Title of Invention	HETERO COMPOUND
Abstract	ABSTRACT To provide a useful compound as an active ingredient for a preventing and/or treating agent for rejection in the transplantation of an organ, bone marrow, or a tissue, an autoimmune disease, or the like, which has an excellent SIP1 agonist activity. [Means for solving] Since the compound of the invention has an SI Pi agonist activity, it is useful as an active ingredient for a treating or preventing agent for a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or a tissue, a graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, a nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, , - nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, or an inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer and leukemia. [Selected Figure] Nil

Title of Invention

HETERO COMPOUND

Abstract

ABSTRACT To provide a useful compound as an active ingredient for a preventing and/or treating agent for rejection in the transplantation of an organ, bone marrow, or a tissue, an autoimmune disease, or the like, which has an excellent SIP1 agonist activity. [Means for solving] Since the compound of the invention has an SI Pi agonist activity, it is useful as an active ingredient for a treating or preventing agent for a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or a tissue, a graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, a nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, , - nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, or an inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer and leukemia. [Selected Figure] Nil

Full Text	DESCRIPTION HETERO COMPOUND Technical Field [0001] The present invention relates to a novel hetero compound and a medicine containing the same as an active ingredient, particularly an agent for treating immunological diseases. Background Art [0002] Sphingosine-1 -phosphate is a metabolite of sphingolipid which is a physiologically active substance secreted from an activated platelet (Non-Patent Document 1). The sphingosine-1-phosphate receptor is a G protein-binding type, and belongs to an Edg-family which is the endothelial differentiation gene. Up to now, five receptors of SlPi(Edgl), SlP2(Edg5), SlP3(Edg3), SlP4(Edg6) and SlP5(Edg8) have been found. All of these receptors are broadly distributed in cells and tissues throughout the body, but SI Pi, SI P3 and S1P4 are predominantly expressed in lymphocyte and endothelial cell, SIP2 is predominantly expressed in vascular smooth muscle cell, and SIP5 is predominantly expressed in brain and spleen, and amino acid sequences thereof are well-conserved in human and rodent (Non-Patent Document 1). Many receptors bind to G proteins by stimulation of sphingosine-1-phosphate. SIPi bind to Gj/o, S1P2 and S1P3 bind to Gj/o, Gq, G12/13 and Gs, S1P4 binds to Gy0, G12/13 and Gs, SIP5 is coupled to G1/o and G12/13, and cell growth caused by activation of MAPK, change of cytoskeletal system and cell infiltration caused by activation of Rac (and/or Rho), and generation of cytokine and mediator caused by activation of PLC and calcium influx into cell, and the like (Non-Patent Document 1) are induced. It has been known that by the stimulating action of S1P1 of sphingosine-1 -phosphate, migration of lymphocyte, inhibition of apoptosis, generation of cytokine, sequestering lymphocyte in thymus and other secondary lymphoid tissues are induced, and angioplasty in vascular endothelial cell is promoted (Non-Patent Document 2). On the other hand, expression of S1P3 is also found on cardiomyocyte, and transiently-decrease in heart rate (infrequent pulse) or in blood pressure by stimulation of sphingosine-1 -phosphate is observed (Non-Patent Document 3) while infrequent pulse is not observed by stimulation of sphingosine-1-phosphate in a knockout mouse wherein SIP3 is genetically deleted (Non-Patent Document 4). It has been reported that FTY720 phosphate ester which is an active body of FTY720 currently in a clinical trial has non¬ selective agonist activity for SIPi, S1P3, S1P4 and S1P5 (Non-Patent Document 5), and especially infrequent pulse induced by the stimulation effect through SIP3 is frequently expressed as an undesirable side effect in clinical trial (Non-Patent Document 6). Accordingly, it is considered that for sequestering lymphocyte through a sphingosine-1 - phosphate receptor, the stimulation from SI Pi is essential (Non-Patent Document 7), while the stimulation from SIP3 is not essential which is rather considered to be related to the induction of undesirable side effect. Thus, for the development of .. . ,..-.