyrrolidinylmethoxy] benzoic acid methyl ester hydrochloride (2.04 g, 6.76 mmol) and 5% -rhodium / alumina (2.04 g) in methanol (60 ml) It was suspended and stirred at room temperature under 20 kg / cm ² of hydrogen for 20 hours. The catalyst in the reaction mixture was filtered off, and the filtrate was concentrated under reduced pressure to give the title as a light brown oil. This compound was used in the next reaction without further purification.

(Process 3)
Synthesis of 4- [1-tert-butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester
4-[(5S) -Hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester hydrochloride (6.76 mmol) and saturated aqueous sodium hydrogen carbonate (100 ml) were stirred in dioxane (100 ml) at room temperature. (Boc) ₂ O (1.40 g, 6.42 mmol) was added. The reaction mixture was stirred for 3 days and extracted with ethyl acetate. The extract was washed with 1 N HCl, then saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title as a colorless oil. This compound was used in the next reaction without further purification.

(Process 4)
Synthesis of trans-4-[(5S) -benzyloxymethyloxymethyl-1-tert-butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester
4- [1-tert-Butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (6.76 mmol) and diisopropylethylamine (3.53 ml, 20.3 mmol) were added to methylene chloride (100 ml) and benzyloxymethyl chloride (BOM-Cl) (1.41 ml, 10.2 mmol) was added at room temperature with stirring. The reaction mixture was stirred at room temperature for 20 minutes, diisopropylethylamine (3.53 ml, 20.3 mmol) and BOM-Cl (1.41 ml, 10.2 mmol) were further added, and the mixture was stirred at room temperature for 22 hours. Ice water (100 ml) was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with 1 N HCl, saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [silica gel = 200 g, hexane / ethyl acetate (1/2, v / v)] 4-[(5S ) -Benzyloxymethyloxymethyl-1-tert-butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester [2.32 g, 70% (total yield over 3 steps)] was obtained as a colorless oil. . This compound was used in the next isomerization reaction without further purification.

  To a solution of 4-[(5S) -benzyloxymethyloxymethyl-1-tert-butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (2.32 g, 4.72 mmol) in methanol (100 ml), Sodium methoxide (2.55 g, 47.2 mmol) was added with stirring at room temperature, and the reaction mixture was heated to reflux for 19 hours. The reaction solution was cooled to room temperature and then concentrated to dryness under reduced pressure. 1 N HCl was added to the residue, and the mixture was acidified at room temperature and extracted with ethyl acetate. 4-[(5S) -benzyloxymethyloxy-1-tert-butoxycarbonyl- (2S) -pyrrolidini obtained by washing the extract with water, washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. L-methoxy] cyclohexanecarboxylic acid was used in the next reaction without further purification.

The obtained 4-[(5S) -benzyloxymethyloxymethyl-1-tert-butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid (4.72 mmol) was added to methanol (10 ml) and toluene (100 ml ) And 2.0 M trimethylsilyldiazomethane in hexane (5.00 ml, 10.0 mmol) was added dropwise with stirring at room temperature. The reaction solution was further stirred at room temperature for 30 minutes, and then the reaction solution was concentrated to dryness under reduced pressure. The obtained residue was purified by column chromatography using silica gel [Biotage flash-chromatography systems, KP-SIL 32-63 nm, 60A, hexane / ethyl acetate (10/1, v./v)] [478 mg, 21% (2 steps)] was obtained as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 1.15-1.29 (2H, m), 1.37-1.68 (11H, m, including 1.44 and 1.45 total 9H, each s, amide isomers), 1.82-2.12 (8H, m), 2.20 -2.31 (1H, m), 3.15-3.61 (4H, m), 3.65 and 3.66 (total 3H, each s, amide isomers), 3.67-3.99 (3H, m),
4.58 (2H, s), 4.71 (1H, dd, J = 6.4, 2.7 Hz), 4.75 (1H, dd, J = 6.9, 3.4 Hz), 7.26-7.34 (5H, m);
MS (ESI) m / z: 492 (M ⁺ +1).

(Process 5)
Trans-4- [1-tert-Butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester synthesis trans-4-[(5S) -benzyloxymethyloxymethyl- 1-tert-butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (738 mg, 1.50 mmol) and 10% palladium hydroxide / carbon (740 mg) were suspended in methanol (40 ml), Catalytic reduction was performed for 10 hours under 1 atmosphere of hydrogen with stirring at room temperature. After the catalyst in the reaction mixture was filtered off, the filtrate was concentrated to dryness. The obtained residue was purified by column chromatography using silica gel to obtain silica gel = [50 g, chloroform / acetone (20/1, v / v)] and the title product (550 mg, 99%) as a colorless oil. It was.
¹ H NMR (CDCl ₃ ) δ: 1.19-1.33 (3H, m), 1.48 (9H, s), 1.56-1.66 (1H, m), 1.81-2.33 (7H, m), 3.20 (1H, m), 3.32 (1H, t, J = 8.8 Hz), 3.41-3.53 (1H, m), 3.58 (2H, dd, J = 8.8, 2.4 Hz), 3.66 (3H, s), 367-3.72 (1H, m) , 3.80-4.05 (2H, m), 4.29 (1H, br). (CH0718).

(Process 6)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester Oxalyl chloride (0.26 ml, 2.96 mmo) in methylene chloride (10 ml) To the solution, a solution of DMSO (0.32 ml, 4.44 mmol) in methylene chloride (1 ml) was added dropwise with stirring at −78 ° C. under a nitrogen stream. The reaction mixture was stirred at the same temperature for 20 min, and at the same temperature, trans-4- [1-tert-butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (550 mg , 1.48 mmol) in methylene chloride (5 ml) was added, triethylamine (1.44 ml, 10.4 mmol) was added, and the reaction mixture was further stirred at −78 ° C. for 40 minutes. A saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title product as a bowl. This compound was used in the next reaction without further purification.

(Process 7)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5S) -dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester trans-4- [1-tert- Butoxycarbonyl- (5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (1.48 mmol) and dimethylamine (0.74 ml, 1.48 mmol) in tetrahydrofuran (THF) (30 ml) at room temperature Below, sodium triacetoxyborohydride (1.5 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 hours, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [Silica gel = 50 g, chloroform / methanol (20/1, v / v)] From the fraction, the title [470 mg, 80% (2 steps)] Was obtained as a colorless oil. This compound was used in the next reaction without further purification.
¹ H NMR (CDCl ₃ ) δ: 1.18-1.32 (3H, m), 1.39-1.42 (1H, m), 1.46 and 1.47 (total 9H, each s, amide isomers), 1.58 (1H, m), 1.83- 2.19 (10H, m), 2.25 (3H, s), 2.28 (3H, s), 3.17-3.24 (1H, m), 3.32 and 3.36 (total 1H, each t, each J = 8.8 Hz, amide isomers). , 3.58 (1H, dd, J = 8.6, 2.7 Hz), 3.65 and 3.66 (total 3H, each s, amide isomers), 3.71-3.91 (2H, m);
MS (ESI) m / z: 399 (M ⁺ +1).

(Process 8)
Trans-4-[(5S) -Dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester dihydrochloride synthesis trans-4- [1-tert-butoxycarbonyl- (5S) -dimethylamino Methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (470 mg, 1.18 mmol) in 4
N HCl / dioxane solution (20 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to dryness, ether was added to the residue, and the precipitated solid was collected and dried to give the title compound (373 mg, 85%) as a colorless solid.
¹ H NMR (DMSO) δ: 1.14-1.29 (2H, m), 1.31-1.43 (2H, m), 1.52-1.73 (3H, m), 1.89-2.09 (4H, m), 2.16-2.32 (1H, m), 2.43 (1H, m), 2.50 (3H, s), 2.51 (2H, d, J =
1.7 Hz), 2.84 (3H, br, 3.27-3.42 (2H, m), 3.51-3.69 (5H, m, including 3.59 3H, s), 3.80 and 4.03 (total 1H, each m, amide isomers), 8.85 and 9.14 (total 1H, amide isomers), 9.74 and 10.77 (total 1H, each m, amide isomers);
MS (ESI) m / z: 299 (M ⁺ +1).

(Process 9)
Trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrole Synthesis of Dinylmethoxy] cyclohexanecarboxylic acid methyl ester trans-4-[(5S) -Dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester dihydrochloride
[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid (159 mg, 0.50 mmol), trans-4-[(5S) -dimethylaminomethyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester dihydrochloride (186 mg, 0.50 mmol), EDC · HCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol) and triethylamine (1.40
ml, 10.0 mmol) was stirred in DMF (5 ml) at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with ice water, saturated brine and dried over anhydrous sodium sulfate, and the solvent was concentrated to dryness under reduced pressure. The obtained residue was purified by thin layer column chromatography using silica gel [development with chloroform / methanol (10/1, v / v)] to obtain the title compound (219 mg, 73%) as a colorless oil. It was.
¹ H NMR (CDCl ₃ ) δ: 1.13-1.55 (5H, m), 1.91-2.96 (18H, m, including 2.28, 3H, s, and 2.31, 6H, s), 3.14 and 3.24 (total 1H, each m , amide isomers), 3.37-3.93 (6H, m, including, 3.62 and 3.67, total 3H, each s, amide isomers), 4.07 and 4.13 (total 1H, m and q, J = 5.6 Hz, amid isomers), 4.20 (1H, br), 6.74 (1H, dt, J = 5.9 Hz), 7.09-7.32 (4H, m), 8.05-8.12 (1H, m);
MS (ESI) m / z: 599 (M ⁺ +1).

(Process 10)
Trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrole Synthesis of Dinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)- Dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (219 mg, 0.366 mmol) was dissolved in tetrahydrofuran / methanol (2: 1, v / v, 12 ml) and 1 N NaOH (4 ml) was added and stirred at room temperature for 14 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was acidified with 1 N HCl and extracted with chloroform / methanol (10/1, v / v). The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was solidified by adding an ether / hexane mixture to give the title product (132 mg, 62%) as a pale yellow amorphous product.
IR (ATR) ν: 2937, 2864, 1712, 1637, 1577, 1452 cm ^-1 ;
¹ H NMR (DMSO) δ: 1.12-1.47 (6H, m), 1.83-2.27 (7H, m), 2.30 (3H, s), 2.51 (3H, s), 2.76 (5H, m), 2.91-3.68 (6H, m), 3.90-4.07 (1H, m), 6.91 (1H, t, J = 8.3,
2.2 Hz), 7.11 (1H, t, J = 6.6 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.27 (2H, t, J = 7.3 Hz), 7.90 and 7.93 (total 1H, each s, amide isomers), 9.60 (1H, m), 10.05 (1H, s);
MS (ESI) m / z: 585 (M ⁺ +1).

Example 2
Trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrole Dinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4-[(5S) -dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester trans-4- [1-tert-butoxycarbonyl- (5S) -dimethylaminomethyl- ( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (522 mg, 1.31 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution to make it alkaline, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title product (347 mg, 89%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.30 (2 H, m), 1.40-1.60 (4 H, m), 1.91-2.30 (total 14H, series of m, including 6 H, s, at δ 2.27 ), 2.37-2.43 (1 H, m), 3.22-3.29 (1H, m), 3.41-3.52 (4 H, m), 3.66 (3 H, s), 3.95 (1 H, broad s).
MS (LC-MS) m / z: 299.6 (M ⁺⁺ 1).

(Process 2)
Trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrole Synthesis of methyl ester of dinylmethoxy] cyclohexanecarboxylic acid
[7-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -6-benzoxazolyl] acetic acid (199 mg, 0.60 mmol), trans-4-[(5S) -dimethylaminomethyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (178 mg, 0.60 mmol), EDC · HCl (172 mg, 0.90 mmol), HOBt (120 mg, 0.89 mmol) and triethylamine (125 μl, 0.90 mmol) in DMF ( 7 ml) and stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by column chromatography using silica gel, and the title compound (237 mg, 65%) was obtained as a colorless foam from the chloroform / methanol (30: 1 to 10: 1, v / v) fraction. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.53 (4 H, m), 1.93-2.61 (total 17 H, series of m, including total 6 H, each s, at δ2.27 and 2.30), 3.12- 3.27 (1 H, m), 3.36-3.90 (total 7 H, series of m, including total 3 H, each s, at δ3.63 and 3.67), 3.92 (3 H, s), 4.01-4.14 (1 H , m), 4.19 (1 H, m), 6.69-6.74 (1 H, m), 6.81-6.84 (1 H, m), 7.12-7.19 (1 H, m), 7.26-7.28 (1 H, m ), 7.76 (1 H, broad s), 8.27-8.31 (1 H, m).
MS (LC-MS) m / z: 615.6 (M ⁺ +1).

(Process 3)
Trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrole Synthesis of Dinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)- Dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (237 mg, 0.39 mmol) is dissolved in THF (3 ml), 0.5 N NaOH (2.30 ml, 1.15 mmol) is added, and at room temperature. Stir for 15 hours. The reaction mixture was acidified with 1 N HCl (1.15 ml, 1.15 mmol), and extracted with chloroform / methanol (9: 1, v / v). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by column chromatography using silica gel, and from chloroform / methanol (10: 1, v / v) to chloroform / methanol / H ₂ O (7: 3: 1, v / v) flow fraction The title product (187 mg, 81%) was obtained as a white amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.11-1.40 (4 H, m), 1.77-2.36 (total 17 H, series of m, including 6 H, s at δ 2.23), 3.09-3.41 (2 H , m), 3.50-3.57 (1 H, m), 3.76-3.98 (total 6 H, series of m, including 3 H, s, at δ 3.85), 4.11-4.15 (1 H, m), 6.86-6.91 (1 H, m), 7.06-7.15 (2 H, m), 7.25-7.27 (1 H, m), 8.17-8.20 (1 H, m), 10.15 (1 H, broad s), 12.03 (1 H , broad s).
MS (LC-MS) m / z: 601.8 (M ⁺ +1).
Anal.Calcd.for C ₃₁ H ₃₈ F ₂ N ₄ O ₆ : C, 61.99; H, 6.38; N, 9.33; F, 6.33.
Found: C, 62.40; H, 7.64; N, 7.72; F, 6.07.

Example 3
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] Cyclohexanecarboxylic acid (process 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] Synthesis of cyclohexanecarboxylic acid methyl ester In a manner similar to Example 2, (Step 2), using [7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid. The title product (318 mg, 99%) was prepared as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.52 (4 H, m), 1.92-2.61 (total 17 H, series of m, including 6 H, s, at δ 2.30), 3.12-3.26 (1 H, m), 3.35-3.89 (total 7 H, series of
m, including total 3 H, each s, at δ 3.62 and 3.66), 3.94 (3 H, s), 4.01-4.04 and 4.08-4.13 (total 1 H, each m), 4.19 (1 H, broad s), 6.91-6.93 (1 H, m), 7.02-7.17 (3 H, m), 7.24-7.26 (1 H, m), 7.72 (1 H, broad s), 8.37-8.40 (1 H, m).
MS (LC) m / z: 597.8 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S) -dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] Synthesis of cyclohexanecarboxylic acid Trans-4- [1-[[7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl was synthesized in the same manner as in Example 2, (Step 3). ]-(5S) -Dimethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester was used to produce the title product (223 mg, 72%) as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (4 H, m), 1.77-2.39 (total 17 H, series of m, including 6 H, s, at δ 2.22), 3.09-3.41 (2 H, m), 3.50-3.57 (1 H, m), 3.74-3.89
(total 5 H, m, including 3 H, s, at δ 3.85), 3.96-3.98 (1 H, m), 4.10-4.15 (1 H, m), 6.99-7.13 (4 H, m), 7.17 ( 1 H, d, J = 8.1 Hz), 8.13 (1 H, d, J = 7.8 Hz),
9.84 (1 H, broad s), 12.02 (1 H, broad s).
MS (LC-MS) m / z: 583.6 (M ⁺ +1).
Anal.Calcd.for C ₃₁ H ₃₉ FN ₄ O ₆ : C, 63.90; H, 6.75; N, 9.62; F, 3.26.
Found: C, 62.60; H, 7.66; N, 7.76; F, 2.56.

Example 4
Trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidini Rumethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester In a manner analogous to Example 1, (Step 7), diethylamine To give the title product (446 mg, 72%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.98-1.07 (6 H, m), 1.19-1.30 (2 H, m), 1.46-1.47 (total 13 H, m, including 9 H, s, at δ 1.47) , 1.86-2.30 (total 9 H, series of m), 2.38-2.51 (2 H, m), 2.60-2.68 (2 H, m), 3.16-3.25 and 3.33-3.37 (total 2 H, each m), 3.57-3.92 (total 6 H, series of m, including 3 H, s, at δ 3.66).
MS (LC-MS) m / z: 427.8 (M ⁺⁺ 1).

(Process 2)
Synthesis of trans-4-[(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester In a manner similar to Example 2, (Step 1), trans-4- [1-tert The title compound (340 mg, 100%) was prepared as a white solid by using -butoxycarbonyl- (5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (6 H, t, J = 7.1 Hz), 1.20-1.31 (2 H, m), 1.41-1.52 (3 H, m), 1.58-1.67 (1 H, m), 1.93-2.11 (6 H, m), 2.23-2.30 (1 H, m), 2.44-2.46 (2 H, m), 2.54-2.72 (4 H, m), 3.24-3.31 (1 H, m), 3.41-3.59 (4 H, m), 3.66 (3 H, s), 4.97 (1 H, broad s.)
MS (LC-MS) m / z: 327.4 (M ⁺ +1).

(Process 3)
Trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidini Synthesis of rumethoxy] cyclohexanecarboxylic acid methyl ester Trans-4-[(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester in a manner similar to Example 2, (Step 2) To give the title product (243 mg, 75%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.01-1.14 (6 H, m), 1.17-1.53 (4 H, m), 1.93-2.41 (total 11 H, series of m), 2.46-2.66 (4 H, m), 3.13-3.24 (1 H, m), 3.36-4.19 (total 12 H, series of m, including total 3 H, each s, at δ 3.63 and 3.67, and including 3
H, s, at δ 3.92), 6.69-6.74 (1 H, m), 6.81-6.84 (1 H, m), 7.12-7.18 (1 H, m), 7.26-7.28 (1 H, m), 7.75 (1 H, broad s), 8.27-8.31 (1 H, m).
MS (LC-MS) m / z: 643.6 (M ⁺ +1).

(Process 4)
Trans-4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidini Synthesis of rumethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[2- (5-fluoro-2-methoxyphenylamino) -7-fluoro-6] was prepared in a manner similar to Example 2, (Step 3). -Benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester to produce the title compound (159 mg, 67%) as a white amorphous did.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98-1.40 (total 10 H, series of m), 1.78-2.65 (total 15
H, series of m), 3.07-4.26 (total 10 H, series of m, including 3 H, s at δ 3.86), 6.87-6.91 (1 H, m), 7.06-7.14 (2 H, m), 7.26 -7.28 (1 H, m), 8.17-8.20 (1 H, m), 10.16 (1 H, broad s), 12.04 (1 H, broad s).
MS (LC-MS) m / z: 629.6 (M ⁺⁺ 1).
Anal.Calcd.for C ₃₃ H ₄₂ F ₂ N ₄ O ₆ : C, 60.03; H, 6.95; N, 8.49; F, 5.75.
Found: C, 59.93; H, 6.76; N, 8.26; F, 5.52.

Example 5
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexane Carboxylic acid (process 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexane Synthesis of carboxylic acid methyl ester The title compound was prepared in a manner similar to Example 4, (Step 1) using [7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid. Product (270 mg, 75%) was produced as a colorless amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.03 (6 H, t, J = 7.1 Hz), 1.12-1.53 (4 H, m), 1.93-2.67 (total 15 H, series of m), 3.13-3.27 ( 1 H, m), 3.36-4.19 (total 12 H, series of m, including total 3 H, each s, at δ 3.63 and 3.67, and including 3 H, s, at δ 3.94), 6.91-6.94 (1 H , m), 7.02-7.17 (3 H, m), 7.24 and 7.25 (total 1 H, each s), 7.72 (1 H, broad s), 8.38-8.41 (1 H, m).
MS (LC-MS) m / z: 625.4 (M ⁺⁺ 1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexane Synthesis of carboxylic acid Trans-4- [1-[[7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl] was prepared in a manner similar to Example 4, (Step 4). The title compound (171 mg, 65%) was prepared as a white amorphous by using-(5S) -diethylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 0.97-1.40 (total 10 H, series of m), 1.75-2.64 (total 15
H, series of m), 3.07-4.23 (total 10 H, series of m, including 3 H, s at δ 3.85), 6.99-7.19 (5 H, m), 8.12-8.13 (1 H, m), 9.85 (1 H, broad s), 12.06 (1 H, broad s).
MS (LC-MS) m / z: 611.6 (M ⁺ +1).
_{.. Anal Calcd for C 33 H} 43 FN 4 O 6 · 3 / 2H 2 O: C, 62.15; H, 7.27; N, 8.79; F, 2.98.
Found: C, 62.37; H, 7.24; N, 8.36; F, 2.85.

Example 6
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino ) Methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4- [1- (tert-butoxycarbonyl)-(5S) -cyclopropylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester
The title compound (1.19 g, 88%) was obtained as a pale yellow oil by the same method as in Example 1, (Step 7), but using cyclopropylamine.
MS (LC-ESI) m / z: 411 (M ⁺ +1).

(Process 2)
Synthesis of trans-4- [1- (tert-butoxycarbonyl)-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester
Trans 4- [1- (tert-butoxycarbonyl)-(5S) -cyclopropylaminomethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (1.19 g, 2.90 mmol) and formalin (1.18 g, 14.50 mmol) was dissolved in tetrahydrofuran (15 ml), sodium triacetoxyborohydride (1.23 g, 5.80 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography using silica gel (eluent n-hexane: ethyl acetate = 2: 1) to give the title product (1.05 g, 85%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.24-0.30 (1H, m), 0.38-0.49 (3H, m), 1.17-1.32 (2H, m), 1.40-1.48 (total 12H, m, including 9H, s , at δ 1.48), 1.64-2.05 (8H, m), 2.21-2.41 (5H, m), 2.54-2.57 and 2.73-2.76 (total 1H, each m), 3.17-3.24 and 3.33-3.40 (total 2H, each m), 3.57-3.94 (6H, m).
MS (LC-ESI) m / z: 425 (M ⁺ +1).

(Process 3)
Synthesis of trans-4-[(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester trans 4- [1- (tert-butoxycarbonyl) -(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (1.05 g, 2.47 mmol) was dissolved in dichloromethane (5 ml) Fluoroacetic acid (5 ml) was added and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it weakly basic, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.79 g, 98%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.35-0.53 (4H, m), 1.20-1.30 (2H, m), 1.42-1.60 (3H, m), 1.69-1.81 (2H, m), 1.98-2.40 ( total 10H, series of m, including 3H, s, at δ 2.36), 2.53 (1H, dd, J = 12.7, 5.4 Hz), 2.72 (1H, dd, J = 12.7, 10.0 Hz), 3.27-3.34 (1H , m), 3.48-3.76 (total 8H, m, including 3H, s, at δ 3.66).
MS (LC-ESI) m / z: 325 (M ⁺ +1).

(Process 4)
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino ) Synthesis of methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester trans-4-[(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] Cyclohexanecarboxylic acid methyl ester is condensed with [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in a manner analogous to Example 2, (Step 2) By performing the reaction, the title product (84%) was produced as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.24-0.54 (4H, m), 1.11-1.53 (4H, m), 1.69-1.72 (1H, m), 1.88-2.40 (total 12H, series of m), 2.60 -2.62 (1H, m), 3.12-3.27 (1H, m), 3.35-3.96 (total 11H, series of m, including 3H, s, at δ 3.92), 4.08-4.27 (2H, m), 6.69-6.74 (1H, m), 6.81-6.84 (1H, m), 7.13-7.20 (1H, m), 7.23-7.28 (1H, m), 7.76 (1H, broad s), 8.27-8.31 (1H, m).
MS (LC-ESI) m / z: 641 (M ⁺ +1).

(Process 5)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methyl Synthesis of amino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid In a manner similar to Example 2, (Step 3), trans-4- [1-[[7-fluoro-2- (5- Fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester To give the title product (yield = 85%) as a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 0.20-0.49 (4H, m), 1.09-1.40 (4H, m), 1.62-2.35 (total 13H, series of m), 2.56-2.67 (1H, m) , 3.08-3.40 (2H, m), 3.50-3.56 (1H, m), 3.76-4.04 (total 7H, m, including 3H, s, at δ 3.85), 4.14-4.16 (1H, m), 6.86-6.91 (1H, m), 7.06-7.15 (2H, m), 7.26 (1H, d, J = 8.1 Hz), 8.17-8.21 (1H, m), 10.17 (1H, broad s), 12.07 (1H, broad s ).
IR (ATR) cm ^-1 : 1639, 1577, 1448, 1217, 1068.
MS (LC-ESI) m / z: 627 (M ⁺ +1).
Anal. Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₆ 1 / 2H ₂ O: C, 62.35; H, 6.50; N, 8.81; F, 5.98. Found: C, 62.02; H, 6.20; N, 8.79 ; F, 5.85.

Example 7
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester [7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl in a manner similar to Example 6, (Step 3) The title product (yield 96%) was prepared as a pale yellow amorphous product by using [l] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 0.24-0.54 (4H, m), 1.09-1.53 (4H, m), 1.68-1.75 (1H, m), 1.87-2.40 (total 12H, series of m), 2.60 -2.62 (1H, m), 3.12-3.27 (1H, m), 3.34-3.98 (total 11H, series of m, including 3H, s, at δ 3.94), 4.08-4.25 (2H, m), 6.91-6.94 (1H, m), 7.02-7.18 (3H, m), 7.23-7.24 (1H, m), 7.72 (1H, s), 8.37-8.41 (1H, m).
MS (LC-ESI) m / z: 623 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[7-fluoro-2- (2-methoxyphenyl) amino] was synthesized in the same manner as in Example 6, (Step 4). -6-Benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (Yield 73%) was produced as a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 0.20-0.45 (4H, m), 1.11-1.39 (4H, m), 1.62-2.35 (total 13H,
series of m), 2.55-2.67 (1H, m), 3.08-3.40 (2H, m), 3.49-3.55 (1H, m), 3.74-4.02 (total 7H, m, including 3H, s, at δ 3.85) , 4.13-4.16 (1H, m), 6.99-7.19 (5H, m), 8.13 (1H, d, J = 8.1 Hz), 9.86 (1H, broad s), 12.13 (1H, broad s).
IR (ATR) cm ^-1 : 1637, 1579, 1452, 1252, 1068, 746.
MS (LC-ESI) m / z: 609 (M ⁺ +1).
Anal. Calcd for C ₃₃ H ₄₁ FN ₄ O ₆・ 1 / 2H ₂ O: C, 64.17; H, 6.85; N, 9.07; F, 3.08. Found:
C, 63.91; H, 6.54; N, 9.04; F, 3.01.

Example 8
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S)- Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S)- Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester A condensation reaction is carried out using [2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in a manner similar to Example 6, (Step 3). This produced the title product (yield 100%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.25-0.52 (4H, m), 1.07-1.51 (4H, m), 1.70-1.73 (1H, m), 1.85-2.39 (total 12H, series of m), 2.57 -2.58 (1H, m), 3.12-3.22 (1H, m), 3.28-3.95 (total 11H, series of m, including 3H, s, at δ 3.94), 4.04-4.25 (2H, m), 6.90-6.93 (1H, m), 7.00-7.12 (3H, m), 7.35-7.36 (1H, m), 7.42-7.44 (1H, m), 7.62 (1H, s), 8.39-8.41 (1H, m).
MS (LC-ESI) m / z: 605 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrole Dinylmethoxy] cyclohexanecarboxylic acid In a manner analogous to Example 6, (Step 4), trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]- (5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester was used to obtain the title product (yield 73%) as a colorless amorphous product. Manufactured as.
¹ H-NMR (DMSO-d ₆ ) δ: 0.21-0.48 (4H, m), 1.07-1.38 (4H, m), 1.63-2.34 (total 13H,
series of m), 2.52-2.65 (1H, m), 3.07-3.55 (4H, m), 3.63-3.68 (1H, m), 3.80-3.85 (total 4H, m, including 3H, s, at δ 3.85) , 3.98-4.12 (2H, m), 6.98-7.08 (4H, m), 7.32-7.33 (2H, m), 8.15-8.18 (1H, m), 9.53-9.55 (1H, m), 12.05 (1H, broad s).
IR (ATR) cm ^-1 : 1637, 1574, 1250, 1113, 744.
MS (LC-ESI) m / z: 591 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₂ N ₄ O ₆・ 1 / 4H ₂ O: C, 66.59; H, 7.20; N, 9.41.Found: C, 66.39; H, 7.29; N, 9.38.

Example 9
Trans 4- [1-[[7-Fluoro-2- (2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- ( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester [7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] The title compound (yield 100%) was produced as a pale yellow oil by conducting a condensation reaction with [l] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 0.24-0.54 (4H, m), 1.11-1.52 (4H, m), 1.68-1.75 (1H, m), 1.87-2.40 (total 15H, series of m), 2.60 -2.62 (1H, m), 3.08-3.26 (1H, m), 3.34-3.92 (8H, m), 4.08-4.25 (2H, m), 7.01-7.35 (6H, m), 8.07-8.10 (1H, m).
MS (LC-ESI) m / z: 607 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[7-Fluoro-2- (2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- ( Synthesis of 2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid In a manner similar to Example 6, (Step 4), trans-4- [1-[[7-fluoro-2- (2-methylphenyl) amino- By performing a condensation reaction with 6-benzoxazolyl] acetyl]-(5S)-(N-cyclopropyl-N-methylamino) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester The title product (yield 78%) was prepared as a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 0.21-0.49 (4H, m), 1.06-1.40 (4H, m), 1.60-2.35 (16H, m), 2.55-2.67 (1H, m), 3.06- 3.55 (4H, m), 3.73-4.16 (4H, m), 7.04-7.13 (3H, m), 7.24-7.27 (2H, m), 7.80 (1H, d, J = 8.3 Hz), 9.89 (1H, broad s), 12.10 (1H, broad s) .IR (ATR) cm ^-1 : 1637, 1577, 1452, 1068, 748.
MS (LC-ESI) m / z: 593 (M ⁺ +1).
Anal. Calcd for C ₃₃ H ₄₁ FN ₄ O ₅・ 3 / 4H ₂ O: C, 65.38; H, 7.07; N, 9.24; F, 3.13. Found:
C, 65.35; H, 6.72; N, 9.22; F, 3.08.

Example 10
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4- [1- (tert-butoxycarbonyl)-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester trans-4- [1- (tert -Butoxycarbonyl)-(5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (623 mg, 1.69 mmol) and piperidine (334 μl, 3.37 mmol) dissolved in tetrahydrofuran (10 ml) Sodium triacetoxyborohydride (536 mg, 2.53 mmol) was added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography using silica gel (eluent: chloroform: methanol = 30: 1-15: 1) to give the title compound (628 mg, 85%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.14-1.28 (2H, m), 1.39-1.57 (total 17H, series of m, including 9H, s, at δ 1.47), 1.87-2.11 (9H, m), 2.22 -2.52 (6H, m), 3.18-3.37 (2H, m), 3.57-3.87 (total 6H, m, including 3H, s, at δ 3.67).
MS (LC-ESI) m / z: 438 (M ⁺ ).

(Process 2)
Synthesis of trans-4-[(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester trans-4- [1- (tert-butoxycarbonyl)-(5S)- (1-Piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (628 mg, 1.43 mmol) is dissolved in dichloromethane (5 ml), trifluoroacetic acid (5 ml) is added, and the mixture is brought to room temperature. And stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it weakly basic, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (467 mg, 96%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.31 (2H, m), 1.42-1.80 (8H, m), 1.99-2.30 (9H, m), 2.48-2.68 (6H, m), 3.30-3.35 ( 1H, m), 3.57-3.69 (total 6H, m, including 3H, s, at δ 3.66), 3.79-3.85 (1H, m), 6.39 (1H, broad s).
MS (LC-ESI) m / z: 339 (M ⁺ +1).

(Process 3)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester
[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetic acid (139 mg, 0.42 mmol), trans-4-[(5S)-(1-piperidinyl) methyl -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (141 mg, 0.42 mmol), EDC · HCl (120 mg, 0.63 mmol), HOBt (84 mg, 0.62 mmol), and triethylamine (87 μl, 0.62
mmol) was dissolved in N, N-dimethylformamide (5 ml) and stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography using silica gel (eluent: chloroform: methanol = 30: 1-15: 1) to obtain the title compound (181 mg, 66%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.13-2.49 (total 24H, series of m), 3.12-3.26 (1H, m), 3.37-3.93 (total 11H, series of m, including 3H, s, at δ 3.92 ), 4.08-4.19 (2H, m), 6.69-6.74 (1H, m), 6.81-6.84 (1H, m), 7.12-7.28 (2H, m), 7.74-7.77 (1H, m), 8.27-8.31 (1H, m).
MS (LC-ESI) m / z: 655 (M ⁺ +1).

(Process 4)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-( 5S)-(1-Piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester (181 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 ml) and 0.5 N aqueous sodium hydroxide solution (1.70 ml) , 0.85 mmol) and stirred at room temperature for 7 hours. The reaction mixture was made weakly acidic by adding 1 N hydrochloric acid, and extracted with 10% methanol-chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography using silica gel (elution solvent chloroform: methanol = 10: 1 to chloroform: methanol: water = 7: 3: 1 lower layer) to give the title compound (138 mg, 78%) Obtained as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-2.35 (total 24H, series of m), 3.09-3.57 (5H, m), 3.83-4.16 (6H, m), 6.87-6.91 (1H, m) , 7.07-7.13 (2H, m), 7.26 (1H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 10.8, 2.9 Hz), 10.15 (1H, broad s), 12.04 (1H, broad s ).
IR (ATR) cm ^-1 : 1639, 1577, 1448, 1404, 1068.
MS (LC-ESI) m / z: 641 (M ⁺ +1).
Anal. Calcd for C ₃₄ H ₄₂ F ₂ N ₄ O ₆・ 7 / 4H ₂ O: C, 60.75; H, 6.82; N, 8.33; F, 5.65. Found: C, 60.99; H, 6.63; N, 7.95 ; F, 5.50.

Example 11
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidini Rumethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidini Synthesis of L-methoxy] cyclohexanecarboxylic acid methyl ester In a manner similar to Example 10, (Step 3), using [7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid The title product (yield 86%) was produced as a yellow oil by conducting a condensation reaction.
¹ H-NMR (CDCl ₃ ) δ: 1.11-2.81 (total 24H, series of m), 3.13-3.24 (1H, m), 3.36-3.55 (1H, m), 3.59-3.98 (total 10H, series of m , including 3H, s, at δ 3.94), 4.05-4.30 (2H, m), 6.91-6.94 (1H, m), 7.00-7.17 (3H, m), 7.20-7.24 (1H, m), 7.72 (1H , broad s), 8.37-8.41 (1H, m).
MS (LC-ESI) m / z: 637 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidini Synthesis of rumethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[7-fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] was prepared in a manner similar to Example 10, (Step 4). The title product (yield 72%) was obtained as a pale yellow amorphous product by using [Lu] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester Manufactured.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-2.13 (total 24H, series of m), 3.11-4.18 (total 11H, series of m, including 3H, s, at δ 3.85), 6.99-7.19 (5H , m), 8.11-8.13 (1H, m), 9.84 (1H, broad s), 12.04 (1H, broad s).
IR (ATR) cm ^-1 : 1635, 1577, 1450, 1402, 1252, 1068.
MS (LC-ESI) m / z: 622 (M ⁺ ).
Anal. Calcd for C ₃₄ H ₄₃ FN ₄ O ₆・ 2H ₂ O: C, 61.99; H, 7.19; N, 8.50; F, 2.88. Found: C, 62.07; H, 7.00; N, 8.31; F, 2.78 .

Example 12
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexane Carboxylic acid (process 1)
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexane Synthesis of carboxylic acid methyl ester The title compound was obtained by conducting a condensation reaction with [2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in the same manner as in Example 10, (Step 3). (Yield 86%) Prepared as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.60 (total 9H, series of m), 1.91-2.66 (total 15H, series of m), 3.12-3.22 (1H, m), 3.45-3.49 (1H, m ), 3.65-4.05 (total 11H, series of m, including 3H, s, at δ 3.94), 4.18-4.20 (1H, m), 6.92 (1H, d, J = 7.6 Hz), 7.00-7.13 (3H, m), 7.35 (1H, s), 7.41-7.43 (1H, m), 7.62 (1H, broad s), 8.40 (1H, d, J = 7.6 Hz).
MS (LC-ESI) m / z: 619 (M ⁺ ).

(Process 2)
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexane Synthesis of carboxylic acid Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S) was prepared in a manner similar to Example 10, (Step 4). The title product (yield 64%) was prepared as a pale yellow amorphous product by using-(1-piperidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.11-2.30 (total 24H, series of m), 3.10-3.54 (5H, m), 3.66-4.18 (6H, m, including 3H, s, at δ 3.85) , 6.98-7.08 (4H, m), 7.31-7.34 (2H, m), 8.16 (1H, d, J = 8.1 Hz), 9.53-9.55 (1H, m), 12.05 (1H, broad s).
IR (ATR) cm ^-1 : 1637, 1574, 1244, 746.
MS (LC-ESI) m / z: 605 (M ⁺ ).
Anal. Calcd for C ₃₄ H ₄₄ N ₄ O ₆ , 3.25H ₂ O: C, 61.57; H, 7.67; N, 8.45. Found: C, 61.36; H, 6.76; N, 8.32.

Example 13
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4- [1- (tert-butoxycarbonyl)-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester Example 10 (Step 1) and In a similar manner, the title product (96% yield) was prepared as a pale yellow oil by using pyrrolidine.
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.28 (2H, m), 1.38-1.49 (total 13H, m), 1.75-2.05 (10H, m), 2.22-2.27 (1H, m), 2.43-2.60 (6H, m), 3.19-3.38 (2H, m), 3.58-3.69 (5H, m), 3.79-3.89 (1H, m).
MS (LC-ESI) m / z: 425 (M ⁺ +1).

(Process 2)
Synthesis of trans-4-[(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester In a manner similar to Example 10 (Step 2), trans-4- By using [1- (tert-butoxycarbonyl)-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester, the title product (yield 85%) was obtained. Prepared as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.30 (2H, m), 1.40-1.57 (4H, m), 1.80-2.11 (10H, m), 2.25-2.30 (1H, m), 2.39-2.43 ( 1H, m), 2.59-2.74 (5H, m), 3.21-3.53 (6H, m), 3.66 (3H, s).
MS (LC-ESI) m / z: 325 (M ⁺ +1).

(Process 3)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester synthesis trans-4- [1- (tert-butoxycarbonyl)-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid The acid methyl ester was condensed in the same manner as in Example 10, (Step 3) using [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -6-benzoxazolyl] acetic acid. The title product (yield 98%) was prepared as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.53 (4H, m), 1.78-2.32 (total 14H, series of m), 2.47-2.68 (5H, m), 3.12-3.27 (1H, m), 3.37 -3.69 (5H, m), 3.77-3.88 (2H, m), 3.92 (3H, s), 4.05-4.26 (2H, m), 6.69-6.74 (1H, m), 6.81-6.84 (1H, m) , 7.12-7.19 (1H, m), 7.26-7.28 (1H, m), 7.76 (1H, broad s), 8.27-8.31 (1H, m).
MS (LC-ESI) m / z: 641 (M ⁺ +1).

(Process 4)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid In a manner similar to Example 10 (Step 4), trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methoxyphenyl] ) Amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester to give the title compound (yield 67 %) As a pale yellow amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.40 (4H, m), 1.84-2.21 (total 14H, series of m), 3.12-3.56 (9H, m), 3.85-3.92 (5H, m) , 4.15-4.23 (1H, m), 6.87-6.92 (1H, m), 7.06-7.14 (2H, m), 7.26 (1H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 10.9, 3.1 Hz), 10.15 (1H,
broad s), 12.05 (1H, broad s).
IR (ATR) cm ^-1 : 1639, 1577, 1448, 1402, 1068.
MS (LC-ESI) m / z: 627 (M ⁺ +1).
Anal. Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₆・ 3H ₂ O: C, 58.22; H, 6.81; N, 8.23; F, 5.58. Found: C, 58.08; H, 6.67; N, 8.08; F , 5.39.

Example 14
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidini Rumethoxy] cyclohexanecarboxylic acid
(Process 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidini Synthesis of methyl ester of rumethoxy] cyclohexanecarboxylic acid using [7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in a manner similar to (Step 3) of Example 13 The title product (83% yield) was produced as a pale yellow oil by conducting a condensation reaction.
¹ H-NMR (CDCl ₃ ) δ: 1.14-1.53 (4H, m), 1.76-1.80 (5H, m), 1.93-2.31 (9H, m), 2.48-2.68 (5H, m), 3.14-3.24 ( 1H, m), 3.36-3.69 (5H, m), 3.76-3.92 (2H, m), 3.94 (3H, s), 4.06-4.24 (2H, m), 6.91-6.94 (1H, m), 7.02- 7.17 (3H, m), 7.24-7.26 (1H, m), 7.71-7.73 (1H, m), 8.38-8.41 (1H, m).
MS (LC-ESI) m / z: 623 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidini Synthesis of rumethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[7-fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] was prepared in a manner similar to Example 13 (Step 4). [L] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester to give the title product (yield 64%) as a colorless amorphous product Manufactured.
¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.40 (4H, m), 1.84-2.21 (total 14H, series of m), 3.09-3.14 (1H, m), 3.24-3.56 (8H, m) , 3.77-3.96 (5H, m), 4.15-4.22 (1H, m), 6.99-7.03 (1H, m), 7.06-7.13 (3H, m), 7.17-7.19 (1H, m), 8.11-8.13 ( 1H, m), 9.85 (1H, broad s), 12.06 (1H, broad s).
IR (ATR) cm ^-1 : 1635, 1577, 1450, 1402, 1252, 1068.
MS (LC-ESI) m / z: 609 (M ⁺ +1).
_{. Anal Calcd for C 33 H 41} FN 4 O 6 · 3H 2 O:. C, 59.81; H, 7.15; N, 8.45; F, 2.87 Found: C, 59.96; H, 6.74; N, 8.38; F, 2.77 .

Example 15
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexane Carboxylic acid (process 1)
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexane Synthesis of carboxylic acid methyl ester The title compound was obtained by conducting a condensation reaction with [2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in the same manner as in Example 13, (Step 3). (Yield 87%) was produced as a colorless amorphous product.
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.48 (4H, m), 1.75-1.80 (5H, m), 1.90-2.28 (9H, m), 2.43-2.66 (5H, m), 3.12-3.22 ( 1H, m), 3.30-3.88 (7H, m), 3.94 (3H, s), 4.00-4.06 (1H, m), 4.20-4.24 (1H, m), 6.91-6.93 (1H, m), 7.01- 7.12 (3H, m), 7.35 (1H, s), 7.43 (1H, d, J = 8.1 Hz), 7.62 (1H, s), 8.40 (1H, dd, J = 7.7, 1.8 Hz).
MS (LC-ESI) m / z: 605 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexane Synthesis of carboxylic acid Trans-4- [1-[[2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S) was prepared in a manner analogous to Example 13, (Step 4). The title product (yield 76%) was prepared as a colorless amorphous product by using-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.38 (4H, m), 1.86-2.19 (total 14H, series of m), 3.10-3.54 (9H, m), 3.66-3.98 (5H, m) , 4.17-4.20 (1H, m), 6.98-7.03 (1H, m), 7.07-7.08 (3H, m), 7.32 (2H, d, J = 8.1 Hz), 8.16 (1H, d, J = 8.1 Hz ), 9.54 (1H, broad s), 12.05 (1H, broad s).
IR (ATR) cm ^-1 : 1635, 1577, 1450, 1402, 1252, 1068.
MS (LC-ESI) m / z: 591 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₂ N ₄ O ₆・ 3H ₂ O: C, 61.47; H, 7.50; N, 8.69. Found: C, 61.69; H, 7.23; N, 8.60.

Example 16
Trans-4- [1-[[2- (4-Chloro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidini Rumethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[2- (4-Chloro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidini Synthesis of methyl ester of rumethoxy] cyclohexanecarboxylic acid In a manner similar to Example 13, (Step 3), using [2- (4-chloro-2-methoxyphenylamino) -6-benzoxazolyl] acetic acid. The title product (52% yield) was produced as a pale yellow oil by conducting a condensation reaction.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.48 (4H, m), 1.78-2.31 (total 14H, series of m), 2.43-2.65 (5H, m), 3.14-3.20 (1H, m), 3.33 -3.68 (5H, m), 3.73-3.88 (2H, m), 3.94 (3H, s), 3.97-4.04 (1H, m), 4.18-4.20 (1H, m), 6.90 (1H, d, J = 2.2 Hz), 7.03 (1H, dd, J = 8.8, 2.2 Hz), 7.10-7.13 (1H, m), 7.34-7.36 (1H, m), 7.42 (1H, d, J = 8.1 Hz), 7.52 ( 1H, s), 8.37 (1H, dd, J = 8.5, 1.7 Hz).
MS (LC-ESI) m / z: 639 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[2- (4-Chloro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidini Synthesis of rumethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[2- (4-chloro-2-methoxyphenyl) amino-6-benzoxazolyl] was prepared in a manner similar to Example 13, (Step 4). [L] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester to give the title product (yield 72%) as a colorless amorphous product Manufactured.
¹ H-NMR (DMSO-d ₆ ) δ: 1.09-1.38 (4H, m), 1.70-2.19 (total 14H, series of m), 2.56-2.66 (5H, m), 3.09-3.54 (4H, m) , 3.66-4.17 (6H, m), 7.06-7.09 (2H, m), 7.14-7.15 (1H, m), 7.33-7.35 (2H, m), 8.23 (1H, d, J = 8.6 Hz), 9.72 (1H, broad s), 12.05 (1H, broad s).
IR (ATR) cm ^-1 : 1635, 1574, 1406, 1250, 1095.
MS (LC-ESI) m / z: 625 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₁ ClN ₄ O ₆・ 2H ₂ O: C, 59.95; H, 6.86; N, 8.47. Found: C, 59.93;
H, 6.79; N, 8.38.

Example 17
Trans-4- [1-[[2- (4-Chloro-2-methoxyphenyl) amino-7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[2- (4-Chloro-2-methoxyphenyl) amino-7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester Synthesis of [2- (4-chloro-2-methoxyphenylamino) -7-fluoro-6-benzoate in a manner similar to Example 13, (Step 3) The title product (81% yield) was produced as a brown oil by conducting a condensation reaction with [oxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.14-1.52 (4H, m), 1.76-2.31 (14H, m), 2.48-2.68 (5H, m), 3.13-3.24 (1H, m), 3.37-3.69 ( 5H, m), 3.76-3.94 (total 5H, m, including 3H, s, at δ 3.94), 4.07-4.24 (2H, m), 6.90 (1H, d, J = 2.0 Hz), 7.04 (1H, dd , J = 8.6, 2.2 Hz), 7.12-7.16 (1H, m), 7.24-7.25 (1H, m), 7.62-7.63 (1H, m), 8.36 (1H, dd, J = 8.6, 2.7 Hz).
MS (LC-ESI) m / z: 657 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[2- (4-Chloro-2-methoxyphenyl) amino-7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid In a manner similar to Example 13, (Step 4), trans-4- [1-[[2- (4-chloro-2-methoxyphenyl) amino-7 -Fluoro-6-benzoxazolyl] acetyl]-(5S)-(1-pyrrolidinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid methyl ester to give the title product (yield 82 %) As a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.40 (4H, m), 1.77-2.20 (total 14H, series of m), 3.09-3.55 (9H, m), 3.80-4.21 (total 6H, series of m, including 3H, s, at δ 3.88), 7.07-7.12 (2H, m), 7.17-7.21 (2H, m), 8.17-8.20 (1H, m), 10.01 (1H, broad s), 12.05 ( 1H, broad s).
IR (ATR) cm ^-1 : 1637, 1577, 1406, 1068.
MS (LC-ESI) m / z: 643 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₀ ClFN ₄ O ₆・ 5 / 2H ₂ O: C, 57.59; H, 6.59; N, 8.14.
Found: C, 57.75; H, 6.45; N, 7.95.

Example 18
Trans 4- [1-[[(7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(CN, O-dimethylhydroxylaminomethyl)-(2S ) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of tert-butyl (2S, 5S) -2-({[trans-4- (ethoxycarbonyl) cyclohexyl] oxy} methyl) -5-formyl-1-pyrrolidinecarboxylate Oxalyl chloride (3.74 ml, 42.9 mmol) Dissolved in dichloromethane (90 ml), a mixed solution of DMSO (6.09 ml, 85.8 mmol) and dichloromethane (10 ml) was added dropwise at −78 ° C. under a nitrogen gas atmosphere. After stirring for 30 minutes, trans 4- [1-tert-butoxycarbonyl- (5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester dissolved in dichloromethane (40 ml) (8.27 g, 21.5 mmol) was added at −78 ° C., and the mixture was stirred for 60 minutes at the same temperature. Triethylamine (17.9 ml, 128 mmol) was added, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added, the temperature was raised to room temperature, and the organic layer obtained by separating from dichloromethane was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (Biotage 40 M +, hexane / ethyl acetate, 3: 1 to 1: 3) to obtain the title compound (7.55 g, 92%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.17-1.33 (6H, m), 1.42 (9H, s), 1.81-2.33 (10H, m), 3.16-3.65 (3H, m), 3.98-4.29 (4H, m), 9.55 (1H, dd, J = 27.0, 2.0 Hz).

(Process 2)
Synthesis of trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester trans 4- [1-tert- Butoxycarbonyl- (5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (660 mg, 1.72 mmol) and N, O-dimethylamine hydrochloride (503 mg, 5.16 mmol) in tetrahydrofuran ( 20 ml), sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was added and stirred for 14 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and stirred for a while, followed by extraction with ethyl acetate. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (SiO ₂ 50 g, ethyl acetate: n-hexane = 4: 1 v / v) to obtain the title compound (490 mg, 67%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.16-1.32 (5H, m), 1.39-1.52 (12H, m), 1.89-2.51 (9H, m), 2.57 and 2.59 (total 3H, each s, amide isomers) , 2.81-3.41 (3H, m), 3.46 and 3.47 (total 3H, each m, amide isomers), 4.11 (2H, q, J = 7.1 Hz).
MS (ESI) m / z: 429 (M ⁺ +1).

(Process 3)
Trans 4-[(5S)-(N, O-Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester trans 4- [1-tert-butoxycarbonyl- (5S)- (N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (490 mg, 1.14 mmol) in dichloromethane (20 ml) was treated with TFA (2 ml) at room temperature. The mixture was further stirred for 15 hours. The reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, the pH was adjusted to 10 with 1 N aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (370 mg, 99%) as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.31 (5H, m), 1.37-1.52 (3H, m), 1.54-2.34 (9H, m), 2.52-2.56 (2H, m), 2.56 (3H, s), 3.18-3.48 (5H, m), 3.52 (3H, s), 4.11 (2H, q, J = 7.1 Hz).
MS (ESI) m / z: 329 (M ⁺ +1).

(Process 4)
Trans 4- [1-[[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetic acid (169 mg, 0.563 mmol), trans 4-[(5S)-(N, O-dimethylhydroxylaminomethyl)- (2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (185 mg, 0.563 mmol), EDC.HCl (154 mg, 0.804 mmol) and HOBt (109 mg, 0.804 mmol) in dichloromethane solution (6 ml) Triethylamine (0.39 ml, 2.82 mmol) was added at room temperature and stirred for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (ethyl acetate: n-hexane = 4: 1 v / v) to give the title compound (274 mg, 80%) as a yellow oil Obtained as a thing.
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.69 (8H, m), 1.89-2.33 (7H, m), 2.43-2.67 (3H, m), 2.70
(4H, s), 2.80 (1H, d, J = 12.9 Hz), 3.04-4.26 (13H, m), 7.00-7.36 (6H, m), 8.05-8.12 (1H, m).
MS (ESI) m / z: 611 (M ⁺ +1).

(Process 5)
Trans 4- [1-[[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid synthesis trans 4- [1-[[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (274 mg, 0.449 mmol) in tetrahydrofuran / methanol mixture (4 ml / 2 ml) at room temperature with 1 N water An aqueous sodium oxide solution (4 ml, 4 mmol) was added and stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 4 with 1 N hydrochloric acid and extracted with a chloroform / methanol mixed solution [10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (chloroform / methanol = 20/1 v / v) to obtain the title compound (181 mg) as a colorless glassy solid, which was lyophilized from dioxane. 178 mg (68%) was obtained as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.13-1.52 (4H, m), 1.83-2.27 (4H, m), 2.31 (3H, s), 2.53-2.61 (1H, m), 2.62 (3H, s) , 2.75-2.84 (1H, m), 3.06-3.31 (1H, m), 3.34-3.51 (3H, m), 3.52 (3H, s), 3.64-4.00 (2H, m), 4.03-4.32 (3H, m), 4.04-4.04 (4H, m), 6.74 (1H, td, J = 8.2, 2.5 Hz), 7.11-7.25 (5H, m), 8.04-8.13 (1H, m).
MS (ESI) m / z: 583 (M ⁺ +1).
IR (ATR) cm ^-1 : 2935, 2860, 1724, 1697, 1637, 1577, 1500.
Anal.Calcd for C ₃₁ H ₃₉ FN ₄ O ₆・ 0.5H ₂ O: C, 62.93; H, 6.81; F, 3.21; N, 9.47.
Found: C, 62.86; H, 6.80; F, 3.11; N, 9.05.

Example 19
Trans 4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [7-fluoro-2- (5-fluoro-2-methylphenylamino)-in the same manner as in Example 18, (Step 4) The title product (yield 81%) was produced as a yellow oil by conducting a condensation reaction with 6-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.13-1.52 (7H, m), 1.83-2.27 (5H, m), 2.31 (3H, s), 2.53-2.61 (1H, m), 2.62 (3H, s) , 2.75-2.84 (1H, m), 3.06-3.31 (1H, m), 3.34-3.51 (3H, m), 3.52 (3H, s), 3.64-4.00 (2H, m), 4.03-4.32 (3H, m), 4.04-4.04 (4H, m), 6.74 (1H, td, J = 8.2, 2.5 Hz), 7.11-7.25 (4H, m), 8.04-8.13 (1H, m).
MS (ESI) m / z: 629 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid Trans 4- [1-[[2- (5-fluoro-2-methylphenylamino)] in a manner analogous to Example 18, (Step 5) -7-Fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester The title product (66% yield) was prepared as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.54 (4H, m), 1.87-2.47 (12H, m), 2.52-2.68 (4H, m), 2.76 and 2.79 (total 1H, each d, J = 12.7 and 13.1 Hz respectively, amide isomers),
3.02-3.30 (1H, m), 3.33-4.05 (7H, m), 4.10-4.29 (2H, m), 6.75 (1H, t, J = 8.3 Hz), 7.09-7.24 (4H, m), 7.78 and 7.87 (total 1H, dd and d, J = 10.5, 2.4 and 11.0Hz respectively, amide isomers).
MS (ESI) m / z: 601 (M ⁺ +1).
IR (ATR) cm ^-1 : 2937, 2862, 1701, 1639, 1610, 1577, 1550.
Anal.Calcd for C ₃₁ H ₃₈ F ₂ N ₄ O ₆ , 0.5H ₂ O: C, 61.07; H, 6.46; F, 6.23; N, 8.99.
Found: C, 61.15; H, 6.46; F, 6.23; N, 8.99.

Example 20
Trans 4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester In a manner similar to Example 18, (Step 4), [7-Fluoro-2- (5-fluoro-2-methoxyphenylamino)- The title product (yield 81%) was produced as a yellow oil by conducting a condensation reaction with 6-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.00-1.57 (7H, m), 1.84-2.34 (9H, m), 2.53-2.64 (4H, m), 2.81 (1H, d, J = 12.7 Hz), 3.02 -3.31 (2H, m), 3.35-3.58 (4H, m), 3.62-3.98 (5H, m), 4.02-4.29 (4H, m), 6.70 (1H, td, J = 8.3, 2.9 Hz), 6.80 and 6.83 (total 1H, each d, J = 10.0 and 4.6 Hz respectively, amide isomers), 7.16 (1H, dd, J = 14.7, 6.4
Hz), 7.28-7.24 (1H, m), 7.79 (1H, s), 8.28 (1H, dt, J = 10.3, 2.5Hz).
MS (ESI) m / z: 645 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid synthesis
In a manner similar to Example 18, (Step 5), trans 4- [1-[[2- (5-fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was used to produce the title product (90% yield) as a colorless glassy solid .
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.57 (4H, m), 1.88-2.46 (9H, m), 2.52-2.67 (4H, m), 2.81 (1H, d, J = 12.7 Hz), 3.03 -3.57 (6H, m), 3.61-4.00 (6H, m), 4.06-4.30 (2H, m), 6.67-6.74 (1H, m), 6.78-6.85 (1H, m), 7.14 and 7.16 (total 1H , each t, each J = 6.4 Hz, amide isomers), 7.23 (1H, s), 7.25 and 7.27 (total 1H, each s, amide isomers), 8.20 (1H, dt, J = 10.1, 2.6 Hz).
MS (ESI) m / z: 617 (M ⁺ +1).
IR (ATR) cm ^-1 : 2934, 2860, 1724, 1641, 1577, 1533.

Example 21
Trans 4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) Synthesis of [-pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester [7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in a manner similar to Example 18, (Step 4) The title product (yield 64%) was produced as a yellow oil by performing a condensation reaction using.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.56 (7H, m), 1.82-2.29 (8H, m), 2.51-2.65 (4H, m), 2.80 (1H, d, J = 12.7 Hz), 3.04 -3.30 (1H, m), 3.36-3.58 (4H, m), 3.65-3.87 (2H, m), 3.90-3.98 (4H, m), 4.04-4.32 (5H, m), 6.89-6.97 (1H, m), 7.01-7.10 (2H, m), 7.11-7.18 (1H, m), 7.24 (1H, d, J = 10.0 Hz), 7.73 (1H, s), 8.35-8.42 (1H, m).
MS (ESI) m / z: 627 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[7-Fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) Synthesis of 2-pyrrolidinylmethoxy] cyclohexanecarboxylic acid Trans 4- [1-[[7-fluoro-2- (2-methoxyphenylamino) -6-benzo] was prepared in a similar manner to Example 18 (Step 5). Oxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was used to obtain the title compound (yield 99%) Was produced as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.56 (4H, m), 1.84-2.45 (9H, m), 2.50-2.65 (4H, m), 2.80 (1H, d, J = 12.7 Hz), 3.03 -3.58 (6H, m), 3.65-4.00 (6H, m), 4.06-4.30 (2H, m), 6.88-6.95 (1H, m), 7.00-7.08 (2H, m), 7.11-7.18 (1H, m), 7.21 and 7.23 (total 1H, each s, amide isomers), 8.35-8.27 (1H, m).
MS (ESI) m / z: 599 (M ⁺ +1).
IR (ATR) cm ^-1 : 2937, 2860, 1724, 1637, 1604, 1577, 1529.
Anal.Calcd for C ₃₁ H ₃₉ FN ₄ O ₇・ 0.5H ₂ O: C, 61.27; H, 6.63; F, 3.13; N, 9.22.
Found: C, 60.99; H, 6.64; F, 3.20; N, 8.82.

Example 22
Trans 4- [1-[[2- (5-Chloro-2-pyridinylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (5-Chloro-2-pyridinylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [2- (5-chloropyridylamino) -7-fluoro-6-benzoxazolyl] in an analogous manner to Example 18 (Step 4) The title product (yield 59%) was produced as a yellow glassy solid by conducting a condensation reaction with acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.15-1.51 (7H, m), 1.92-2.27 (8H, m), 2.55-2.63 (4H, m), 2.82 (1H, d, J = 13.2 Hz), 3.16 (1H, td, J = 9.8, 4.9 Hz), 3.40-3.59 (4H, m), 3.69-4.23 (7H, m), 7.16-7.21 (1H, m), 7.26 (2H, dd, J = 9.3, 7.4 Hz), 7.78 (1H, dd, J = 8.8, 2.5 Hz), 8.39 (1H, q, J = 4.6 Hz), 8.53 (1H, d, J = 2.5 Hz), 10.62 (1H, s).
MS (ESI) m / z: 632 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (5-Chloro-2-pyridinylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of 2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid Trans 4- [1-[[2- (5-chloro-2-pyridinylamino) -7-fluoro was prepared in an analogous manner to Example 18, (Step 5). -6-Benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester 82%) as a yellow glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 0.82-1.17 (4H, m), 1.41-2.19 (8H, m), 2.34-2.49 (1H, m), 2.53-2.67 (4H, m), 2.76-2.90 ( 2H, m), 3.07-3.67 (6H, m), 3.74-3.97 (1H, m), 4.07-4.17 (1H, m), 4.26 (1H, d, J = 14.2 Hz), 4.44 (1H, t, J = 8.1 Hz), 7.28 and 7.30 (total 1H, each s, amide isomers), 7.35 and 7.37 (total 1H, each d, each J = 6.4 Hz, amide isomers), 7.77 (1H, dd, J = 8.8, 2.5 Hz), 8.50-8.34 (2H, m).
MS (ESI) m / z: 604 (M ⁺ +1).
IR (ATR) cm ^-1 : 2939, 2862, 1726, 1637, 1610, 1579, 1547.
Anal. Calcd for C ₂₉ H ₃₅ ClFN ₅ O ₆・ 0.5H ₂ O: C, 56.81; H, 5.92; Cl, 5.78; F, 3.10; N, 11.42. Found: C, 56.51; H, 5.96; Cl, 5.71; F, 3.11; N, 11.12.

Example 23
Trans 4- [1-[[7-Fluoro-2- (2-fluorophenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[7-Fluoro-2- (2-fluorophenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [7-fluoro-2- (2-fluorophenylamino) -6-benzoxazolyl] acetic acid in an analogous manner to Example 18, (Step 4) The title product (61% yield) was produced as a colorless glassy solid by performing a condensation reaction using.
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.55 (7H, m), 1.87-2.33 (8H, m), 2.50-2.66 (4H, m), 2.81 (1H, d, J = 13.2 Hz), 3.08 -3.31 (1H, m), 3.34-3.60 (4H, m), 3.70 and 3.72 (total 1H, each d, J = 2.9 and 3.4 Hz respectively, amide isomers), 3.75 (1H, d, J = 6.9 Hz) , 3.90 and 3.96 (total 1H, each d, J = 16.2 and 15.7 Hz respectively, amide isomers), 4.03-4.32 (4H, m), 7.00-7.25 (5H, m), 7.80 (1H, s), 8.36- 8.43 (1H, m).
MS (ESI) m / z: 615 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[7-Fluoro-2- (2-fluorophenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) Of 2-pyrrolidinylmethoxy] cyclohexanecarboxylic acid
In a manner analogous to Example 18, (Step 5), trans 4- [1-[[7-fluoro-2- (2-fluorophenylamino) -6-benzoxazolyl] acetyl]-(5S)- The title product (89% yield) was prepared as a colorless glassy solid by using (N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester.
¹ H-NMR (CDCl ₃ ) δ: 1.05-1.56 (4H, m), 1.85-2.48 (9H, m), 2.51-2.67 (4H, m), 2.80 (1H, d, J = 12.7 Hz), 3.04 -3.31 (1H, m), 3.43-3.58 (4H, m), 3.61-4.03 (3H, m), 4.09-4.34 (2H, m), 7.00-7.23 (5H, m), 8.26-8.17 (1H, m), 8.98 (1H, s).
MS (ESI) m / z: 587 (M ⁺ +1).
IR (ATR) cm ^-1 : 2937, 2860, 1724, 1637, 1576, 1495.
Anal.Calcd for C ₃₀ H ₃₆ F ₂ N ₄ O ₆・ 0.75H ₂ O: C, 60.04; H, 6.30; F, 6.33; N, 9.34.
Found: C, 60.29; H, 6.28; F, 6.12; N, 8.92.

Example 24
Trans 4- [1-[[2- (3-Fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (3-Fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester In a manner similar to Example 18, (Step 4), [7-fluoro-2- (3-fluoro-4-methoxyphenylamino)- The title product (yield 52%) was produced as a colorless oil by conducting a condensation reaction with 6-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.57 (7H, m), 1.76-2.37 (9H, m), 2.47-2.69 (4H, m), 2.86 (1H, d, J = 12.3 Hz), 3.14 -3.35 (1H, m), 3.42-3.63 (5H, m), 3.67-3.90 (4H, m),
3.93-4.18 (3H, m), 4.22-4.43 (2H, m), 6.77-7.01 (3H, m), 7.30-7.45 (2H, m), 9.00 and 9.12 (total 1H, each s, amide isomers).
MS (ESI) m / z: 645 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (3-Fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid synthesis
In a manner similar to Example 18, (Step 5), trans 4- [1-[[2- (3-fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester is used to produce the title product (yield 75%) as a colorless glassy solid did.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.56 (4H, m), 1.84-2.35 (9H, m), 2.45-2.66 (4H, m), 2.82 (1H, d, J = 12.7 Hz), 3.14 -3.14 (1H, m), 3.37-3.60 (5H, m), 3.66-3.77 (1H, m), 3.87 (3H, s), 3.90-4.05 (1H, m), 4.17-4.41 (3H, m) , 6.87-6.95 (1H, m), 6.97-7.07
(1H, m), 7.20-7.25 (1H, m), 7.32-7.45 (1H, m).
MS (ESI) m / z: 617 (M ⁺ +1).
IR (ATR) cm ^-1 : 2934, 2860, 1724, 1641, 1577, 1533.
Anal.Calcd for C ₃₁ H ₃₈ F ₂ N ₄ O ₇・ H ₂ O: C, 58.67; H, 6.35; F, 5.99; N, 8.83.
Found: C, 58.94; H, 6.24; F, 5.87; N, 8.53.

Example 25
Trans 4- [1-[[2- (5-Chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (5-Chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [2- (5-chloro-2-methoxyphenylamino) -7-fluoro- in a similar manner to Example 18 (Step 4) The title product (yield 58%) was produced as a yellow oil by conducting a condensation reaction with [6-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.56 (7H, m), 1.82-2.45 (7H, m), 2.47-2.70 (4H, m), 2.81 (1H, d, J = 12.7 Hz), 3.12 -3.30 (1H, m), 3.33-3.59 (4H, m), 3.63-3.87 (2H, m), 3.90-3.98 (4H, m), 4.03-4.31 (5H, m), 6.82 (1H, d, J = 8.3 Hz), 6.99 (1H, dd, J = 8.8, 2.5 Hz), 7.12-7.21 (1H, m), 7.25-7.30 (1H, m), 7.71 (1H, s), 8.50 and 8.52 (total 1H, each d, J = 2.0 and 2.5 Hz respectively, amide isomers).
MS (ESI) m / z: 661 (M ⁺ +1), 663 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (5-Chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) Of-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 5), trans 4- [1-[[2- (5-chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester is used to produce the title product (yield 80%) as a colorless glassy solid did.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.58 (4H, m), 1.81-2.48 (9H, m), 2.49-2.88 (5H, m), 3.01-3.30 (1H, m), 3.34-3.60 ( 5H, m), 3.61-4.03 (6H, m), 4.08-4.33 (2H, m), 6.81 (1H, d, J = 8.8 Hz), 6.99 (1H, dd, J = 8.5, 2.4 Hz), 7.12 -7.20 (1H, m), 7.25 and 7.27 (total 1H, each s, amide isomers), 8.42 and 8.43 (total 1H, each d, J = 2.4 and 2.7 Hz respectively, amide isomers).
MS (ESI) m / z: 633 (M ⁺ +1), 635 (M ⁺ +3).
IR (ATR) cm ^-1 : 3406, 2939, 2858, 1724, 1637, 1601, 1574.

Example 26
Trans 4- [1-[[7-Fluoro-2- (2,5-dimethylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[7-Fluoro-2- (2,5-dimethylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [7-fluoro-2- (2,5-dimethylphenylamino) -6-benzooxa The title compound (yield 36%) was produced as a colorless oil by conducting a condensation reaction with [zolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.56 (7H, m), 1.74-2.48 (7H, m), 2.29 (3H, s), 2.38 (3H, s), 2.48-2.87 (5H, m) , 3.06-3.29 (1H, m), 3.32-3.60 (5H, m), 3.63-4.01 (2H, m), 4.04-4.32 (5H, m), 6.89 (1H, d, J = 7.6 Hz), 7.06 -7.26 (4H, m), 7.82 and 7.84 (total 1H, each s, amide isomers).
MS (ESI) m / z: 625 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[7-Fluoro-2- (2,5-dimethylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 5), trans 4- [1-[[7-fluoro-2- (2,5-dimethylphenylamino) -6-benzoxazolyl] acetyl]-(5S )-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester produced the title product (68% yield) as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 0.99-1.58 (4H, m), 1.85-2.26 (7H, m), 2.29 and 2.30 (total 3H, each s, amide isomers), 2.37 and 2.38 (total 3H, each s, amide isomers), 2.51-2.82 (6H, m), 3.00-3.30 (2H, m), 3.41-3.61 (6H, m), 3.64-3.89 (2H, m), 4.07-4.31 (2H, m) , 6.91 (1H, d, J = 7.8 Hz), 7.04-7.23 (3H, m), 7.67 and 7.76 (total 1H, each s, amide isomers).
MS (ESI) m / z: 597 (M ⁺ +1).
IR (ATR) cm ^-1 : 2935, 2860, 1724, 1697, 1639, 1616, 1579.
Anal.Calcd for C ₃₂ H ₄₁ FN ₄ O ₆・ 0.5H ₂ O: C, 63.46; H, 6.91; F, 3.14; N, 9.25.
Found: C, 63.39.15; H, 7.01; F, 3.11; N, 8.96.

Example 27
Trans 4- [1-[[2- (5-Chloro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (5-Chloro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) -(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [2- (5-chloro-2-methylphenylamino) -7-fluoro- in a similar manner to Example 18, (Step 4) The title compound (yield 97%) was produced as a colorless oil by conducting a condensation reaction with 6-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.56 (7H, m), 1.86-2.28 (7H, m), 2.30 (3H, s), 2.52-2.85 (5H, m), 3.07-3.31 (1H, m), 3.35-3.61 (5H, m), 3.64-4.00 (3H, m), 4.03-4.31 (5H, m), 7.02 (1H, dd, J = 8.3, 2.5 Hz), 7.06-7.17 (2H, m), 7.18 and 7.20 (total 1H, each d, J = 8.8 and 7.8 Hz respectively, amide isomers), 7.38 (1H, s), 8.19 and 8.21 (total 1H, each d, each J = 2.0 Hz, amide isomers ).
MS (ESI) m / z: 645 (M ⁺ +1), 647 (M ⁺ +3).

(Process 2)
Trans 4- [1-[[2- (5-Chloro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl) Of-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 5), trans 4- [1-[[2- (5-chloro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester produced the title product (yield 83%) as a colorless glassy solid did. ¹ H-NMR (CDCl ₃ ) δ: 1.04-1.57 (4H, m), 1.87-2.34 (10H, m), 2.52-2.83 (5H, m), 3.01-3.31 (2H, m), 3.33-3.65 ( 6H, m), 3.68-4.04 (2H, m), 4.06-4.32 (3H, m), 7.01-7.06 (1H, m), 7.07-7.22 (3H, m), 7.92 and 7.97 (total 1H, each d , each J = 2.0 Hz,
amide isomers).
MS (ESI) m / z: 617 (M ⁺ +1), 619 (M ⁺ +3).
IR (ATR) cm ^-1 : 2937, 2860, 1724, 1701, 1637, 1576, 1541.

Example 28
Trans 4- [1-[[2- (2,5-difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (2,5-difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of 2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester [2- (2,5-difluorophenylamino) -7-fluoro-6-benzoxoxalate in a manner similar to Example 18, (Step 4) The title compound (yield 93%) was produced as a colorless oil by conducting a condensation reaction with [zolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.09-1.57 (7H, m), 1.84-2.35 (9H, m), 2.42-2.66 (4H, m), 2.83 (1H, d, J = 12.7 Hz), 3.11 -3.32 (1H, m), 3.36-3.63 (4H, m), 3.68-4.01 (2H, m), 4.03-4.38 (5H, m), 6.65-6.73 (1H, m), 7.00-7.10 (2H, m), 7.12 and 7.14 (total 1H, each s, amide isomers), 8.22-8.30 (1H, m), 8.44 (1H, br s).
MS (ESI) m / z: 633 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (2,5-difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 5), trans 4- [1-[[2- (2,5-difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S )-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester produced the title product (yield quantitative.) As a colorless glassy solid . ¹ H-NMR (CDCl ₃ ) δ: 1.08-1.58 (4H, m), 1.86-2.46 (9H, m), 2.53-2.64 (4H, m), 2.81 (1H, d, J = 13.2 Hz), 3.06 -3.32 (1H, m), 3.36-3.59 (5H, m), 3.60-4.03 (3H, m), 4.07-4.32 (2H, m), 6.68-6.76 (1H, m), 7.03-7.24 (3H, m), 8.14-8.24 (1H, m).
MS (ESI) m / z: 605 (M ⁺ +1).
IR (ATR) cm ^-1 : 2939, 2860, 1724, 1701, 1633, 1576, 1495.

Example 29
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-3-methyl-1 -Azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans 4- [1-tert-butoxycarbonyl- (5S)-(3-methoxy-3-methyl-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
In a manner similar to Example 18, (Step 2), the title product (61% yield) was prepared as a colorless oil by using 3-methoxy-3-methylazetidine.
¹ H-NMR (CDCl ₃ ) δ: 1.13-1.33 (5H, m), 1.41-1.50 (12H, m), 1.60 (3H, s), 1.80-2.09 (7H, m), 2.16-2.29 (1H, m), 2.38-2.73 (1H, m), 2.99-3.43 (8H, m), 3.53-3.80 (2H, m), 3.84 (1H, dd, J = 8.7, 1.1 Hz), 3.96 (1H, d, J = 9.8 Hz), 4.04-4.16 (3H, m).
MS (ESI) m / z: 469 (M ⁺ +1).

(Process 2)
Trans 4-[(5S)-(3-methoxy-3-methyl-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid dihydrochloride synthesis trans 4- [1-tert- Butoxycarbonyl- (5S)-(3-methoxy-3-methyl-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.40 g, 2.99 mmol) was added to 4 N hydrochloric acid / Dissolved in dioxane (30 ml) and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the resulting light brown solid was subjected to the next reaction.

(Process 3)
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-3-methyl-1 Of -azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetic acid (159mg, 0.50mmol), trans 4-[(5S)-(3-methoxy-3-methyl -1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid dihydrochloride (221 mg, 0.50 mmol), EDC · HCl (144 mg, 0.75 mmol) and HOBt (101 mg, 0.75 mmol) ) In dichloromethane solution (10 ml) at room temperature was added triethylamine (349 μl, 2.50 mmol) and stirred for 19 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (Biotage 25S, methanol: ethyl acetate = 0-30%), and the title compound (138 mg, 41%) was obtained as a yellow oil. Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.05-1.54 (10H, m), 1.71-2.35 (10H, m), 2.40-2.79 (2H, m), 3.04-3.57 (10H, m), 3.59-4.35 ( 8H, m), 6.75 (1H, td, J = 8.2, 2.6 Hz), 7.03-7.39 (4H, m), 8.03-8.14 (1H, m).
MS (ESI) m / z: 669 (M ⁺ +1).

(Process 4)
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-3-methyl-1 -Azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid synthesis trans 4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzo Oxazolyl] acetyl]-(5S)-(3-methoxy-3-methyl-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (138 mg, 0.21 mmol) To a tetrahydrofuran / methanol mixed solution (4 ml / 2 ml) was added 1 N aqueous sodium hydroxide solution (2 ml, 2 mmol) at room temperature, and the mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 7 with 1 N hydrochloric acid and extracted with a chloroform / methanol mixed solution [10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by thin layer chromatography (chloroform: ethanol = 10/1 v / v), 80 mg as the low polarity fraction and 19 as the high polarity fraction. Each mg was obtained as a colorless glassy solid, and each was lyophilized from dioxane to give 74 mg (60%) and 20 mg (14%), respectively, as a colorless glassy solid.
Low polarity fraction (74 mg, 60%):
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.55 (7H, m), 1.82-2.15 (7H, m), 2.16-2.34 (5H, m), 2.58-2.81 (1H, m), 3.67-3.68 ( 16H, m), 6.74 (1H, ddd, J = 15.5, 8.0, 2.6 Hz), 7.05-7.22 (3H, m), 7.85 and 7.98 (total 1H, each dd, J = 10.8, 2.7 and 10.8, 2.5 Hz respectively, amide isomer).
MS (ESI) m / z: 641 (M ⁺ +1).
IR (ATR) cm ^-1 : 2933, 2858, 1712, 1637, 1610, 1577, 1552.
Anal.Calcd for C ₃₄ H ₄₂ F ₂ N ₄ O ₆・ H ₂ O: C, 61.99; H, 6.73; F, 5.77; N, 8.51.
Found: C, 62.17; H, 6.57; F, 5.73; N, 8.22. (CH836801)
High polarity fraction (20 mg, 14%):
¹ H-NMR (CDCl ₃ ) δ: 1.16-1.35 (2H, m), 1.38-1.56 (5H, m), 1.76-2.15 (7H, m), 2.15-2.34 (4H, m), 2.71-4.31 ( 19H, m), 6.70-6.79 (1H, m), 7.04-7.16 (1H, m), 7.18-7.25 (1H, m), 7.90 and 8.01 (total 1H, each dd, J = 10.5, 2.5 and 10.8, 2.7 Hz respectively, amide isomers).
MS (ESI) m / z: 641 (M ⁺ +1).

Example 30
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(2-isoxazolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of isoxazolidine-2-carboxylic acid ethyl ester To a solution of urethane (Tokyo Kasei) (5.0 g, 47.6 mmol) in ethanol (21 ml) at room temperature with potassium hydroxide (2.67 g, 47.6 mmol) and 1,3-dibromo Propane (2.33 ml, 23.0 mmol) was added and the mixture was heated to 90 ° C. and stirred for 6 hours. The reaction solution was returned to room temperature, potassium hydroxide (1/34 g, 24.0 mmol) and 1,3-dibromopropane (1.21 ml, 12.0 mmol) were added, and the mixture was stirred again at 90 ° C. for 15 hours. After returning the reaction solution to room temperature, ether was added and ultrasonic cleaning was performed. The precipitated insoluble material was removed by filtration, and the residue obtained by concentrating the mother liquor was purified by flash chromatography (Biotage 40S, ethyl acetate: n-hexane = 10-100%), and the title compound (860 mg, 14% ) Was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.17-1.35 (3H, m), 2.22-2.31 (2H, m), 3.63-3.71 (2H, m), 3.94 (2H, td, J = 7.1, 2.9 Hz) , 4.23 (2H, dq, J = 14.2, 3.5 Hz).

(Process 2)
Synthesis of Isoxazolidine Hydrochloride Isoxazolidine-2-carboxylic acid ethyl ester (370 mg, 2.55 mmol) and concentrated hydrochloric acid (1 ml) were heated to 100 ° C. and stirred for 1 hour. After returning the reaction solution to room temperature, ether was added and the organic layer was separated. The obtained aqueous layer was concentrated under reduced pressure to obtain a solid partially containing the title compound as an oily substance, and subsequently subjected to the next reaction.

(Process 3)
Synthesis of trans 4- [1-tert-butoxycarbonyl- (5S)-(2-isoxazolidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
The title product (yield 39% (2 steps)) was prepared as a colorless oil in a manner similar to Example 18 (Step 2) using isoxazolidine hydrochloride.
¹ H-NMR (CDCl ₃ ) δ: 1.15-1.32 (6H, m), 1.34-1.57 (11H, m), 1.75-2.42 (14H, m), 2.83-3.13 (1H, m), 3.13-3.27 ( 1H, m), 3.30-3.41 (1H, m), 3.54-3.72 (1H, m), 3.71-4.02 (3H, m), 4.21-4.02 (2H, m).
MS (ESI) m / z: 441 (M ⁺ +1).

(Process 4)
Trans 4-[(5S)-(2-isoxazolidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride synthesis trans 4- [1-tert-butoxycarbonyl- (5S )-(2-Isoxazolidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (110 mg, 0.25 mmol) dissolved in 4 N hydrochloric acid / dioxane (10 ml) at room temperature Stir for 24 hours. The reaction solution was concentrated under reduced pressure, and the resulting brown oil was subjected to the next reaction.
MS (ESI) m / z: 341 (M ⁺ +1).

(Process 5)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(2-isoxazolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetic acid (80 mg, 0.25 mmol), trans 4-[(5S)-(1-isoxazolidinini Rumethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride (94 mg, 0.25 mmol), EDC · HCl (72 mg, 0.38 mmol) and HOBt (51 mg, 0.38 mmol) in DMF (10 ml) was added with triethylamine (174 μl, 1.25 mmol) at room temperature and stirred for 22 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined extracts were washed with ice water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (Biotage 25S, ethyl acetate: n-hexane = 50-100%), and the title compound (101 mg, 63%) was purified colorless. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.06-1.56 (8H, m), 1.85-2.37 (14H, m), 2.88 and 2.96 (total 3H, each s, amide isomers), 3.09-3.60 (2H, m) , 3.66-4.02 (4H, m), 4.04-4.40 (4H, m), 6.74 (1H, td, J = 8.1, 2.5 Hz), 6.98-7.24 (3H, m), 7.40 (1H, s), 8.00 -8.09 (2H, m).
MS (ESI) m / z: 641 (M ⁺ +1).