„..,. : immunosuppressive agent with few side effects, development of agonist having weak effect on SIP3 and selectively effecting on SIPi is desired. [0003] For example, as a compound having SIPi agonist activity, a carboxylic acid derivative represented by the following formula has been known (Patent Document 1). [Chem. 1] [For symbol in the formula, refer to the publication.] As a compound having SI Pi agonist activity, an indane derivative represented by the following formula has been known (Patent Document 2). [Chem. 2] [For symbol in the formula, refer to the publication.] As a compound having SIPi agonist activity, an oxadiazole derivative represented as follows has been known (following figure, Patent Documents 3, 4, 5, and 6). [Chem. 3] (Patent Document 5) (Patent Document 6) [For symbol in the formula, refer to the publication.] As a compound having SI Pi agonist activity, a derivative represented as follows has been known (following figure, Patent Document 7). [0004] [Chem. 4] [For symbol in the formula, refer to the publication.] [0005] However, the compound of the present invention has not been disclosed in any document. [0006] Non-Patent Document 1: Annual Review Biochemistry, 2004, 73, 321-354 Non-Patent Document 2: Nature Review Immunology, 2005, 5, 560-570 Non-Patent Document 3: Japanese Journal of Pharmacology, 2000, 82, 338- 342 Non-Patent Document 4: Journal of Pharmacology and Experimental Therapeutics, 2004, 309, 758-768 Non-Patent Document 5: Science, 2002,296, 346-349 Non-Patent Document 6: Journal of American Society of Nephrology, 2002, 13,1073-1083 Non-Patent Document 7: Nature, 2004, 427, 355-360 Patent Document 1: International Publication WO 2005/058848 brochure Patent Document 2: International Publication WO 2004/058149 brochure Patent Document 3: International Publication WO 2003/105771 brochure Patent Document 4: International Publication WO 2004/103279 brochure i Patent Document 5: International Publication WO 2005/032465 brochure Patent Document 6: International Publication WO 2006/047195 brochure Patent Document 7: International Publication WO 2006/001463 brochure DISCLOSURE OF THE INVENTION > PROBLEM THAT THE INVENTION IS TO SOLVE [0007] Inventors of the present inventors have carried out research in order to provide a compound useful for preventing and/or treating rejection in transplantation of organ/bone marrow/tissue or for autoimmune diseases, based on SIPi agonist activity, ) and furthermore to provide a medicine containing the same. MEANS FOR SOLVING THE PROBLEM [0008] Inventors of the present invention have made extensive studies about a compound having SI Pi agonist activity, and as a result, they found that a novel hetero compound is useful as SI Pi agonist, thus completing the present invention. In the other words, according to the present invention, a novel hetero compound represented by following the general formula (I) or a pharmaceutically acceptable salt thereof can be provided. [0009] A compound represented by the formula (I): [Chem. 5] or a pharmaceutically acceptable salt thereof. [In the formula, the symbols mean as follows; the ring A is: [Chem. 6] X is a single bond, -CH2-, -NR3-, -0-, -S-, -S(=0)-, or -S(=02>, R1 is -H; halogen; aryl; heteroaryl; (C3.C8)cycloalkyl; (C3.C8)cycloalkenyl; (C3.C8)heterocycloalkyl; or (Ci.C6)alkyl or (C2-C6)alkenyl, each of which may contain halogen, -CONH2, aryl, or (C3.C8)cycloalkyl, as a substituent, R2 is -CN, -0-(Ci.C6)alkyl, -C(=0)H, halogen; or (d.C6)alkyl which may be substituted with halogen or -OH, ■7 >j R is -H; wherein R may form morpholino, 1-pyrrolidinyl or 3,4-dehydropipelidin-1-yl, together with R1 and nitrogen, wherein, when -X- is a single bond, R1 and R2 may in combination form a 5 membered ring and further contain (Ci_C6)alkyl, as a substituent, R4 is a following ring: wherein any one of a bond from the ring is bound to an oxadiazole ring, [Chem. 7] R5 is -H; (Ci.Ce)alkyl which may be substituted with at least one group selected from the group consisting of-CN, -C(=0)NRxRY, -NHRX, -SRx, -S(=0)2Rx, and -ORx, (this is defined as R°-(C1-C6)alkyl); R0-(CrC6)alkyl-O-; R0-(CrC6)alkyl-C(=O)-; R°-(C1-C6)alkyl-S(=0)2; R°-0-(Ci-C6)alkyl-; R0-C(=O)-(CrC6)alkyl-; R°-S(=0)2-(Ci-C6)alkyl-; (C2-C6)alkenyl-; -C(=0)H; -0RX; -S(=0)2RX; halogen; =0; -NRXRY; -C(=0)NRxRY; Rx and RY may be the same with or different from each other, and is -H; or (Ci-C6)alkyl which may be substituted with -OH, -NH2 which may be protected with a protecting group, or heteroaryl, wherein Rx and RY may form (C3-Cg)heterocycloalkyl, together with nitrogen. [0010] As -X- in the formula (I), preferred is a single bond or -0-, and more preferred is -0-. As R1, preferred is (Ci-C4)alkyl or (C2.C4)alkenyl, each of which may be substituted with halogen or (C3-C6)cycloalkyl, and further more preferred is (Ci.C4)alkyl which may be substituted with F. As the ring A, preferred is: [Chem. 8] As R2, preferred is halogen, -CN, (Ci.C4)alkyl which may be substituted with halogen, and more preferred is -CI, -CF3. As R4, preferred is: [Chem. 9] and more preferred is: [Chem. 10] As R5, preferred is -H; (Ci.C6)alkyl which may be substituted with -C(=0)NRxRY As Rx, preferred is -H; (Ci.C6)alkyl which may be substituted with -OH. As RY, preferred is -H; (Ci.C6)alkyl which may be substituted with -OH. [0011] A compound of the present invention represented by the formula (I) is characterized in a chemical structure from the point that a bicyclic nitrogen-containing unsaturated hetero ring or a bicyclic nitrogen-containing partially unsaturated hetero ring is bound to 3-position of oxadiazole, and has pharmacological characteristics from the point that the compound has SI Pi agonist activity. EFFECTS OF THE INVENTION [0012] Since the compound of the invention has an SI Pi agonist activity, it is useful as an active ingredient of an agent for treating or an agent for preventing a disease caused by unfavorable lymphocytic infiltration, for example, graft rejection in the transplantation of an organ, bone marrow, or tissue or graft-versus-host disease, an autoimmune disease or an inflammatory disease such as rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, imTammatory bowel disease, atherosclerosis, or ischemia-reperfusion injury, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer or leukemia. BEST MODE FOR CARRYING OUT THE INVENTION [0013] Hereinafter, the present invention will be described in more detail. In the specification, "alkyl" means a linear or branched mono-valent group. "C1-C6 alkyl" means a C1-C6 linear or branched alkyl, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-propyl, and n-hexyl, preferably C1-C4 alkyl, and particularly preferably, methyl, ethyl, n-propyl, and isopropyl. [0014] In the specification, "halogen" represents F, CI, Br, and I, and preferable examples thereof include F or CI. [0015] In the specification, "C2-C6 alkenyl" means C2-C6 linear or branched alkenyl which has a double bond in a given site, and specific examples thereof include ethenyl (vinyl), 1-propenyl, 2-propenyl, 1-methylethen-l-yl, 1-buten-l-yl, 2-buten-l-yl, 3- buten-1-yl, 1 -methyl- 1-propen-l-yl, 2-methyl-l-propen-l-yl, l-methyl-2-propen-l-yl, and2-methyl-2-propen-l-yl, and preferably, l-methyl-2-propen-l-yl or 1-pentenyl. [0016] In the specification, "C3-C8 cycloalkyl" means a mono-valent group of a non-aromatic carbon ring having a reduction number of 3 to 8, which may have partially unsaturated bonds. Thus, specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [0017] In the specification, "C3-Cg heterocycloalkyl" means a mono-valent group of a non-aromatic carbon ring having a reduction number of 4 to 9, containing one or more heteroatoms that are the same as or different from each other, selected from the group consisting of nitrogen, oxygen, and optionally oxidized sulfur, which may have partial unsaturations. Specific examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydropyranyl, and - , . tetrahydrothiopyranyl. [0018] In the specification, "aryl" means an aromatic hydrocarbon group, but preferred is an aryl group having 6 to 14 carbon atoms. Specific examples thereof include phenyl, naphthyl, and anthryl, and more preferred is phenyl. [0019] In the specification, "heteroaryl" means a 5- or 6-membered ring aromatic heterocycle, containing one or more heteroatoms that are the same as or different from each other, selected from the group consisting of nitrogen, oxygen, and sulfur. Specific examples thereof include pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazolyl, and thiadiazolyl. Preferred is a 6-membered heteroaryl, and particularly preferred is pyridyl. [0020] The compound of the present invention may exist in the form of a geometrical isomer or a tautomer in some cases depending on the kind of the substituents. Further the compound of the present invention may have asymmetric carbons. The present invention includes either of the isolated counterparts of these isomers, and a mixture thereof. Also, the labeled compounds, that is, the compounds having at least one element in the compounds of the present invention substituted with radioactive isotopes or non-radioactive isotopes are also included in the present invention. Furthermore, the pharmaceutically acceptable, so-called prodrugs of the compounds of the present invention are also included in the present invention. The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxylic group, or the like of