(Process 6)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(2-isoxazolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] Acetyl]-(5S)-(2-isoxazolidinylmethyl) (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (101 mg, 0.16 mmol) in tetrahydrofuran / methanol mixture (2 ml / 1 ml ) Was added 1 N aqueous sodium hydroxide solution (1 ml, 1 mmol) at room temperature and stirred for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 7 with 1 N hydrochloric acid and extracted with a chloroform / methanol mixed solution [10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by thin layer chromatography (ethyl acetate: acetic acid = 100/1 v / v) to obtain the title compound (77 mg) as a colorless oil. Lyophilization from dioxane gave 66 mg (67%) as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.03-1.60 (4H, m), 1.87-2.36 (17H, m), 2.89 and 2.96 (total 3H, each s, amide isomers), 3.33-3.71 (2H, m) , 3.74-4.02 (4H, m), 4.08-4.39 (2H, m), 6.76 (1H, tt, J = 8.1, 2.3 Hz), 7.18-7.08 (3H, m), 7.84-7.74 (1H, m) .
MS (ESI) m / z: 613 (M ⁺ +1).

Example 31
Trans-4- [1-[[7-Fluoro-2-[[5-fluoro-2-methylphenyl] amino] -6-benzoxazolyl] acetyl]-(5S)-(4-morpholinyl) methyl- (2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5S)-(4-morpholinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester trans-4- [1-tert-butoxycarbonyl -(5S) -Hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.54 g, 4.0 mmol) was dissolved in methylene chloride (20 ml), and isocyanuric acid (1.02 g, 4.4) at 0 ° C. mmol), and TEMPO (62.5 mg, 0.4 mmol) were added. After stirring at room temperature for 30 minutes, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloroethane (20 ml), and morpholine (0.7 ml, 8.0 mmol), acetic acid (0.48 ml, 8.0 mmol), and triacetoxyborohydride (1.7 g, 8.0 mmol) were added. Stir overnight at room temperature under a nitrogen atmosphere. Sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel, and the title compound (1.4 g, 77%) was obtained as a yellow oil from a fraction eluted with methylene chloride: methanol (95: 5).
¹ H-NMR (CDCl ₃ ) δ: 1.22-1.26 (5H, m), 1.40-1.46 (11H, m), 1.85-2.62 (13H, m), 3.20-3.90 (11H, m), 4.10-4.13 ( 2H, m).

(Process 2)
Trans-4-[(5S)-(4-Morpholinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride synthesis trans-4- [1-tert-butoxycarbonyl- (5S)- (4-Morpholinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.4 g, 3.1 mmol) was dissolved in 4N hydrochloric acid dioxane solution (20 ml) and stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was used in the next reaction without purification.

(Process 3)
Trans-4- [1-[[7-Fluoro-2-[[5-fluoro-2-methylphenyl] amino] -6-benzoxazolyl] acetyl]-(5S)-(4-morpholinyl) methyl- Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester trans-4-[(5S)-(4-morpholinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride (0.5 mmol), [7-fluoro-2-[[5-fluoro-2-methylphenyl] amino] -6-benzoxazolyl] acetic acid (159 mg, 0.5 mmol), EDC (144 mg, 0.75 mmol), HOBt (68 mg, 0.5 mmol) and triethylamine (0.42 ml, 3.0 mmol) were dissolved in methylene chloride (20 ml) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was preparative TLC (Merck, Silica gel 60, F ₂₅₄ , 2 mm; developed with methanol: methylene chloride = 6: 94 and eluted with methanol: methylene chloride = 3: 7) To give the title compound (260 mg, 80%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.55 (7H, m), 1.90-2.75 (16H, m), 3.15-4.22 (15H, m), 6.72-6.77 (1H, m), 7.13-7.27 ( 3H, m), 8.09-8.12 (1H, m).

(Process 4)
Trans-4- [1-[[7-Fluoro-2-[[5-fluoro-2-methylphenyl] amino] -6-benzoxazolyl] acetyl]-(5S)-(4-morpholinyl) methyl- Synthesis of (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[7-fluoro-2-[[5-fluoro-2-methylphenyl] amino] -6-benzoxazolyl] Acetyl]-(5S)-(4-morpholinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (260 mg, 0.40 mmol) was dissolved in THF (10 ml) and 1N
Aqueous sodium hydroxide (1.5 ml, 1.5 mmol) and methanol (5 ml) were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, a small amount of water was added, neutralized with 1N hydrochloric acid, and water was distilled off under reduced pressure while azeotroping with methanol. Preparative TLC (Merck, Silica gel 60, F ₂₅₄ , 2 mm; elution with methanol: methylene chloride = 9: 91, elution with chloroform: methanol: water = 7: 3: 1 lower layer) The product was dissolved in a small amount of methylene chloride, and solidified by adding ethyl acetate and n-hexane to solidify to obtain the title compound (170 mg, 69%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (4H, m), 1.75-2.28 (9H, m), 2.30 (3H, s), 2.35-2.60 (4H, m), 3.10-4.20 ( 13H, m), 6.87-6.90 (1H, m), 7.09-7.28 (3H, m), 7.29 (1H, dd, J = 2.7, 11.3 Hz).
IR (ATR) cm ^-1 : 3224, 1716, 1637, 1610, 1577, 1452.
MS (LC-ESI) m / z: 627 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₆・ 0.7H ₂ O: C, 62.00; H, 6.53; N, 8.76.
Found: C, 61.79; H, 6.25; N, 8.72.

Example 32
Trans-4- [1-[[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(4-morpholinyl) methyl- (2S) -pyrrolidini Rumethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(4-morpholinyl) methyl- (2S) -pyrrolidini Synthesis of [Lumethoxy] cyclohexanecarboxylic acid ethyl ester Using [7-fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetic acid in a manner analogous to Example 31, (Step 3). The title product was produced as an amorphous product by performing a condensation reaction.
¹ H-NMR (CDCl ₃ ) δ: 1.13-1.56 (7H, m), 1.88-2.68 (16H, m), 3.12-4.21 (15H, m), 6.80-7.35 (5H, m), 8.11 (1H, d, J = 8.1 Hz).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(4-morpholinyl) methyl- (2S) -pyrrolidini Synthesis of rumethoxy] cyclohexanecarboxylic acid
In a manner analogous to Example 18, (Step 4), trans-4- [1-[[7-fluoro-2- (2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S) The title was prepared as amorphous by using-(4-morpholinyl) methyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (4H, m), 1.72-2.26 (9H, m), 2.31 (3H, s), 2.35-2.60 (4H, m), 3.10-4.20 ( 13H, m), 7.05-7.12 (3H, m), 7.23-7.26 (2H, m), 7.79-7.81 (1H, m).
IR (ATR) cm ^-1 : 2935, 1720, 1635, 1577, 1452.
MS (LC-ESI) m / z: 609 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₁ FN ₄ O ₆・ 0.6H ₂ O: C, 63.79; H, 6.88; N, 9.02.
Found: C, 63.55; H, 6.58; N, 8.95.

Example 33
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4-morpholinyl ) Methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4-morpholinyl ) Synthesis of methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid ethyl ester
The title product was converted to an amorphous product by conducting a condensation reaction with [7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in a manner similar to Example 18 (Step 3). Manufactured as.
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.53 (7H, m), 1.88-2.70 (13H, m), 3.10-4.21 (18H, m), 6.90-7.28 (4H, m), 7.70-7.75 ( 1H, m), 8.38-8.39 (1H, m).

(Process 2)
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4-morpholinyl ) Methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid synthesis
In a manner analogous to Example 18, (Step 4), trans-4-[((2S, 5S) -1-{[7-fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazole The title was prepared as amorphous by using -6-yl] acetyl} -5- (4-morpholinyl) methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid ethyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.39 (4H, m), 1.78-2.28 (9H, m), 2.35-2.60 (4H, m), 3.10-4.20 (16H, m), 7.00- 7.11 (4H, m), 7.17 (1H, d, J = 7.8 Hz), 8.12 (1H, d, J = 8.1 Hz). IR (ATR) cm ^-1 : 2937, 1720, 1637, 1604.
MS (LC-ESI) m / z: 625 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₁ FN ₄ O ₇・ 0.5H ₂ O: C, 62.55; H, 6.68; N, 8.84.
Found: C, 62.28; H, 6.48; N, 8.66.

Example 34
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4-Morpholinyl) methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- Synthesis of (4-Morpholinyl) methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid ethyl ester
By conducting a condensation reaction with [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -6-benzoxazolyl] acetic acid in a manner similar to Example 18 (Step 3) The title was produced as an amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.55 (3H, m), 1.89-2.72 (13H, m), 3.12-4.21 (18H, m), 6.71-6.83 (2H, m), 7.10-7.21 ( 1H, m), 7.75 (1H, br s), 8.28-8.30 (1H, m).

(Process 2)
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- Synthesis of (4-morpholinyl) methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 4), trans-4-[((2S, 5S) -1-{[7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -1, The title was prepared as an amorphous by using 3-benzoxazol-6-yl] acetyl} -5- (4-morpholinyl) methylpyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid ethyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (4H, m), 1.80-2.28 (9H, m), 2.31-2.60 (4H, m), 3.10-4.20 (16H, m), 6.86- 6.91 (1H, m), 7.06-7.13 (2H, m), 7.26 (1H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 3.2, 11.0 Hz).
IR (ATR) cm ^-1 : 2937, 2859, 1720, 1641, 1577, 1448.
MS (LC-ESI) m / z: 643 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₇ , 0.5H ₂ O: C, 60.82; H, 6.34; N, 8.60.
Found: C, 60.53; H, 6.12; N, 8.51.

Example 35
Trans-4-{[(2S, 5S) -1-{[7-Chloro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4-Morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid (Step 1)
Trans-4-{[(2S, 5S) -1-{[7-Chloro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- Synthesis of (4-Morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid ethyl ester
By conducting a condensation reaction with [7-chloro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetic acid in a manner similar to Example 18 (Step 3). The title was produced as an amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.54 (7H, m), 1.88-2.74 (16H, m), 3.13-4.24 (15H, m), 6.73-6.79 (1H, m), 6.96-7.40 ( 3H, m), 8.08-8.16 (1H, m).

(Process 2)
Trans-4-{[(2S, 5S) -1-{[7-Chloro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- Synthesis of (4-morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 4), trans-4-{[(2S, 5S) -1- {2- [7-chloro-2- (5-fluoro-2-methylphenylamino)- The title was prepared as amorphous by using 1,3-benzoxazol-6-yl] acetyl} -5- (4-morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid ethyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (4H, m), 1.78-2.30 (12H, m), 2.32-2.60 (4H, m), 3.10-4.20 (13H, m), 6.87- 6.91 (1H, m), 7.15-7.19 (1H, m), 7.24-7.28 (1H, m), 7.33 (1H, d, J = 8.1 Hz), 7.85-7.95 (1H, m).
IR (ATR) cm ^-1 : 2933, 1720, 1639, 1608, 1569, 1434.
MS (LC-ESI) m / z: 643 (M ⁺ +1).
Anal.Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₇ , 0.5H ₂ O: C, 60.82; H, 6.34; N, 8.60.
Found: C, 60.53; H, 6.12; N, 8.51.

Example 36
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (4- Morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid (Step 1)
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (4- Synthesis of (morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid ethyl ester
In a manner similar to Example 18, (Step 3), the title compound was obtained by performing a condensation reaction with [2- (3,4-dichlorophenylamino) -7-fluoro-6-benzoxazolyl] acetic acid. Manufactured as amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.56 (7H, m), 1.86-2.84 (13H, m), 3.17-4.35 (15H, m), 6.79-6.98 (2H, m), 7.36 (1H, d, J = 8.8 Hz), 7.54-7.56 (1H, m), 7.73-7.74 (1H, m).

(Process 2)
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (4- Synthesis of (morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid
In a manner similar to Example 18, (Step 4), trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzo The title was prepared as an amorphous by using oxazol-6-yl] acetyl} -5- (4-morpholinyl) methylpyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid ethyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.39 (4H, m), 1.75-2.28 (9H, m), 2.30-2.60 (4H, m), 3.10-4.22 (13H, m), 7.10- 7.16 (1H, m), 7.28 (1H, d, J = 8.1 Hz), 7.63-7.64 (1H, m), 8.10 (1H, s).
IR (ATR) cm ^-1 : 2937, 1724, 1639, 1573, 1475.
MS (LC-ESI) m / z: 663 (M ⁺ +1).
Anal.Calcd for C ₃₂ H ₃₇ Cl ₂ FN ₄ O ₆・ 0.7H ₂ O: C, 56.84; H, 5.72; N, 8.29.
Found: C, 56.60; H, 5.45; N, 8.37.

Example 37
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinini Rumethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (step 1)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5S)-(3-methoxy-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
The title product (85% yield) was prepared as a yellow oil in a similar manner as in Example 18 (Step 2) using 3-methoxyazetidine.
¹ H-NMR (CDCl ₃ ) δ: 1.09-1.31 (6H, m), 1.42-1.51 (11H, m), 1.74-2.30 (9H, m), 2.35-2.78 (1H, m), 2.88-3.27 ( 5H, m), 3.28-3.93 (7H, m), 3.97-4.06 (1H, m), 4.06-4.16 (2H, m).
MS (ESI) m / z: 455 (M + +1).

(Process 2)
Trans-4-[(5S)-(3-Methoxy-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride synthesis trans-4- [1-tert-butoxy Carbonyl- (5S)-(3-methoxy-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.01 g, 2.22 mmol) in 4 N hydrochloric acid / dioxane (100 ml) And stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the resulting light brown solid was subjected to the next reaction.
MS (ESI) m / z: 355 (M ⁺ +1).

(Process 3)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinini Synthesis of (rumethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetic acid (159 mg, 0.50 mmol), trans-4-[(5S)-(3-methoxy-1 -Azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride (214 mg, 0.50 mmol), EDC · HCl (144 mg, 0.75 mmol) and HOBt (101 mg, 0.75 mmol) To a dichloromethane solution (10 ml) of triethylamine (349 μl, 2.50 mmol) was added at room temperature and stirred for 19 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to flash chromatography (Biotage 25S, methanol: ethyl acetate = 5%), followed by thin layer chromatography (chloroform: methanol = 10/1 v / v). The title compound (182 mg, 56%) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.55 (8H, m), 1.83-2.67 (10H, m), 2.77-4.40 (20H, m), 6.74 (1H, t, J = 8.2 Hz), 7.06 -7.16 (2H, m), 7.20 and 7.21 (total 1H, each t, each J = 2.2 Hz, amide isomers), 7.41 (1H, s), 8.00-8.07 (1H, m).
MS (ESI) m / z: 656 (M ⁺ +1).

(Process 4)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinini Synthesis of (Rumethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazoli [Lu] acetyl]-(5S)-(3-methoxy-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (182 mg, 0.278 mmol) in tetrahydrofuran / methanol ( 4 ml / 2 ml) was added with 1 N aqueous sodium hydroxide solution (2 ml, 2 mmol) at room temperature and stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 7 with 1 N hydrochloric acid and extracted with a chloroform / methanol mixed solution [10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by thin layer chromatography (chloroform: ethanol = 5/1 v / v) to obtain the title compound (130 mg) as a colorless glassy solid. Lyophilization from dioxane gave 129 mg (74%) as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.54 (4H, m), 1.81-2.13 (7H, m), 2.13-2.39 (5H, m), 2.54-2.74 (2H, m), 2.92-3.29 ( 7H, m), 3.34-4.23 (10H, m), 6.70-6.78 (1H, m), 7.04-7.23 (3H, m), 7.85 and 7.95 (total 1H, each dd, each J = 10.8, 2.5 Hz, amide isomers).
MS (ESI) m / z: 627 (M ⁺ +1).
IR (ATR) cm ^-1 : 2933, 2858, 1712, 1637, 1610, 1576, 1552.
Anal.Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₆・ H ₂ O: C, 61.48; H, 6.57; F, 5.89; N, 8.69.
Found: C, 61.44; H, 6.53; F, 5.65; N, 8.30.

Example 38
Trans-4- [1-[[2- (2,5-Difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinylmethyl )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[2- (2,5-Difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinylmethyl )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [7-fluoro-2- (2,5-difluorophenylamino) -6 in a manner similar to Example 37, (Step 3) The title product (yield 37%) was produced as a yellow oil by conducting a condensation reaction with [-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.08-1.54 (7H, m), 1.84-2.49 (10H, m), 2.55-2.68 (1H, m), 2.79-3.05 (2H, m), 3.08-3.32 ( 5H, m), 3.35-3.84 (5H, m), 3.84-4.30 (6H, m), 6.67-6.74 (1H, m), 7.03-7.15 (2H, m), 7.18 (1H, dd, J = 8.1 , 2.5 Hz), 8.33-8.25 (1H, m).
MS (ESI) m / z: 659 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[2- (2,5-Difluorophenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinylmethyl )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid In a manner similar to Example 37, (Step 4), trans-4- [1-[[2- (2,5-difluorophenylamino) -7-Fluoro-6-benzoxazolyl] acetyl]-(5S)-(3-methoxy-1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester This produced the title (quantitative yield) as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.09-1.56 (4H, m), 1.78-2.38 (8H, m), 2.60-2.88 (1H, m), 3.03-3.30 (5H, m), 3.33-3.57 ( 6H, m), 3.60-3.91 (3H, m), 3.92-4.32 (5H, m), 6.63-6.75 (1H, m), 7.15 (1H, d, J = 8.1 Hz), 7.12-6.98 (2H, m), 8.28-8.16 (1H, m).
MS (ESI) m / z: 631 (M ⁺ +1).
IR (ATR) cm ^-1 : 2935, 2858, 1712, 1633, 1577, 1495, 1444.
(CH8325)

Example 39
Trans-4-({(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5-[(dimethyl Amino) methyl] pyrrolidin-2-yl} methoxy) cyclohexanecarboxylic acid (Step 1)
Synthesis of trans- [1- (tert-butoxycarbonyl)-(5S)-(dimethylaminomethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Example 18 (step 2) and In a similar manner, the title product (0.81 g, 75%) was prepared as a colorless oil by using dimethylamine.
MS (ESI) m / z: 413 (M ⁺ +1).

(Process 2)
Trans-4-({(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5-[(dimethyl Synthesis of (amino) methyl] pyrrolidin-2-yl} methoxy) cyclohexanecarboxylic acid
Trans- [1- (tert-butoxycarbonyl)-(5S)-(dimethylaminomethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (270 mg, 0.654 mmol) was added to dichloromethane (10 To the mixture was added TFA (5 ml) at room temperature, and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure and azeotroped three times with toluene. The obtained residue was dissolved in DMF (4 ml), [2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetic acid (232 mg, 0.650 mmol), EDC (0.135 mL, 0.980 mmol), TEA (0.274 mmol, 1.96 mmol) and HOBt (17.7 mg, 0.130 mmol) were added and stirred at room temperature for 24 hours. The reaction solution was poured into a mixed solution of dichloromethane (20 ml) and saturated brine (20 ml) and separated. This operation was further repeated twice. All the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel column chromatography (High Flash L: Yamazen Co., Ltd .: diameter 26 mm, total length 100 mm, chloroform / methanol, 99: 1 to 9: 1) to obtain an ester. . The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol (30 ml, 2: 1), 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with dichloromethane (20 ml), 1N aqueous hydrochloric acid solution (10 ml) was added, and the mixture was separated after stirring. The aqueous layer was extracted twice with a mixed solvent of chloroform / methanol (9: 1), and all organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to medium pressure silica gel column chromatography (Yamazen High Flash L: diameter 26 mm, total length 100 mm, chloroform / methanol / water, 99: 0.9: 0.1 to 90: 9: 1, flow rate 20 ml / The resulting fraction of the title compound was concentrated. The resulting oily title compound was precipitated from chloroform / hexane / diethyl ether to give the title compound (306 mg, 75%) as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.40 (4H, m), 1.74-2.43 (15H, m), 3.04-3.59 (7H, m), 3.73-4.21 (3H, m), 7.14 ( 1H, dd, J = 14.8, 8.0 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.64 (1H, d, J = 8.8 Hz), 7.67 (1H, dd, J = 8.8, 2.5 Hz), 8.13 (1H, t, J = 2.5 Hz), 11.33 (1H, s).
IR (ATR) cm ^-1 : 2935, 2859, 1637, 1571, 1475.
MS (ESI) m / z: 621 (M ⁺ +1).
MS (FAB) m / z: 621 (M ⁺ +1).
MS (FAB) m / z: 621.2091 (Calcd for C 30 H 36 Cl 2 FN 4 O 5:. 621.2047).
Anal.Calcd for C ₃₀ H ₃₅ Cl ₂ FN ₄ O ₅・ 0.75HCl ・ H ₂ O: C, 54.03; H, 5.71; Cl, 14.62; F, 2.85; N, 8.40.
Found: C, 53.89; H, 5.39; Cl, 14.51; F, 3.03; N, 8.14.

Example 40
Trans-4-({(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5-[(dimethylamino) methyl] Pyrrolidin-2-yl} methoxy) cyclohexanecarboxylic acid (Step 1)
Trans-4-({(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5-[(dimethylamino) methyl] Synthesis of pyrrolidin-2-yl} methoxy) cyclohexanecarboxylic acid [2- (3,4-dichlorophenylamino) -1,3-benzoxazol-6-yl] in a manner analogous to Example 39, (Step 2) The title product (282 mg, 71%) was produced as a colorless amorphous solid by using acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.40 (4H, m), 1.74-2.43 (15H, m), 3.04-3.59 (6H, m), 3.73-4.21 (4H, m), 7.14 ( 1H, dd, J = 14.8, 8.0 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.64 (1H, d, J = 8.8 Hz), 7.67 (1H, dd, J = 8.8, 2.5 Hz), 8.13 (1H, t, J = 2.5 Hz),
11.33 (1H, s).
IR (ATR) cm ^-1 : 2933, 2859, 1635, 1567, 1475.
MS (ESI) m / z: 603 (M ⁺ +1).
MS (FAB) m / z: 603 (M ⁺ +1).
MS (FAB) m / z: 603.2154 (Calcd. For C ₃₀ H ₃₇ Cl ₂ N ₄ O ₅ : 603.2141).
Anal.Calcd for C ₃₀ H ₃₆ Cl ₂ N ₄ O ₅・ 0.45HCl ・ 1.75H ₂ O: C, 55.31; H, 6.18; Cl, 13.33; N, 8.60.
Found: C, 54.99; H, 5.70; Cl, 12.92; N, 8.35.

Example 41
Trans-4-({(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl} -5- [ (Dimethylamino) methyl] pyrrolidin-2-yl} methoxy) cyclohexanecarboxylic acid In a manner similar to Example 39, (Step 2), [2- (3,4-dichlorophenylamino) -4,7-difluoro-1 , 3-Benzoxazol-6-yl] acetic acid gave the title product (145 mg, 35%) as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.40 (4H, m), 1.77-2.46 (16H, m), 3.11-4.18 (8H, m), 7.07-7.13 (1H, m), 7.66- 7.67 (2H, m), 8.05-8.07 (1H, m), 11.44 (1H, br s).
IR (ATR) cm ^-1 : 2937, 2859, 1639, 1577, 1128.
MS (ESI) m / z: 639 (M ⁺ +1).
MS (FAB) m / z: 639 (M ⁺ +1).
MS (FAB) m / z: 639.1953 (Calcd. For C ₃₀ H ₃₅ Cl ₂ F ₂ N ₄ O ₅ ). Found: 639.1946.
Anal.Calcd for C ₃₀ H ₃₄ Cl ₂ F ₂ N ₄ O ₅・ 0.5HCl ・ 2.0H ₂ O: C, 51.94; H, 5.59; Cl, 12.78; F, 5.48; N, 8.08.
Found: C, 51.51; H, 5.15; Cl, 13.09; F, 5.10; N, 7.76.

Example 42
Trans-4-({(2S, 5S) -1-{[2- (4-Chlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl} -5-[(dimethyl Amino) methyl] pyrrolidin-2-yl} methoxy) cyclohexanecarboxylic acid In a manner analogous to Example 39, (Step 2), [2- (4-chlorophenylamino) -4,7-difluoro-1,3-benzo The title product (174 mg, 42%) was prepared as a colorless amorphous solid by using oxazol-6-yl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.40 (4H, m), 1.77-2.39 (16H, m), 3.09-4.19 (8H, m), 7.05-7.11 (1H, m), 7.47 ( 2H, d, J = 9.1 Hz), 7.76 (2H, d, J = 9.1 Hz), 11.21 (1H, br s).
IR (ATR) cm ^-1 : 2935, 2859, 1639, 1581, 1492.
MS (ESI) m / z: 605 (M ⁺ +1).
MS (FAB) m / z: 605 (M ⁺ +1).
MS (FAB) m / z: 605.2342 (Calcd. For C ₃₀ H ₃₆ ClF ₂ N ₄ O ₅ ). Found: 605.2359.
Anal.Calcd for C ₃₀ H ₃₅ ClF ₂ N ₄ O ₅・ 0.5HCl ・ 1.75H ₂ O: C, 55.03; H, 6.00; Cl, 8.12; F,
5.80; N, 8.56.
Found: C, 55.38; H, 5.53; Cl, 7.87; F, 5.91; N, 8.37.

Example 43
Trans-4-[((2S, 5S) -1-{[2- (4-chlorophenylamino) -1,3-benzoxazol-6-yl] acetyl} pyrrolidin-2-yl) methoxy] -5- ( 1-dimethylaminomethyl) -cyclohexanecarboxylic acid
The title compound (207 mg, 76%) was obtained as a colorless amorphous compound by carrying out the same procedure as in Example 39 (Step 2) using [2- (4-chlorophenylamino) -6-benzoxazolyl] acetic acid. Manufactured as.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.38 (6H, m), 1.75-2.36 (10H, m), 3.07-4.11 (12H, m), 7.07-7.12 (1H, m), 7.38 ( 2H, dd, J = 4.4, 3.2 Hz), 7.42 (2H, d, J = 8.8 Hz), 7.78 (2H, d, J = 8.8 Hz), 10.77 (1H, br s).
IR (ATR) cm ^-1 : 2933, 2857, 1637, 1569, 1490.
MS (ESI) m / z: 569 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₇ ClN ₄ O ₅・ H ₂ O ・ 0.5 Et ₂ O: C, 61.58; H, 7.11; Cl, 5.68; N, 8.98.
Found: C, 61.51; H, 6.87; Cl, 5.54; N, 8.79.

Example 44
Trans-4-[((2S, 5S) -1- {2- [7-fluoro-2- (4-fluorophenylamino) -5-[(dimethylamino) methyl] -1,3-benzoxazole-6 -Yl] acetyl} pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid In a manner analogous to Example 39, (Step 2), [7-fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl The title compound (154 mg, 68%) was produced as a colorless amorphous product by using [r] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.42 (4H, m), 1.77-2.22 (9H, m), 2.42-3.14 (7H, m), 3.43-4.23 (8H, m), 7.07- 7.14 (1H, m), 7.20-7.27 (4H, m), 7.73-7.78 (2H, m), 10.90 (1H, s).
IR (ATR) cm ^-1 : 2937, 2861, 1639, 1579, 1508.
MS (ESI) m / z: 571 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₆ F ₂ N ₄ O ₅・ 1.4HCOOH ・ 0.1TFA: C, 58.71; H, 6.07; F, 6.76; N, 8.67.Found: C, 58.47; H, 6.28; F, 6.60; N, 8.95.

Example 45
Trans-4-[((2S, 5S) -1- {2- [4-Fluoro-2- (4-fluorophenylamino) -5-[(dimethylamino) methyl] -1,3-benzoxazole-6 -Yl] acetyl} pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid In a manner analogous to Example 39, (Step 2), [4-fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl The title compound (162 mg, 71%) was produced as a colorless amorphous product by using [r] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.38 (4H, m), 1.77-2.20 (9H, m), 2.38-4.22 (15H, m), 7.02 (1H, dd, J = 11.2, 4.3 Hz), 7.21-7.28 (4H, m), 7.76 (2H, dd, J = 8.8, 4.9 Hz), 10.82-10.84 (1H, m).
IR (ATR) cm ^-1 : 2935, 2859, 1714, 1643, 1587, 1508.
MS (ESI) m / z: 571 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₆ F ₂ N ₄ O ₅・ 1.3HCOOH ・ 0.1TFA: C, 58.94; H, 6.08, F, 6.81; N, 8.73. Found: C, 58.64; H, 6.26; F, 6.51; N, 8.98.

Example 46
Trans 4-[((2S, 5S) -1- {2- [4-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -5-[(dimethylamino) methyl] -1,3-benzo Oxazol-6-yl] acetyl} pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid In a manner analogous to Example 39, (Step 2), [4-fluoro-2- (5-fluoro-2-methoxyphenylamino] ) -6-Benzoxazolyl] acetic acid to give the title product (171 mg, 41%) as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.08-1.38 (4H, m), 1.76-2.44 (11H, m), 2.54-4.25 (16H, m), 6.90 (1H, dt, J = 3.2, 8.1 Hz), 7.00-7.10 (2H, m), 7.27 (1H, d, J = 6.9 Hz), 8.15 (1H, dt, J = 10.7, 2.6 Hz), 10.09 (1H, s).
IR (ATR) cm ^-1 : 3407, 2938, 2861, 1643, 1583.
MS (ESI) m / z: 601 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ F ₂ N ₄ O ₆・ 0.35HCOOH ・ 0.65TFA: C, 56.76; H, 5.74; F, 10.86; N, 8.11. Found: C, 56.84; H, 5.65; F, 10.65; N, 7.97.

Example 47
Trans-4-[((2S, 5S) -5- (1-azetidinylmethyl) -1- {2- [2- (4-chlorophenylamino) -1,3-benzoxazol-6-yl] acetyl } Pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans- [1-((5S)-(1-azetidinylmethyl) -tert-butoxycarbonyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester trans- [1- ( tert-butoxycarbonyl)-(5S)-(1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (1.00 g, 2.61 mmol) and azetidine hydrochloride (1.22 g , 13.1 mmol) was suspended in toluene and azeotroped three times. The residue was suspended in THF (20 ml), NaBH (OAc) ₃ (1.66 g, 7.83 mmol) was added at room temperature, and the mixture was stirred for 24 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to separate the solution, and the resulting organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (Biotage 40S ⁺ , flow rate 30 ml / min, dichloromethane / ethyl acetate, 10: 0 to 0:10, dichloromethane / methanol, 9: 1 to 1: 1) and colorless. The title compound (0.62 g, 56%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.16-1.28 (4H, m), 1.47 (9H, s), 1.49-1.51 (1H, m), 1.85-1.87
(24H, m), 4.08-4.15 (2H, m).
MS (ESI) m / z: 425 (M ⁺ +1).

(Process 2)
Trans-4-[((2S, 5S) -5- (1-azetidinylmethyl) -1-{[2- (4-chlorophenylamino) -1,3-benzoxazol-6-yl] acetyl} pyrrolidine Synthesis of 2-yl) methoxy] cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(1-azetidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexane Carrying out the carboxylic acid ethyl ester in a manner analogous to Example 39 (Step 2) using [2- (4-chlorophenylamino) -6-benzoxazolyl] acetic acid gave the title (160 mg, 59 %) As a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 0.86 (1H, t, J = 6.6 Hz), 1.00-1.38 (6H, m), 1.68-2.53 (14H, m), 3.01-4.13 (7H, m) , 7.10 (1H, t, J = 6.6 Hz), 7.36-7.44 (4H, m), 7.79 (2H, dd, J = 8.8, 2.9 Hz).
IR (ATR) cm ^-1 : 2931, 2857, 1637, 1569, 1490.
MS (ESI) m / z: 581 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₇ ClN ₄ O ₅・ H ₂ O ・ 0.25Et ₂ O: C, 62.23; H, 6.77; Cl, 5.74; N, 9.07.
Found: C, 62.29; H, 6.69; Cl, 6.14; N, 8.86.

Example 48
Trans-4-[((2S, 5S) -1- {2- [4,7-difluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O-Dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2) [4,7-difluoro-2- (2- Methylphenylamino) -6-benzoxazolyl] acetic acid was used to produce the title product (197 mg, 82%) as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.39 (5H, m), 1.79-2.19 (9H, m), 2.30 (3H, s), 2.46-2.89 (7H, m), 3.08-4.15 ( 10H, m), 7.02 (1H, dt, J = 5.4, 10.8 Hz), 7.13 (1H, dt, J = 1.0, 7.8 Hz), 7.25-7.30 (2H, m), 7.75 (1H, d, J = 8.3 Hz), 10.11 (1H, br s), 12.06 (1H, br s).
IR (ATR) cm ^-1 : 2937, 2859, 1637, 1587, 1432.
MS (ESI) m / z: 601 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ F ₂ N ₄ O ₆・ 0.5H ₂ O ・ 0.25Et ₂ O: C, 61.18; H, 6.66; F, 6.05; N, 8.92.
Found: C, 61.07; H, 6.51; F, 5.82; N, 8.71.

Example 49
Trans-4-[((2S, 5S) -1-[(2-phenylamino-1,3-benzoxazol-6-yl) acetyl] -5- (N, O-dimethylhydroxylaminomethyl) pyrrolidine-2 -Yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrole prepared in Example 18 (Step 2) The title compound (zinylmethoxy) cyclohexanecarboxylic acid ethyl ester was obtained in a manner analogous to Example 39 (Step 2) using [2- (phenylamino) -6-benzoxazolyl] acetic acid. 134 mg, 61%) was produced as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04-1.38 (4H, m), 1.73-2.34 (9H, m), 2.43-3.13 (7H, m), 3.21-3.45 (3H, m), 3.51- 4.13 (5H, m), 7.03 (1H, t, J = 7.1 Hz), 7.06-7.10 (1H, m), 7.34-7.39 (5H, m), 7.75 (2H, d, J = 8.1 Hz), 10.58 (1H, s).
IR (ATR) cm ^-1 : 2935, 2859, 1641, 1602, 1571.
MS (ESI) m / z: 551 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₈ N ₄ O ₆・ 0.25HCOOH: C, 64.63; H, 6.90; N, 9.97.
Found: C, 64.41; H, 6.98; N, 9.83.

Example 50
Trans-4-[((2S, 5S) -1-{[2- (4-Fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O-dimethylhydroxylamino Methyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid (step 1)
Synthesis of [2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetic acid
(4-Amino-3-hydroxyphenyl) -acetic acid methyl ester (3.00 g, 16.6 mmol) and 4-fluorophenyl isothiocyanate (2.79 g, 18.2 mmol) were dissolved in THF (50 ml) and stirred at room temperature for 24 hours. did. Mercury oxide (4.66 g, 21.5 mmol) was added, and the mixture was stirred at 70 ° C. for 30 min, allowed to cool to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography (Φ50 × 150 mm, hexane / ethyl acetate, 4: 1, flow rate 40 ml / min) to give the ester obtained as THF / MeOH / 1M-NaOH (14 / 7/7 ml), and the mixture was stirred at room temperature for 2 hours and concentrated. A 1N aqueous hydrochloric acid solution was added to the resulting residue to acidify the solution, and the resulting precipitate was collected by filtration to give the title compound (3.53 g, 74%) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (2H, s), 7.11 (1H, dd, J = 8.1, 1.5 Hz), 7.20-7.24 (2H, m), 7.36 (1H, d, J = 8.1 Hz), 7.40 (1H, d, J = 1.5 Hz), 7.75-7.79 (2H, m), 10.63 (1H, s), 12.30 (1H, s).
MS (ESI) m / z: 287 (M ⁺ +1).

(Process 2)
Trans-4-[((2S, 5S) -1-{[2- (4-Fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O-dimethylhydroxylamino Synthesis of methyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl) prepared in Example 18 (Step 2) )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2), using [2- (4-fluorophenylamino) -1,3-benzoxazole- The title product (134 mg, 59%) was produced as a colorless amorphous by using 6-yl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.38 (4H, m), 1.75-2.33 (9H, m), 2.46 (1H, s), 2.54-3.12 (5H, m), 3.20-4.16 ( 9H, m), 7.08 (1H, ddd, J = 8.3, 3.2, 1.0 Hz), 7.19-7.24 (2H, m), 7.34-7.37 (3H, m), 7.73-7.79 (2H, m), 10.63 ( 1H, s)
IR (ATR) cm ^-1 : 2937, 2859, 1639, 1577, 1508.
MS (ESI) m / z: 551 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₇ FN ₄ O ₆・ 0.25HCOOH: C, 62.23; H, 6.52; F, 3.27; N, 9.66.
Found: C, 62.47; H, 6.60; F, 3.23; N, 9.51.

Example 51
Trans-4-[((2S, 5S) -1-[(7-Fluoro-2-phenylamino-1,3-benzoxazol-6-yl) acetyl] -5- (N, O-dimethylhydroxylaminomethyl ) Pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(prepared in (Step 2) of Example 18 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner similar to Example 39, (Step 2), with [7-fluoro-2- (phenylamino) -6-benzoxazolyl] acetic acid To give the title product (134 mg, 59%) as a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.40 (4H, m), 1.79-2.35 (9H, m), 2.46 (1H, s), 2.54-3.14 (5H, m), 3.21-4.14 ( 9H, m), 7.05 (1H, t, J = 7.4 Hz), 7.09-7.14 (1H, m), 7.22 (1H, dd, J = 8.1, 2.2 Hz), 7.36-7.41 (3H, m), 7.74 (2H, d, J = 7.6 Hz), 10.82 (1H, s).
IR (ATR) cm ^-1 : 2938, 2859, 1641, 1577 1450.
MS (ESI) m / z: 569 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₇ FN ₄ O ₆・ 0.25HCOOH: C, 62.63; H, 6.52; F, 3.27; N, 9.66.
Found: C, 62.51; H, 6.60; F, 3.23; N, 9.53.

Example 52
Trans-4-[((2S, 5S) -1-{[7-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O -Dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxyl) prepared in Example 18, (Step 2) Aminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2), using [7-fluoro-2- (4-fluorophenylamino) -6 The title product (121 mg, 51%) was prepared as a colorless amorphous by using [-benzoxazolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.40 (4H, m), 1.79-2.35 (9H, m), 2.46 (1H, s), 2.61-3.14 (5H, m), 3.21-4.14 ( 9H, m), 7.06-7.27 (4H, m), 7.73-7.77 (3H, m), 10.87 (1H, s).
IR (ATR) cm ^-1 : 2937, 2859, 1643, 1581, 1508.
MS (ESI) m / z: 587 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₆ F ₂ N ₄ O ₆・ 0.25HCOOH: C, 60.74; H, 6.15; F, 6.35; N, 9.37.Found: C, 60.62; H, 6.24; F, 6.23; N , 9.17.

Example 53
Trans-4-[((2S, 5S) -1-{[4-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O -Dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxyl) prepared in Example 18, (Step 2) Aminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2), using [4-fluoro-2- (4-fluorophenylamino) -6 The title product (63 mg, 27%) was prepared as a colorless amorphous by using -benzoxazolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04-1.38 (4H, m), 1.76-2.34 (9H, m), 2.46 (1H, s), 2.54-3.19 (5H, m), 3.50-4.18 ( 9H, m), 6.99 (1H, dd, J = 11.2, 7.0 Hz), 7.26 (4H, dt, J = 16.4, 9.6 Hz), 7.74-7.77 (2H, m), 10.82 (1H, s).
IR (ATR) cm ^-1 : 2935, 1643, 1587, 1508, 1209.
MS (ESI) m / z: 587 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₆ F ₂ N ₄ O ₆・ 0.40HCOOH: C, 60.35; H, 6.13; F, 6.28; N, 9.26.Found: C, 60.48; H, 6.16; F, 6.34; N , 9.31.

Example 54
Trans 4-[((2S, 5S) -1-{[2- (2-methylphenylamino) -5- (N, O-dimethylhydroxylaminomethyl) -1,3-benzoxazol-6-yl] acetyl } Pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(prepared in Example 18 (Step 2) 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was used in a manner similar to Example 39, (Step 2), using [2- (2-methylphenylamino) -6-benzoxazolyl] acetic acid. The title product (69 mg, 31%) was produced as a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 1.01-1.37 (5H, m), 1.76-2.20 (9H, m), 2.29 (3H, s), 2.46-4.07 (14H, m), 6.99-7.10 ( 2H, m), 7.22-7.31 (3H, m), 7.44 (2H, q, J = 3.0 Hz), 7.81 (1H, dd, J = 7.8, 3.2 Hz), 9.61 (1H, br s).
IR (ATR) cm ^-1 : 2937, 2859, 1637, 1573, 1438.
MS (ESI) m / z: 565 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₄₀ N ₄ O ₆・ 0.2HCOOH: C, 65.30; H, 7.10; N, 9.76.
Found: C, 65.31; H, 6.91; N, 9.73.