the compound of the present invention, by solvolysis or under a physiological condition. Examples of the group capable of forming a prodrug include the groups as described in "Prog. Med., vol. 5,2157-2161 (1985), and "Iyakuhin no Kaihatsu (Development of Medicines) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198. [0021] The compound represented by the formula (I) may form salts with acids or bases. These salts can be any one that are pharmaceutically acceptable, and specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts. In addition, of the present invention also includes various hydrates and solvates, and polymorphic substances of the compound represented by the formula (I) and a salt thereof. [0022] In the specification, the following abbreviations were used. Pr: preparation method, AcOH: acetic acid, n-BuLi: normal butyl lithium, t-BuOH: tertiary butanol, n-BuOH: normal butanol, BrCN: cyanogen bromide, CDI: 1,1'-carbonyl bis-lH-imidazole, DBU: l,8-diazabicyc!o[5.4.0]undeca-7-ene, DMAP: 4- (N,N-dimethylamino)pyridine, DIC: N,N'-diisopropylcarbodimide, DMF: N,N'- .. dimethylformamide, DCC: dicyclohexylcarbodimide, DMA: N,N-dimethylacetamide, DMSO: dimethylsulfoxide, DPPA: diphenylphosphorylazide, Et: ethyl, EDCI/HC1: N- [3-(dimethylamino)propyl]-N'-ethylcarboxamide hydrochloride, EtOH: ethanol, Et3N: triethylamine, EtOAc: ethyl acetate, HOBt: 1-hydroxy-lH-benzotriazole, HPLC: high performance liquid chromatography, IPE: diisopropyl ether, i-PrOH: 2-propanol, K2CO3: potassium carbonate, KCN: potassium cyanide, KHC03: potassium hydrogen carbonate, KO^Bu: potassium tertiary butoxide, LC-MS: liquid chromatography-mass spectroscopy, LiH: lithium hydride, MeOH: methanol, NaH: sodium hydride, NaOH: sodium hydroxide, NaBU: sodium borohydride, NaCN: sodium cyanide, NaHCC>3: sodium hydrogen carbonate, Na2C03i sodium carbonate, NaOMe: sodium methoxide, NaOEt: sodium ethoxide, NCS: N-chlorosuccinimide, NH4CI: ammonium chloride, NMP: N-methylpyrrolidone, POCI3: phorphorous oxychloride, P2O5: phorphorous pentaoxide, THF: tetrahydrofuranj TLC: thin layer chromatography, TMEDA: ,,..,.,,, N,N,N'N'-tetramethylethylenediamine, Zn(CN)2: zinc cyanide [0023] (Preparation Method) The compound (I) of the present invention and a pharmaceutically acceptable salt thereof may be prepared by applying various known synthetic methods, taking advantages of the characteristics based on their basic backbones or the kind of the substituents. Here, depending on the kind of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to protect the functional group with an appropriate protecting group, or to replace it by a group which may be easily converted into the functional group, during the steps of from starting materials to intermediates. Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group, and examples of a protecting group thereof include the protecting groups as described in "Protective Groups in Organic Synthesis", edited by T.W. Greene and P.G.M. Wuts, (USA) (3rd edition, 1999), which may be optionally selected and used in response to the reaction conditions. By such a method, the desired compound can be obtained bv introducing a protecting group to carry out the reaction, and then, if desired, removing the protecting group or converting it into a desired group. In addition, a prodrug of the compound (I) of the present invention can be prepared by introducing a specific group during the steps of from starting materials to intermediates, similar to the aforementioned protecting groups, or by carrying out the reaction using the obtained compound (I) of the present invention. The reaction may be carried out by employing common esterification, amidation, dehydration, or a method conventionally known to a person skilled in the art. [Chem. 11] [0024] [wherein R or R' means lower alkyl which may be substituted with at least one substituent selected from the group consisting of-CN, -C(=0)OH, -C(=0)OR , -C(=0)NRxRY, -C(=0)NHS02Rx, -C(=0)-(Ci-C8 heterocycloalkyl), -NHRx, -OH, -SRX, -S(=02)Rx, halogen, and -ORx (which is defined as Rz-lower alkyl); R0-(CrC6)alkyl-O-; R°-(C1-C6)alkyl-C(=0)-; R°-(C1-C6)alkyl-S(=0)2-; R°-0-(Ci-C6)alkyl-; R0-C(=O)-(C1-C6)alkyl-; R°-S(=0)2-(Ci-C6)alkyl-; (C2-C6)alkenyl-; -C(=0)H; -ORx; -S(=0)2Rx; halogen; =0; -NRxRY; or -C(=0)NRxRY; Rx and RY are the same as or different from each other, and each mean -H; (Ci-C6)alkyl that may be substituted with -OH or pyridyl. Also, Rx may be bonded with RY and a nitrogen atom to form (C3-Cg)heterocycloalkyl. [0025] This preparation method is a method for preparing a benzimidazole compound represented by the formula (1-c) by allowing an aldehyde compound to undergo the reaction with a 