Example 55
Trans 4-[((2S, 5S) -1-{[2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O-dimethylhydroxylaminomethyl ) Pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(prepared in (Step 2) of Example 18 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was used in a manner analogous to Example 39, (Step 2) using [2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid. The title product (134 mg, 58%) was produced as a colorless amorphous product.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.38 (4H, m), 1.75-2.33 (10H, m), 2.46-4.09 (17H, m), 6.98-7.03 (1H, m), 7.04- 7.10 (3H, m), 7.27-7.34 (2H, m), 8.16 (1H, q, J = 4.0 Hz), 9.54 (1H, br s).
IR (ATR) cm ^-1 : 3417, 2937, 2859, 1724, 1602, 1573.
MS (ESI) m / z: 581 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₄₀ N ₄ O ₇・ 0.2HCOOH: C, 63.53; H, 6.90; N, 9.50.
Found: C, 63.56; H, 6.96; N, 9.45.

Example 56
Trans 4-[((2S, 5S) -1-{[4-Fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O- Dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylamino) prepared in (Step 2) of Example 18 Methyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2), using [4-fluoro-2- (2-methoxyphenylamino) -6- The title product (118 mg, 50%) was prepared as a colorless amorphous by using benzoxazolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.39 (4H, m), 1.76-2.32 (9H, m), 2.46-4.14 (18H, m), 6.92-7.21 (5H, m), 8.06- 8.11 (1H, m).
IR (ATR) cm ^-1 : 3415, 2937, 2859, 1704, 1644, 1583.
MS (ESI) m / z: 599 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₉ FN ₄ O ₇・ 0.2HCOOH: C, 61.65; H, 6.53; F, 3.13; N, 9.22.
Found: C, 61.67; H, 6.53; F, 3.15; N, 9.22.

Example 57
Trans 4-[((2S, 5S) -1-{[4-Chloro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18, (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a similar manner to Example 39, (Step 2), using The title product (44 mg, 17%) was prepared as a colorless amorphous by using -methoxyphenylamino) -6-benzoxazolyl] acetic acid.
¹ H-NMR (CD ₃ OD) δ: 1.02-1.50 (4H, m), 1.82-2.46 (9H, m), 2.65-4.22 (18H, m), 6.76 (1H, dt, J = 3.2, 8.1 Hz ), 6.98 (1H, q, J = 4.7 Hz), 7.20 (1H, dd, J = 13.5, 1.2 Hz), 7.30 (1H, dd, J = 10.4, 1.3 Hz), 8.24 (1H, ddd, J = (10.7, 5.0, 3.1 Hz).
IR (ATR) cm ^-1 : 3407, 2937, 2859, 1704, 1641, 1573.
MS (ESI) m / z: 633 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ ClFN ₄ O ₇・ 0.5H ₂ O: C, 57.99; H, 6.12; Cl, 5.52; F, 2.96; N, 8.73.
Found: C, 57.98; H, 6.01; Cl, 5.44; F, 2.96; N, 8.54.

Example 58
Trans 4-[((2S, 5S) -1-{[2- (5-chloro-2-methoxyphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18, (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in an analogous manner to Example 39 (Step 2) [4-fluoro-2- (5-chloro-2 The title product (93 mg, 37%) was prepared as a colorless amorphous by using -methoxyphenylamino) -6-benzoxazolyl] acetic acid.
¹ H-NMR (CD ₃ OD) δ: 1.05-1.50 (4H, m), 1.86-2.45 (9H, m), 2.53-4.24 (18H, m), 6.94-7.01 (2H, m), 7.03 (1H , dd, J = 8.8, 2.5 Hz), 7.20 (1H, dd, J = 12.0, 1.2 Hz), 8.37 (1H, dd, J = 4.9, 2.5 Hz).
IR (ATR) cm ^-1 : 3407, 2937, 2861, 1704, 1643, 1598, 1577.
MS (ESI) m / z: 633 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ ClFN ₄ O ₇・ 0.5H ₂ O: C, 57.99; H, 6.12; Cl, 5.52; F, 3.06; N, 8.60. Found: C, 58.15; H, 6.02; Cl , 5.37; F, 3.06; N, 8.60.

Example 59
Trans 4-[((2S, 5S) -1-{[4-Fluoro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18, (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a similar manner as in Example 39, (Step 2) [4-fluoro-2- (5-fluoro-2 The title product (77 mg, 32%) was prepared as a colorless amorphous by using -methylphenylamino) -6-benzoxazolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.06-1.46 (4H, m), 1.81-2.24 (10H, m), 2.31 (3H, s), 2.54-4.19 (14H, m), 6.83 (1H, dt, J = 2.5, 8.1 Hz), 6.96 (1H, t, J = 10.8 Hz), 7.20 (1H, d, J = 11.0 Hz), 7.23 (1H, d, J = 7.6 Hz), 7.74 (1H, dt, J = 10.9, 3.6 Hz).
IR (ATR) cm ^-1 : 2937, 2861, 1698, 1644, 1606, 1583.
MS (ESI) m / z: 601 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ F ₂ N ₄ O ₆ , 0.5H ₂ O: C, 61.07, H, 6.45; F, 6.23; N, 9.19.
Found: C, 61.29; H, 6.36; F, 6.48; N, 9.00.

Example 60
Trans 4-[((2S, 5S) -1-{[2- (4-chloro-2-methoxyphenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18 (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2) [2- (4-Chloro-2-methoxyphenylamino). ) -7-Fluoro-6-benzoxazolyl] acetic acid to give the title product (74 mg, 29%) as a colorless amorphous.
¹ H-NMR (CD ₃ OD) δ: 1.11-1.49 (4H, m), 1.91-2.28 (10H, m), 2.52-4.30 (17H, m), 7.00 (1H, dd, J = 8.7, 2.3 Hz ), 7.05 (1H, d, J = 2.2 Hz), 7.07-7.19 (2H, m), 8.17 (1H, dd, J = 8.6, 2.2 Hz).
IR (ATR) cm ^-1 : 3409, 2937, 2861, 1724, 1700, 1637, 1577.
MS (ESI) m / z: 633 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ ClFN ₄ O ₇・ 0.5H ₂ O: C, 57.99; H, 6.12; Cl, 5.52; F, 2.96; N, 8.73.
Found: C, 58.12; H, 6.01; Cl, 5.30; F, 3.26; N, 8.57.

Example 61
Trans 4-[((2S, 5S) -1-{[4-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18 (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39 (Step 2) [4-fluoro-2- (5-fluoro-2 The title product (97 mg, 39%) was prepared as a colorless amorphous by using -methoxyphenylamino) -6-benzoxazolyl] acetic acid.
¹ H-NMR (CD ₃ OD) δ: 1.04-1.50 (4H, m), 1.85-2.45 (10H, m), 2.53-4.23 (17H, m), 6.76 (1H, dt, J = 3.2, 8.1 Hz ), 6.98 (2H, dd, J = 9.4, 5.3 Hz), 7.21 (1H, d, J = 11.8 Hz), 8.19 (1H, ddd, J = 10.7, 4.4, 3.1 Hz).
IR (ATR) cm ^-1 : 3409, 2937, 2861, 1704, 1644, 1585.
MS (ESI) m / z: 617 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ F ₂ N ₄ O ₇・ 0.5H ₂ O: C, 59.51; H, 6.28; F, 6.07; N, 8.95.
Found: C, 59.69; H, 6.17; F, 6.38; N, 8.72.

Example 62
Trans 4-[((2S, 5S) -1-{[2- (5-chloro-2-methoxyphenylamino) -4-methoxy-1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18, (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39 (Step 2) [2- (5-Chloro-2-methoxyphenylamino). ) -4-Methoxy-6-benzoxazolyl] acetic acid to give the title product (65 mg, 25%) as a colorless amorphous.
¹ H-NMR (CD ₃ OD) δ: 1.02-1.49 (4H, m), 1.83-2.43 (9H, m), 2.53-4.36 (21H, m), 6.79 (1H, dd, J = 14.0, 1.0 Hz ), 6.95-7.03 (3H, m), 8.37 (1H, t, J = 2.7 Hz).
IR (ATR) cm ^-1 : 3415, 2935, 2859, 1722, 1704, 1637, 1598, 1577.
MS (ESI) m / z: 645 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₄₁ ClN ₄ O ₈・ 0.5H ₂ O: C, 58.76; H, 6.47; Cl, 5.42; N, 8.56.
Found: C, 58.47; H, 6.24; Cl, 5.74; N, 8.33.

Example 63
Trans 4-[((2S, 5S) -1-{[7-chloro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18 (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a similar manner to Example 39 (Step 2) in the [7-chloro-2- (5-fluoro-2 The title product (87 mg, 35%) was prepared as a colorless amorphous by using -methylphenylamino) -6-benzoxazolyl] acetic acid.
¹ H-NMR (CD ₃ OD) δ: 1.13-1.52 (4H, m), 1.94-2.28 (9H, m), 2.31 (3H, s), 2.35-4.31 (15H, m), 6.82 (1H, dt , J = 2.7, 8.1 Hz), 7.14-7.28 (3H, m), 7.75 (1H, dd, J = 10.8, 2.5 Hz).
IR (ATR) cm ^-1 : 2935, 2859, 1639, 1608, 1569.
MS (ESI) m / z: 617 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ ClFN ₄ O ₆・ 0.5H ₂ O: C, 59.47; H, 6.28; Cl, 5.66; F, 3.03; N, 8.95.
Found: C, 59.69; H, 6.14; Cl, 5.56; F, 3.14; N, 8.86.

Example 64
Trans 4-[((2S, 5S) -1-{[7-chloro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (N, O- Dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylamino) prepared in (Step 2) of Example 18 Methyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2), [7-chloro-2- (2-methoxyphenylamino) -6- The title product (70 mg, 28%) was prepared as a colorless amorphous by using benzoxazolyl] acetic acid.
¹ H-NMR (CD ₃ OD) δ: 1.13-1.52 (4H, m), 1.94-2.46 (9H, m), 2.53-4.30 (18H, m), 7.00 (1H, dt, J = 1.7, 7.1 Hz ), 7.02-7.05 (1H, m), 7.07-7.11 (1H, m), 7.17 (1H, dd,
J = 10.8, 8.1 Hz), 7.27 (1H, dd, J = 8.1, 1.2 Hz), 8.13 (1H, dd, J = 8.0, 1.6 Hz).
IR (ATR) cm ^-1 : 3416, 2935, 2861, 1724, 1639, 1571.
MS (ESI) m / z: 615 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₉ ClN ₄ O ₇・ 0.5H ₂ O: C, 59.66; H, 6.46; Cl, 5.68; N, 8.98.
Found: C, 59.79, H, 6.37; Cl, 5.47; N, 8.89.

Example 65
Trans 4-[((2S, 5S) -1-{[2- (5-chloro-2-methylphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18, (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2) [2- (5-chloro-2-methylphenylamino) ) -4-Fluoro-6-benzoxazolyl] acetic acid to give the title product (69 mg, 28%) as a colorless amorphous.
¹ H-NMR (CD ₃ OD) δ: 1.03-1.49 (4H, m), 1.82-2.28 (9H, m), 2.31 (3H, s), 2.40-4.25 (15H, m), 6.96 (1H, t , J = 10.7 Hz), 7.10 (1H, dd, J = 8.1, 2.2 Hz), 7.18-7.24 (2H, m), 7.92 (1H, dd, J = 4.4, 2.2 Hz).
IR (ATR) cm ^-1 : 2937, 2859, 1700, 1635, 1581.
MS (ESI) m / z: 617 (M ⁺ +1).
Anal.Calcd for.C ₃₁ H ₃₈ ClFN ₄ O ₆・ 0.5H ₂ O: C, 59.47; H, 6.28; Cl, 5.66; F, 3.03; N, 8.95.
Found: C, 59.63; H, 6.20; Cl, 5.44; F, 3.12; N, 8.80.

Example 66
Trans 4-[((2S, 5S) -1-{[2- (4-Chlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (N, O-dimethyl Hydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid Trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl) prepared in Example 18, (Step 2) )-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2) and [7-fluoro-2- (4-chlorophenylamino) -6-benzoxa The title product (71 mg, 29%) was prepared as a colorless amorphous product by using zolyl] acetic acid.
¹ H-NMR (CD ₃ OD) δ: 1.08-1.52 (4H, m), 1.88-2.47 (9H, m), 2.53-4.29 (15H, m), 7.06-7.18 (2H, m), 7.32-7.38 (2H, m), 7.65-7.70 (2H, m).
IR (ATR) cm ^-1 : 2937, 2861, 1700, 1639, 1575, 1492.
MS (ESI) m / z: 603 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₆ ClFN ₄ O ₆・ 0.5H ₂ O: C, 58.87; H, 6.09; Cl, 5.79; F, 3.10; N, 9.15.
Found: C, 58.88; H, 5.87; Cl, 6.06; F, 3.31; N, 9.21.

Example 67
Trans 4-[((2S, 5S) -1-{[2- (3,4-difluorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl} -5- ( N, O-dimethylhydroxylaminomethyl) pyrrolidin-2-yl) methoxy] cyclohexanecarboxylic acid trans 4- [1-tert-butoxycarbonyl- (5S)-(N, O) prepared in Example 18 (Step 2) -Dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 39, (Step 2) [4,7-difluoro-2- (3,4 -Difluorophenylamino) benzoxazolyl] acetic acid was used to produce the title product (74 mg, 30%) as a colorless amorphous.
¹ H-NMR (CD ₃ OD) δ: 1.09-1.53 (4H, m), 1.93-2.28 (9H, m), 2.42-4.27 (15H, m), 6.95 (1H, dq, J = 20.7, 5.0 Hz ), 7.25 (1H, dd, J = 19.1, 9.1 Hz), 7.35-7.42 (1H, m), 7.78-7.88 (1H, m).
IR (ATR) cm ^-1 : 3060, 2938, 2863, 1594, 1513.
MS (ESI) m / z: 623 (M ⁺ +1).
Anal.Calcd for.C ₃₀ H ₃₄ F ₄ N ₄ O ₆・ 0.35H ₂ O: C, 57.29; H, 5.56; F, 12.08; N, 8.91.
Found: C, 56.95; H, 5.43; F, 12.45; N, 8.87.

Example 68
Trans-4- [1-[[2- (2,3,4-trifluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of [2- (2,4,5-trifluorophenyl) amino-6-benzoxazolyl] acetic acid methyl ester
2,4,5-trifluoroaniline (2.00 g, 13.6 mmol) and thiocarbonyldiimidazole (2.83 g, 14.3 mmol) were dissolved in tetrahydrofuran (50 ml) and stirred at room temperature for 17 hours. The reaction mixture was concentrated, the residue was dissolved in ethanol (50 ml), methyl 4-amino-3-hydroxyphenylacetic acid (2.34 g, 12.9 mmol) was added, and the mixture was stirred at room temperature for 24 hr. Mercury (II) oxide (3.53 g, 16.3 mmol) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (Biotage 40M, elution solvent n-hexane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (1.23 g, 27%) as an orange-red solid. It was.
¹ H-NMR (CDCl ₃ ) δ: 3.71 (5H, s), 7.00-7.09 (2H, m), 7.18 (1H, dd, J = 8.1, 1.7 Hz), 7.33-7.34 (1H, m), 7.47 (1H, d, J = 8.1 Hz), 8.49-8.56 (1H, m).
MS (LC-ESI) m / z: 337 (M ⁺ +1).

(Process 2)
Synthesis of [2- (2,4,5-trifluorophenyl) amino-6-benzoxazolyl] acetic acid
[2- (2,4,5-trifluorophenyl) amino-6-benzoxazolyl] acetic acid methyl ester (1.23 g, 3.66 mmol) was dissolved in tetrahydrofuran (15 ml) and 0.5 N aqueous sodium hydroxide solution ( 14.6 ml, 7.30 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice-1N hydrochloric acid, and the precipitated solid was collected by suction filtration and dried under reduced pressure to obtain the title compound (1.17 g, 99%) as a light brown solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.65 (2H, s), 7.14 (1H, dd, J = 8.1, 1.2 Hz), 7.39-7.43 (2H, m), 7.64-7.71 (1H, m) , 8.38-8.45 (1H, m).
MS (LC-ESI) m / z: 323 (M ⁺ +1).

(Process 3)
Trans-4- [1-[[2- (2,4,5-trifluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of [2- (2,4,5-trifluorophenylamino) -6-benzoxazolyl in a manner similar to Example 18, (Step 4) The title compound (yield 89%) was produced as a pale yellow oil by conducting a condensation reaction with [l] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.51 (7H, m), 1.88-2.26 (9H, m), 2.48-2.61 (total 4H, m, inclulding 3H, s, at δ 2.61), 2.70-2.78 (1H, m), 3.10-3.17 (1H, m), 3.31-3.67 (total 5H, m, including 3H, s, at δ 3.54), 3.74-3.93 (2H, m), 4.06-4.17 (4H, m ), 7.00-7.06 (1H, m), 7.13-7.21 (1H, m), 7.41-7.46 (2H, m), 8.50-8.57 (1H, m).
MS (LC-ESI) m / z: 633 (M ⁺ +1).

(Process 4)
Trans-4- [1-[[2- (2,4,5-trifluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of 2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[2- (2,4,5-trifluorophenyl) amino] was prepared in an analogous manner to Example 18 (Step 5). -6-Benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester 52%) was produced as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.33 (4H, m), 1.74-2.08 (9H, m), 2.29-3.83 (total 13H, series of m, including 3H, s, at δ 2.55 and including 3H, s, at δ 3.44), 3.96-4.06 (2H, m), 7.06-7.08 (1H, m), 7.29-7.36 (2H, m), 7.56-7.64 (1H, m), 8.36-8.43 ( 1H, m).
IR (ATR) cm ^-1 : 1637, 1577, 1435, 1248, 1200, 872.
MS (LC-ESI) m / z: 605 (M ⁺ +1).
Anal.Calcd for C ₃₀ H ₃₅ F ₃ N ₄ O ₆・ 1 / 2H ₂ O: C, 58.72; H, 5.91; N, 9.13; F, 9.29.
Found: C, 58.88; H, 5.82; N, 9.07; F, 9.27.

Example 69
Trans-4- [1-[[2- (2,3,4-trifluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( 2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of 2,3,4-trifluoroaniline
2,3,4-trifluoronitrobenzene (5.00 g, 28.2 mmol) was dissolved in methanol (50 ml), 10% Pd (OH) ₂ / C (1.00 g) was added, and hydrogenated at room temperature for 16 hours. . After removing the catalyst by suction filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40M, elution solvent n-hexane: ethyl acetate = 7: 1-3: 1), and the title compound
(2.70 g, 65%) was obtained as a light brown oil.
¹ H-NMR (CDCl ₃ ) δ: 3.66 (2H, broad s), 6.41-6.47 (1H, m), 6.69-6.80 (1H, m).

(Process 2)
Synthesis of [2- (2,3,4-trifluorophenyl) amino-6-benzoxazolyl] acetic acid methyl ester
2,3,4-trifluoroaniline (2.10 g, 14.3 mmol) and thiocarbonyldiimidazole (2.97 g, 15.0 mmol) were dissolved in tetrahydrofuran (50 ml) and stirred at room temperature for 18 hours. The reaction mixture was concentrated, the residue was dissolved in ethanol (50 ml), methyl 4-amino-3-hydroxyphenylacetic acid (2.46 g, 13.6 mmol) was added, and the mixture was stirred at room temperature for 3 hr. Mercury (II) oxide (3.71 g, 17.1 mmol) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated. The obtained residue was purified by flash column chromatography (Biotage 40M, elution solvent n-hexane: ethyl acetate = 4: 1 to 1: 1) and recrystallized (ethyl acetate-acetone-n-hexane system). The title compound (1.24 g, 26%) was obtained as pale yellow needles.
¹ H-NMR (CDCl ₃ ) δ: 3.71 (5H, s), 7.02-7.18 (3H, m), 7.33-7.34 (1H, m), 7.45 (1H, d, J = 8.1 Hz), 8.18-8.24 (1H, m).
MS (LC-ESI) m / z: 337 (M ⁺ +1).

(Process 3)
Synthesis of [2- (2,3,4, -trifluorophenyl) amino-6-benzoxazolyl] acetic acid
[2- (2,3,4-trifluorophenyl) amino-6-benzoxazolyl] acetic acid methyl ester (1.24 g, 3.69 mmol) was dissolved in tetrahydrofuran (13 ml) and 1 N aqueous sodium hydroxide solution ( 7.40 ml, 7.40 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-1N hydrochloric acid, and the precipitated solid was collected by suction filtration and dried under reduced pressure to give the title compound (1.15 g, 97%) as a colorless powdery solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.63 (2H, s), 7.11 (1H, d, J = 7.8 Hz), 7.34-7.41 (3H, m), 8.02 (1H, broad s), 10.84 ( 1H, broad s).
MS (LC-ESI) m / z: 323 (M ⁺ +1).

(Process 4)
Trans-4- [1-[[2- (2,3,4-trifluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of 2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester [2- (2,3,4, -trifluorophenyl) amino-6-benzoxa was synthesized in a manner similar to Example 18, (Step 4). The title product (yield 75%) was prepared as a colorless amorphous by conducting a condensation reaction with [zolyl] acetic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.14-1.44 (total 7H, series of m), 1.88-2.21 (total 9H, series of m), 2.48-2.78 (total 5H, m, including 3H, s, at δ 2.61), 3.11-3.67 (total 6H, m, including 3H, s, at δ 3.53), 3.74-3.94 (2H, m), 4.06-4.17 (4H, m), 7.01-7.19 (2H, m), 7.39 -7.55 (3H, m), 8.17-8.22 (1H, m).
MS (LC-ESI) m / z: 633 (M ⁺ +1).

(Process 5)
Trans-4- [1-[[2- (2,3,4-trifluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-( Synthesis of 2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid Trans-4- [1-[[2- (2,3,4-trifluorophenyl) amino] was prepared in an analogous manner to Example 18 (Step 5). -6-Benzoxazolyl] acetyl]-(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester 64%) was produced as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.33 (4H, m), 1.74-2.08 (total 9H, series of m), 2.45-2.85 (total 5H, series of m), 3.06-3.83 (total 8H, series of m), 3.96-4.06 (2H, m), 7.06-7.08 (1H, m), 7.31-7.33 (3H, m), 8.02 (1H, broad s).
IR (ATR) cm ^-1 : 1637, 1581, 1512, 1439, 1248, 953.
MS (LC-ESI) m / z: 605 (M ⁺ +1).
Anal.Calcd for C ₃₀ H ₃₅ F ₃ N ₄ O ₆・ 1 / 2H ₂ O: C, 58.72; H, 5.91; N, 9.13; F, 9.29.
Found: C, 58.95; H, 5.93; N, 8.77; F, 8.90.

Example 70
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (1- Piperidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid (Step 1)
Synthesis of trans- [1- (tert-butoxycarbonyl)-(5S)-(1-piperidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester trans- [1- ( tert-butoxycarbonyl)-(5S) -formyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (383 mg, 0.803 mmol) was dissolved in ethanol (10 mL) and piperidine (0.177 ml , 2.41 mmol) was added and stirred and azeotroped with toluene. The residue was dissolved in ethanol (10 mL), triacetoxyborohydride (511 mg, 0.511 mmol) was added, and the mixture was stirred at room temperature for 24 hours. To the reaction solution are added saturated brine and ethyl acetate, and the mixture is separated, and the obtained organic layer is dried over anhydrous sodium sulfate and concentrated. The residue was purified by medium pressure silica gel column chromatography (Biotage 25M +: chloroform / methanol, 99: 1 to 9: 1, 10 ml / min) to give the title compound (335 mg, 92%) as a colorless oil. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.62 (20H, m), 1.88-2.54 (17H, m), 3.16-3.38 (2H, m), 3.63 (1H, ddd, J = 32.4, 9.3, 3.1 Hz), 3.72-3.81 (1H, m), 3.84-3.93 (1H, m), 4.07-4.14 (2H, m).
MS (ESI) m / z: 453 (M ⁺ +1).

(Process 2)
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (1- Synthesis of piperidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(1-piperidinylmethyl)-(2S) -pyrrolidinyl Methoxy] -1-cyclohexanecarboxylic acid ethyl ester (335 mg, 0.74 mmol) was dissolved in dichloromethane (10 ml), TFA (5 ml) was added at room temperature, and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure and azeotroped three times with toluene. The obtained residue was dissolved in DMF (4 ml), [2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetic acid (263 mg, 0.740 mmol), EDC (0.195 mL, 1.11 mmol), TEA (0.309 mmol, 3.22 mmol) and HOBt (20.0 mg, 0.150 mmol) were added and stirred at room temperature for 24 hours. The reaction solution was poured into a mixed solution of dichloromethane (20 ml) and saturated brine (20 ml) and separated. This operation was further repeated twice. All the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel column chromatography (High Flash L: Yamazen Co., Ltd .: diameter 26 mm, total length 100 mm, chloroform / methanol, 99: 1 to 9: 1) to obtain an ester. . The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol (30 ml, 2: 1), 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with chloroform (20 ml), 1N aqueous hydrochloric acid solution (10 ml) was added, and the mixture was stirred and separated. The aqueous layer was extracted twice with a mixed solvent of chloroform / methanol (9: 1), and all organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to medium pressure silica gel column chromatography (High Flash L manufactured by Yamazen Co., Ltd .: diameter 26 mm, total length 100 mm, chloroform / methanol / water, 99: 0.9: 0.1 to 90: 9: 1, flow rate 20 ml) / min), and the resulting fraction of the title compound was concentrated. The resulting oily title compound was precipitated from chloroform / hexane / diethyl ether to give the title compound (380 mg, 78%) as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ: 0.84-2.33 (21H, m), 2.69-3.17 (2H, m), 3.23-3.59 (7H, m), 3.81-4.34 (2H, m), 7.14 ( 1H, t, J = 7.4 Hz), 7.30 (1H, d, J = 7.8 Hz), 7.64-7.66 (2H, m), 8.11-8.14 (1H, m), 9.45-9.72 (1H, m), 11.25 -11.32 (1H, m).
IR (ATR) cm ^-1 : 2935, 2859, 1635, 1571, 1450.
MS (ESI) m / z: 661 (M ⁺ +1).
MS (FAB) m / z: 661 (M ⁺ +1).
MS (FAB) m / z: 661.2383 (Calcd. For C ₃₃ H ₄₀ Cl ₂ FN ₄ O ₅ : 661.2360).
Anal.Calcd for C ₃₃ H ₃₉ Cl ₂ FN ₄ O ₅・ HCl ・ 1.5H ₂ O: C, 54.66; H, 5.98; Cl, 14.67; F, 2.62; N, 7.73.
Found: C, 54.50; H, 5.70; Cl, 14.33; F, 2.68; N, 7.62.

Example 71
Trans-4-{[(2S, 5S) -1-{[2- (4-Chlorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1-piperidinylmethyl) pyrrolidine 2-yl] methoxy} cyclohexanecarboxylic acid Performed in a manner similar to Example 70, (Step 2) using [2- (4-chlorophenylamino) -6-benzoxazolyl] acetic acid. (205 mg, 72%) was produced as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.61 (7H, m), 1.72-2.42 (16H, m), 3.03-3.05 (5H, m), 3.65-3.75 (1H, m), 3.84 ( 1H, d, J = 15.9 Hz), 3.94-4.17 (2H, m), 7.09 (1H, d, J = 8.3 Hz), 7.35-7.49 (5H, m), 7.78 (2H, d, J = 8.8 Hz ), 10.76 (1H, s).
IR (ATR) cm ^-1 : 2933, 2857, 1712, 1637, 1569.
MS (ESI) m / z: 609 (M ⁺ +1).
MS (FAB) m / z: 609.2823 (calcd. For C ₃₃ H ₄₂ ClN ₄ O ₅ : 609.2844).
Anal.Calcd for.C ₃₃ H ₄₁ ClN ₄ O ₅・ 0.9H ₂ O ・ 0.1hexane ・ 0.1HCl: C, 63.31; H, 6.97; Cl,
6.12; N, 8.99. Found: C, 63.42; H, 7.01; Cl, 6.12; N, 8.46.

Example 72
Trans-4-{[(2S, 5S) -1-{[7-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1-pi Peridinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 70, (Step 2), [7-fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl The title product (164 mg, 67%) was produced as a colorless amorphous product by using acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.11-2.22 (15H, m), 2.77-4.24 (17H, m), 7.10 (1H, t, J = 7.4 Hz), 7.20-7.26 (3H, m) , 7.74-7.77 (2H, m), 8.14 (1H, s), 10.90 (1H, s).
IR (ATR) cm ^-1 : 2938, 1716, 1637, 1579, 1508.
MS (ESI) m / z: 611 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ F ₂ N ₄ O ₅・ 1.6HCOOH ・ 0.1TFA: C, 60.06; H, 6.27; F, 6.28; N, 8.05.Found: C, 59.80; H, 6.42; F, 6.25; N, 8.30.

Example 73
Trans-4-{[(2S, 5S) -1-{[4-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1-pi Peridinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 70, (Step 2), [4-Fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl The title product (119 mg, 49%) was produced as a colorless amorphous product by using acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-2.20 (20H, m), 2.75-4.23 (12H, m), 7.02 (1H, dd, J = 11.0, 6.1 Hz), 7.22-7.28 (3H, m), 7.75-7.78 (2H, m), 10.81-10.83 (1H, m).
IR (ATR) cm ^-1 : 2937, 2861, 1712, 1641, 1587, 1508.
MS (ESI) m / z: 611 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ F ₂ N ₄ O ₅・ HCOOH ・ H ₂ O: C, 60.52; H, 6.57; F, 5.63; N, 8.30.
Found: C, 60.30; H, 6.49; F, 5.92; N, 8.42.

Example 74
Trans 4-{[(2S, 5S) -1-{[4-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( 1-piperidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 70, (Step 2), [4-Fluoro-2- (5-fluoro-2-methoxyphenylamino) The title product (144 mg, 47%) was prepared as a colorless amorphous by using [6-benzoxazolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-2.19 (15H, m), 2.55-4.27 (20H, m), 6.90 (1H, dt, J = 3.2, 8.6 Hz), 7.00-7.10 (2H, m), 7.27 (1H, d, J = 10.8 Hz), 8.13-8.17 (1H, m), 10.09 (1H, s).
IR (ATR) cm ^-1 : 3411, 2940, 2859, 1644, 1585.
MS (ESI) m / z: 641 (M ⁺ +1).
Anal.Calcd for.C ₃₄ H ₄₂ F ₂ N ₄ O ₆・ 0.35HCOOH ・ 0.65TFA: C, 58.58; H, 5.98; F, 10.27; N, 7.66. Found: C, 58.59; H, 5.72; F, 10.06; N, 7.57.

Example 75
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (1- Pyrrolidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid (step 1)
Synthesis of trans- [1- (tert-butoxycarbonyl)-(5S)-(1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Example 18 (step The title compound (294 mg, 84%) was produced as a colorless oil by carrying out with pyrrolidine in a manner similar to 2).
¹ H-NMR (CDCl ₃ ) δ: 1.17-1.31 (6H, m), 1.42-1.48 (9H, m), 1.60 (4H, br s), 1.75 (4H, br s), 1.87-2.08 (6H, m), 2.17-2.27 (1H, m), 2.41-2.66 (6H, m), 3.15-3.38 (2H, m), 3.63 (1H, ddd, J = 33.5, 9.1, 2.9 Hz), 3.75-3.83 ( 1H, m), 3.85-3.95 (1H, m), 4.11 (2H, ddd, J = 14.2, 7.1, 2.6 Hz).
MS (ESI) m / z: 439 (M ⁺ +1).

(Process 2)
Trans-4-{[(2S, 5S) -1-{[2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (1- Synthesis of pyrrolidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(1-pyrrolidinylmethyl)-(2S) -pyrrolidinyl Methoxy] -1-cyclohexanecarboxylic acid ethyl ester (294 mg, 0.670 mmol) was dissolved in dichloromethane (10 ml), TFA (5 ml) was added at room temperature, and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure and azeotroped three times with toluene. The obtained residue was dissolved in DMF (4 ml), [2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetic acid (238 mg, 0.670 mmol), EDC (0.176 mL, 1.01 mmol), TEA (0.280 mmol, 2.01 mmol) and HOBt (18.1 mg, 0.130 mmol) were added and stirred at room temperature for 24 hours. The reaction solution was poured into a mixed solution of dichloromethane (20 ml) and saturated brine (20 ml) and separated. This operation was further repeated twice. All the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel column chromatography (High Flash L: Yamazen Co., Ltd .: diameter 26 mm, total length 100 mm, chloroform / methanol, 99: 1 to 9: 1) to obtain an ester. . The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol (30 ml, 2: 1), 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with dichloromethane (20 ml), 1N aqueous hydrochloric acid solution (10 ml) was added, and the mixture was separated after stirring. The aqueous layer was extracted twice with a mixed solvent of chloroform / methanol (9: 1), and all organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to medium pressure silica gel column chromatography (Yamazen HighFlash L: diameter 26 mm, total length 100 mm, chloroform / methanol / water, 99: 0.9: 0.1 to 90: 9: 1, flow rate 20 ml / min. The resulting fraction of the title compound was concentrated. The obtained oily title compound was precipitated from chloroform / hexane / diethyl ether to give the title compound (335 mg, 77%) as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.40 (4H, m), 1.88-2.21 (12H, m), 3.08-4.24 (15H, m), 7.11-7.17 (1H, m), 7.30 ( 1H, d, J = 8.1 Hz), 7.65 (2H, s), 8.11-8.13 (1H, m), 11.27 (1H, br s).
IR (ATR) cm ^-1 : 2937, 2861, 1637, 1571, 1450.
MS (ESI) m / z: 647 (M ⁺ +1).
MS (FAB) m / z: 647 (M ⁺ +1).
MS (FAB) m / z: 647.2236 (Calcd. For C ₃₂ H ₃₈ Cl ₂ FN ₄ O ₅ : 647.2203).
Anal.Calcd for C ₃₂ H ₃₇ Cl ₂ FN ₄ O ₅・ HCl ・ 1.5H ₂ O: C, 54.05; H, 5.81; Cl, 14.96; F, 2.67; N, 7.88.
Found: C, 53.68; H, 5.42; Cl, 15.20; F, 3.43; N, 7.62.

Example 76
Trans-4-{[(2S, 5S) -1-{[2- (4-Chlorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1-pyrrolidinylmethyl) pyrrolidine 2-yl] methoxy} cyclohexanecarboxylic acid Performed in a manner similar to Example 75, (Step 2) using [2- (4-chlorophenylamino) -6-benzoxazolyl] acetic acid. (217 mg, 76%) was produced as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.41 (4H, m), 1.59-2.20 (8H, m), 2.34-2.64 (5H, m), 3.16-3.48 (9H, m), 3.68 ( 1H, d, J = 15.4 Hz), 3.83 (1H, d, J = 15.9 Hz), 3.94-4.18
(2H, m), 7.09 (1H, d, J = 8.1 Hz), 7.35-7.39 (2H, m), 7.43 (2H, d, J = 8.8 Hz),
7.78 (2H, d, J = 8.8 Hz), 10.75 (1H, br s).
IR (ATR) cm ^-1 : 2933, 2857, 1637, 1569, 1236.
MS (ESI) m / z: 595 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₃₉ ClN ₄ O ₅・ 2.0H ₂ O ・ 0.1hexane ・ 0.2Et ₂ O: C, 61.30; H, 7.12; Cl, 5.42; N, 8.56.
Found: C, 61.51; H, 6.75; Cl, 5.31; N, 8.16.

Example 77
Trans-4-{[(2S, 5S) -1-{[7-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1-pyrroline [Dinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid [7-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazole The title product (154 mg, 68%) was prepared as a colorless amorphous by using -6-yl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.08-1.41 (4H, m), 1.74-2.22 (13H, m), 2.66-4.27 (13H, m), 7.08-7.13 (1H, m), 7.21- 7.26 (3H, m), 7.73-7.79 (2H, m), 10.91 (1H, s).
IR (ATR) cm ^-1 : 2935, 2859, 1639, 1579, 1508.
MS (ESI) m / z: 597 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₃₈ F ₂ N ₄ O ₅・ 1.6HCOOH ・ 0.1TFA: C, 59.55; H, 6.11; F, 6.41; N, 8.22. Found: C, 59.71; H, 6.31; F, 6.21; N, 8.51.

Example 78
Trans-4-{[(2S, 5S) -1-{[4-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1-pyrroline [Difluoromethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 75, (Step 2), [4-Fluoro-2- (4-fluorophenylamino) -1,3-benzoxazole The title compound (127 mg, 53%) was prepared as a colorless amorphous by using -6-yl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.38 (4H, m), 1.76-2.20 (16H, m), 2.80-4.21 (10H, m), 7.02 (1H, dd, J = 11.3, 3.7 Hz), 7.22-7.28 (4H, m), 7.74-7.80 (2H, m), 10.80-10.84 (1H, m).
IR (ATR) cm ^-1 : 2935, 2859, 1716, 1641, 1587, 1508.
MS (ESI) m / z: 597 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₃₈ F ₂ N ₄ O ₅・ 1.5HCOOH ・ 0.1TFA: C, 59.78; H, 6.12; F, 6.45; N, 8.27. Found: C, 59.60; H, 6.28; F, 6.49; N, 8.54.

Example 79
Trans 4-{[(2S, 5S) -1-{[4,7-difluoro-2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (1- Pyrrolidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 75, (Step 2), [4,7-difluoro-2- (4-fluorophenylamino) -1,3 -Benzoxazol-6-yl] acetic acid was used to produce the title compound (116 mg, 47%) as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.08-1.41 (3H, m), 1.61-2.24 (16H, m), 2.50-4.19 (11H, m), 7.03-7.10 (1H, m), 7.26 ( 2H, t, J = 8.7 Hz), 7.72-7.77 (2H, m), 8.14 (1H, s), 11.05 (1H, s).
IR (ATR) cm ^-1 : 2937, 2859, 1643, 1592, 1508.
MS (ESI) m / z: 615 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₃₇ F ₃ N ₄ O ₅・ 0.75HCOOH ・ 0.2TFA: C, 59.25; H, 5.80; F, 10.18; N, 8.34. Found: C, 59.26; H, 5.99; F, 10.03; N, 8.24.

Example 80
Trans 4-{[(2S, 5S) -1-{[2- (3,4-difluorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl} -5- ( 1-pyrrolidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 75, (Step 2), [4,7-difluoro-2- (3,4-difluorophenylamino) The title product (129 mg, 51%) was prepared as a colorless amorphous by using 1,3-benzoxazol-6-yl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.41 (4H, m), 1.68-2.21 (13H, m), 2.49-4.21 (13H, m), 7.09 (1H, dq, J = 10.4, 2.5 Hz), 7.43-7.53 (2H, m), 7.82-7.89 (1H, m), 8.14 (1H, s), 11.29 (1H, s).
IR (ATR) cm ^-1 : 2938, 2861, 1644, 1594, 1513.
MS (ESI) m / z: 633 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₃₆ F ₄ N ₄ O ₅・ 0.5HCOOH ・ 0.4TFA: C, 57.03; H, 5.38; F, 14.09; N, 7.99.
Found: C, 57.09; H, 5.41; F, 13.82; N, 7.93.

Example 81
Trans 4-{[(2S, 5S) -1-{[4-Fluoro-2- (2-methoxy-5-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( 1-pyrrolidinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid In a manner analogous to Example 75, (Step 2), [4-Fluoro-2- (5-methyl-2-methoxyphenylamino) The title product (120 mg, 48%) was prepared as a colorless amorphous by using [6-benzoxazolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.38 (4H, m), 1.71-2.20 (13H, m), 2.30 (3H, s), 2.49-4.19 (16H, m), 6.92 (1H, d, J = 9.1 Hz), 6.95-7.01 (2H, m), 7.21 (1H, d, J = 5.6 Hz), 7.87 (1H, s), 8.14 (1H, s), 9.67-9.71 (1H, m ).
IR (ATR) cm ^-1 : 3407, 2938, 2861, 1643, 1587.
MS (ESI) m / z: 623 (M ⁺ +1).
Anal.Calcd for.C ₃₄ H ₄₃ F ₁ N ₄ O ₆・ 0.5HCOOH ・ 0.4TFA: C, 61.33; H, 6.47; F, 6.05; N, 8.10. Found: C, 61.38; H, 6.48; F, 5.88; N, 8.05.

Example 82
Trans 4-{[(2S, 5S) -1- {2- [2- (4-chlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (4-thio Morpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid (Step 1)
Synthesis of trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester In a similar manner to step 2), the title product (80%) was prepared as a colorless oil by using thiamorpholine.
¹ H-NMR (CDCl ₃ ) δ: 1.17-1.29 (5H, m), 1.40-1.50 (11H, m), 1.60 (2H, s), 1.82-2.27 (10H, m), 2.50-2.91 (8H, m), 3.16-3.39 (2H, m), 3.62 (1H, ddd, J = 29.4, 9.6, 3.7 Hz), 3.69-3.90 (1H, m), 4.08-4.15 (2H, m).
MS (ESI) m / z: 471 (M ⁺ +1).

(Process 2)
Trans 4-{[(2S, 5S) -1-{[2- (4-Chlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- (4-thiomorpholine Synthesis of (Nylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrolidinylmethoxy ] -1-Cyclohexanecarboxylic acid ethyl ester was prepared by a method similar to that in Example 75, (Step 2), using [7-fluoro-2- (4-chlorophenylamino) -7-fluoro-1,3-benzoxazole-6- The title product (65 mg, 25%) was produced as a colorless amorphous by using [Il] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.41 (5H, m), 1.76-2.36 (11H, m), 2.54-4.16 (14H, m), 7.08-7.14 (1H, m), 7.24 ( 1H, d, J = 8.1 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 9.1 Hz), 10.99 (1H, s).
IR (ATR) cm ^-1 : 2935, 2859, 1637, 1575, 1492.
MS (ESI) m / z: 645 (M ⁺ +1).
Anal.Calcd for.C ₃₂ H ₃₈ ClFN ₄ O ₅ S ・ 0.25HCOOH ・ 0.15TFA: C, 58.02; H, 5.78; Cl, 5.26; F, 4.09; N, 8.32; S, 4.76.
Found: C, 57.75; H, 5.54; Cl, 5.53; F, 3.96; N, 8.28; S, 4.83.

Example 83
Trans 4-{[(2S, 5S) -1-{[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( 4-thiomorpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrole Dinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 75 (Step 2) and [7-fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxa The title product (134 mg, 53%) was prepared as a colorless amorphous by carrying out using [zolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.09-1.39 (5H, m), 1.76-2.20 (11H, m), 2.30 (3H, s), 2.54-4.16 (14H, m), 6.90 (1H, dt, J = 2.2, 8.6 Hz), 7.10 (1H, q, J = 6.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.26 (1H, t, J = 7.4 Hz), 7.92 (1H, d, J = 10.8 Hz), 10.03 (1H, s).
IR (ATR) cm ^-1 : 2935, 2861, 1718, 1637, 1610, 1577.
MS (ESI) m / z: 643 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ F ₂ N ₄ O ₅ S ・ 0.25HCOOH ・ 0.15TFA: C, 60.02; H, 6.10; F, 6.93; N, 8.35; S, 4.78.
Found: C, 59.88; H, 5.89; F, 6.77; N, 8.43; S, 4.77.

Example 84
Trans 4-{[(2S, 5S) -1-{[7-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( 4-thiomorpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrole Dinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 75, (Step 2), using [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -6-benzooxa The title product (112 mg, 42%) was prepared as a colorless amorphous by carrying out using [zolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.41 (4H, m), 1.74-2.38 (13H, m), 3.22-3.54 (16H, m), 6.89 (1H, dt, J = 3.4, 8.3 Hz), 7.08 (1H, dd, J = 5.1, 9.1 Hz), 7.13 (1H, t, J =
6.1 Hz), 7.26 (1H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 10.8, 2.9 Hz), 10.15 (1H, s).
IR (ATR) cm ^-1 : 3403, 2935, 2859, 1641, 1579.
MS (ESI) m / z: 659 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ F ₂ N ₄ O ₆ S ・ 0.75HCOOH: C, 58.47; H, 6.03; F, 5.48; N, 8.08; S, 4.63. Found: C, 58.59; H, 5.78; F, 5.62; N, 8.18; S, 4.73.

Example 85
Trans 4-{[(2S, 5S) -1-{[7-Fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4-thiomol Folinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrolidinylmethoxy] 1-Cyclohexanecarboxylic acid ethyl ester is prepared in a manner analogous to Example 75 (Step 2) using [7-fluoro-2- (2-methoxyphenylamino) -6-benzoxazolyl] acetic acid. This produced the title product (93 mg, 36%) as a colorless amorphous.
¹ H-NMR (DMSO-d ₆ ) δ: 1.06-1.41 (4H, m), 1.76-2.46 (10H, m), 2.56-4.20 (19H, m), 6.99-7.14 (4H, m), 7.18 ( 1H, d, J = 8.1 Hz), 8.12 (1H, d, J = 7.8 Hz), 9.84 (1H,
s).
IR (ATR) cm ^-1 : 3413, 2935, 2859, 1720, 1637, 1577.
MS (ESI) m / z: 641 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₁ FN ₄ O ₆ S ・ 0.5HCOOH ・ 0.5TFA: C, 59.95; H, 6.28; F, 3.66; N, 8.30; S, 4.75.
Found: C, 60.13; H, 6.07; F, 3.84; N, 8.41; S, 4.82.

Example 86
Trans 4-{[(2S, 5S) -1-{[4,7-difluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- (4- Thiomorpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrolidinyl Methoxy] -1-cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 75, (Step 2), using [4,7-difluoro-2- (2-methylphenylamino) -1,3-benzoxazole-6 The title product (110 mg, 43%) was prepared as a colorless amorphous by using -yl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.39 (4H, m), 1.76-2.20 (9H, m), 2.30 (3H, s), 2.54-4.15 (17H, m), 6.99-7.05 ( 1H, m), 7.14 (1H, t, J = 7.5 Hz), 7.27 (2H, t, J = 6.7 Hz), 7.75 (1H, d, J = 8.3 Hz), 10.09 (1H, s).
IR (ATR) cm ^-1 : 2935, 2859, 1637, 1589.
MS (ESI) m / z: 643 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ F ₂ N ₄ O ₅ S ・ 0.75HCOOH: C, 59.85; H, 6.18; F, 5.61; N, 8.27; S, 4.73. Found: C, 60.04; H, 5.93; F, 5.60; N, 8.47; S, 4.82.

Example 87
Trans 4-{[(2S, 5S) -1-{[2- (4-Chloro-2-methoxyphenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl} -5- ( 4-thiomorpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrole [Dinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester [2- (4-Chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] analogously to (Step 2) of Example 75 The title compound (107 mg, 40%) was produced as a colorless amorphous product by using [r] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.11-1.39 (5H, m), 1.78-2.33 (10H, m), 2.54-4.17 (18H, m), 7.07-7.12 (2H, m), 7.16 ( 1H, d, J = 2.2 Hz), 7.20 (1H, d, J = 7.8 Hz), 8.19 (1H, d, J = 8.6 Hz), 10.01 (1H, s).
IR (ATR) cm ^-1 : 3415, 2938, 2859, 1637, 1577.
MS (ESI) m / z: 675 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ ClFN ₄ O ₆ S ・ 0.4HCOOH ・ 0.2TFA: C, 56.67; H, 5.61; Cl, 4.93; F, 4.20; N, 7.82; S, 4.48.
Found: C, 56.88; H, 5.61; Cl, 4.93; F, 4.20; N, 7.90; S, 4.54.

Example 88
Trans 4-{[(2S, 5S) -1-{[4-Fluoro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( 4-thiomorpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrole Dinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 75 (Step 2) and [4-fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxa]. The title product (102 mg, 40%) was prepared as a colorless amorphous by carrying out using [zolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.37 (4H, m), 1.75-2.18 (10H, m), 2.29 (3H, s), 2.44-4.14 (16H, m), 6.91 (1H, dt, J = 2.7, 8.3 Hz), 7.01 (1H, d, J = 11.5 Hz), 7.21-7.30 (2H, m), 7.85 (1H, dd, J = 11.3, 2.7 Hz), 9.98 (1H, s ).
IR (ATR) cm ^-1 : 2937, 2861, 1714, 1643, 1583.
MS (ESI) m / z: 643 (M ⁺ +1).
Anal.Calcd for.C ₃₃ H ₄₀ F ₂ N ₄ O ₅ S ・ 0.5HCOOH ・ 0.1TFA: C, 59.77; H, 6.12; F, 6.45; N, 8.27; S, 4.74.
Found: C, 59.86; H, 5.91; F, 6.42; N, 8.45; S, 4.82.

Example 89
Trans 4-{[(2S, 5S) -1-{[4-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl} -5- ( 4-thiomorpholinylmethyl) pyrrolidin-2-yl] methoxy} cyclohexanecarboxylic acid trans- [1- (tert-butoxycarbonyl)-(5S)-(4-thiomorpholinylmethyl)-(2S) -pyrrole Dinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester was prepared in a manner analogous to Example 75 (Step 2) and [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -6-benzoxa The title product (132 mg, 50%) was prepared as a colorless amorphous by carrying out using [zolyl] acetic acid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03-1.39 (4H, m), 1.75-2.38 (11H, m), 2.54-4.14 (18H, m), 6.90 (1H, dt, J = 3.2, 8.6 Hz), 7.03 (1H, d, J = 11.3 Hz), 7.08 (1H, dd, J = 9.1, 5.1 Hz), 7.27 (1H, s), 8.15 (1H, dq, J = 10.9, 1.6 Hz), 10.08 (1H, d, J = 6.1 Hz).
IR (ATR) cm ^-1 : 3413, 2937, 2861, 1718, 1644, 1585.
MS (ESI) m / z: 659 (M ⁺ +1).
_{.. Anal Calcd for C 33 H} 40 F 2 N 4 O 6 S · 0.5HCOOH:. C, 59.02; H, 6.00; F, 5.57; N, 8.22; S, 4.70 Found: C, 58.72; H, 5.81; F, 5.86; N, 8.20; S, 4.81.

Example 90
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrole [Dinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Synthesis of 1- (tert-butoxycarbonyl)-(3R) -fluoropyrrolidine 1- (tert-Butoxycarbonyl)-(3S) -pyrrolidinol (commercially available: Lancaster, etc.) 4.31 g, 23.0 mmol) was added, and dichloromethane (40 ml) was added and dissolved, and then [bis (2-methyltoxylethyl) amino] sulfur trifluoride (DAST) (commercially available, Aldrich) under dry ice-acetone cold stirring. ) (5.0 ml, 27.1 mmol) was added dropwise. The reaction mixture was further stirred at the same temperature for 3 hours under cold stirring. The reaction mixture was slowly warmed to room temperature, stirred at room temperature for 15 hours, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrated residue was subjected to silica gel column chromatography. The fraction obtained from the eluate of n-hexane-ethyl acetate (5: 1, v / v) was concentrated under reduced pressure. Drying gave the title compound (2.87 g, 15.2 mmol, 66%) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.85-2.08 (1H, m), 2.16-2.27 (1H, m), 3.76-3.39 (total 4H, series of m), 5.13 -5.28 (1H, m).

(Process 2)
Synthesis of (3R) -fluoropyrrolidine hydrochloride
Add 1- (tert-butoxycarbonyl)-(3R) -fluoropyrrolidine (2.87 g, 15.2 mmol) to a 100 ml eggplant-shaped flask and add 4 N hydrochloric acid / 1,4-dioxane (16.0 ml, 64.0 mmol). And stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (1.95 g, quant) as a brown solid.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 1.98-2.27 (total 2H, m), 3.20 (1H, td, J = 11.2, 7.2 Hz), 3.27-3.47 (total 3H, series of m), 5.36 and 5.50 (total 1H, each t, each J = 3.8 Hz), 9.78 (2H, s).

(Process 3)
Trans 4- [1- (tert-butoxycarbonyl)-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Composition
In a 200 ml eggplant-shaped flask, trans 4- [1- (tert-butoxycarbonyl)-(5S) -formyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (Step 1 of Example 18) Compound prepared in (1) (1.00 g, 2.61 mmol) and (3R) -fluoropyrrolidine hydrochloride (1.27 g, 10.18 mmol) were added, and toluene (50 ml × 3) was added and azeotroped. After allowing to cool, tetrahydrofuran (32 ml) was added to the residue and dissolved, sodium triacetoxyborohydride (1.66 g, 7.82 mmol) was added, methanol (1 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure to about half volume, saturated aqueous sodium hydrogen carbonate (70 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography, flushed with chloroform-ethyl acetate (5: 1, v / v), and then chloroform-methanol (10: 1, v / v) The fraction obtained from the eluate was concentrated and dried under reduced pressure to give the title compound (1.10 g, 2.40 mmol, 93%) as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.17-1.29 (total 5H, series of m), 1.41-1.55 (total 11H, series of m), 1.55-2.27 (total 12H, series of m), 2.41- 3.07 (total 5H, series of m), 3.15-4.05 (total 5H, series of m), 4.08-4.15 (2H, m), 5.04-5.24 (1H, m).
MS (ESI) m / z: 457 (M ⁺ +1).

(Process 4)
Trans 4-[(5S)-[(3R) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of dihydrochloride
Trans 4- [1- (tert-butoxycarbonyl)-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester ( 4N Hydrochloric acid / 1,4-dioxane solution (4.0 ml, 16.0 mmol) was added to 1.10 g, 2.40 mmol) and stirred at room temperature for 14.5 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the title compound (1.02 g, 2.37 mmol, 99%) as a dark brown oily substance.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.52 (total 7H, series of m, including 3H, t, J = 7.1 Hz, δ 1.24), 1.79-2.86 (total 12H, series of m), 3.33 -4.60 (total 13H, series of m, including 2H, q, J = 7.1 Hz, δ 4.11), 5.37-5.69 (1H, m), 8.96-9.58 (1H, m), 9.82-10.75 (1H, m) , 11.23-12.00 (1H, m).
MS (ESI) m / z: 357 (M ⁺ -2HCl).

(Process 5)
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrole Synthesis of [Dinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester
In a 100 ml eggplant-shaped flask, [7-fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetic acid (161 mg, 0.51 mmol) and trans 4-[(5S)- [(3R) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester dihydrochloride (218 mg, 0.51 mmol) was added, and N, N- Add dimethylformamide (3 ml) and dissolve, then add EDC ・ HCl (145 mg, 0.76 mmol), HOBt ・ H ₂ O (116 mg, 0.76 mmol), and triethylamine (247 μl, 1.77 mmol) at room temperature. Stir for 19 hours. Ice water (70 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layers were washed with saturated brine (100 ml × 2) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in a minimum amount of dichloromethane and subjected to thin layer chromatography (Merck silica gel 60 ^F254 , 2 mm). This was developed with chloroform-ethyl acetate (5: 1, v / v), then developed with chloroform-methanol (30: 1, v / v), the target spot was scraped off, and chloroform-methanol (5: 1 , v / v). The extract was concentrated and dried under reduced pressure to obtain the title compound (150 mg, 0.23 mmol, 45%) as a light brown solid.
IR (ATR) ν: 2939, 1726, 1637, 1610, 1576 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.54 (total 7H, series of m), 1.89-2.32 (total 13H, series of m, including total 3H, each s, δ 2.29 and 2.30), 2.42- 3.07 (total 6H, series of m), 3.09-3.31 (1H, m), 3.38-3.94 (total 5H, series of m), 4.05-4.26 (total 4H, series of m), 5.00-5.27 (1H, m ), 6.74 (1H, td, J = 8.2, 2.7 Hz), 7.05-7.24 (total 3H, series of m), 7.49 (1H, br s), 7.99-8.05 (1H, m).
Anal.Calcd for C ₃₅ H ₄₃ F ₃ N ₄ O ₅・ 0.75 H ₂ O: C, 62.72; H, 6.69; N, 8.36.Found: C, 62.77; H, 6.51; N, 8.45.
MS (LC-MS) m / z: 657 (M ⁺ +1).

(Process 6)
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrole Synthesis of [Dinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid
Trans 4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R ) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (121 mg, 0.18 mmol) was added and dissolved in tetrahydrofuran (2.5 ml). A 0.25 N aqueous sodium hydroxide solution (2.5 ml, 0.62 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 1N aqueous hydrochloric acid solution, water was added and the mixture was extracted with chloroform-methanol (5: 1, v / v), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was dissolved in a minimum amount of chloroform and subjected to thin layer chromatography (Merck silica gel 60 _F254 , 2 mm). This was developed with chloroform-methanol (10: 1, v / v), and the target spot portion was scraped off and extracted with chloroform-methanol-water (7: 3: 1, v / v, lower layer). The extract was concentrated and dried under reduced pressure, then dissolved in 1 ml of chloroform, diluted with 2 ml of ethyl acetate, and then 50 ml of n-hexane was added to precipitate a white precipitate. The precipitate was filtered and dried to obtain the title compound (78 mg, 0.12 mmol, 69%) as a white crystalline powder.
IR (ATR) ν: 2935, 1639, 1610, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.53 (total 5H, series of m), 1.91-2.31 (total 14H, series of m, including 3H, s, δ 2.27), 2.55-3.98 (total 10H , series of m),
4.08-4.30 (2H, m), 5.02-5.26 (1H, m), 6.74 (1H, td, J = 8.2, 2.5 Hz), 7.01-7.16 (total 3H, series of m), 7.76-7.82 (1H, m), 8.28 (2H, br s).
Anal.Calcd for C ₃₃ H ₃₉ F ₃ N ₄ O ₅・ 0.5 H ₂ O: C, 62.16; H, 6.32; N, 8.79. Found: C, 62.08; H, 6.25; N, 8.61.
MS (LC-MS) m / z: 629 (M ⁺ +1).

Example 91
Trans 4- [1-[[2- (5-Fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5 S)-[(3R) -fluoro-1-pyrrolidinylmethyl ]-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (5-Fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5 S)-[(3R) -fluoro-1-pyrrolidinylmethyl ]-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of [2- (5-fluoro-2-methylphenyl) amino-] in an analogous manner to Example 90 (Step 5) The title compound (267 mg, 0.42 mmol, 93%) was obtained as a light brown solid by using 6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2939, 1726, 1637, 1608, 1572 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.98-1.43 (total 7H, series of m), 1.62-4.32 (total 29H, series of m), 4.89-5.16 (1H, m), 6.63 (1H, td , J = 8.1, 2.7 Hz), 6.96-7.31 (total 4H, series of m), 7.46-7.66 (1H, m), 7.85-7.92 (1H, m).
Anal.Calcd for C ₃₅ H ₄₄ F ₂ N ₄ O ₅・ 0.5 H ₂ O: C, 64.90; H, 7.00; N, 8.65.
Found: C, 64.73; H, 6.76; N, 8.42.
MS (LC-MS) m / z: 639 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (5-Fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5 S)-[(3R) -fluoro-1-pyrrolidinylmethyl Synthesis of]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner similar to Example 90 (Step 6), trans 4- [1-[[2- (5-fluoro-2- Methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid The title compound (130 mg, 0.21 mmol, 53%) was obtained as a white crystalline powder by using ethyl ester.
IR (ATR) ν: 2935, 1637, 1608, 1572 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.05-1.52 (total 5H, series of m), 1.71-2.31 (total 14H, series of m), 2.48-3.95 (total 10H, series of m), 4.00- 4.26 (total 2H, series of m), 5.02-5.27 (1H, m), 6.70-6.77 (1H, m), 7.06-7.15 (2H, m), 7.27-7.37 (total 3H, series of m), 7.64 -7.74 (1H, m), 9.49 (1H, br s).
Anal.Calcd for C ₃₃ H ₃₉ F ₃ N ₄ O ₅・ 0.5 H ₂ O: C, 62.16; H, 6.32; N, 8.79. Found: C, 62.08; H, 6.25; N, 8.61.
MS (LC-MS) m / z: 611 (M ⁺ +1). (CH851401)

Example 92
Trans 4- [1-[[2- (4-Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (4-Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of [2- (4-fluorophenyl) amino-6-benzoxazolyl] acetic acid in a manner similar to Example 90 (Step 5) To give the title product (225 g, 0.36 mmol, 76%) as a light brown solid.
IR (ATR) ν: 2937, 1728, 1639, 1608, 1575 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ:
0.86-1.52 (total 7H, series of m), 1.72-3.25 (total 17H, series of m), 3.32-4.30 (total 9H, series of m), 4.96-5.26 (1H, m), 6.98-7.06 (total 3H, series of m), 7.29-7.43 (2H, m), 7.61-7.67 (2H, m), 9.36 (1H, br s).
Anal. Calcd for C ₃₄ H ₄₂ F ₂ N ₄ O ₆・ 0.5 H ₂ O: C, 64.44; H, 6.84; N, 8.84. Found: C, 64.79; H, 6.64; N, 8.46.
MS (LC-MS) m / z: 625 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[2- (4-Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) Synthesis of 4-pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid Trans 4- [1-[[2- (4-fluorophenyl) amino-6-benzoxa] in an analogous manner to Example 90 (Step 6) Zolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (120 mg, 0.20 mmol, 57%) was obtained as a white crystalline powder.
IR (ATR) ν: 2937,1639,1575, 1508 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.95-1.49 (total 5H, series of m), 1.75-2.27 (total 11H, series of m), 2.47-3.95 (total 10H, series of m), 4.02- 4.27 (2H, m), 5.01-5.26 (1H, m), 6.97-7.10 (total 4H, series of m), 7.22-7.41 (2H, m), 7.45-7.51 (2H, m).
Anal.Calcd for C ₃₂ H ₃₈ F ₂ N ₄ O ₅・ H ₂ O: C, 62.53; H, 6.56; N, 9.11.
Found: C, 62.78; H, 6.36; N, 8.91.
MS (LC-MS) m / z: 597 (M ⁺ +1).

Example 93
Trans 4- [1-[[2- (4-Chlorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S)- Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[2- (4-Chlorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S)- Synthesis of pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester In a manner analogous to Example 90, (Step 5), using [2- (4-chlorophenyl) amino-6-benzoxazolyl] acetic acid The title product (138 mg, 0.22 mmol, 42%) was obtained as a light brown solid by performing a condensation reaction.
IR (ATR) ν: 2939, 1726, 1637, 1601, 1572 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.04-1.53 (total 7H, series of m), 1.74-3.68 (total 20H, series of m), 3.72-3.95 (2H, m), 4.02-4.27 (total 4H, series of m), 4.95-5.26 (1H, m), 7.01 (1H, t, J = 6.9 Hz), 7.25-7.34 (3H, series of m), 7.42 (1H, s),
7.61 (2H, dd, J = 8.3, 7.1 Hz), 9.25 (1H, br s).
Anal.Calcd for C ₃₄ H ₄₂ ClFN ₄ O ₅・ 0.75 H ₂ O: C, 62.38; H, 6.70; N, 8.56.
Found: C, 62.30; H, 6.56; N, 8.27.
MS (LC-MS) m / z: 641 [(M ⁺ +1), ³⁵ Cl], 642 (M ⁺ +2).

(Process 2)
Trans 4- [1-[[2- (4-Chlorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S)- Synthesis of pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid Trans 4- [1-[[2- (4-chlorophenyl) amino-6-benzoxazolyl] In an analogous manner to Example 90 (Step 6) ] Acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester mg, 014 mmol, 74%) was obtained as a white powder.
IR (ATR) ν: 2939,1637,1601, 1571 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.00-1.50 (total 4H, series of m), 1.78-2.32 (total 10H, series of m), 2.52-4.30 (total 12H, series of m), 5.01- 5.27 (1H, m), 7.02-7.10 (1H, m), 7.24-7.32 (total 5H, series of m), 7.35-7.42 (1H, m), 7.46-7.53 (2H, m), 8.50 (1H, s).
Anal.Calcd for C ₃₂ H ₃₈ ClFN ₄ O ₅・ 0.75 H ₂ O: C, 61.34; H, 6.35; N, 8.94.
Found: C, 61.34; H, 6.35; N, 8.94.
MS (LC-MS) m / z: 613 [(M ⁺ +1), ³⁵ Cl], 614 (M ⁺ +2).

Example 94
Trans 4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl] -(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans 4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl] Synthesis of-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester [7-Fluoro-2- (2-methoxyphenyl) amino-6 was prepared in a similar manner to Example 90 (Step 5). The title compound (190 mg, 0.29 mmol, 66%) was obtained as a white solid by performing a condensation reaction with [-benzoxazolyl] acetic acid.
IR (ATR) ν: 2939, 1726, 1635, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.54 (total 7H, series of m), 1.70-3.07 (total 16H, series of m), 3.09-3.29 (1H, m), 3.35-3.97 (total 8H, series of m), 4.00-4.23 (total 4H, series of m), 5.01-5.25 (1H, m), 6.88-6.93 (1H, m), 7.00-7.19 (total 3H, series of m), 7.21 -7.26 (1H, m), 7.77 (1H, br s), 8.41-8.36 (1H, m).
Anal.Calcd for C ₃₅ H ₄₄ F ₂ N ₄ O ₆・ H ₂ O: C, 62.49; H, 6.89; N, 8.33.
Found: C, 62.33; H, 6.59; N, 8.02.
MS (LC-MS) m / z: 655 (M ⁺ +1).

(Process 2)
Trans 4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl] Synthesis of-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid Trans 4- [1-[[7-Fluoro-2- (2-methoxy) was prepared in an analogous manner to Example 90 (Step 6). Phenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3R) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester The title compound (98 mg, 0.15 mmol, 56%) was obtained as a white powder.
IR (ATR) ν: 2939, 1714, 1637, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.11-1.54 (total 5H, series of m), 1.90-2.32 (total 11H, series of m), 2.46-3.28 (total 6H, series of m), 3.36- 3.51 (1H, m), 3.52-4.25 (total 8H, series of m, including 3H, s, δ 3.93), 5.03-5.26 (1H, m), 6.90-6.94 (1H, m), 7.01-7.18 (total 3H, series of m), 7.22-7.27 (2H, m), 8.37-8.32 (1H, m).
Anal.Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₆・ 0.25 H ₂ O: C, 62.79; H, 6.47; N, 8.88.
Found: C, 62.64; H, 6.47; N, 8.63.
MS (LC-MS) m / z: 627 (M ⁺ +1).

Example 95
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -Fluoro- (2S ) -Methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Synthesis of 1- (tert-butoxycarbonyl)-(4S) -fluoro- (2S) -methoxymethylpyrrolidine
1- (tert-Butoxycarbonyl)-(4S) -fluoro- (2S) -hydroxymethylpyrrolidine (described in Nakayama et al., WO 2001-000206 and WO 2002-053534) in a 100 ml eggplant-shaped flask (2.01 g, 9.18 After adding N, N-dimethylformamide (10 ml) and dissolving, methyl iodide (commercially available) (857 μl, 13.8 mmol) was added, and sodium hydride (commercially available, 55 %) (801 mg, 18.3 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (80 ml) was added to the reaction mixture, and the mixture was extracted with toluene (80 ml × 2). The combined organic layers were washed with saturated brine (60 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting concentrated residue was subjected to silica gel column chromatography, and the fraction obtained from the eluate of n-hexane-ethyl acetate (4: 1, v / v) was concentrated under reduced pressure. Drying gave the title compound (2.00 g, 8.59 mmol, 94%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.98-2.17 (1H, m), 2.39 (1H, dd, J = 20.3, 15.0 Hz), 3.31 (1H, ddd, J = 9.8, 8.6, 1.5 Hz), 3.37 (3H, s), 3.53-3.73 (total 3H, series of m), 4.02-4.15 (1H, m), 5.13-5.29 (1H, m).

(Process 2)
Synthesis of (4S) -fluoro- (2S) -methoxymethylpyrrolidine hydrochloride
1- (tert-Butoxycarbonyl)-(4S) -fluoro- (2S) -methoxymethylpyrrolidine (2.00 g, 8.59 mmol) was placed in a 100 ml eggplant-shaped flask, and 4 N hydrochloric acid / 1,4-dioxane (10.0 ml, 40.0 mmol) was added and stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (1.46 g, quant) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.20 (1H, dd, J = 21.7, 15.4 Hz), 2.57-2.40 (1H, m), 3.45 (3H, s), 3.54-3.90 (total 4H, series of m), 4.07-4.16 (1H, m), 5.30-5.47 (1H, m), 9.51 (1H, br s), 10.51 (1H, br s).

(Process 3)
Trans-4- [1- (tert-butoxycarbonyl)-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy]- Synthesis of 1-cyclohexanecarboxylic acid ethyl ester
In a 200 ml eggplant-shaped flask, trans-4- [1- (tert-butoxycarbonyl)-(5S) -formyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (1.00 g, 2.61 mmol ) And (4S) -fluoro- (2S) -methoxymethylpyrrolidine hydrochloride (2.21 g, 13.05 mmol) were added, and toluene (50 ml × 3) was added and azeotroped. After allowing to cool, tetrahydrofuran (20 ml) was added to the residue and dissolved, sodium triacetoxyborohydride (1.66 g, 7.82 mmol) was added, methanol (1 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated to about half volume under reduced pressure, water (70 ml) was added and the mixture was extracted with ethyl acetate (100 ml × 2), and the combined organic layers were dried over anhydrous magnesium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography. The fraction obtained from the eluate of n-hexane: ethyl acetate (2: 1, v / v) was concentrated under reduced pressure. Drying gave the title compound (1.13 g, 2.25 mmol, 86%) as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.03-1.31 (total 6H, series of m, including 3H, td, J = 7.1, 2.0 Hz, δ 1.24), 1.39-1.53 (total 11H, series of m) , 1.74-2.09 (total 8H, series of m), 2.19-2.71 (total 6H, series of m), 3.16-3.50 (total 9H, series
of m), 3.64 (1H, ddd, J = 34.2, 9.0, 3.4 Hz), 3.70-3.91 (2H, m), 4.11 (2H, ddd, J = 14.2, 7.1, 2.9 Hz), 5.01-5.20 (1H , m).
MS (ESI) m / z: 501 (M ⁺ +1).

(Process 4)
Trans-4-[(5S)-[(4S) -Fluoro- (2S) -methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester dihydrochloride Salt synthesis
Trans-4- [1- (tert-butoxycarbonyl)-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy]- 4N hydrochloric acid / 1,4-dioxane solution (6.0 ml, 24.0 mmol) was added to 1-cyclohexanecarboxylic acid ethyl ester (1.13 g, 2.25 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried to give the title compound (1.08 g, quant) as a dark brown oil. This compound was used in the next reaction without further purification.

(Process 5)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -Fluoro- (2S ) -Methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetic acid (135 mg, 0.43 mmol) and trans-4-[(5S) in a 100 ml eggplant-shaped flask -[(4S) -Fluoro- (2S) -methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester dihydrochloride (202 mg, 0.43 mmol) After adding N, N-dimethylformamide (4 ml) and dissolving, EDC ・ HCl (122 mg, 0.64 mmol), HOBt ・ H ₂ O (98 mg, 0.64 mmol), and triethylamine (208 μl, 1.49) mmol) was added and stirred at room temperature for 15 hours. Water (70 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layer was washed with saturated brine (100 ml × 2) and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, azeotroped with toluene, and the resulting concentrated residue was dissolved in a minimum amount of dichloromethane and subjected to thin layer chromatography (Merck silica gel 60 ^F254 , 2 mm). . This was developed with chloroform-ethyl acetate (5: 1, v / v), then developed with chloroform-methanol (50: 1, v / v), the target spot was scraped off, and chloroform-methanol (5: 1 , v / v). The extract was concentrated and dried under reduced pressure to obtain the title compound (217 g, 0.31 mmol, 73%) as a light brown solid.
IR (ATR) ν: 2937, 1726, 1637, 1610, 1575 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.11-1.54 (total 7H, series of m), 1.71-1.89 (1H, m), 1.91-2.82 (total 14H, series of m), 2.97-3.06 (1H , m), 3.12-3.28 (1H, m), 3.31-3.92 (total 10H, series of m), 4.00-4.22 (total 4H, series of m), 4.98-5.23 (1H, m), 6.75 (1H, td, J = 8.2, 2.6 Hz), 6.95-7.07 (1H, m), 7.09-7.22 (2H, m), 7.27-7.23 (2H, m), 8.02 (1H, s), 8.11 (1H, dt, J = 10.9, 2.7 Hz).
Anal.Calcd for C ₃₇ H ₄₇ F ₃ N ₄ O ₅・ 0.75 H ₂ O: C, 62.21; H, 6.84; N, 7.84.
Found: C, 62.28; H, 6.64; N, 7.93.
MS (LC-MS) m / z: 701 (M ⁺ +1).

(Process 6)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -Fluoro- (2S ) -Methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid
In a 100 ml eggplant-shaped flask, trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[( 4S) -Fluoro- (2S) -methoxy-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (167 mg, 0.24 mmol) was added, and tetrahydrofuran (2.5 ml )
A 0.25N aqueous sodium hydroxide solution (2.5 ml, 0.62 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 1N aqueous hydrochloric acid solution, water was added and the mixture was extracted with chloroform-methanol (5: 1, v / v), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was dissolved in a minimum amount of chloroform and subjected to thin layer chromatography (Merck silica gel 60 _F254 , 2 mm). This was developed with chloroform-ethyl acetate (5: 1, v / v), then developed with chloroform-methanol (50: 1, v / v), and the target spot was scraped off to obtain chloroform-methanol (5: 1 , v / v). The extract was concentrated and dried under reduced pressure. This was dissolved in 1 ml of chloroform, diluted with 3 ml of ethyl acetate and then added with 100 ml of n-hexane to precipitate a white precipitate. The precipitate was filtered and dried to obtain the title compound (104 mg, 0.15 mmol, 64%) as a white crystalline powder.
IR (ATR) ν: 2937, 1701, 1639, 1610, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.57 (total 5H, series of m), 1.70-1.87 (1H, m), 1.89-2.40 (total 14H, series of m), 2.41-2.83 (total 3H, series of m), 2.88-3.59 (total 9H, series of m), 3.63-4.24 (total 4H, m), 4.95-5.25 (1H, m), 6.76 (1H, td, J = 8.2, 2.4 Hz ), 7.06-7.20 (total 3H, series of m), 7.71-7.80 (1H, m), 8.54 (1H, br s).
Anal.Calcd for C ₃₅ H ₄₃ F ₃ N ₄ O ₅・ 0.25 H ₂ O: C, 62.07; H, 6.47; N, 8.27. Found: C, 61.96; H, 6.59; N, 8.10.
MS (LC-MS) m / z: 673 (M ⁺ +1).

Example 96
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl -1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl Synthesis of 1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester In a manner similar to Example 95, (Step 5), [7-Fluoro-2- ( The title compound (219 mg, 0.31 mmol, 75%) was obtained as a white solid by performing a condensation reaction using 2-methoxyphenyl) amino-6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2937, 1728, 1635, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.54 (total 7H, series of m), 1.71-1.89 (total 2H, series of m), 1.90-2.81 (total 14H, series of m), 2.95- 3.59 (total 10H, series of m), 3.66-3.90 (total 3H, series of m), 3.94 (3H, s), 3.97-4.22 (total 3H, series of m), 4.98-5.23 (1H, m), 6.90-6.95 (1H, m), 7.02-7.19 (total 3H, series of m), 7.23 and 7.25 (total 1H, each d, each J = 2.9 Hz), 7.69-7.75 (1H, m), 8.37-8.42 (1H, m).
Anal.Calcd for C ₃₇ H ₄₈ F ₂ N ₄ O ₇・ H ₂ O: C, 62.21; H, 6.84; N, 7.84.
Found: C, 61.86; H, 6.76; N, 7.87.
MS (LC-MS) m / z: 699 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl Synthesis of 1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner similar to Example 95 (Step 6), trans-4- [1-[[7 -Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrolidinylmethyl]-( The title compound (147 mg, 0.22 mmol, 73%) was obtained as a white crystalline powder by using 2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester.
IR (ATR) ν: 2935, 1724, 1701, 1637, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.08-1.55 (total 4H, series of m), 2.80-1.72 (total 15H, series of m), 2.95-3.58 (total 9H, series of m), 3.66- 4.05 (total 6H, series of m), 4.08-4.23 (2H, m), 4.98-5.22 (1H, m), 6.89-6.94 (1H, m), 7.02-7.24 (total 4H, series of m), 7.98 (1H, br s), 8.29-8.33 (1H, m).
Anal.Calcd for C ₃₅ H ₄₃ F ₃ N ₄ O ₅・ 0.25 H ₂ O: C, 62.26; H, 6.64; N, 8.30.
Found: C, 62.23; H, 6.77; N, 8.11.
MS (LC-MS) m / z: 671 (M ⁺ +1).

Example 97
Trans-4- [1-[[2- (4-Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrole [Dinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[2- (4-Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrole Synthesis of [Dinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester In a manner similar to Example 95 (Step 5), [2- (4-Fluorophenyl) amino-6 The title compound (193 g, 0.29 mmol, 66%) was obtained as a light brown solid by performing a condensation reaction with [-benzoxazolyl] acetic acid.
IR (ATR) ν: 2937, 1728, 1641, 1608, 1508 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.06-1.54 (total 7H, series of m), 1.67-2.82 (total 14H, series of m), 2.98-3.91 (total 12H, series of m), 3.98- 4.26 (total 3H, series of m), 4.91-5.24 (1H, m), 6.99-7.07 (tota 3H, series of m), 7.32 (1H, dd, J =
8.0, 4.8 Hz), 7.41-7.43 (1H, m), 7.58-7.65 (2H, m), 8.92 (1H, br s).
Anal.Calcd for C ₃₆ H ₄₆ F ₂ N ₄ O ₆・ 0.5 H ₂ O: C, 63.80; H, 6.99; N, 8.27.
Found: C, 63.52; H, 6.88; N, 7.99.
MS (LC-MS) m / z: 669 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[2- (4-Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrole Synthesis of dinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner analogous to Example 95 (Step 6), trans-4- [1-[[2- (4- Fluorophenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(4S) -fluoro- (2S) -methoxymethyl-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] The title compound (126 mg, 0.20 mmol, 73%) was obtained as a white crystalline powder by using ethyl ester of -1-cyclohexanecarboxylic acid.
IR (ATR) ν: 2937, 1639, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.94-1.54 (total 4H, series of m), 1.70-2.81 (total 14H, series of m), 2.95-3.88 (total 12H, series of m), 4.00- 4.23 (2H, m), 4.97-5.24 (1H, m), 6.98-7.10 (total 3H, series of m), 7.26-7.31 (2H, m), 7.41-7.50 (total 3H, m).
Anal.Calcd for C ₃₅ H ₄₃ F ₃ N ₄ O ₅・ 0.25 H ₂ O: C, 63.29; H, 6.64; N, 8.68.
Found: C, 63.11; H, 6.67; N, 8.55.
MS (LC-MS) m / z: 641 (M ⁺ +1).

Example 98
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (step 1)
Synthesis of 1- (tert-butoxycarbonyl) -3-pyrrolidinol
Add 1-benzyl-3-pyrrolidinol (commercially available, Tokyo Kasei) (9.06 g, 51.1 mmol) to a 200 ml eggplant-shaped flask, dissolve in ethanol (50 ml), and 10% palladium hydroxide (2.00 g) And stirred for 16 hours while introducing hydrogen gas at one atmospheric pressure. The catalyst was removed by filtration through celite, and the residue obtained by concentrating and drying the reaction solution under reduced pressure was dissolved in dichloromethane (50 ml), and di-tert-butyl dicarbonate (commercially available, domestic chemical ) (11.1 g, 51.1 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, then separated with a saturated saline-ethyl acetate system, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was subjected to flash column chromatography (75s) manufactured by Biotage, and obtained from the eluate of n-hexane-ethyl acetate (2: 1, v / v). The fractions were concentrated under reduced pressure to give the title compound (8.56 g, 45.7 mmol, 89%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.87-2.05 (total 2H, m), 2.42-2.56 (1H, m), 3.29-3.52 (total 4H, series of m), 4.41-4.46 (1H, m).

(Process 2)
Synthesis of 1- (tert-butoxycarbonyl) -3-pyrrolidone Dichloromethane (40 ml) was placed in a 200 ml three-necked flask in a dry ice-acetone bath at -78 ° C under nitrogen flow, and oxalyl chloride (6.99 ml, 80.1 mmol) ) And dimethyl sulfoxide (11.4 ml, 160 mmol) dissolved in dichloromethane (5 ml) was added dropwise over 10 minutes. After stirring for 20 minutes, 1- (tert-butoxycarbonyl) -3-pyrrolidinol (5.00 g, 26.7 mmol) dissolved in dichloromethane (5 ml) was added dropwise over 10 minutes and stirred for 1 hour. Triethylamine (33.5 ml, 240 mmol) was added dropwise, and the reaction system was gradually warmed to room temperature. The reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was dissolved in dichloromethane, and silica gel (20 g) was added, followed by concentration and drying. This was packed in a precolumn, connected to a flash column chromatography (40M) manufactured by Biotage, flushed with n-hexane-ethyl acetate (9: 1, v / v), and then n-hexane-ethyl acetate (7: 3, v / v) The fraction obtained from the eluate was concentrated and dried under reduced pressure to give the title compound (4.00 g, 21.6 mmol, 81%) as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.49 (9H, s), 2.59 (2H, t, J = 7.8 Hz), 3.73-3.80 (total 4H, series of m).