1,2-diaminobenzene compound represented by the formula (1 -b) that can be obtained by reduction of a compound represented by the formula (1 -a). [0026] The step represented by Step 1-1 is a step for reducing a nitro group of the compound represented by the formula (1-a) to an amino group, that can be carried out at normal pressure or under elevated pressure, in a solvent inert to the reaction. In the step represented by Step 1-2 wherein R' is H, an imidazole ring can be constructed, for example, by allowing an orthoformic ester such as ethyl orthoformate to undergo the reaction with the compound represented by the formula (1-b) in the presence of an acid catalyst. Furthermore, in the step represented by Step 1-2 wherein R'is not H, for example, a method in which an amino group of the compound represented by the formula (1-a) is preliminarily acylated using a carboxylic acid, an acid chloride, a carboxylic acid anhydride, or the like, and cyclized under heating or in the presence of an acid, a method in which tetraalkyl orthocarbonate, CDI, or BrCN is used instead of an orthoformic ester, or other methods can be exemplified. Furthermore, as other methods, a method in which a nitrobenzene compound of the formula (1-a) is subject to carbamoylation of its amine moiety, induced into an acylamine compound (1-e), subject to reduction of its nitro group, and cyclized with heat can also be exemplified (Step 1-3, Step 1-4). All of these reactions can be carried out in a solvent inert to the reaction, or without a solvent, from at room temperature to under heating, or from under heating or under reflux. [0027] [Chem. 12] [wherein R has the same meanings as defined above]. This preparation method is a method for preparing an imidazo[l,2-a]pyridine substituted with a nitrile group represented by the formula (2-b), by using a 2-aminopyridine compound represented by the formula (2-a) as a starting material. The step represented by Step 2-1 is a reaction for constructing an imidazo[l,2-a]pyridine ring by allowing a chloroacetaldehyde or a-chloroketone to undergo the reaction with the compound represented by the formula (2-a). It is preferably carried out in the presence of a base, and specific examples of the base include alkali carbonates such as Na2CC>3 and K2CO3; alkali hydrogen carbonates such as NaHC03 and KHCO3; alkoxides such as NaOMe, NaOEt, and KOlBu; tertiary amines such as Et3N and DIPEA; and organic amines such as DBU, pyridine, and lutidine. All of these reactions can be carried out in a solvent inert to the reaction, or without a solvent, from at room temperature to under heating, or under heating with reflux. [0028] [Chem. 13] [wherein R has the same meanings as defined above.] This preparation method is a method for preparing an indazole compound represented by the formula (3-c) by allowing a hydrazine hydrate with a nitrile group to undergo the reaction with a cyanobenzene compound represented by the formula (3-b) obtained by substituting a halogen group of a compound represented by the formula (3-a). The step represented by Step 3-1 is a reaction for substituting a halogen bonding with an aromatic ring with a nitrile group. It is exemplified by a method for reaction of Zn (CN)2 in the presence of tetrakistriphenylphosphine palladium (0), a method for allowing TMEDA and Pd catalysts to undergo the reaction in the presence of Na2CC>3 in DMA, and a method for allowing KCN, NaCN, or the like to undergo the reaction instead of Zn(CN)2. Usually, the compound represented by the formula (3-b) can be obtained by reacting the compound represented by the formula (3-a) with tris(dibenzylideneacetone)dipalladium (0), l'-bis(diphenylphosphino)ferrocene, and Zn(CN)2. Here, examples of the leaving group include halogen such as Br and CI; methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy. [0029] The step represented by Step 3-2 is a reaction for constructing an indazole ring from a cyanobenzaldehyde compound represented by the formula (3-b). Usually, a hydrazine hydrate is used in this reaction, which can be carried out without a solvent, or in a solvent inert to the reaction such as MeOH and toluene, from at room temperature to under heating, or under heating with reflux. In addition, a method using copper cyanide can also be exemplified, and a base such as pyridine may be added. Also, this > reaction is preferably carried out under a nitrogen atmosphere. [0030] [Chem. 14] [wherein R has the same meanings as defined above. Z represents -CH= or-N=]. This preparation method is a method for preparing a benzotriazole or benzimidazole compound represented by the formula (4-c) by dehydrating an acid amide compound represented by the formula (4-b), obtained using a carboxylic acid compound represented by the formula (4-a) as a starting material. The step represented by Step 4-1 is a reaction for condensing a carboxylic acid compound with ammonia represented by the formula (4-a), and constructing an acid amide group represented by the formula (4-b). The compound represented by the formula (4-a) can be used in the reaction as free acid, but a reactive derivative thereof may also be used in the reaction. Examples of the reactive derivative induced from the compound represented by the formula (4-b) include acid halides such as acid chloride and acid bromide; common esters such as methyl ester, ethyl ester, and benzyl ester; acid azides; active esters such as HOBt, p-nitrophenol, and N-hydroxysuccinirnide; symmetrical acid anhydrates; a mixed acid anhydrate of a halocarboxylic acid alkyl ester such as an alkyl carbonic acid halide, a pivaloyl halide, and p-toluene sulfonic acid chloride; and a mixed acid anhydrate such as a mixed phosphoric mixed acid anhydrate, such as those obtained by the reaction of diphenylphosphoryl chloride with N-methyl morpholine. In a case where the compound represented by the formula (4-a) is reacted as a free acid, or without isolation to an active ester, or the like, a condensing agent such as DCC, CDI, DPP A, diethylphosphoryl cyanide, and EDCI/HC1 is preferably used. The reaction solvent varies depending on a reactive derivative or a condensing agent to be used, but the reaction is carried out in an organic solvent inert to the reaction such as hydrocarbon halides, aromatic hydrocarbons, ethers, esters such as EtOAc, acetonitrile, DMF, and DMSO, or a mixed solvent thereof. Also, the reaction is carried out under cooling, from under cooling to at room temperature, or from at room temperature to under heating. Furthermore, in the reaction, it is in some cases advantageous in advancing the reaction smoothly to carry out the reaction with an excessive amount of ammonia or in the presence of a base such as N-methylmorpholine, trimemylamine, Et3N, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline, and lutidine. Pyridine may be used in combination with the solvent. The step represented by Step 4-2 is dehydration, for which a base may or may not exist, and a dehydrating agent such as trifluoroacetic anhydrate, POCI3, and P2O5 may be used. Furthermore, in a case for synthesizing a condensed, intermediate heterocycle other than those described in the above-described intermediate preparation methods, the methods described in Reference Examples or Examples in the present specification, or equivalent methods may be employed, or additionally, well-known methods or methods apparent to a person skilled in the art can also be used for the preparation. [wherein A, X, R1, and R4 are as described above. Lv represents a leaving group. A carboxylic acid represented by the formula (5-c), (5-d), and (5-g) can be purchased as a commercially available product, or prepared to a commercially available product]. This preparation method is a method for preparing the compound of the present invention represented by the formula (I) by reacting a hydroxyamidine represented by the formula (5-b) obtained by allowing hydroxylamine to undergo the reaction with an aromatic nitrile compound represented by the formula (5-a), with a carboxylic acid represented by the formula (5-c). In a step represented by Step 5-1, the hydroxyamidine represented by the formula (5-b) can be prepared by allowing a free hydroxylamine or hydroxylamine hydrochloride to undergo the reaction in the presence of a base. This reaction can be carried out in a solvent inert to the reaction. Specific examples of the solvent include alcohols such as MeOH, EtOH, and i-PrOH; aromatic hydrocarbons such as toluene and xylene; ethers such as ether, THF, dioxane, and diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; acetonitriles; aprotic polar solvents such as DMF, l,3-dimethyl-2-imidazolidinone, and DMSO; water; or a mixed solvent thereof. Usually, alcohols are used in the reaction. As described above, in a case where hydroxylamine hydrochloride is used in this reaction, the reaction is preferably used in the presence of a base, and specific examples of the base include alkali carbonates such as Na2C03 and K2CO3; alkali hydrogen carbonates such as ( NaHCC>3 and KHCO3; alkoxides such as NaOMe, NaOEt, and KOlBu; tertiary amines such as Et3N and DIPEA; and organic amines such as DBU, pyridine, and lutidine. The reaction temperature varies depending on the kinds of the starting material compounds, the reaction conditions, or the like, but the reaction can be carried out usually from at room temperature to at