(Process 3)
Synthesis of 1- (tert-butoxycarbonyl) -3,3-difluoropyrrolidine 1- (tert-butoxycarbonyl) -3-pyrrolidone (2.98 g, 16.1 mmol) was placed in a 200 ml eggplant-shaped flask under a nitrogen stream, Add dichloromethane (50 ml) and dissolve, then slowly add [bis (2-methoxymethyl) amino] sulfur trifluoride (commercially available, Aldrich) (6.52 ml, 35.4 mmol) under dry ice-acetone cold stirring. The mixture was stirred for 2 hours under cold stirring. The mixture was stirred for an additional 14 hours while slowly warming to room temperature, ice water (100 ml) was added to the reaction mixture, extracted with dichloromethane (100 ml × 2), and the combined organic layer was washed with saturated brine (200 ml). After washing, it was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting concentrated residue was subjected to silica gel column chromatography, and the fraction obtained from the eluate of n-hexane-ethyl acetate (2: 1, v / v) was concentrated under reduced pressure. Drying gave the title compound (2.48 g, 12.0 mmol, 74%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.26-2.37 (2H, m), 3.52-3.73 (4H, m).).
MS (LC-MS); m / z: 208 (M + H).

(Process 4)
Synthesis of 3, 3-difluoropyrrolidine trifluoroacetate
Add 1- (tert-butoxycarbonyl) -3,3-difluoropyrrolidine (2.48 g, 12.0 mmol) to a 200 ml eggplant-shaped flask, dissolve in dichloromethane (30.0 ml), and add trifluoroacetic acid (5.0 ml). And stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to give the title compound (4.05 g, quant) as a dark brown oil.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 2.46-2.59 (2H, m), 3.54 (2H, t, J = 7.6 Hz), 3.66 (2H, t, J = 12.2 Hz), 7.34 (1H , br s), 10.55 (1H, br s).

(Process 5)
Trans-4- [1- (tert-butoxycarbonyl)-(5S)-[3,3-difluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of
In a 200 ml eggplant-shaped flask, trans-4- [1- (tert-butoxycarbonyl)-(5S) -formyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (3.20 g, 8.34 mmol ) And 3,3-difluoropyrrolidine trifluoroacetate (1.27 g, equivalent to 18.6 mmol) were added, and toluene (100 ml × 3) was added and azeotroped. After allowing to cool, tetrahydrofuran (50 ml) was added to the residue for dissolution, sodium triacetoxyborohydride (5.30 g, 25.0 mmol) was added, and the mixture was stirred at room temperature for 14.5 hours. The reaction solution was concentrated to about half volume under reduced pressure, saturated brine was added and the mixture was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography, flushed with n-hexane-ethyl acetate (2: 1, v / v), and then n-hexane-ethyl acetate. The fraction obtained from the (1: 1, v / v) eluate was concentrated and dried under reduced pressure to obtain the title compound (3.32 g, 6.99 mmol, 84%) as a brown oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.19-1.30 (total 5H, series of m), 1.35-1.56 (total 11H, series of m), 1.86-2.08 (total 8H, series of m), 2.16- 2.29 (total 3H, series of m), 2.37-3.94 (total 10H, series of m), 4.07-4.15 (total 2H, m).
MS (ESI) m / z: 475 (M ⁺ +1).

(Process 6)
Trans-4-[(5S)-(3,3-Difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of 2 × trifluoroacetate trans -4- [1- (tert-butoxycarbonyl)-(5S)-[3,3-difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester ( 3.32 g, 6.99 mmol) was dissolved in dichloromethane (20 ml), trifluoroacetic acid (5.0 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and dried to give the title compound (5.35 g, quant) as a dark brown oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.16-1.29 (total 5H, series of m, including 1.25, 3H, t, J = 7.2 Hz), 1.39-1.52 (2H, m), 1.89-2.08 (total 6H, series of m), 2.13-2.70 (total 6H, series of m), 3.21-3.45 (2H, m), 3.49-3.91 (8H, series of m), 3.96-4.16 (total 3H, series of m, including 4.12, 2H, q, J = 7.2 Hz), 9.81 (2H, br s).

(Process 7)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Synthesis of pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetic acid (207 mg, 0.65 mmol) and trans-4-[(5S) in a 100 ml eggplant-shaped flask -(3,3-Difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester 2trifluoroacetate (equivalent to 500 mg, 0.65 mmol) and N , N-dimethylformamide (6.0 ml) was added and dissolved, and then EDC · HCl (280 mg, 1.46 mmol), HOBt · H ₂ O (221 mg, 1.46 mmol), and triethylamine (477 μl, 3.42 mmol) were added. And stirred at room temperature for 42 hours. Ice water (40 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The combined organic layer was washed with saturated brine (50 ml × 2) and then dried over anhydrous sodium sulfate. . After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in a minimum amount of dichloromethane and subjected to thin layer chromatography (Watman). This was developed with chloroform-ethyl acetate (4: 1, v / v), and the target spot portion was scraped off and extracted with chloroform-methanol (5: 1, v / v). The extract was concentrated and dried under reduced pressure to obtain the title compound (336 mg, 0.50 mmol, 77%) as a white solid.
IR (ATR) ν: 2939, 1724, 1637, 1610, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.12-1.53 (total 7H, series of m), 1.79-3.28 (total 21H, series of m), 3.34-3.98 (total 4H, series of m), 4.00- 4.24 (total 4H, series of m), 6.72 (1H, td, J = 8.2, 2.6 Hz), 7.02-7.23 (total 4H, series of m), 8.02-8.05 (1H, m).
Anal.Calcd for C ₃₅ H ₄₂ F ₄ N ₄ O ₅・ H ₂ O: C, 60.68; H, 6.40; N, 8.09.
Found: C, 60.67; H, 6.03; N, 8.21.
MS (LC-MS) m / z: 675 (M ⁺ +1).

(Process 8)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Synthesis of (pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid
In a 100 ml eggplant-shaped flask, trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3 , 3-Difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (336 mg, 0.50 mmol) was added and dissolved in tetrahydrofuran (4.0 ml). 0.25 N sodium hydroxide aqueous solution (4.0 ml, 1.0 mmol) was added, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was washed with diethyl ether. The aqueous layer was neutralized with 1N aqueous hydrochloric acid and extracted with chloroform-methanol (5: 1, v / v). The extracted organic layer was dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was dissolved in a minimum amount of chloroform and subjected to thin layer chromatography (Watman). This was developed with chloroform-methanol (15: 1, v / v), and the target spot portion was scraped off and extracted with chloroform-methanol (5: 1, v / v). The extract was concentrated and dried under reduced pressure, dissolved in 1 ml of chloroform, diluted with 3 ml of ethyl acetate, and then added with 100 ml of n-hexane to precipitate a white precipitate. The precipitate was filtered and dried to obtain the title compound (202 mg, 0.31 mmol, 62%) as a white crystalline powder.
IR (ATR) ν: 2939, 1639, 1610, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.84-1.55 (total 5H, series of m), 1.67-2.47 (total 14H, series of m, including 3H, s, δ 2.26), 2.53-3.04 (total 6H , series of m), 3.16-3.30 (1H, m), 3.35-4.25 (total 6H, series of m), 6.74 (1H, t, J = 6.7 Hz), 7.00-7.17 (total 3H, series of m) , 7.69-7.76 (1H, m), 9.28 (1H, br s).
Anal.Calcd for C ₃₃ H ₃₈ F ₄ N ₄ O ₅・ 0.75 H ₂ O: C, 60.04; H, 6.03; N, 8.49.
Found: C, 60.05; H, 5.88; N, 8.44.

Example 99
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of [7-fluoro-2- (2-methoxyphenyl) amino- The title compound (281 mg, 0.42 mmol, 85%) was obtained as a white solid by conducting a condensation reaction using 6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2939, 1726, 1635, 1604, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.11-1.53 (total 7H, series of m), 1.70-2.40 (total 11H, series of m), 2.52-3.30 (total 6H, series of m), 3.35- 4.21 (total 11H, series of m), 6.91-6.95 (1H, m), 7.02-7.19 (total 3H, series of m), 7.23-7.27 (2H, m), 7.73 (1H, s), 8.37-8.41 (1H, m).
Anal.Calcd for C ₃₅ H ₄₃ F ₃ N ₄ O ₆・ 1.25 H ₂ O: C, 60.46; H, 6.60; N, 8.06.
Found: C, 60.27; H, 6.26; N, 7.98.
MS (LC-MS) m / z: 673 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner similar to Example 98, (Step 8), trans-4- [1-[[7-fluoro-2- (2 -Methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid The title compound (78 mg, 0.12 mmol, 40%) was obtained as a white crystalline powder by using ethyl ester.
IR (ATR) ν: 2940, 2860, 1637, 1604, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.11-1.57 (total 4H, series of m), 1.92-2.41 (total 11H, series of m), 2.69- 3.10 (total 6H, series of m), 3.12-3.29 (1H, m), 3.36-3.66 (2H, m), 3.71-3.89 (2H, m), 3.94 (3H, s), 4.00-4.21 (2H, m), 6.91-6.94 (1H, m), 7.02-7.19 (total 3H, series of m), 7.23-7.26 (2H,
m), 7.80 (1H, br s), 8.34-8.38 (1H, m).
Anal.Calcd for C ₃₅ H ₃₉ F ₃ N ₄ O ₆・ 0.5 H ₂ O: C, 60.63; H, 6.17; N, 8.57.
Found: C, 60.64; H, 6.11; N, 8.47.
MS (LC-MS) m / z: 645 (M ⁺ +1).

Example 100
(Process 1)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Synthesis of pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester In a manner analogous to Example 98 (Step 7), [7-Fluoro-2- (5-fluoro The title compound (300 mg, 0.43 mmol, 67%) was obtained as a white solid by performing a condensation reaction with -2-methoxyphenyl) amino-6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2939, 1726, 1639, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.09-1.53 (total 7H, series of m), 1.81-2.41 (total 11H, series of m), 2.52-3.30 (total 6H, series of m), 3.37- 4.21 (total 12H, series of m, including δ 3.90, 3H, s), 6.69 (1H, td, J = 8.4, 2.9 Hz), 6.80 and 6.82 (total 1H, each d, J = 4.6 Hz, amide isomers) , 7.05-7.19 (1H, m), 7.23-7.27 (1H, m), 7.85 (1H, s), 8.27 (1H, dd, J = 10.3, 2.9 Hz).
Anal.Calcd for C ₃₅ H ₄₂ F ₄ N ₄ O ₆・ 1,25 H ₂ O: C, 58.94; H, 6.29; N, 7.86.
Found: C, 58.90; H, 5.95; N, 7.79.
MS (LC-MS) m / z: 691 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Synthesis of pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner analogous to Example 98 (Step 8), trans-4- [1-[[7-fluoro- 2- (5-Fluoro-2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinyl The title compound (191 mg, 029 mmol, 68%) was obtained as a white crystalline powder by using methoxy] -1-cyclohexanecarboxylic acid ethyl ester.
IR (ATR) ν: 2939, 1709, 1641, 1579 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.03-1.50 (total 5H, series of m), 1.78-2.40 (total 11H, series of m), 2.51-3.27 (total 6H, series of m), 3.34- 3.93 (total 7H, series of m, including 3H, s, δ 3.88), 3.98-4.19 (2H, m), 6.68 (1H, td, J = 8.3, 2.6
Hz), 6.78 and 6.80 (total 1H, each d, each J = 4.9 Hz, amide isomers), 7.02-7.18 (1H, m), 7.20-7.25 (1H, m), 7.90 (2H, br s), 8.16 -8.24 (1H, m).
Anal.Calcd for C ₃₃ H ₃₈ F ₄ N ₄ O ₆・ H ₂ O: C, 58.23; H, 5.92; N, 8.23.
Found: C, 58.05; H, 5.67; N, 8.16.
MS (LC-MS) m / z: 663 (M ⁺ +1).

Example 101
(Process 1)
Trans-4- [1-[[7-Chloro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Synthesis of pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester In a manner analogous to Example 98 (Step 7), [7-chloro-2- (5-fluoro The title compound (258 mg, 0.37 mmol, 57%) was obtained as a light brown solid by performing a condensation reaction with -2-methylphenyl) amino-6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2939, 1726, 1637, 1570 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.05-1.56 (total 7H, series of m), 1.64-2.49 (total 14H, series of m), 2.53-3.09 (total 6H, series of m), 3.14- 3.33 (1H, m), 4.27-3.37 (total 8H, series of m, including δ 4.12, 2H, q, J = 7.2 Hz), 6.74-6.68 (1H,
m), 7.05-7.13 (total 2H, m), 7.23-7.31 (1H, m), 7.71-8.07 (total 2H, m).
Anal.Calcd for C ₃₅ H ₄₂ ClF ₃ N ₄ O ₅・ 0.75 H ₂ O: C, 59.65; H, 6.22; N, 7.95.
Found: C, 59.61; H, 6.12; N, 8.01.
MS (LC-MS) m / z: 691 [(M ⁺ +1), ³⁵ Cl], 693 [(M ⁺ +3), ³⁷ Cl].

(Process 2)
Trans-4- [1-[[7-Chloro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1- Synthesis of pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner analogous to Example 98 (Step 8), trans-4- [1-[[7-chloro- 2- (5-Fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinyl The title compound (180 mg, 0.27 mmol, 75%) was obtained as a white crystalline powder by using methoxy] -1-cyclohexanecarboxylic acid ethyl ester.
IR (ATR) ν: 2935, 1641, 1608, 1570 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ:
1.12-1.51 (total 4H, series of m), 1.83-2.46 (total 15H, series of m, including 3H, s, δ 2.30), 2.55-3.06 (6H, series of m), 3.15-3.30 (1H, m ), 3.36-4.25 (total 6H, series of m), 6.75 (1H, td, J = 8.2, 2.5 Hz), 7.11-7.16 (total 2H, m), 7.27-7.30 (1H, m), 7.82-7.87 (1H, m), 8.62 (1H, br s).
Anal.Calcd for C ₃₃ H ₃₈ ClF ₃ N ₄ O ₅・ 0.5 H ₂ O: C, 58.97; H, 5.85; N, 8.34.
Found: C, 58.79; H, 5.74; N, 8.29.
MS (LC-MS) m / z: 663 [(M ⁺ +1), ³⁵ Cl], 665 [(M ⁺ +3), ³⁷ Cl].

Example 102
Trans-4- [1-[[7-Chloro-2- (2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Chloro-2- (2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of [7-chloro-2- (2-methylphenyl) amino-] in an analogous manner to Example 98 (Step 7) The title compound (188 mg, 0.28 mmol, 43%) was obtained as a light brown solid by performing a condensation reaction using 6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2935, 1728, 1637, 1610, 1570 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.17-1.55 (total 7H, series of m), 1.79-2.49 (total 13H, series of m), 2.54-3.07 (total 6H, series of m), 3.15- 3.30 (1H, m), 3.33-4.26 (total 9H, series of m, including δ 4.12, 2H, q, J = 7.2 Hz), 7.03-7.30 (total 5H, series of m), 7.59-7.79 (1H, m), 7.93-8.04 (1H, m).
Anal.Calcd for C ₃₅ H ₄₃ ClF ₂ N ₄ O ₅・ 0.5 H ₂ O: C, 61.62; H, 6.50; N, 8.21.
Found: C, 61.80; H, 6.65; N, 7.86.
MS (LC-MS) m / z: 673 [(M ⁺ +1), ³⁵ Cl], 675 [(M ⁺ +3), ³⁷ Cl].

(Process 2)
Trans-4- [1-[[7-Chloro-2- (2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl )-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner similar to Example 98, (Step 8), trans-4- [1-[[7-chloro-2- (2 -Methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-(3,3-difluoro-1-pyrrolidinylmethyl)-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid The title product (127 mg, 0.20 mmol, 73%) was obtained as a white crystalline powder by using ethyl ester.
IR (ATR) ν: 2935, 1637, 1601, 1570 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.17-1.54 (total 5H, series of m), 1.78-2.37 (total 14H, series of m), 2.53-3.05 (total 5H, series of m), 3.18- 3.27 (1H, m), 3.34-4.23 (total 6H, series of m), 7.06-7.14 (total 2H, m), 7.22 (1H, d, J = 7.1 Hz), 7.26-7.31 (total 3H, series of m), 7.92 (1H, t, J = 7.1 Hz).
Anal.Calcd for C ₃₃ H ₃₉ ClF ₂ N ₄ O ₅・ 0.75 H ₂ O: C, 60.18; H, 6.20; N, 8.51.
Found: C, 59.98; H, 6.06; N, 8.43.
MS (LC-MS) m / z: 645 [(M ⁺ +1), ³⁵ Cl], 646 (M ⁺ +2).

Example 103
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -Fluoro-1- Pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Synthesis of 1- (tert-butoxycarbonyl)-(3R) -hydroxypyrrolidine
(3R) -Hydroxypyrrolidine (commercially available, Aldrich) (476 mg, 5.46 mmol) was placed in a 100 ml eggplant-shaped flask, dissolved in dichloromethane (20 ml), and di-tert-butyldicarboxylate with stirring on ice. Nart (commercial, domestic chemistry) (1.19 g, 5.46 mmol) was added. This was stirred at room temperature for 3 hours. The concentrated residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography, and the fraction obtained from the eluate of n-hexane-ethyl acetate (1: 1, v / v) was concentrated under reduced pressure to give the title compound. (815 mg, 4.35 mmol, 80%) was obtained as a white oil.
MS (LC-MS) m / z: 188 (M ⁺ +1).

(Process 2)
Synthesis of 1- (tert-butoxycarbonyl)-(3S) -fluoropyrrolidine In a 100 ml eggplant-shaped flask under nitrogen flow, After adding dichloromethane (10 ml) and dissolving, slowly add (diethylamino) sulfur trifluoride (commercially available, Aldrich) (687 μl, 5.20 mmol) under dry ice-acetone cooling and stirring. Stir for 2.5 hours. The mixture was stirred for an additional 16 hours while slowly warming to room temperature, ice water (50 ml) was added to the reaction mixture, extracted with dichloromethane (50 ml × 2), and the combined organic layer was washed with saturated brine (50 ml). After washing, it was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting concentrated residue was subjected to silica gel column chromatography, and the fraction obtained from the eluate of n-hexane-ethyl acetate (4: 1, v / v) was concentrated under reduced pressure. Drying gave the title compound (490 mg, 2.59 mmol, 60%) as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.85-2.27 (2H, m), 3.39-3.76 (total 4H, series of m), 5.13- 5.29 (1H, m).
MS (LC-MS) m / z: 190 (M ⁺ +1).

(Process 3)
Synthesis of (3S) -fluoropyrrolidine hydrochloride
Add 1- (tert-butoxycarbonyl)-(3S) -fluoro-pyrrolidine (490 mg, 2.59 mmol) to a 100 ml eggplant-shaped flask, and add 4 N hydrochloric acid / 1,4-dioxane (4.0 ml, 16.0 mmol). In addition, the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (6) (328 mg, quant) as a brown solid. This compound was used in the next reaction without further purification.

(Process 4)
Trans-4- [1- (tert-Butoxycarbonyl)-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of
In a 200 ml eggplant-shaped flask, trans-4- [1- (tert-butoxycarbonyl)-(5S) -formyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (1.24 g, 3.23 mmol ) And (3S) -fluoropyrrolidine hydrochloride (1.21 g, 9.62 mmol) were added, and toluene (30 ml × 3) was added and azeotroped. After allowing to cool, tetrahydrofuran (30 ml) was added to the residue for dissolution, and sodium triacetoxyborohydride (2.05 g, 9.69 mmol) was added, followed by stirring at room temperature for 11.5 hours. To the reaction was added saturated brine, and the mixture was extracted with ethyl acetate (100 ml × 2). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was subjected to Biotage flash column chromatography (column size 40 s), and n-hexane-ethyl acetate (3: 2, v / v) was eluted from the eluate. The obtained fraction was concentrated and dried under reduced pressure to give the title compound (701 mg, 1.53 mmol, 47%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.15-1.29 (total 5H, series of m), 1.39-1.49 (total 11H, series of m), 1.88-2.29 (total 12H, series of m), 2.43- 3.04 (total 5H, series of m), 3.16-3.40 (total 2H, m), 3.63 (1H, ddd, J = 31.3, 9.1, 3.0 Hz), 3.75-3.81 (1H, m), 3.85-3.92 (1H , m), 4.08-4.15 (2H, m), 5.05-5.23 (1H, m).
MS (LC-MS) m / z: 457 (M ⁺ +1).

(Process 5)
Trans-4-[(5S)-[(3S) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester synthesis trans-4- [1- (tert-Butoxycarbonyl)-(5S)-[(3S) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (701 mg, 1.53 mmol) 4N hydrochloric acid / 1,4-dioxane solution (3.0 ml, 12.0 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, basified with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform-methanol (5: 1, v / v). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and dried to obtain the title compound (590 mg, quant) as a dark brown solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.20-1.30 (total 5H, series of m), 1.39-1.61 (total 4H, series of m), 1.90-2.28 (total 9H, series of m), 2.33- 2.55 (2H, m), 2.63 and 2.66 (total 1H, each d, each J = 8.6 Hz), 2.95-2.74 (total 3H, series of m), 3.25 (1H, tt, J = 10.5, 4.1 Hz), 3.39-3.51 (total 4H, series of m), 4.11 (2H, td, J = 7.6, 6.1 Hz), 4.37 (1H, br s), 5.24-5.06 (1H, m).

(Process 6)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -Fluoro-1- Synthesis of pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetic acid (188 mg, 0.59 mmol) and trans-4-[(5S) in a 100 ml eggplant-shaped flask -[(3S) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (210 mg, 0.59 mmol) was added, and N, N-dimethylformamide ( 4.0 ml) was added and dissolved, and then EDC · HCl (169 mg, 0.88 mmol), HOBt (135 mg, 0.88 mmol), and triethylamine (123 μl, 0.88 mmol) were added, and the mixture was stirred at room temperature for 13.5 hours. Ice water (40 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The combined organic layer was washed with saturated brine (50 ml × 2) and then dried over anhydrous sodium sulfate. . After filtration, the filtrate was concentrated under reduced pressure, the resulting concentrated residue was dissolved in a minimum amount of dichloromethane was subjected to thin-layer chromatography ^{(Merck silicagel 60 F 254, 2} mm). This was developed three times with chloroform-methanol (30: 1, v / v), and the target spot portion was scraped off and extracted with chloroform-methanol (5: 1, v / v). The extract was concentrated and dried under reduced pressure to obtain the title compound (308 mg, 0.47 mmol, 80%) as a yellow solid.
IR (ATR) ν: 2939, 1726, 1637, 1610, 1575 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.55 (total 7H, series of m), 1.88-2.32 (total 14H, series of m), 2.38-2.50 (1H, m), 2.54-2.91 (total 4H, series of m), 2.93-3.05 (1H, m), 3.11-3.29 (1H, m), 3.41 and 3.47 (total 1H, each dd, each J = 9.3, 7.3 Hz), 3.54-3.95 (total 3H , series of m), 4.05-4.26 (total 4H, series of m), 4.98-5.26 (1H, m), 6.72 (1H, td, J = 8.2, 2.5 Hz), 7.18-7.00 (total 3H, series of m), 8.04-7.77 (2H, m).
Anal.Calcd for C ₃₅ H ₄₃ F ₃ N ₄ O ₅・ 1.25 H ₂ O: C, 61.89; H, 6.75; N, 8.25.
Found C, 61.95: H, 6.59; N, 8.13.
MS (LC-MS) m / z: 657 (M ⁺ +1).

(Process 7)
Trans-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -Fluoro-1- Synthesis of pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid
In a 100 ml eggplant-shaped flask, trans-4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[( 3S) -Fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (301 mg, 0.46 mmol) was added, and tetrahydrofuran (4.0 ml) was added and dissolved. , 0.25 N aqueous sodium hydroxide solution (4.0 ml, 1.0 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, washed with diethyl ether, the aqueous layer was neutralized with 1N aqueous hydrochloric acid, water was added, and the mixture was extracted with chloroform-methanol (5: 1, v / v). The organic layer was dried over anhydrous sodium sulfate. After filtration, the concentrated residue obtained by concentrating the filtrate under reduced pressure was dissolved in a minimum amount of chloroform and subjected to thin layer chromatography (Merck silica gel 60 _F254 , 2 mm). This was developed with chloroform-methanol (10: 1, v / v), then developed with chloroform-methanol (5: 1, v / v), the target spot was scraped off, and chloroform-methanol (5: 1 , v / v). The extract was concentrated and dried under reduced pressure, then dissolved in chloroform-ethyl acetate, and n-hexane was added to precipitate a precipitate. The precipitate was filtered and dried to obtain the title compound (213 mg, 0.34 mmol, 74%) as a pale yellow powder.
IR (ATR) ν: 2937, 1639, 1610, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ:
1.08-1.61 (total 5H, series of m), 1.84-2.33 (total 13H, series of m), 2.53-3.96 (total 11H, series of m), 4.07-4.26 (2H, m), 5.00-5.26 (1H , m), 6.71-6.77 (1H, m), 7.02-7.15 (total 3H, series of m), 7.75-7.83 (1H, m), 8.54 (2H, br s).
Anal.Calcd for C ₃₃ H ₃₉ F ₃ N ₄ O ₅・ 0.25 H ₂ O: C, 62.60; H, 6.29; N, 8.78.
Found C, 62.44: H, 6.09; N, 8.78.
MS (LC-MS) m / z: 629 (M ⁺ +1).

Example 104
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl ]-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid (Step 1)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl ]-(2S) -Pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester Synthesis of [7-fluoro-2- (2-methoxyphenyl) amino-] in an analogous manner to Example 103 (Step 6) The title compound (331 mg, 0.51 mmol, 82%) was obtained as a yellow solid by performing a condensation reaction with 6-benzoxazolyl] acetic acid.
IR (ATR) ν: 2939, 1726, 1635, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.10-1.53 (total 7H, series of m), 1.89-2.30 (total 11H, series of m), 2.38-3.06 (total 6H, series of m), 3.12- 3.28 (1H, m), 3.35-3.95 (total 7H, series of m, including 3H, s, δ 3.91), 4.23-4.02 (total 4H, series of m), 5.00-5.25 (1H, m), 6.88- 6.92 (1H, m), 7.00-7.08 (total 2H, m), 7.09-7.18 (1H, m), 7.21-7.26 (1H, m), 7.77 (1H, br s), .36-8.40 (1H, m).
Anal.Calcd for C ₃₅ H ₄₄ F ₂ N ₄ O ₆・ 1.5 H ₂ O: C, 61.66; H, 6.95; N, 8.22.
Found: C, 61.40; H, 6.67; N, 8.02.
MS (LC-MS) m / z: 655 (M ⁺ +1).

(Process 2)
Trans-4- [1-[[7-Fluoro-2- (2-methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl Synthesis of]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid In a manner similar to Example 103, (Step 7), trans-4- [1-[[7-fluoro-2- (2 -Methoxyphenyl) amino-6-benzoxazolyl] acetyl]-(5S)-[(3S) -fluoro-1-pyrrolidinylmethyl]-(2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid To give the title compound (278 mg, 0.44 mmol, 91%) as a pale yellow crystalline powder.
IR (ATR) ν: 2937, 1716, 1637, 1577 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.13-1.63 (total 4H, series of m), 1.91-2.27 (total 11H, series of m), 2.54-3.28 (total 7H, series of m), 3.33- 3.56 (2H, m), 3.62-3.97 (total 5H, series of m), 3.99-4.28 (2H, m), 5.04-5.26 (1H, m), 7.48-6.86 (total 7H, series of m), 8.28 -8.32 (1H, m).
Anal.Calcd for C ₃₃ H ₄₀ F ₂ N ₄ O ₆・ 0.5 H ₂ O: C, 62.35; H, 6.50; N, 8.81.
Found C, 62.74: H, 6.48; N, 8.44.
MS (LC-MS) m / z: 627 (M ⁺ +1).

Example 105
Cis-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino- (5S)-(N, O-dimethylhydroxylaminomethyl) -6-benzoxazolyl] acetyl ]-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of 4- [1-tert-butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
4- [3-oxo- (8S) -tetrahydro-pyrrolo [1,2-c] oxazolyl- (5S) -methoxy] cyclohexanecarboxylic acid ethyl ester (7.12 g, 22.87 mmol) was dissolved in ethanol (100 ml). 3N sodium hydroxide aqueous solution (38 ml, 114 mmol) was added, and the mixture was heated to reflux for 21 hours. The mixture was allowed to cool to room temperature, neutralized with 4N hydrochloric acid-dioxane solution, and the solvent was evaporated under reduced pressure. The resulting residue was azeotroped twice with toluene to give a white solid. This white solid was dissolved in ethanol (100 ml), concentrated sulfuric acid (1.5 ml) was added, and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was azeotroped with toluene to give a pale yellow oil. This pale yellow oil was dissolved in a mixed solution of tetrahydrofuran (100 ml) and saturated aqueous sodium hydrogencarbonate (100 ml), di-tert-butyl dicarbonate (7.49 g, 34.30 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Stir. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40 M, n-hexane: ethyl acetate = 4: 1 to 1: 1, v / v), and the title compound (8.64 g, 98%, cis: trans = 7: 3) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.34 (4H, m), 1.42-1.67 (total 13H, series of m, including 9H, s, at δ 1.47), 1.78-2.35 (8H, m), 3.19 -3.72 (5H, m), 3.90-4.17 (4H, m), 4.23-4.31 (1H, m).
MS (LC-ESI) m / z: 286 (M ⁺ + 1-Boc).

(Process 2)
Synthesis of cis-4-[(5S) -Benzyloxymethyloxy-1-tert-butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
4- [1-tert-Butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (8.64 g, 22.4 mmol, cis: trans = 7: 3) was added to dichloromethane (80 Diisopropylethylamine (5.80 ml, 33.30 mmol) and benzyl chloromethyl ether (4.61 ml, 33.30 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, made weakly acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40M, n-hexane: ethyl acetate = 9: 1 to 3: 1, v / v) to obtain a diastereomeric mixture (11.0 g) as a colorless oil. Obtained. The diastereomeric mixture was again purified by flash column chromatography (Biotage 75M, n-hexane: ethyl acetate = 7: 1, v / v) to give the title compound (4.80 g, 44%) as a colorless oil. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.22-1.66 (total 16H, m, including 9H, each s, at δ 1.44 and 1.45), 1.79-2.15 (8H, m), 2.30-2.31 (1 H, m) , 3.23-3.59 (4H, m), 3.70-3.99 (3H, m), 4.09-4.15 (2H, m), 4.59 (2H, s), 4.71-4.77 (2H, m), 7.29-7.35 (5H, m).
MS (LC-ESI) m / z: 406 (M ⁺ + 1-Boc), 528 (M ⁺ +23).

(Process 3)
Synthesis of cis-4- [1-tert-butoxycarbonyl- (5S) hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester cis-4-[(5S) -benzyloxymethyloxy-1- tert-Butoxycarbonyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (4.80 g, 9.49 mmol) is dissolved in methanol (50 ml) and 10% palladium hydroxide / carbon catalyst (1 g) is added. Hydrogenation was performed at room temperature for 18 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 to 1: 1, v / v) to obtain the title compound (3.55 g, 97%).
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.66 (total 15H, m, including 3H, t, J = 7.1 Hz, at δ 1.25 and including 9H, s, at δ 1.47), 1.78-2.33 (9H, m ), 3.30-3.72 (6H, m), 3.90-4.30 (5H, m, including 2H, q, J = 7.1 Hz, at δ 4.12).
MS (LC-ESI) m / z: 286 (M ⁺ + 1-Boc), 408 (M ⁺ +23).

(Process 4)
Synthesis of cis-4- [1-tert-butoxycarbonyl- (5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Oxalyl chloride (0.62 ml) at -78 ^° C under nitrogen atmosphere , 7.06 mmol) in dichloromethane (30 ml) was added dropwise dimethyl sulfoxide (0.75 ml, 10.58 mmol). To this reaction solution, cis-4- [1-tert-butoxycarbonyl- (5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.36 g, 3.53 mmol) in dichloromethane solution (10 ml) was added dropwise and stirred for 2 hours while maintaining at -78 ^° C. Triethylamine (2.46 ml, 17.64 mmol) was added dropwise to the reaction solution, and the mixture was stirred for 2 hours while gradually warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1-3: 1, v / v) to obtain the title compound (1.14 g, 84%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.41-1.67 (total 13H, m, including 9H, each s, at δ 1.42 and 1.48), 1.74-2.05 (7H, m), 2.24-2.37 (2H, m), 3.37-3.67 (3H, m), 4.02-4.31 (4H, m, including 2H, q, J = 7.1 Hz, at δ 4.12), 9.52-9.60 (1H, m).
MS (LC-ESI) m / z: 284 (M ⁺ + 1-Boc), 406 (M ⁺ +23).

(Process 5)
Synthesis of cis-4- [1-tert-butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
Cis-4- [1-tert-butoxycarbonyl- (5S) -formyl- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.14 g, 2.97 mmol) and N, O-dimethylhydroxylamine hydrochloride ( 0.72 g, 7.43 mmol) was dissolved in 1,2-dichloroethane (20 ml), sodium triacetoxyborohydride (3.15 g, 14.86 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1, v / v) to obtain the title compound (1.01 g, 79%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.46-1.66 (total 13H, m, including 9H, s, at δ 1.46), 1.80-2.09 (7H, m), 2.31-2.45 (2H, m), 2.57 and 2.59 (total 3H, each s), 2.81-3.56 (total 8H, series of m, including 3H, s, at δ 3.47), 3.82-3.90 (2H, m), 4.12 (2H, q, J = 7.1 Hz).
MS (LC-ESI) m / z: 429 (M + +1).

(Process 6)
Cis-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino- (5S)-(N, O-dimethylhydroxylaminomethyl) -6-benzoxazolyl] acetyl Synthesis of]-(2S) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester cis- [1-tert-Butoxycarbonyl- (5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinyl Methoxy] cyclohexanecarboxylic acid ethyl ester (1.01 g, 2.36 mmol) was dissolved in 4N hydrochloric acid-dioxane (15 ml) and stirred at room temperature for 5 hours. After concentrating the reaction solution, the residue was azeotroped twice with toluene to give cis-[(5S)-(N, O-dimethylhydroxylaminomethyl)-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride Was obtained as a white solid. This white solid (2.36 mmol), [7-fluoro-2- (5-fluoro-2-methylphenyl) amino-6-benzoxazolyl] acetic acid (0.75 g, 2.36 mmol), EDC · HCl (0.68 g, 3.54 mmol), HOBt (0.32 g, 2.36 mmol) and triethylamine (1.64 ml, 11.80 mmol) were dissolved in N, N-dimethylformamide (20 ml) and stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (Biotage 40 M, n-hexane: ethyl acetate = 2: 1 to 1: 1, v / v) to give the title compound (1.31 g, 88%) as pale yellow Obtained as an amorphous solid.
[α] ²⁰ _D = -56.5 (c 1, THF)
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.37-2.44 (total 16H, series of m, including 3H, s, at δ 2.30), 2.56-2.62 (4H, m ), 2.79-2.83 and 3.09-3.11 (total 1H, each m), 3.33-3.56 (6H, m), 3.75-3.96 (2H, m), 4.07-4.26 (4H, m, including 2H, q, J = 7.1 Hz, at δ 4.13), 6.74 (1H, td, J = 8.2, 2.6 Hz), 7.10-7.15 (3H, m), 7.21-7.23 (1H, m), 8.06-8.11 (1H, m).
IR (ATR) cm ^-1 : 1726, 1637, 1610, 1576, 1450, 1421, 1068, 1041.
MS (FAB) m / z: 629 (M ⁺ +1).
MS (LC-ESI) m / z: 629 (M ⁺ +1).
Anal. Calcd for C ₃₃ H ₄₂ F ₂ N ₄ O ₆ : C, 63.04; H, 6.73; N, 8.91; F, 6.04. Found: C, 62.84; H, 6.78; N, 8.79; F, 6.16.

(Process 7)
Cis-4- [1-[[7-Fluoro-2- (5-fluoro-2-methylphenyl) amino- (5S)-(N, O-dimethylhydroxylaminomethyl) -6-benzoxazolyl] acetyl Synthesis of]-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid cis-4- [1-[[7-fluoro-2- (5-fluoro-2-methylphenyl) amino- (5S)-(N, O-dimethylhydroxylaminomethyl) -6-benzoxazolyl] acetyl]-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.31 g, 2.08 mmol) in tetrahydrofuran (4 ml) and methanol (1 ml 1N aqueous sodium hydroxide solution (4 ml, 4.00 mmol) was added, and the mixture was stirred at room temperature for 20 hours. 1N Hydrochloric acid (4 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: acetic acid = 50: 150: 1, v / v) to obtain a colorless oil. After azeotroping twice with toluene, the product was purified again by silica gel column chromatography (chloroform: methanol = 60: 1-30: 1, v / v) to give the title compound (1.02 g, 82%) as a colorless amorphous solid. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.38-2.35 (total 16H, series of m, including 3H, s, at δ 2.30), 2.47-2.91 (total 5H, m, including 3H, each s, at δ 2.47 and 2.57), 3.32-3.48 (6H, m), 3.75-4.19 (4H, m), 6.89 (1H, td, J = 8.3, 2.7 Hz), 7.07-7.13 (1H, m), 7.20-7.28 ( 2H, m), 7.91-7.94 (1H, m), 10.05 (1H, broad s), 12.02 (1H, broad s).
IR (ATR) cm ^-1 : 1639, 1610, 1577, 1450, 1423, 1281, 1201, 1068.
MS (LC-ESI) m / z: 601 (M ⁺ +1).
MS (FAB) m / z: 601 (M ⁺ +1).
MS (FAB) m / z: 601.2845 (Calcd for C ₃₁ H ₃₉ N ₄ F ₂ O ₆ : 601.2838).

Example 106a
Cis-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl )-(2R) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of 1-benzyloxy- (2S) -hydroxy-5-hexene
To a tetrahydrofuran solution (500 ml) of (S) -benzylglycidyl ether (Daiso, SBG01927) (16.42 g, 100 mmol) at 0 ° C in a nitrogen atmosphere, 2 M allylmagnesium chloride-tetrahydrofuran solution (55 ml, 110 mmol ) Was added dropwise over 20 minutes and stirred at the same temperature for 1.5 hours. Saturated ammonium chloride aqueous solution was added at the same temperature, and left still for a while. The organic layer was separated and washed with water. The washed aqueous solution was added to the insoluble precipitate and dissolved, and extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (21.5 g, over yield) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.50-1.63 (2H, m), 2.07-2.32 (2H, m), 3.34 (1H, dd, J = 9.4, 7.7 Hz), 3.51 (1H, dd, J = 9.4, 3.1 Hz), 3.63 (1H, dq, J = 20.4, 4.6 Hz), 3.80-3.88 (1H, m), 4.56 (2H, s), 4.94-4.99 (1H, m), 5.03 (1H, dq , J = 17.2, 1.5 Hz), 5.77-5.88 (1H, m), 7.27-7.39 (5H, m).
MS (ESI) m / z: 207 (M ⁺ +1).

(Process 2)
Synthesis of 1-benzyloxy- (2R) -phthalimidyl-5-hexene
1-Benzyloxy- (2S) -hydroxy-5-hexene (20.6 g, 100 mmol) in tetrahydrofuran (400 ml) was added to phthalimide (16.2 g, 110 mmol) and triphenylphosphine (31.5 g, 120 mmol) at room temperature. mmol) was added and stirred for a while. The reaction mixture was cooled to 0 ° C., diisopropyl azodicarboxylate (24.9 ml, 120 mmol) was added dropwise over 10 minutes, and the mixture was stirred for 15 hours while gradually returning to room temperature. The reaction mixture was concentrated, a mixed solution of ethyl acetate / n-hexane = 1/2 (v / v) was added, the precipitated insoluble material was removed by filtration, and the obtained mother liquor was concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO ₂ 500 g, ethyl acetate: n-hexane = 1: 5 v / v), and the title compound [31.0 g, 92% (2 steps)] was purified as a colorless oil. Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.75-1.85 (1H, m), 2.02-2.10 (2H, m), 2.12-2.23 (1H, m), 3.69 (1H, dd, J = 9.8, 5.1 Hz) , 4.00 (1H, t, J = 9.6 Hz), 4.45 (1H, d, J = 12.0 Hz), 4.49-4.60 (2H, m), 4.89-5.00 (2H, m), 5.70-5.81 (1H, m ), 7.20-7.35 (5H, m), 7.68-7.75 (2H, m), 7.78-7.87 (2H, m).
MS (ESI) m / z: 336 (M ⁺ +1).

(Process 3)
Synthesis of (2R) -amino-1-benzyloxy-5-hexene
Add hydrazine monohydrate (13.7 ml, 276.8 mmol) to ethanol solution (200 ml) of 1-benzyloxy- (2R) -phthalimidyl-5-hexene (31.0 g, 92.3 mmol) at room temperature The mixture was warmed and stirred for 1.5 hours. After returning the reaction solution to room temperature, the precipitated solid was removed by filtration. The obtained mother liquor was diluted with water and extracted with a mixed solution of chloroform / methanol [= 10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (14.6 g, 78%) as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26-1.42 (1H, m), 1.26 (1H, s), 2.00-2.24 (2H, m), 2.97-3.05 (1H, m), 3.25 (1H, dd, J = 9.1, 7.6 Hz), 3.46 (1H, dd, J = 9.1, 4.2 Hz), 4.53 (2H, s), 4.94-4.98 (1H, m), 5.03 (1H, ddd, J = 17.2, 3.4, 1.7 Hz), 5.75-5.87 (1H, m), 7.38-7.26 (5H, m).
MS (ESI) m / z: 206 (M ⁺ +1).

(Process 4)
Synthesis of (2R) -N-benzoylamino-1-benzyloxy-5-hexene
(2R) -Amino-1-benzyloxy-5-hexene (14.6 g, 71.3 mmol) in dichloromethane (500 ml) was added at 0 ° C with triethylamine (14.9 mml, 107.0 mmol) and benzoyl chloride (9.93 ml, 85.6 mmol) was added and stirred for 21 hours. To the reaction solution was added 1 N aqueous sodium hydroxide solution, and the mixture was stirred for a while and extracted with chloroform. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (22.3 g, over yield) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 1.79 (2H, q, J = 7.5 Hz), 2.10-2.18 (2H, m), 3.57-3.64 (2H, m), 4.25-4.38 (1H, m), 4.52 (1H, d, J = 12.0 Hz), 4.57 (1H, d, J = 12.0 Hz), 4.94-5.07 (2H, m), 5.78-5.90 (1H, m), 6.37 (1H, d, J = 8.1 Hz), 7.26-7.55 (8H, m), 7.72-7.77 (2H, m).
MS (ESI) m / z: 310 (M ⁺ +1).

(Process 5)
Synthesis of 1-tert-butoxycarbonyl- (2R) -benzoyloxymethyl- (5R) -benzyloxymethylpyrrolidine
(2R) -N-benzoylamino-1-benzyloxy-5-hexene (22.6 g, 71.3 mmol) in acetonitrile / water (300 ml / 300 ml) mixed solution at room temperature with iodine (54 g, 213.9 mmol) And stirred for 2.5 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for a while, and further saturated aqueous sodium hydrogen carbonate was added and stirred. Extraction was performed with a mixed solution of chloroform / methanol [= 10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of (2R) -benzoyloxymethyl- (5R) -benzyloxymethylpyrrolidine.
A crude solution of (2R) -benzoyloxymethyl- (5R) -benzyloxymethylpyrrolidine in dichloromethane (500 ml) was added to Boc ₂ O (23.4 g, 107 mml), triethylamine (12.9 ml, 92.7 mmol) and DMAP ( 4.36 g, 35.7 mmol) was added and stirred for 15 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (SiO ₂ 500 g, ethyl acetate: n-hexane = 1: 5 v / v) to give the title compound [8.8 g, 29% (2 steps)] was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.39-1.61 (9H, m), 1.80-2.35 (3H, m), 3.32-3.39 (1H, m), 3.51-3.75 (2H, m), 3.88-4.34 ( 2H, m), 4.35-4.67 (4H, m), 7.22-7.57 (8H, m), 7.99-8.05 (2H, m).
MS (ESI) m / z: 426 (M ⁺ +1).

(Process 6)
Synthesis of 1-tert-butoxycarbonyl- (2R) -benzyloxymethyl- (5R) -hydroxymethylpyrrolidine
1-tert-Butoxycarbonyl- (2R) -benzoyloxymethyl- (5R) -benzyloxymethylpyrrolidine (8.80 g, 20.68 mmol) in tetrahydrofuran / methanol (60 ml / 60 ml) mixed solution at room temperature with 1 N Aqueous sodium hydroxide (60 ml) was added and stirred for 18 hours. The reaction mixture was concentrated and extracted with ether. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 30% -80%), and the title compound (6.24 g, 94%) was purified. Obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.41 and 1.44 (total 9H, each s, amide isomers), 1.79-2.01 (2H, m), 2.07-2.15 (1H, m), 3.36 (1H, t, J = 8.5 Hz), 3.48-3.76 (3H, m), 3.90-4.08 (2H, m), 4.23 (1H, dd, J = 7.6, 2.9 Hz), 4.47-4.56 (3H, m), 7.27-7.39 (5H , m).
MS (ESI) m / z: 322 (M ⁺ +1).

(Process 7)
Synthesis of 4- [1-tert-butoxycarbonyl- (5R) -benzyloxymethyl- (2R) -pyrrolidinylmethoxy] benzoic acid ethyl ester
1-tert-Butoxycarbonyl- (2R) -benzyloxymethyl- (5R) -hydroxymethylpyrrolidine (6.24 g, 19.41 mmol), p-hydroxybenzoic acid ethyl ester (4.84 g, 29.1 mmol) and triphenylphosphine (7.64 g, 29.1 mmol) in tetrahydrofuran (200 ml) was added dropwise diisopropyl azodicarboxylate (6.04 ml, 29.1 mmol) at 0 ° C. over 5 minutes and stirred at 70 ° C. for 1.5 hours. The reaction solution was returned to room temperature and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ 200 g, ethyl acetate: n-hexane = 1: 3 v / v) followed by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = (8% -60%) and the title compound (7.69 g, 85%) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.54 (9H, s), 1.90-2.20 (4H, m), 3.35 (1H, t, J = 8.1 Hz), 3.53-3.62 (1H, m), 3.81-4.22 (3H, m), 4.22-4.41 (3H, m), 4.44-4.60 (2H, m), 6.89-6.98 (2H, m), 7.27-7.34 (5H , m), 7.94-8.01 (2H, m).
MS (ESI) m / z: 470 (M ⁺ +1).

(Process 8)
Synthesis of 4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] benzoic acid ethyl ester
4- [1-tert-Butoxycarbonyl- (5R) -benzyloxymethyl- (2R) -pyrrolidinylmethoxy] benzoic acid ethyl ester (7.69 g, 16.4 mmol) and 10% palladium hydroxide on carbon (3.5 g) The ethanol suspension (100 ml) was stirred at room temperature for 3 days under a hydrogen atmosphere of 1 atm. After deaeration, the catalyst was removed by filtration and the reaction mixture was concentrated. The obtained residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 30% -60%) to obtain the title compound (5.10 g, 82%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 1.97-2.26 (4H, m), 3.54-3.80 (2H, m), 3.93 (1H , t, J = 9.8 Hz), 4.00-4.29 (5H, m), 6.91 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 380 (M ⁺ +1).

(Process 9)
Synthesis of 4-[(5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] benzoic acid ethyl ester trifluoroacetate
Triethyl 4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] benzoic acid ethyl ester (5.10 g, 13.4 mmol) in dichloromethane (50 ml) at room temperature. Fluoroacetic acid (10 ml) was added and stirred for 15 hours. The reaction mixture was concentrated to give the title compound as a brown oil. This compound was used in the next reaction without further purification.

(Process 10)
4-[(5R) -Hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Synthesis of trifluoroacetate
4-[(5R) -Hydroxymethyl- (2R) -pyrrolidinylmethoxy] benzoic acid ethyl ester trifluoroacetate (13.4 mmol), 5% rhodium alumina (1.0 g) and acetic acid (10 ml) in ethanol suspension The solution (50 ml) was stirred at room temperature for 1 day under a hydrogen atmosphere of 10 atm. After degassing, the catalyst was removed by filtration, and the reaction mixture was concentrated to give the title compound as a brown oil. This compound was used in the next reaction without further purification.

(Process 11)
Synthesis of 4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
4-[(5R) -Hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester To a dioxane solution (200 ml) of trifluoroacetate (13.4 mmol) was added saturated aqueous sodium bicarbonate (100 ml). Stir for 23 hours. The insoluble material was filtered off and extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 30% to 100%), and the title compound [4.15 g, 80% (3 teps )] As a colorless oil. This compound was used in the next reaction without further purification.
MS (ESI) m / z: 386 (M ⁺ +1).

(Process 12)
Synthesis of cis-4-[(5R) -benzyloxymethoxymethyl-1-tert-butoxycarbonyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
To a solution of 4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (CH926201) (4.15 g, 10.77 mmol) in dichloromethane (100 ml), Under a nitrogen atmosphere, diisopropylethylamine (5.63 ml, 32.3 mmol) and benzyloxymethyl chloride (2.24 ml, 16.15 mmol) were added at room temperature and stirred for 3 days. The reaction mixture was poured into water and extracted with dichloromethane. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 20%) to give the title compound (1.76 g, 32%) as a colorless oil. Got as. Also, 2.75 g was obtained as an isomer mixed fraction containing more trans-isomer than the further stream.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 1.44 and 1.45 (total 9H, each s, amide isomers), 1.45-1.54 (2H, m), 1.58-1.70 (2H , m), 1.72-1.96 (4H, m), 1.96-2.23
(2H, m), 2.26-2.38 (2H, m), 3.16-3.61 (4H, m), 3.63-4.05 (4H, m), 4.08-4.17 (2H, m), 4.54-4.64 (2H, m) , 4.69-4.78 (2H, m), 7.18-7.38 (5H, m).
MS (ESI) m / z: 505 (M ⁺ +1).

(Process 13)
Synthesis of cis-4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester cis-4-[(5R) -benzyloxymethoxymethyl-1 -tert-butoxycarbonyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.76 g, 3.48 mmol) and 10% palladium hydroxide on carbon (1.0 g) in ethanol suspension (100 ml) Stir for 18 hours at room temperature under atmosphere. After deaeration, the catalyst was removed by filtration and the reaction mixture was concentrated. The obtained residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 50%) to obtain the title compound (1.51 g, 100%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.28 (4H, m), 1.45-1.49 (11H, m), 1.60-1.71 (2H, m), 1.73-2.02 (5H, m), 2.09-2.45 ( 2H, m), 3.22-3.77 (5H, m), 3.80-4.07 (2H, m), s4.12 (2H, q, J = 7.1 Hz), 4.31 (1H, dd, J = 7.5, 3.1 Hz) .
MS (ESI) m / z: 386 (M ⁺ +1).

(Process 14)
Synthesis of cis-4- [1-tert-butoxycarbonyl- (5R) -formyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Oxalyl chloride (1.03 ml, 11.75 mmol) in dichloromethane (20 ml ), A dichloromethane solution (5 ml) of dimethyl sulfoxide (1.67 ml, 23.5 mol) was added dropwise over 5 minutes at −78 ° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 35 minutes. To this reaction mixture, cis-4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.51 g, 3.92 mmol) in dichloromethane (15 ml ) Was added dropwise over 10 minutes, and the mixture was stirred for 1 hour while gradually warming to -40 ° C. Triethylamine (4.91 ml, 35.25 mmol) was added dropwise at −40 ° C., and the mixture was stirred for 1 hour while raising the temperature to −10 ° C. A saturated aqueous ammonium chloride solution was added to the reaction solution and stirred for a while, followed by extraction with chloroform. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 20% -40%) to give the title compound (0.96 g, 64%). Obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.30 (4H, m), 1.41 and 1.48 (total 9H, each s, amide isomers), 1.59-2.05 (8H, m), 2.13-2.41 (1H, m) , 3.31-3.53 (3H, m), 3.62 (1H, dd, J = 9.4, 5.8 Hz), 3.98-4.22 (4H, m), 4.29 (1H, d, J = 9.3 Hz), 4.70 (1H, d , J = 6.9 Hz), 9.53 and 9.59 (total 1H, d, J = 2.5 and 1.7 Hz respectively, amide isomers).
MS (ESI) m / z: 406 (M ⁺ + Na).

(Process 15)
Synthesis of cis-4- [1-tert-butoxycarbonyl- (5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester cis-4- [1- tert-Butoxycarbonyl- (5R) -formyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (960 mg, 2.50 mmol) and N, O-dimethylamine hydrochloride (611 mg, 6.26 mmol) in dichloroethane To the solution (50 ml), sodium triacetoxyborohydride (2.65 g, 12.5 mmol) was added and stirred for 17 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and stirred for a while, followed by extraction with dichloromethane. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 30% -60%) to obtain the title compound (0.74 g, 69%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.15-1.32 (5H, m), 1.46 and 1.46 (total 9H, each s, amide isomers), 1.49-1.69 (4H, m), 1.69-2.15 (7H, m) , 2.22-2.50 (2H, m), 2.57 and 2.59 (total 3H, each s, amide isomers), 2.71-3.03 (1H, m), 3.14-3.57 (5H, m), 3.71-4.00
(2H, m), 4.12 (2H, q, J = 7.2 Hz).
MS (ESI) m / z: 429 (M ⁺ +1).

(Process 16)
Cis-4-[(5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride synthesis cis-4- [1-tert-butoxycarbonyl- (5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (740 mg, 1.73 mmol) was dissolved in 4 N hydrochloric dioxane solution (20 ml), Stir at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil. This compound was used in the next reaction without further purification.
MS (ESI) m / z: 329 (M ⁺ +1).

(Process 17)
Cis-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl )-(2R) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetic acid (550mg, 1.73mmol), cis-4-[(5R)-(N, O-dimethylhydroxyl Aminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride (690 mg, 1.73 mmol), EDC · HCl (500 mg, 2.60 mmol) and HOBt (350 mg, 2.60 mmol) in DMF (20 ml) was added with triethylamine (1.21 ml, 8.65 mmol) at room temperature and stirred for 3 days. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined extracts were washed in order with ice water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 50%, Biotage 40M, ethyl acetate / n-hexane = 40% -70%), and the title compound (810 mg, 75%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.33 (5H, m), 1.32-1.92 (6H, m), 1.92-2.18 (3H, m), 2.20-2.46 (4H, m), 2.50-2.69 ( 4H, m), 2.81 and 3.10 (total 1H, d and dd, J = 13.0 and 12.0, 1.7 Hz respectively, amide isomers), 3.31-3.60 (6H, m), 3.70-4.00 (2H, m), 4.05- 4.32 (5H, m), 6.74 (1H, td, J = 8.2, 2.6 Hz), 7.09-7.25 (4H, m), 8.02-8.11 (1H, m).
MS (FAB) m / z: 629 (M ⁺ +1).
HR-MS (FAB). Calcd for C ₃₃ H ₄₃ F- ₂ N ₄ O ₆ : 629.3151. Found: 629.3127.

(Process 18)
Cis-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl )-(2R) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid cis-4- [1-[[2- (5-fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] Acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (810 mg, 1.29 mmol) in tetrahydrofuran / methanol (4 ml / 2 1N aqueous sodium hydroxide solution (2 ml) was added to room temperature and stirred for 2 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 4 with 1 N hydrochloric acid and extracted with a chloroform / methanol mixed solution [10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. Distilled off the solvent under reduced pressure and purified by thin layer chromatography (ethyl acetate / n-hexane / acetic acid = 150/50/1 v / v) to give the title compound (730 mg) as a colorless oil. The title compound (547 mg, 71%) was obtained as a colorless glassy solid by lyophilization from dioxane.
¹ H-NMR (CDCl ₃ ) δ: 1.34-2.18 (12H, m), 2.18-2.64 (9H, m), 2.80 (1H, d, J = 12.7 Hz), 3.31-3.55 (5H, m), 3.60 (1H, dd, J = 9.3, 5.9 Hz), 3.75-3.99 (2H, m), 4.10-4.31 (2H, m), 6.75 (1H, td, J = 8.2, 2.6 Hz), 7.10-7.19 (3H , m), 7.87-7.81 (1H, m).
MS (FAB) m / z: 601 (M ⁺ +1)
IR (ATR) cm ^-1 : 2939, 2862, 1701, 1639, 1610, 1576, 1550.
Anal.Calcd for C ₃₁ H ₃₈ F ₂ N ₄ O ₆・ 0.75H ₂ O: C, 60.62; H, 6.48; F, 6.19; N, 9.12.
Found: C, 60.79; H, 6.49; F, 5.95; N, 8.70.

Example 106b
Trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl )-(2R) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid (Step 1)
Synthesis of trans-4-[(5R) -benzyloxymethoxymethyl-1-tert-butoxycarbonyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester obtained in Example 106a, (Step 12) 4-[(5R) -Benzyloxymethoxymethyl-1-tert-butoxycarbonyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (cis / trans mixed fraction) (2.75 g, 5.44 mmol) in DMF To the solution (30 ml), 60% sodium hydride (566 mg, 14.1 mmol) and ethanol (0.76 ml, 13.1 mmol) were added at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours while gradually returning to room temperature. Water (0.137 ml, 7.62 mmol) was added to the reaction solution and stirred for 19 hours. Furthermore, potassium carbonate (3.76 g, 27.2 mmol) and ethyl iodide (2.18 ml, 27.2 mmol) were added to the reaction solution, and the mixture was stirred for 20 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined reaction solution was washed with ice water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was obtained and purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 20%-) together with a separately synthesized product (CH926703) containing the desired product. 30%) and the title compound (1.69 g) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.17-1.31 (5H, m), 1.44 and 1.46 (total 9H, each s, amide isomers), 1.47-1.60 (4H, m), 1.81-2.11 (6H, m) , 2.14-2.29 (1H, m), 3.00-4.05 (7H, m), 4.07-4.15 (2H, m), 4.55-4.63 (2H, m), 4.68-4.78 (2H, m), 7.23-7.40 ( 5H, m).
MS (ESI) m / z: 528 (M ⁺ +1).

(Process 2)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester trans-4-[(5R) -benzyloxymethoxymethyl-1 -tert-Butoxycarbonyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.69 g, 3.34 mmol) and 10% palladium hydroxide on carbon (800 mg) in ethanol suspension (50 ml) The mixture was stirred at room temperature for 20 hours under an atmosphere. After deaeration, the catalyst was removed by filtration and the reaction mixture was concentrated. The obtained residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 40%) to obtain the title compound (1.38 g, 100%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.16-1.33 (5H, m), 1.38-1.54 (11H, m), 1.72-2.32 (7H, m), 3.12-3.38 (2H, m), 3.37-3.76 ( 3H, m), 3.76-4.06 (3H, m), 4.12 (2H, q, J = 7.1 Hz), 4.27 (1H, dd, J = 7.4, 2.5 Hz).
MS (ESI) m / z: 386 (M ⁺ +1).

(Process 3)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5R) -formyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester Oxalyl chloride (0.92 ml, 10.74 mmol) in dichloromethane (30 ml ) Was added dropwise a dichloromethane solution (10 ml) of dimethyl sulfoxide (1.52 ml, 21.48 mol) at −78 ° C. in a nitrogen atmosphere over 5 minutes, and the mixture was stirred at the same temperature for 35 minutes. To this reaction solution was added trans-4- [1-tert-butoxycarbonyl- (5R) -hydroxymethyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (1.38 g, 3.58 mmol) in dichloromethane (15 ml ) Was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes while gradually warming to -40 ° C. Triethylamine (4.49 ml, 32.22 mmol) was added dropwise at -20 ° C, and the mixture was stirred for 40 minutes while raising the temperature to -5 ° C. A saturated aqueous ammonium chloride solution was added to the reaction solution and stirred for a while, followed by extraction with chloroform. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 20% -50%) to give the title compound (0.53 g, 39%). Obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.31 (5H, m), 1.37-1.69 (11H, m), 1.76-2.09 (7H, m), 2.12-2.35 (2H, m), 3.16-3.27 ( 1H, m), 3.36-3.44 (1H, m), 3.44-3.68 (2H, m), 4.08-4.16 (3H, m), 9.52 and 9.59 (total 1H, each d, J = 2.5 and 1.7 Hz respectively, amide isomers).
MS (ESI) m / z: 384 (M ⁺ +1).

(Process 4)
Synthesis of trans-4- [1-tert-butoxycarbonyl- (5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester trans-4- [1- tert-Butoxycarbonyl- (5R) -formyl- (2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (530 mg, 1.38 mmol) and N, O-dimethylamine hydrochloride (337 mg, 3.46 mmol) in dichloroethane To the solution (30 ml), sodium triacetoxyborohydride (1.46 g, 6.90 mmol) was added and stirred for 2 days. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and stirred for a while, followed by extraction with dichloromethane. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40S, ethyl acetate / n-hexane = 20% -60%) to obtain the title compound (0.40 g, 68%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.14-1.33 (5H, m), 1.39-1.54 (11H, m), 1.88-2.51 (9H, m), 2.57 and 2.59 (total 3H, each s, amide isomers) , 2.82 (1H, d, J = 11.8 Hz), 3.15-3.30 (2H, m), 3.33-3.53 (4H, m), 3.60 and 3.68 (total 1H, each dd, J = 9.3, 2.7 and 9.1, 2.9 Hz respectively, amide isomers), 3.95-4.02 (2H, m), 4.07-4.16 (2H, m).
MS (ESI) m / z: 429 (M ⁺ +1).

(Process 5)
Trans-4-[(5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride synthesis trans-4- [1-tert-butoxycarbonyl- (5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (400 mg, 0.933 mmol) was dissolved in 4 N hydrochloric dioxane solution (20 ml) Stir at room temperature for 4 days. The reaction solution was concentrated under reduced pressure to obtain a mixture containing the title compound. (Because it was partially hydrolyzed) It was added to the reaction solution separately prepared from ethanol (50 ml) and thionyl chloride (5 ml) and stirred for 7 hours. . The reaction solution was concentrated to obtain the title compound as a colorless solid, which was subsequently subjected to the next reaction.
MS (ESI) m / z: 329 (M ⁺ +1).

(Process 6)
Trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl )-(2R) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester
[7-Fluoro-2- (5-fluoro-2-methylphenylamino) -6-benzoxazolyl] acetic acid (300 mg, 0.93 mmol), trans-4-[(5R)-(N, O-dimethylhydroxyl Aminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester hydrochloride (370 mg, 0.93 mmol), EDC · HCl (270 mg, 1.40 mmol) and HOBt (190 mg, 1.40 mmol) in DMF (10 ml) was added with triethylamine (0.65 ml, 4.67 mmol) at room temperature and stirred for 22 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined extracts were washed in order with ice water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40M, ethyl acetate / n-hexane = 30% -70%) to obtain the title compound (600 mg, over yield) as a colorless glassy solid.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.58 (7H, m), 1.87-2.47 (12H, m), 2.50-2.64 (4H, m), 2.81 (1H, d, J = 12.7 Hz), 3.04 -3.31 (1H, m), 3.33-3.59 (5H, m), 3.65-3.99 (2H, m), 4.03-4.31 (4H, m), 6.74 (1H, td, J = 8.2, 2.5 Hz), 7.06 -7.38 (4H, m), 8.01-8.12 (1H, m).
IR (ATR) cm ^-1 : 2937, 2862, 1726, 1637, 1610, 1576, 1550.
Anal.Calcd for C ₃₃ H ₄₂ F ₂ N ₄ O ₆・ 0.25H ₂ O: C, 62.59; H, 6.77; F, 6.00; N, 8.85.
Found: C, 62.61; H, 6.86; F, 6.01; N, 8.87.
MS (FAB) m / z: 629 (M ⁺ +1).
HR-MS (FAB) .Calcd for C ₃₃ H ₄₃ F- ₂ N ₄ O ₆ : 629.3151.
Found: 629.3177.

(Process 7)
Trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl )-(2R) -Pyrrolidinylmethoxy] cyclohexanecarboxylic acid trans-4- [1-[[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] Acetyl]-(5R)-(N, O-dimethylhydroxylaminomethyl)-(2R) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid ethyl ester (600 mg, 0.95 mmol) in tetrahydrofuran / methanol (4 ml / 2 1N aqueous sodium hydroxide solution (2 ml) was added to room temperature and stirred for 2 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 4 with 1 N hydrochloric acid and extracted with a chloroform / methanol mixed solution [10/1 (v / v)]. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (ethyl acetate / n-hexane / acetic acid = 150/50 / 1v / v) to obtain the title compound (432 mg) as a colorless oil. The title compound (425 mg, 75%) was obtained as a colorless glassy solid by lyophilization from dioxane.
¹ H-NMR (CDCl ₃ ) δ: 1.00-1.58 (4H, m), 1.89-2.27 (10H, m), 2.29 and 3.32 (total 3H, each s, amide isomers), 2.52-2.65 (4H, m) , 2.79 (1H, d, J = 13.0 Hz), 3.01-3.30 (1H, m), 3.34-4.04 (8H, m), 4.09-4.30 (2H, m), 6.73-6.81 (1H, m), 7.10 -7.23 (3H, m), 7.76-7.90 (1H, m).
MS (FAB) m / z: 601 (M ⁺ +1)
IR (ATR) cm ^-1 : 2935, 2861, 1724, 1701, 1639, 1610, 1577, 1550.
Anal.Calcd for C ₃₁ H ₃₈ F ₂ N ₄ O ₆・ H ₂ O: C, 60.18; H, 6.52; F, 6.14; N, 9.06.
Found: C, 60.17; H, 6.37; F, 5.83; N, 8.85.

Example 107
2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid (step 1)
Synthesis of 7-fluoro-2-mercapto-6-benzoxazoleacetic acid methyl ester [Method A: Synthesis method using O-ethyl potassium dithiocarbonate]
To a solution of 4-amino-2-fluoro-3-hydroxyphenylacetic acid methyl ester (13.2 g, 66.2 mmol) in pyridine (130 ml) was added O-ethyl potassium dithiocarbonate (11.7 g, 73.2 mmol), Heated to reflux for 2 hours. The reaction solution is cooled to room temperature, poured into a 10% aqueous hydrochloric acid solution under ice-cooling (about pH = 2.0), the reaction mixture is stirred for 0.5 hours, the precipitated crystals are collected by filtration, washed with water, dried and dried. Product (15.8 g, 99%) was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.62 (3 H, s), 3.82 (2 H, s), 703 (1 H, d, J = 7.2 Hz), 7.25 (1 H, t, J = 7.2 Hz).
MS (LC-ESI) m / z: 242 (M + H) ⁺ .
[Method B: Synthesis Method Using Carbon Disulfide]
Methanol (5 ml) and sodium methoxide (814 mg, 15.1 mmol) were added to a screw tube (glass tube and plastic cap; 20 ml), and carbon disulfide (1) (453 μl, 7.53 mmol) was added at 0 ° C. And stirred for 5 minutes. 4-Amino-2-fluoro-3-hydroxyphenylacetic acid methyl ester (1 g, 5.02 mmol) was added as a powder. The reaction solution was stirred at room temperature for 10 minutes, sealed, and heated and stirred at 95 ° C. for 30 minutes. The reaction solution was returned to room temperature, 5 ml of methanol was added, concentrated sulfuric acid (1.5 ml) was gradually added under ice-cooling and stirring, and the mixture was acidified and stirred again at 95 ° C. for 5 minutes in a sealed tube. The reaction solution is allowed to cool and then poured into ice (20 ml) and 1N aqueous hydrochloric acid (20 ml) with ice-cooling. The precipitated crystals are collected by filtration and dried to give 1.0 g (83%) of the desired product as white crystals. Obtained as a powder. The behavior of the compound obtained here in TLC and various instrument spectral data were completely in agreement with the standard obtained in the above [Method A].

(Process 2)
Synthesis of 2-chloro-7-fluoro-6-benzoxazoleacetic acid methyl ester [Method C: Synthesis method using thionyl chloride as a solvent]
7-Fluoro-2-mercapto-6-benzoxazoleacetic acid methyl ester (15 g, 62.2 mmol) was dissolved in thionyl chloride (100 ml), and then a catalytic amount of N, N-dimethylformamide (a few drops) was added. The mixture was stirred at an internal temperature of 70 to 73 ° C. for 4 hours. After cooling, the reaction solution was dried under reduced pressure. Toluene (100 ml × 3 times) was added to the residue and reconcentrated to dryness to obtain a residue (23.4 g). The residue was purified by column chromatography using silica gel. The main effluent fraction obtained from the eluate of n-hexane: ethyl acetate (4: 1, v / v) was concentrated under reduced pressure and then dried under reduced pressure to give the title ( 8.4 g, 55.7%) was obtained as a pale yellow crystalline solid.
¹ H-NMR (DMSO-d ₆ ) δ: 3.63 (3 H, s), 3.91 (2 H, d, J = 1.4 Hz), 7.40 (1 H, dd, J = 6.6 and 8.3 Hz), 7.55 ( (1 H, d, J = 8.3 Hz).
MS (LC-ESI) m / z: 244 [(M + H) ⁺ , ³⁵ Cl], 246 [(M + H) ⁺ , ³⁷ Cl].

[Method D: Synthesis method using toluene as a solvent]
Thionyl chloride (42 ml, 580.8 mmol) in 7-fluoro-2-mercapto-6-benzoxazole acetic acid methyl ester (46.7 g, 193.6 mmol) and toluene (2 l) with stirring at room temperature over about 5 minutes It was dripped. After completion of the dropwise addition, a catalytic amount of N, N-dimethylformamide (a few drops) was added to the reaction solution, followed by stirring at an internal temperature of 55 to 75 ° C. for 3 hours. After cooling, the reaction solution was dried under reduced pressure. Toluene (500 ml × 2 times) was added to the residue, and it was re-concentrated to dryness to obtain a residue (54 g). The residue was purified by column chromatography using silica gel, and the main effluent fraction obtained from the eluate of n-hexane: ethyl acetate (4: 1, v / v) was concentrated under reduced pressure and then dried under reduced pressure. 31.4 g, 66.5%) was obtained as a pale yellow crystalline solid. The behavior of the compound obtained here in TLC and various instrument spectral data were completely in agreement with the standard obtained in the above [Method C].

(Process 3)
Synthesis of [2- (5-fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester 2-Chloro-7-fluoro-6-benzoxazole acetic acid methyl ester (9.90 g , 40.6 mmol) and 5-fluoro-2-methylaniline (15.3 g, 122 mmol) in THF (100 ml) are heated to reflux with stirring for 20 hours. The reaction mixture is cooled to room temperature, made weakly acidic by adding 1N HCl, and extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was solidified by adding n-hexane / ethyl acetate, and the crystalline powder was collected by filtration under reduced pressure and dried to give the title compound (11.58 g, 86%) as a white crystalline powder. Further, the filtrate after the above crystal filtration is dried under reduced pressure. The obtained residue was purified by column chromatography using silica gel, and the n-hexane: ethyl acetate (5: 1 to 1: 1, v / v) stream was concentrated under reduced pressure, and n-hexane / ethyl acetate was added to the residue. The solid was added and solidified, and the crystalline powder was collected by filtration under reduced pressure and dried to obtain the title product (1.06 g), which was combined with the previous crystalline powder to obtain the title product (12.64 g, 94%).
¹ H NMR (CDCl ₃ ) δ: 2.32 (s, 3 H), 3.72 (s, 3 H), 3.76 (s, 2 H), 6.75 (dt, J = 8.1, 2.7 Hz, 1 H), 6.87 ( br, 1 H), 7.11 (t, J = 6.6 Hz, 1 H), 7.15 (t, J = 6.9 Hz, 1 H), 8.11 (dd, J = 11.0, 6.7 Hz, 1 H).
MS (ESI) m / z: 333 (M + H) ⁺ .

(Process 4)
Synthesis of 2- (5-fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid
[2- (5-Fluoro-2-methylphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester (12.64 g, 38 mmol) was added to THF (80 ml) and 1N NaOH (76 ml, 76 mmol). ) And stirred at room temperature for 2 hours. The reaction mixture is poured into 1N HCl (85 ml, 85 mmol) with ice-cooling. The precipitated crystals are collected by filtration under reduced pressure, and the crude crystals are dissolved in ethyl acetate (300 ml), washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was solidified by adding methanol / chloroform / ether / n-hexane, and after drying, the title product (11.5 g, 95%) was obtained as a pale purple crystalline powder.
¹ H NMR (DMSO) δ: 2.29 (s, 3 H), 3.68 (s, 2 H), 6.89 (dt, J = 7.0, 1.7 Hz, 1 H), 7.14 (t, J = 6.4 Hz, 1 H ), 7.20 and 7.22 (each s, total 1 H, amide isomers), 7.25 (t, J = 7.4 Hz, 1 H), 7.90 (d, J = 11.3 Hz, 1H), 10.06 (br, 1H).
MS (ESI) m / z: 319 (M + H) ⁺ .
Anal.Calcd for C ₁₆ H ₁₂ F ₂ N ₂ O ₃ : C, 60.38; H, 3.80; N, 8.80.
Found: C, 60.23; H, 3.78; N, 8.59.

Example 107a
[2- (5-Fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid (step 1)
Synthesis of [2- (5-fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7 -The title product (2.55 g, 89%) was obtained as a white powder by using -fluoro-6-benzoxazole acetic acid methyl ester and 5-fluoro-2-methoxyaniline.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.63 (3 H, s), 3.82 (2 H, s), 3.84 (3 H, s), 6.88 (1 H, dt, J = 8.6, 3.0 Hz), 7.06 (1 H, dd, J = 8.6, 5.0 Hz), 7.17 (1 H, t, J = 8.0 Hz), 7.27 (1 H, d, J = 8.0 Hz), 8.15 (1 H , dd, J = 10.0, 3.0 Hz), 10.18 (1 H, s).
MS (ESI) m / z: 349 (M + H) ⁺ .

(Process 2)
Synthesis of [2- (5-fluoro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid In a manner similar to Example 107 (Step 3), [2- (5-Fluoro 2-Methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester gave the title product (1.13 g, 98%) as a white powder.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.70 (2 H, s), 3.84 (3 H, s), 6.88 (1 H, dt, J = 8.6, 3.0 Hz), 7.06 (1 H, dd, J = 8.6, 5.0 Hz), 7.15 (1 H, t, J = 8.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 8.16 (1 H, dd, J = 10.0, 3.0 Hz), 10.17 (1 H, s), 12.47 (1 H, br s).
IR (ATR) cm ^-1 : 3326, 1704, 1646, 1587, 1511.
MS (FAB) m / z: 335 (M + H) ⁺ .

Example 107b
[2- (3-Fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid (step 1)
Synthesis of [2- (3-Fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7 The title compound (730 mg, 2.10 mmol, 85%) was obtained as a colorless solid by using -fluoro-6-benzoxazoleacetic acid methyl ester and 3-fluoro-4-methoxyaniline.
MS (ESI) m / z: 349 (M + H) ⁺ .

(Process 2)
Synthesis of [2- (3-Fluoro-4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid In a manner analogous to Example 107 (Step 4), [2- (3-Fluoro -4-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester and the reaction mixture was evaporated to dryness [2- (3-fluoro-4-methoxyphenylamino)- The sodium salt of 7-fluoro-6-benzoxazolyl] acetic acid was obtained as a colorless solid. This compound was used in the next reaction without further purification.

Example 107c
[7-Fluoro-2- (2,5-dimethylphenylamino) -6-benzoxazolyl] acetic acid (Step 1)
Synthesis of [7-fluoro-2- (2,5-dimethylphenylamino) -6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7-fluoro The title product (870 mg, 2.65 mmol, 81%) was obtained as a colorless solid by using -6-benzoxazoleacetic acid methyl ester and 2,5-dimethylaniline.
MS (ESI) m / z: 329 (M + H) ⁺ .

(Process 2)
[7-Fluoro-2- (2,5-dimethylphenylamino) -6-benzooxazolyl] acetic acid [7-Fluoro-2- (2,5 -Dimethylphenylamino) -6-benzoxazolyl] acetic acid methyl ester was used to dry the reaction mixture to give the title sodium salt as a colorless solid. This compound was used in the next reaction without further purification.

Example 107d
[7-Fluoro-2- (2,5-difluorophenylamino) -6-benzoxazolyl] acetic acid (Step 1)
Synthesis of [7-Fluoro-2- (2,5-difluorophenylamino) -6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7-fluoro The title product (1.21 g, 3.60 mmol, 73%) was obtained as a colorless solid by using -6-benzoxazole acetic acid methyl ester and 2,5-dimethylaniline.
MS (ESI) m / z: 337 (M + H) ⁺ .

(Process 2)
Synthesis of [7-Fluoro-2- (2,5-difluorophenylamino) -6-benzoxazolyl] acetic acid In a manner similar to Example 107 (Step 4), [7-Fluoro-2- (2 , 5-Difluorophenylamino) -6-benzoxazolyl] acetic acid methyl ester, and the reaction mixture was evaporated to give the title sodium salt as a colorless solid. This compound was used in the next reaction without further purification.

Example 107e
[2- (4-Chlorophenylamino) -6-benzoxazolyl] acetic acid methyl ester 2-Chloro-6-benzoxazole acetic acid methyl ester synthesized in a similar manner to Example 107 (Step 2) The title product (500 mg, 1.58 mmol, 74%) was obtained as a colorless amorphous powder by carrying out the same procedure as in [Step 3] of Example 107) using 4-chloroaniline.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.70 (2 H, s), 3.71 (3 H, s), 7.10-7.20 (1 H, m), 7.25-7.45 (5 H, m), 7.50 -7.60 (2 H, m).
IR (ATR) cm ^-1 : 2921, 2852, 1731, 1671, 1573, 1486, 1434, 1240, 1139, 1093, 1010,975, 821, 802.
MS (FAB) m / z: 317 [(M + H) ⁺ , Cl ³⁵ ], 319 [(M + H) ⁺ , Cl ³⁷ ].
HRMS (FAB) Calcd for C ₁₆ H ₁₄ ClN ₂ O ₃ : 317.0693. Found: 317.0679.

(Process 2)
Synthesis of [2- (4-chlorophenylamino) -6-benzoxazolyl] acetic acid In a manner similar to Example 107, (Step 4), [2- (4-chlorophenylamino) -6-benzoxazolyl ] By using acetic acid methyl ester, the title product (476 mg, 1.57 mmol, 99%) was obtained as a pale yellow amorphous powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.64 (2 H, s), 7.12 (1 H, d, J = 8.3 Hz), 7.30-7.45 (4 H, m), 7.78 (2H, d, J = 8.8 Hz), 10.76 (1 H, s), 12.31 (1 H, s).
IR (ATR) cm ^-1 : 3073, 1681, 1575, 1492, 1265, 1243, 1091, 985, 819, 804.
MS (FAB) m / z: 303 [(M + H) ⁺ , Cl ³⁵ ], 305 [(M + H) ⁺ , Cl ³⁷ ].
HRMS (FAB) Calcd for C ₁₅ H ₁₂ ClN ₂ O ₃ : 303.0536. Found: 303.0541.

Example 107f
[7-Fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl] acetic acid (Step 1)
Synthesis of [7-fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7-fluoro-6 -Using benzoxazole acetic acid methyl ester and 4-fluoroaniline gave the title product (0.370 g, 95%) as a white powder.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.63 (3 H, s), 3.81 (2 H, s), 7.15 (1 H, t, J = 8.0 Hz), 7.20-7.25 (3 H, m), 7.73 (2 H, dd, J = 9.2, 4.9 Hz), 10.90 (1 H, br s).
MS (ESI) m / z: 319 (M + H) ⁺ .

(Process 2)
Synthesis of [7-fluoro-2- (4-fluorophenylamino) -6-benzoxazolyl] acetic acid In a manner similar to Example 107, (Step 4), [7-Fluoro-2- (4-fluoro Phenylamino) -6-benzoxazolyl] acetic acid methyl ester gave the title product (0.332 g, 94%) as a white powder.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.69 (2 H, s), 7.14 (1 H, t, J = 8.0 Hz), 7.20-7.25 (3 H, m), 7.73 (2 H, dd, J = 9.2, 4.9 Hz), 10.88 (1 H, br s), 12.50 (1 H, br s).
IR (ATR) cm ^-1 : 3072, 1685, 1654, 1592, 1508.
MS (FAB) m / z: 305 (M + H) ⁺ .

Example 107g
[2- (4-Chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid (Step 1)
Synthesis of [2- (4-Chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7 -The title compound (0.367 g, 82%) was obtained as a purple powder by using -fluoro-6-benzoxazole acetic acid methyl ester and 4-chloro-2-methoxyaniline.
¹ H NMR (400 MHz, CDCl ₃ ) δ; 3.72 (3 H, s), 3.75 (1 H, s), 3.76 (1 H, s), 3.94 (3H, s), 6.91 (1 H, d, J = 2.2 Hz), 7.04 (1 H, dd, J = 8.8, 2.2 Hz), 7.09 (1 H, t, J = 8.0 Hz), 7.24 (1 H, d, J = 8.0 Hz), 7.63 (1 H, br s), 8.35 (1 H, d, J = 8.8 Hz).
MS (ESI) m / z: 365 [(M + H) ⁺ , ³⁵ Cl], 367 [(M + H) ⁺ , ³⁷ Cl].