about a reflux temperature of the solvent. Typically, in the presence of a base such as Na2C(>3, the reaction can be carried out in an organic solvent inert to the reaction, such as MeOH, from at room temperature to under heating. The step represented by Step 5-2 consists of two steps, i.e., a step of acylation of a hydroxyamidine product, and a step of a cyclization reaction in this order. The acylation step can be carried out in the following manner. The compound represented by the formula (5-c) can be used in the reaction as a free acid, but a reactive derivative thereof may also be used in the reaction. Examples of the reactive derivative include acid halides such as acid chloride and acid bromide; common esters such as methyl ester, ethyl ester, and benzyl ester; acid azides; active esters such as HOBt, p-nitrophenol, and N-hydroxysuccinimide; symmetrical acid anhydrates; a mixed acid anhydrate of a halocarboxylic acid alkyl ester such as an alkyl carbonic acid halide, a pivaloyl halide, and p-toluene sulfonic acid chloride; and a mixed acid anhydrate such as a mixed phosphoric mixed acid anhydrate, such as those obtained by the reaction of diphenylphosphoryl chloride with N-methyl morpholine. 1 In a case where the compound represented by the formula (5-c) is reacted as a free acid, or without isolation to an active ester, or the like, a condensing agent such as DCC, CDI, DPP A, diethylphosphoryl cyanide, and EDCI/HC1 is preferably used. The reaction solvent varies depending on a reactive derivative or a condensing agent to be used, but the reaction is carried out in an organic solvent inert to the reaction ) such as hydrocarbon halides, aromatic hydrocarbons, ethers, esters such as EtOAc, acetonitrile, DMF, and DMSO, or a mixed solvent thereof, under cooling, from under cooling to at room temperature, or from at room temperature to under heating. In the reaction, the reaction may be smoothly advanced in some cases to parry out the reaction in the presence of a base such as N-methylmorpholine, trimethylamine Et3N, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline, and lutidine. Also, pyridine may be used in combination with the solvent. An acylated product as an intermediate can be purified by isolation, and heated in an organic solvent inert to the reaction, such as EtOH, dioxane, toluene, and water. Usually, this two-step reaction can be carried out in one operation, by heating or microwave-radiating the product as it is or as a reaction mixture, after acylation. Specific examples of the solvent include aromatics such as toluene, xylene, and pyridine; ethers such as diethyl ether, THF, dioxane, and diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; acetonitriles; aprotie polar solvents such as DMF, DMA, l,3-dimethyl-2-imidazolidinone, NMP, and DMSO; water; or a mixed solvent thereof. The reaction temperature varies depending on the kinds of the starting material compounds, the reaction conditions, or the like, but the reaction can be carried out usually from at room temperature to under heating. [0031] In a case where X represents -O- or -NH-, synthesis can be made by the following preparation method. The steps represented by Step 5-3 and Step 5-5 can be carried out in the same manner as the step represented by Step 5-2. The steps represented by Step 5-4 and Step 5-6 are steps for preparing the compound of the present invention represented by the formula (I) by allowing phenol, aniline, alcohol, or amine represented by the formula (5-e) or the formula (5-i) to undergo the reaction with a compound having a leaving group, represented by the formula (5-f) or the formula (5-h). Here, examples of the leaving group include halogens such as chlorine and bromine; and sulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and trifluoromethanesulfonyloxy. The reaction is carried out at normal pressure or under elevated pressure, without a solvent or in an appropriate solvent. Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and methylethylketone; ethers such as ether, THF, dioxane, and diethoxyethane; alcohols such as MeOH, EtOH, i-PrOH, and n-BuOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; acetonitriles; aprotic polar solvents such as DMF, [,3-dimethyl-2-imidazolidinone, NMP, and DMSO; water; or a mixed solvent thereof. This reaction is preferably used in the presence of a base, and specific examples of the >ase include NaH; alkali carbonates such as Na2CC>3 and K2CO3; alkali hydrogen carbonates such as NaHCC>3 and KHCO3; alkoxides such as NaOMe, NaOEt, and iCOlBu; tertiary amines such as Et3N, tributylamine, and DIPEA; and organic amines iuch as DBU, pyridine, and lutidine, but an excessive amount can be