(Process 2)
Synthesis of [2- (4-chloro-2-methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid In a manner analogous to Example 107 (Step 4), [2- (4-chloro 2-Methoxyphenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester gave the title product (0.340 g, 96%) as a pale purple powder.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.69 (2 H, s), 3.87 (3 H, s), 7.07 (1 H, dd, J = 8.8, 2.2 Hz), 7.11-7.15 (2 H, m), 7.19 (1 H, d, J = 8.0 Hz), 8.17 (1 H, d, J = 8.8 Hz), 10.02 (1 H, br s).
IR (ATR) cm ^-1 : 3382, 1720, 1646, 1583, 1521.
MS (FAB) m / z: 351 [(M + H) ⁺ , ³⁵ Cl], 353 [(M + H) ⁺ , ³⁷ Cl].

Example 107h
[2- (4-Chlorophenylamino) -7-fluoro-6-benzoxazolyl] acetic acid (Step 1)
Synthesis of [2- (4-chlorophenylamino) -7-fluoro-6-benzoxazolyl] acetic acid methyl ester In a manner analogous to Example 107 (Step 3), 2-chloro-7-fluoro-6- The title compound (0.422 g, quantitative yield) was obtained as a white powder by using benzoxazole acetic acid methyl ester and 4-chloroaniline.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.62 (3 H, s), 3.81 (2 H, s), 7.16 (1 H, t, J = 8.0 Hz), 7.24 (1 H, d, J = 8.0 Hz), 7.43 (2 H, d, J = 8.8 Hz), 7.74 (2 H, d, J = 8.8 Hz), 11.03 (1 H, br s).
MS (ESI) m / z: 335 [(M + H) ⁺ , ³⁵ Cl], 337 [(M + H) ⁺ , ³⁷ Cl].

(Process 2)
Synthesis of [2- (4-chlorophenylamino) -7-fluoro-6-benzoxazolyl] acetic acid In a manner similar to Example 107 (Step 4), [2- (4-chlorophenylamino) -7- Fluoro-6-benzoxazolyl] acetic acid methyl ester gave the title product (0.381 g, 94%) as a white powder.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ; 3.70 (2 H, s), 7.15 (1 H, t, J = 8.0 Hz), 7.23 (1 H, d, J = 8.0 Hz), 7.43 ( 2 H, d, J = 8.8 Hz), 7.75 (2 H, d, J = 8.8 Hz), 11.02 (1 H, br s), 12.52 (1 H, br s).
IR (ATR) cm ^-1 : 3316, 1683, 1654, 1600, 1575.
MS (FAB) m / z: 321 [(M + H) ⁺ , ³⁵ Cl], 323 [(M + H) ⁺ , ³⁷ Cl].

Example 107i
[2- (3,4-Dichloroanilino) -7-fluoro-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.71 (2H, s), 7.17 (1H, t, J = 7.4 Hz), 7.29 (1H, d, J = 8.1 Hz), 7.63 (2H, s), 8.09 (1H, s), 11.24 (1H, s), 12.48 (1H, s).
MS (ESI) m / z: 355 (M ⁺ +1).

Example 107j
[2- (3,4-Dichlorophenylamino) -1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (2H, s), 7.13 (1H, dd, J = 8.1, 1.2 Hz), 7.42 (1H, s),
7.43 (1H, d, J = 5.6 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.65 (1H, dd, J = 8.8, 2.5 Hz), 8.13 (1H, d, J = 2.5 Hz), 11.02 (1H, s).
MS (ESI) m / z: 338 (M ⁺ +1).

Example 107k
[2- (3,4-Dichlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.73 (2H, s), 7.17 (1H, q, J = 5.1 Hz), 7.66 (2H, s), 8.04 (1H, s), 11.39 (1H, s ) .MS (ESI) m / z: 373 (M ⁺ +1).

Example 107l
[2- (4-Chlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.72 (2H, s), 7.15 (1H, q, J = 5.1 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 Hz), 11.19 (2H , s) .MS (ESI) m / z: 338 (M + +1).

Example 107m
[4,7-Difluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 3.70 (2H, s), 7.08-7.16 (3H, m), 7.25-7.30 (2H, m), 7.75 (1H, d, J = 7.8 Hz), 10.12 (1H, s), 12.56 (1H, s).
MS (ESI) m / z: 319 (M ⁺ +1).

Example 107n
(2-Phenylamino-1,3-benzoxazol-6-yl) acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (2H, s), 7.03 (1H, t, J = 7.4 Hz), 7.11 (1H, dd, J = 8.0, 1.6 Hz), 7.37 (4H, tt , J = 8.7, 2.7 Hz), 7.75 (2H, dd, J = 8.8, 1.0 Hz), 10.60 (1H, s), 12.33 (1H, br s).
MS (ESI) m / z: 269 (M ⁺ +1).

Example 107o
[2- (4-Fluorophenylamino) -1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (2H, s), 7.11 (1H, dd, J = 8.1, 1.5 Hz), 7.20-7.24 (2H, m), 7.36 (1H, d, J = 8.1 Hz), 7.40 (1H, d, J = 1.5 Hz), 7.75-7.79 (2H, m), 10.63 (1H, s), 12.30 (1H, s).
MS (ESI) m / z: 287 (M ⁺ +1).

Example 107p
[4-Fluoro-2- (4-fluorophenylamino) benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.67 (2H, s), 7.04 (1H, d, J = 11.0 Hz), 7.24 (2H, t, J = 8.8 Hz), 7.30 (1H, s), 7.74-7.78 (2H, m), 10.82 (1H, s), 12.42 (1H, br s).
MS (ESI) m / z: 305 (M ⁺ +1).

Example 107q
[4-Fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.66 (2H, s), 3.85 (3H, s), 7.00-7.04 (2H, m), 7.07-7.14 (2H, m), 7.26 (1H, s) , 8.09 (1H, d, J = 8.3 Hz), 9.81 (1H, s), 12.41 (1H, s).
MS (ESI) m / z: 317 (M ⁺ +1).

Example 107r
[4-Chloro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.68 (2H, s), 3.86 (3H, s), 6.91 (1H, dt, J = 2.9, 8.3 Hz), 7.09 (1H, dd, J = 8.8, 5.1 Hz), 7.23 (1H, s), 7.41 (1H, s), 8.17 (1H, dd, J = 10.9, 3.1 Hz), 10.17 (1H, s).
ESI-MS m / z: 351 (M ⁺ +1).

Example 107s
[2- (5-Chloro-2-methoxyphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetic acid The title compound was obtained in a similar manner to that of Example 107.
¹ H-NMR (DMSO-d ₆ ) δ: 3.70 (2H, d, J = 14.7 Hz), 3.87 (3H, s), 7.06 (1H, d, J = 11.3 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.12-7.15 (1H, m), 7.30 (1H, s), 8.32 (1H, d,
J = 2.2 Hz), 10.09 (1H, s). ESI-MS m / z: 351 (M ⁺ +1).

Example 107t
[2- (5-Fluoro-2-methylphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (s, 3H), 3.67 (s, 2H), 6.91 (dt, 1H, J = 3.2, 8.6 Hz), 7.04 (d, 1H, J = 11.5 Hz ), 7.26 (t, 1H, J = 7.8 Hz), 7.30 (s, 1H), 7.86 (dd, 1H, J = 11.3, 2.7 Hz), 9.99 (s, 1H) .ESI-MS m / z: 319 (M ⁺ +1).

Example 107u
[4-Fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.67 (2H, s), 3.85 (3H, s), 6.87-6.92 (1H, m), 7.03-7.10 (2H, m), 7.30 (1H, s) , 8.16 (1H, dd, J = 11.0, 2.9 Hz), 10.11 (1H, s).
ESI-MS m / z: 335 (M ⁺ +1)

Example 107v
[2- (5-Chloro-2-methoxyphenylamino) -4-methoxy-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (2H, s), 3.86 (3H, s), 3.94 (3H, s), 6.78 (1H, s), 7.03 (1H, s), 7.08 (2H , s), 7.09-7.11 (1H, m), 8.41 (1H, s).
ESI-MS m / z: 363 (M ⁺ +1)

Example 107w
[7-Chloro-2- (5-fluoro-2-methylphenylamino) benzoxazol-6-yl] acetic acid
In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H, s), 3.78 (3H, s), 6.90 (1H, td, J = 8.4, 2.8 Hz), 7.24 (2H, d, J = 7.8 Hz ), 7.26 (1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.88 (1H, dd, J = 10.7, 2.2 Hz), 10.11 (1H, br s).
ESI-MS m / z: 335 (M ⁺ +1)

Example 107x
[7-Chloro-2- (2-methoxyphenylamino) benzoxazol-6-yl] acetic acid
In the same manner as in Example 107, the title product was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 3.53 (3H, s), 3.77 (2H, s), 7.11 (1H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7.8 Hz), 7.26 (2H, d, J = 7.6 Hz), 7.26-7.32 (1H, m), 7.78 (1H, d, J = 8.3 Hz), 9.96 (1H, s), 12.44 (1H, br s).
MS (ESI) m / z: 333 (M ⁺ +1).

Example 107y
[2- (5-Chloro-2-methylphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (s, 3H), 3.67 (s, 2H), 7.04 (d, 1H, J = 11.3 Hz), 7.14 (dd, 1H, J = 8.2, 2.1 Hz ), 7.28 (d, 1H, J = 8.3 Hz), 7.30 (s, 1H), 8.03 (d, 1H, J = 2.2 Hz), 1 ¹ (s, 1H), 12.38 (br s, 1H).
ESI-MS m / z: 335 (M ⁺ +1).

Example 107z
[2- (3,4-Difluorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetic acid In the same manner as in Example 107, the title product was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 3.72 (2H, s), 7.16 (1H, q, J = 5.1 Hz), 7.42-7.52 (2H, m), 7.85 (1H, ddd, J = 13.0, 7.1, 2.5 Hz), 11.29 (1H, s), 12.58 (1H, br s).
MS (ESI) m / z: 340 (M ⁺ +1).

Example 108
(2S, 5S) -1- (tert-Butoxycarbonyl) -2,5-bis (hydroxymethyl) pyrrolidine (Step 1)
Synthesis of dimethyl-2,5-dibromoadipate Adipoid chloride (4.2 L, 28.4 mol) was placed in 10 L Kolben and heated until the internal temperature reached 80 ° C. or higher. After the temperature increase, anhydrous bromine (100 kg, 2.2 equivalents) was dropped into the reaction vessel over 10 hours. After completion of the dropwise addition, the reaction mixture was heated to reflux for 2 hours. After confirming the completion of the reaction, the reaction mixture was allowed to cool to room temperature and dropped into methanol (5.8 L) with stirring. After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature. Ethyl acetate (5.2 L, 10 times v / W) and saturated aqueous Na ₂ SO ₃ solution (26.9 L, 5 times v / W) were continuously added and stirred, and liquid separation was performed to collect the organic layer. . The collected organic layer was further washed with a saturated aqueous Na ₂ CO ₃ solution (26.9 L, 5 times v / W). The solvent of the washed organic layer was distilled off, and 7.98 Kg (yield considering content: 91%) was obtained using the above compound as a concentrated residue.

(Process 2)
Synthesis of (2S, 5S) -1-[(R) -1-phenylethyl]]-2,5-bis (methoxycarbonyl) pyrrolidine In dimethylacetamide (105 L) in reaction vessel 1, (R) -phenylethylamine (17.5 L), tetrabutylammonium bromide (2.9 kg, 10 mol%) and sodium carbonate (19.1 kg) were continuously added and stirred at 40 ° C. Dimethyl-2,5-dibromoadipate (30 kg) was dissolved in dimethylacetamide (45 L) in the reaction vessel 2 and added dropwise to the reaction vessel 1 over 7 hours. After completion of dropping, the mixture was stirred at 40 ° C. for 12 hours. After completion of the reaction, ethyl acetate (90 L) was added and collected by filtration to remove unnecessary inorganic salts. Ethyl acetate (120 L) was added, the organic layer was washed twice with water (150 L), and the solvent was distilled off. After distilling off the solvent, 1N-hydrochloric acid (150 L) and ethyl acetate (60 L) were added, and a liquid separation operation was performed. The organic layer was washed with 1N HCl (60 L), and the hydrochloric acid layers were combined. IPE (150 L) was added to the combined hydrochloric acid layer, and neutralized with sodium carbonate so that the pH of the water tank became 7.0 to 8.0. After neutralization, the organic layer was separated by a liquid separation operation, and the solvent was distilled off. The above operation was performed continuously for 3 batches. Three batches of the solvent evaporation residue were combined, methanol (56.5 L) was added, and the mixture was cooled to 10 ° C. or lower. 4N-LiOH (17.7 L) was dripped there over 2 hours. The mixture was stirred for 4 hours after the completion of dropping. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid until the pH reached 8-10. After neutralization, methanol was distilled off, IPE (75 L) and water (56 L) were added, and a liquid separation operation was performed. The organic layer after the liquid separation operation was treated with activated carbon (2.1 kg), and the activated carbon was removed by filtration, and then the solvent of the organic layer was distilled off. IPE (5.5 L) and heptane (55 L) were added to the concentrated residue and cooled gradually. After cooling to −10 ° C., the mixture was stirred for 1 hour, and the crystals were collected by filtration to give the title compound (12.0 kg, 18%) as colorless crystals. The optical purity of the obtained crystal was 99% de by HPLC analysis.
¹ H-NMR (CDCl ₃ ) δ: 1.36 (d, J = 6.6 Hz, 3H), 1.77-1.85 (m, 2H), 2.33-2.38 (m, 2H) 3.45 (s, 6H), 3.91-4.01 (m, 3H), 7.18-7.33 (m, 5H)

(Process 3)
Synthesis of (2S, 5S) -1-[(R) -1-phenylethyl]]-2,5-bis (hydroxymethyl) pyrrolidine (2S, 5S) -1-[(R) -1-phenylethyl] ] -2,5-bis (methoxycarbonyl) pyrrolidine (100 g, 343 mmol) was dissolved in dimethoxyethane (1 L) and cooled to 10 ° C. or lower. A 65% solution of Red-Al in toluene (245 g, 789 mmol) was slowly added dropwise. After completion of dropping, the temperature was raised to room temperature and stirred for 2 hours. After completion of stirring, 10N NaOH (300 ml) was added dropwise to stop the reaction. Separation operation was performed by adding 100 ml of saturated saline. The organic layer was washed again with 300 ml of Showa brine, and then the solvent of the organic layer was distilled off. After distilling off the solvent, 1 L of toluene and 500 ml of heptane were added and cooled to 10 ° C. or lower for crystallization. After filtering the final, the title compound (68.7 g, 85%) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.53 (d, J = 6.3 Hz, 3H), 1.74-1.79 (m, 2H), 1.93-2.04 (m, 2H) 3.02 (dd, J = 10.4, 5.4 Hz, 2H), 3.23-3.28 (m, 2H), 3.43 (d, J = 10.4 Hz, 2H), 98 (q, J = 6.5 Hz, 1H) 7.24-7.36 (m, 5H)

(Process 4)
Synthesis of (2S, 5S) -2,5-bis (hydroxymethyl) pyrrolidine
(2S, 5S) -1-[(R) -1-phenylethyl] -2,5-bis (hydroxymethyl) pyrrolidine (1.72 kg) was dissolved in ethanol (8.6 L). 7.5% Pd / C (344 g) was added to this solution and stirred at a hydrogen pressure of 20 kg / cm ² for 15 hours. After completion of the reaction, the catalyst was removed by Celite filtration, and the organic layer was concentrated to dryness to obtain 911 g (yield 95%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.38-1.45 (m, 2H), 1.82-1.88 (m, 2H), 3.28-3.30 (m, 2H), 3 .37-3.41 (m, 2H), 3.58 (dd, J = 11.1, 3.6 Hz, 2H)

(Process 5)
Synthesis of (2S, 5S) -1- (tert-butoxycarbonyl) -2,5-bis (hydroxymethyl) pyrrolidine
An ethanol solution of Boc ₂ O (adjusted by dissolving 1.98 kg in 800 ml of ethanol) was added dropwise to a 95% ethanol solution (7.7 L, 8.5 v / w) containing DOH (911 g). After completion of dropping, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate (17.8 L), 10% -KHCO ₃ aqueous solution (7.12 L), and saturated brine (3.56 L) were added and stirred for 30 minutes, followed by liquid separation operation. The aqueous layer was re-extracted with ethyl acetate (5.34 L), and the organic layers were combined and washed with saturated brine (5.34 L). The organic layer was dried over sodium sulfate (3.56 kg), and the solvent was distilled off. An azeotropic operation with ethyl acetate (5.34 L) was performed twice, and after drying under reduced pressure, 763 g of the title compound was obtained as white crystals. The spectral data of the compounds obtained here are reported in the literature [N. A. Sasaki, I .; Sagnard, Tetrahedron, 50 (24), 7093-7108 (1994). And S. Takano, M .; Moriya, Y .; Iwabuchi, K .; Ogasawara, Tetrahedron Letters, 30 [29], 3805-3806 (1989). ].

Example 109
Trans-4- [1- (tert-Butoxycarbonyl)-(5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester (step 1)
Synthesis of 1- (tert-butoxycarbonyl)-(2S, 5S) -bis (methanesulfonyloxymethyl) pyrrolidine
1- (tert-Butoxycarbonyl)-(2S, 5S) -bis (hydroxymethyl) pyrrolidine (2.32 g, 10.0 mmol) was dissolved in methylene chloride (50 ml), and triethylamine (4.2 ml) was stirred at 0 ° C. 30.0 mmol) followed by methanesulfonyl chloride (1.8 ml, 24.0 mmol). After stirring for 30 minutes at the same temperature, the reaction was terminated by pouring into 1N aqueous hydrochloric acid (50 ml). Next, the mixture was extracted with chloroform (2 × 100 ml), and the extract was dried over Na ₂ SO ₄ , and then the solvent was distilled off with an evaporator. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate = 4: 1) to obtain the desired title compound (3.11 g, 80%) as a colorless crystalline solid.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.91-2.02 (2H, m), 2.09-2.30 (2H, m), 3.00 and 3.02 (total 6H, s, each, due to double bond character of the C (O) -N bond in amide), 4.02-4.14 (2H, m), 4.16-4.23 (1H, m), 4.24-4.32 (2H, m), 4.47 (1H, dd, J = 10.0 , 5.6 Hz).
MS (ESI) m / z, 288 (M ⁺ -99).

(Process 2)
4-[[(5S, 7aS) -3-Oxo-1H, 3H-tetrahydropyrrolo [1,2-c] oxazol-5-yl] methoxy] benzoic acid ethyl ester
1- (tert-Butoxycarbonyl)-(2S, 5S) -bis (methanesulfonyloxymethyl) pyrrolidine (500 mg, 1.39 mmol), 4-hydroxybenzoic acid ethyl ester (257 mg, 1.55 mmol), potassium carbonate (428 mg, 3.10 mmol), and N, N-dimethylformamide (15 ml) were mixed and stirred at 90 ° C. for 5 hours. The reaction mixture was allowed to cool, water (100 ml) and EtOAc (300 ml) were added and dissolved, and the organic layer was separated. The organic layer was washed with saturated brine (100 ml), dried over Na ₂ SO ₄ , and the solvent was distilled off with an evaporator. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1) to obtain the desired title compound (327 mg, 82%) as a colorless crystalline solid.
¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.1 Hz), 1.97-2.09 (2H, m), 2.13-2.22 (1H, m), 2.27-2.38 (1H, m), 3.97 -4.57 (8H, m), 6.95-6.89 (2H, m), 8.02-7.96 (2H, m).

(Process 3)
Synthesis of cis and trans-4-[[((5S, 7aS) -3-oxo-1H, 3H-tetrahydropyrrolo [1,2-c] oxazol-5-yl] methoxy] -1-cyclohexanecarboxylic acid ethyl ester
4-[[((5S, 7aS) -3-oxo-1H, 3H-tetrahydropyrrolo [1,2-c] oxazol-5-yl] methoxy] benzoic acid ethyl ester (1.59 g, 5.21 mmol) was treated with EtOH-acetic acid It was dissolved in (10: 1, 44 ml) and subjected to catalytic hydrogenation (15 atm) for 4 hours with stirring in an autoclave in the presence of 10% Rh / Al ₂ O ₃ (1.6 g). The reaction vessel was purged with nitrogen, the catalyst was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1) to obtain a mixture of cis-trans isomers of the title compound (1.01 g, 62%) as a colorless oily substance.
Next, this compound (1.01 g, 3.24 mmol) was dissolved in N, N-dimethylformamide (10 ml), sodium hydride (259 mg, 6.49 mmol) was added at 0 ° C. with stirring, and then EtOH ( 457 μl, 8.10 mmol) was added. After stirring for 1 hour, 1N aqueous hydrochloric acid solution (100 ml) was poured, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine (100 ml), dried over Na ₂ SO ₄ and evaporated. The obtained residue was dissolved in N, N-dimethylformamide (7 ml), potassium carbonate (448 mg, 3.24 mmol) and iodoethane (777 μl, 9.72 mmol) were added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was allowed to cool, diluted with EtOAc (200 ml), washed with saturated brine (100 ml), dried over Na ₂ SO ₄ , and evaporated with an evaporator. The obtained residue is silica gel column chromatography.
Purification with (hexane-ethyl acetate = 1: 1) gave an approximately 1: 1 mixture of cis-trans isomers of the title compound (1.01 g, 62%) as a colorless oil.
Cis-trans 1: 1 mixture:
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.32 (10H, m), 1.40-1.55 (4H, m), 1.62-1.71 (1H, m), 1.75-2.39 (17H, m), 3.22-3.32 ( 1H, m), 3.47-3.55 (4H, m), 3.89-4.19 (11H, m), 4.53-4.45 (2H, m).
MS (ESI) m / z, 312 (M ⁺ +1).

(Process 4)
Synthesis of trans-4-[[(5S, 7aS) -3-oxo-1H, 3H-tetrahydropyrrolo [1,2-c] oxazol-5-yl] methoxy] -1-cyclohexanecarboxylic acid ethyl ester
4-[[(5S, 7aS) -3-oxo-1H, 3H-tetrahydropyrrolo [1,2-c] oxazol-5-yl] methoxy] -1-cyclohexanecarboxylic acid ethyl ester cis-trans 1: 1 Isolation of the mixture (3.30 g) was performed using a Biotage column system (75M, hexane-ethyl acetate = 1: 1) to obtain a trans isomer (1.47 g) and a cis isomer (1.80 g).
Trans form:
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.34 (5H, m), 1.40-1.57 (3H, m), 1.78-2.32 (8H, m), 3.21-3.34 (1H, m), 3.51-3.57 ( 2H, m), 3.89-4.20 (5H, m), 4.54-4.45 (1H, m).

(Process 5)
Synthesis of trans-4- [1- (tert-butoxycarbonyl)-(5S) -hydroxymethyl- (2S) -pyrrolidinylmethoxy] -1-cyclohexanecarboxylic acid ethyl ester trans-4-[[(5S, 7aS ) -3-Oxo-1H, 3H-tetrahydropyrrolo [1,2-c] oxazol-5-yl] methoxy] -1-cyclohexanecarboxylic acid ethyl ester (1.47 g, 4.72 mmol) dissolved in EtOH (20 ml) Then, 4N aqueous sodium hydroxide solution (9.4 ml, 37.6 mmol) was added with stirring, and the mixture was heated to reflux for 19 hours. After allowing to cool, the mixture was neutralized with 4N hydrochloric acid / dioxane solution and concentrated with an evaporator to obtain a white powder. Subsequently, it diluted with EtOH (100 ml), concentrated sulfuric acid (0.5 ml) was added, and it heated and refluxed for 26 hours, stirring. After standing to cool, it was concentrated with an evaporator and made alkaline with saturated aqueous sodium bicarbonate. Then, THF (100 ml) and Boc ₂ O (2.06 g, 9.44 mmol) were added and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (300 ml), washed with saturated brine (100 ml), dried over Na ₂ SO ₄ and evaporated using an evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate = 4: 1 to 1: 1) to give the desired title compound
(1.80 g, 99%) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.30 (5H, m), 1.39-1.66 (11H, m), 1.86-2.17 (8H, m), 2.19-2.30 (1H, m), 3.15-3.25 ( 1H, m), 3.32 (1H, t, J = 8.7 Hz), 3.56-3.63 (1H, m), 3.66-3.73 (1H, m), 3.85-3.97 (1H, m), 4.06-3.98 (1H, m), 4.12 (2H, ddd, J = 14.3, 7.1, 2.3 Hz), 4.25 (1H, dd, J = 7.4, 3.1 Hz).
MS (ESI) m / z, 386 (M ⁺ +1).

Example 110
Trans 4- [3-Oxo- (8S) -tetrahydro-pyrrolo [1,2-c] oxazolyl- (5S) -methoxy] cyclohexanecarboxylic acid ethyl ester (step 1)
Synthesis of (5S) -triethylsilyloxymethyl- (8S) -tetrahydro-pyrrolo [1,2-c] oxazol-3-one
Dissolve (5S) -hydroxymethyl- (8S) -tetrahydro-pyrrolo [1,2-c] oxazol-3-one (10.6 g, 67.4 mmol) and imidazole (11.5 g, 168.6 mmol) in DMF (120 ml) Chlorotriethylsilane (17.0 ml, 101.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 9: 1-6: 1) to give the title compound (16.2 g, 89%) as a colorless oil. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.61 (6H, q, J = 7.8 Hz), 0.96 (9H, t, J = 7.8 Hz), 1.43-1.53
(1H, m), 1.91-2.17 (3H, m), 3.64-3.74 (2H, m), 3.89-3.98 (2H, m), 4.13-4.15 (1H, m), 4.45-4.50 (1H, m) .
MS (LC-ESI) m / z: 272 (M ⁺ +1).

(Process 2)
Synthesis of trans 4- [3-oxo- (8S) -tetrahydro-pyrrolo [1,2-c] oxazolyl- (5S) -methoxy] cyclohexanecarboxylic acid ethyl ester
(5S) -Triethylsilyloxymethyl- (8S) -tetrahydro-pyrrolo [1,2-c] oxazol-3-one (16.2 g, 59.8 mmol) was dissolved in acetonitrile (100 ml) and triethylsilane was dissolved at 0 ° C. (14.3 ml, 89.7 mmol) was added dropwise, followed by the addition of bismuth (III) bromide (2.68 g, 5.98 mmol) and stirred for 3 minutes. A solution of 4-cyclohexanone carboxylic acid ethyl ester (11.2 g, 65.8 mmol) in acetonitrile (10 ml) was added dropwise to the suspension, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, the precipitated insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by flash column chromatography (Biotage 40M, elution solvent: n-hexane: ethyl acetate = 4: 1 to 1: 1), and a diastereomer mixture (17.4 g, 93%, cis: trans = 3: 5) was obtained. The resulting diastereomer mixture was again purified by flash column chromatography (Biotage 75L, elution solvent: n-hexane: ethyl acetate = 2: 1) to give the title compound (9.05 g, 49%) as a colorless oil Got as.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.31 (5H, m), 1.42-1.56 (3H, m), 1.82-1.89 (1H, m), 1.98-2.28 (7H, m), 3.23-3.30 ( 1H, m), 3.53 (2H, d, J = 4.7 Hz), 3.89-4.03 (2H, m), 4.09-4.16 (3H, m), 4.48 (1H, dd, J = 8.9, 7.7 Hz).
MS (LC-ESI) m / z: 312 (M ⁺ +1).

Test example 1
In vitro evaluation of test substances:
4B4 cells (cells in which VLA-4 molecules (α chain, β chain) are expressed in CHO K1 cells) are seeded on Costar 3599 plates (3 × 10 ⁴ cells / 100 μl / well) for 2 days Cultured. After the medium was washed twice with buffer A ^* , Eu ³⁺ -D1D7-IgG diluted to 2 nM with assay buffer ^** was added at 50 μl / well. Add 50 μl / well of test substance diluted in 2% DMSO-assay buffer (with or without 6% human serum albumin) (added separately to wells for Scatchard analysis) and plate After stirring with a mixer for 5 minutes, the mixture was further allowed to stand at room temperature for 1 hour. Then, wash 4 times with buffer A, add 100 μl / well of enhancement reagent (DELFIA), shake for 5 minutes using a plate mixer, and measure fluorescence intensity with a time-resolved fluorescence intensity meter (DELFIA Wallac) did. The Kd value and Bmax (maximum binding amount) indicating the strength of binding were determined in the range of 0.06 to 20 nM according to the Scachard analysis method. The results are shown in Tables 1-6.
The Ki value was calculated according to the following formula.

{* Buffer A: 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM Ca ²⁺ , 1 mM Mg ²⁺ , 4 mM Mn ²⁺ ; ** assay buffer: 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM Ca ²⁺ , 1 mM Mg ²⁺ , 4 mM Mn ²⁺ , 0.1% BSA, 20 μM DTPA (diethylenetriaminepentaacetic acid), with / without 6% ALBUMIN, HUMAN SERUM (C / N A-1653, SIGMA }

¹ : Compound of WO 00/68213, (R) -3-[(acetylmethyl) amino] -3- [4- [methyl-[(2-o-tolylaminobenzoxazol-6-yl)] acetyl] amino Phenyl] propionic acid

  The above Example compounds showed high VLA-4 / VCAM-1 binding inhibitory activity. On the other hand, (R) -3-[(acetylmethyl) amino] -3- [4- [methyl-[(2-o-tolylaminobenzoxazol-6-yl)] acetyl] aminophenyl] propionic acid (WO 00 Ki value of / 68213 compound) was 163 nM.

Test example 2
In vivo evaluation of test substance Mouse eosinophil infiltration test induced active sensitization by Ascaris (pignus ascarisum antigen):
Induction of eosinophilic cell infiltration by active sensitization of Ascaris has been reported.
{Int. Arch. Immunol. , 108, 11-18, (1995)}. Test compounds were evaluated by this evaluation method. The test substance was orally administered twice / day, the total number of cells and the number of eosinophils in BALF 48 hours after induction were calculated, and the effect was determined in the test substance non-administered group.

  As a result of the mouse eosinophil infiltration test, the compound of the above Example showed a significant inhibitory effect as compared with the test substance non-administered group, and the effect was comparable to the inhibitory effect of the VLA-4 antibody.

Test example 3
Pharmacokinetics and oral absorption studies:
The pharmacokinetic parameters when the test substance was orally administered to dogs at 0.5 mg / kg cassette were as follows. The results are shown in Table 13.

  As a result of the canine pharmacokinetics test, the compound of the above-mentioned example was converted to the representative compound trans-4- [1-[[2,5-dichloro-4- (1-methyl) of WO 02/053534 by oral administration of 0.5 mg / kg. -3-Indolylcarbonylamino) phenyl] acetyl]-(4S) -methoxy- (2S) -pyrrolidinylmethoxy] cyclohexane carboxylic acid has higher AUC, lower systemic clearance, and better blood retention It was a result.

Test example 4
Solubility and Caco-2 membrane permeability test The solubility of the test substance in JP 1st liquid (JP1, pH 1.2) and JP 2nd liquid (JP2, pH 6.8) was evaluated. Moreover, the permeability evaluation (pH = 7.4) using a Caco-2 membrane was carried out, and the numerical value is shown as a relative transmission ratio with Atenolol ^™ . The results are shown in Table 14.

As a result of the measurement of the solubility of the above-mentioned Example compounds, both acidic aqueous solution (Nippon 1st liquid) and neutral aqueous solution (Nippon 2nd liquid) are representative compounds of WO 02/053534 trans-4- [1-[[2, 5-dichloro-4- (1-methyl-3-indolylcarbonylamino) phenyl] acetyl]
-(4S) -Methoxy- (2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid showed a water solubility significantly higher than that. Also, the Caco-2 membrane permeability was good.

Claims (25)

The following general formula (I)

(Wherein W ^a represents an optionally substituted aryl group or an optionally substituted heteroaryl group;
W ^b represents a divalent group consisting of an optionally substituted 1,3-benzoxazole ring or an optionally substituted 1,3-benzothiazole ring;
R ¹ represents a hydrogen atom or a lower alkyl group;
R ² represents the following formula (II)

(In the formula, R ³ and R ⁴ each independently have a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, or a substituent. An optionally substituted lower alkoxy group or an optionally substituted cycloalkyloxy group, or R ³ , R ⁴ and a nitrogen atom together form a 4- to 7-membered heterocyclic ring Or a halogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a lower alkoxy group which may have a substituent on the ring to be formed. And 1 to 3 substituents selected from an amino group, an alkylene group and a cyclic amino group which may have a substituent.
The group of
Y represents a group of — (CH ₂ ) _n —O—, and n represents an integer of 1 or 2;
Z represents a cyclohexane ring. ), A salt thereof, or a solvate thereof. The compound according to claim 1, a salt thereof, or a solvate thereof, wherein W ^a in the formula (I) is ^a phenyl group which may have a substituent or a pyridyl group which may have a substituent. The compound according to claim 1, a salt thereof, or a solvate thereof, wherein W ^a in the formula (I) is ^a phenyl group which may have ^a substituent. The compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof, wherein W ^b in formula (I) is a 1,3-benzoxazole ring which may have a substituent. W ^b in formula (I) is an optionally substituted 1,3-benzoxazole ring, bonded to W ^a —NH— at the 2-position of the 1,3-benzoxazole ring, and at the 6-position Formula (III)

The compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof, which is bonded to a group (wherein R ¹ , R ² , Y and Z are as defined above). . In formula (I),

The compound according to any one of claims 1 to 5, a salt thereof, or a solvate thereof.   N in Formula (I) is 1, The compound in any one of Claim 1 to 6, its salt, or those solvates. The following general formula (Ia)

(Wherein, W ^a , W ^b , R ¹ and R ² have the same meanings as defined above), the compound according to claim 1, a salt thereof, or a solvate thereof. object. The following general formula (Ib)

(Wherein, W ^a , W ^b , R ¹ and R ² have the same meanings as described above.), The compound according to claim 1, a salt thereof, or a solvate thereof. object. A compound represented by formula (I) according to claim 1, wherein the group of (W ^a -NH-W ^b -CH ₂ -C (O)-is
[7-fluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [7-fluoro-2- (5-fluoro-2-methylphenylamino) -1, 3-benzoxazol-6-yl] acetyl group, [7-fluoro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [7-fluoro- 2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-pyridinylamino) -7-fluoro-1,3-benzoxazole-6- Yl] acetyl group, [7-fluoro-2- (2-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (3-fluoro-4 Methoxyphenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methoxyphenylamino) -7-fluoro-1,3-benzoxazole-6 -Yl] acetyl group, [7-fluoro-2- (2,5-dimethylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methyl)- 7-fluorophenylamino] -1,3-benzoxazol-6-yl] acetyl group, [7-fluoro-2- (2,5-difluorophenylamino) -1,3-benzoxazol-6-yl] acetyl Group, [2- (3,4-dichlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (3,4-dichlorophenyl) Nylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (3,4-dichlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl group, [ 2- (4-Chlorophenylamino) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (4-chlorophenylamino) -1,3-benzoxazol-6-yl] Acetyl group, [4,7-difluoro-2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, (2-phenylamino-1,3-benzoxazol-6-yl) ) Acetyl group, [2- (4-fluorophenylamino) -1,3-benzoxazol-6-yl] acetyl group, (7-fluoro-2-phenylamido) No-1,3-benzoxazol-6-yl) acetyl group, [2- (4-fluorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (4 -Fluorophenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [ 2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [4-fluoro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] Acetyl group, [4-chloro-2- (5-fluoro-2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro 2-methoxyphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl group, [4-fluoro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazole -6-yl] acetyl group, [2- (4-chloro-2-methoxyphenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (5-fluoro-2 -Methoxyphenylamino) -4-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methoxyphenylamino) -4-methoxy-1,3-benzoxazole- 6-yl] acetyl group, [7-chloro-2- (5-fluoro-2-methylphenylamino) -1,3-benzoxazol-6-yl] acetyl group, 7-chloro-2- (2-methoxyphenylamino) -1,3-benzoxazol-6-yl] acetyl group, [2- (5-chloro-2-methylphenylamino) -4-fluoro-1,3 -Benzoxazol-6-yl] acetyl group, [2- (4-chlorophenylamino) -7-fluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (3,4-difluorophenylamino) ) -4,7-difluoro-1,3-benzoxazol-6-yl] acetyl group, [2- (2,4,5-trifluorophenylamino) -1,3-benzoxazol-6-yl] acetyl The compound according to claim 1, which is any one of a group and a [2- (2,3,4-trifluorophenylamino) -1,3-benzoxazol-6-yl] acetyl group. , Its salts or solvates thereof.   The pharmaceutical containing the compound in any one of Claim 1 to 10, its salt, or those solvates.   An agent for preventing and / or treating a disease caused by cell adhesion, comprising the compound according to any one of claims 1 to 10, a salt thereof, or a solvate thereof.   The disease caused by cell adhesion is at least one selected from inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, and transplant rejection The inhibitor and / or therapeutic agent according to claim 12, wherein Use of the compound according to any one of claims 1 to 10, a salt thereof or a solvate thereof for the manufacture of a medicament. A method for preventing and / or treating a disease caused by cell adhesion, comprising administering the compound according to any one of claims 1 to 10, a salt thereof, or a solvate thereof.   The disease caused by cell adhesion is at least one selected from inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, and transplant rejection The prevention method and / or treatment method according to claim 15, wherein Formula (4B-1)

(In the formula, R ⁸ represents a lower alkyl group which may have a substituent or a benzyl group which may have a substituent.)
The compound represented by formula (4B-2) is reacted with a sulfonyl chloride or bromide derivative (R ⁹ —Cl or R ⁹ —Br).

(In the formula, R ⁹ represents a lower alkylsulfonyl group which may have a substituent or a benzenesulfonyl group which may have a substituent, and R ⁸ has the same meaning as described above.)
The compound represented by formula (4B-4) is obtained by reacting 4-hydroxybenzoic acid lower alkyl ester with the compound in the presence of a base.

(In the formula, R ⁵ represents a lower alkyl group.)
The manufacturing method of the compound represented by these. Formula (4B-2)

(In the formula, R ⁸ represents a lower alkyl group which may have a substituent or a benzyl group which may have a substituent, and R ⁹ represents a lower alkylsulfonyl group which may have a substituent. Or a benzenesulfonyl group which may have a substituent.
Or a salt or a solvate thereof. Formula (4B-4)

(In the formula, R ⁵ represents a lower alkyl group.)
Or a salt or a solvate thereof. Formula (4B-4)

(In the formula, R ⁵ represents a lower alkyl group.)
The compound represented by formula (4B-5)

(In the formula, R ⁵ has the same meaning as described above.)
Which is isomerized to give a compound of formula (4B-5-trans)

(In the formula, R ⁵ has the same meaning as described above.)
A compound represented by formula (4B-6-trans), wherein the oxazolidinone ring is opened:

(Wherein R ⁸ represents a lower alkyl group which may have a substituent or a benzyl group which may have a substituent, and R ⁵ has the same meaning as described above.)
The manufacturing method of the compound represented by these. Formula (4B-5)

(In the formula, R ⁵ represents a lower alkyl group.)
Or a salt or a solvate thereof. Formula (4B-6-Trans)

(In the formula, R ⁵ represents a lower alkyl group, and R ⁸ represents a lower alkyl group which may have a substituent or a benzyl group which may have a substituent.)
Or a salt or a solvate thereof. Formula (4B-2)

(In the formula, R ⁸ represents a lower alkyl group which may have a substituent or a benzyl group which may have a substituent, and R ⁹ represents a lower alkylsulfonyl group which may have a substituent. Or a benzenesulfonyl group which may have a substituent.
A compound represented by formula (4C-1):

_{^{(R 11 CO) n O-}} M (4C-1)
(Wherein R ¹¹ represents an optionally substituted phenyl group or lower alkyl group, M represents an alkali metal atom or alkaline earth metal atom, and n represents an integer of 1 or 2)
Is reacted with a compound represented by the formula (4C-2)

(In the formula, R ¹¹ has the same meaning as described above.)
A compound represented by formula (4C-3), which is hydrolyzed:

The manufacturing method of the compound represented by these. Formula (4C-2)

(In the formula, R ¹¹ represents an optionally substituted phenyl group or lower alkyl group.)
Or a salt or a solvate thereof. Formula (4C-3)

Or a salt thereof, or a solvate thereof.