combined in an unine represented by -the formula (5-e) or the formula (5-i). The reaction temperature, varies depending on the kinds of the starting material compounds, the reaction conditions, or the like, but the reaction can be carried out usually from at room emperature to at about a reflux temperature of the solvent. Usually, the reaction can 5e carried out in the presence of a base such as NaH and Na2CC>3, in an organic solvent nert to the reaction, such as DMF and DMA, from at -10°C to under heating. Also, :he amine represented by the formula (5-e) or the formula (5-i) can be provided for the ■eaction as a salt thereof. In addition, a microwave may be radiated under heating for he preparation. [0032] Moreover, several compounds represented by the formula (I) can be prepared oy any combination of well-known processes that can be usually employed by a person skilled in the art, such as well-known alkylation, acylation, substitution reaction, Dxidation, reduction, hydrolysis, deprotection, and halogenation from the compound of the present invention as prepared in the above-described manner. For example, for alkylation, the alkylation reaction that can be usually used by a person skilled in the art can be employed, which can be carried out in an organic solvent inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons such as dichloroethane, dichloroethane, and chloroform; DMF, acetonitriles; and aprotic polar solvents, under cooling, from under cooling to at room temperature, or from at room temperature to under heating, in the presence of a base such as NaH; alkali carbonates; alkali hydrogen carbonates; alkoxides; tertiary amines; and organic bases. Furthermore, for example, for acylation, the acylation reaction that can be usually used by a person skilled in the art can be employed, which can be particularly carried out in the presence of HOBt, in a solvent varying depending on a condensing agent such as EDCI/HC1 or CDI, and diphenylphosphorylcyanide, in a solvent varying depending on the reaction condition, but usually in an organic, inert solvent such as ethers; aromatic hydrocarbons; halogenated hydrogen such as dichloromethane, dichloroethane, and chloroform; esters such as EtOAc; acetonitriles; and aprotic solvents, under cooling, from under cooling to at room temperature, or from at room temperature to under heating. [0033] Thus prepared compound is purified by isolation, as it is, or as a salt thereof after a salt-forming treatment by a conventional method. The purification by isolation is carried out by applying common chemical operations such as extraction, concentration, removal by distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various types of the isomers can be isolated by a conventional method, taking advantage of the difference in the physiochemical properties among the isomers. For example, a racemic mixture can be induced into optically pure isomers, for example, by a general resolution method for racemic products, such as an optical resolution method for inducing diastereomer salts with general, optically active acids such as tartaric acid. Also, the diastereomer mixture can be separated, for example, by fractional crystallization, or various types of chromatography. Furthermore, the optically active compounds can also be prepared by using the corresponding, optically active starting materials. [0034] The actions of the compounds of the present invention were confirmed by the following pharmacological tests. [0035] Experimental Example 1: Test for confirming an SI Pi agonist activity [0036] 1) Evaluation of a receptor agonist activity by a GTP[y-35S] bond assay using the membrane of a human SI Pi expressing cell The in vitro SI Pi agonist activity of the compound of the present invention was evaluated by the increase in the functional bonding activity into the G-Protein of a GTP[y-35S] using the membrane of a human SIPi expressing cell. A cDNA encoding a human SIPi was cloned from a human colorectal cDNA library, and introduced to an expression vector pcDNA3.1 to construct a SlPi-pcDNA3.1. Then, by Lipofectamine 2000 (GIBCO), the SIPrpcDNA3.1 was transfected into a CHO cell, and cultured in a Ham's F-12 culture medium containing 10% fetal bovine serum, 100 U/mL Penicillin, 100 ug/mL Streptomycin, and 1 mg/mL G418 disulfate, to obtain a stable, G418-resistant strain. The cultured human SI Pi expressing cells were isolated in a 1 mM EDTA/2Na-containing PBS, and disrupted under ice-cooling by a homogenizer made of glass in a 1 mM Tris HC1 (pH 7.4) buffer solution containing 0.1 mM EDTA and a protein inhibitor. It was centrifuged at 1,400x 10 min, and a supernatant was further centrifuged at 4°C for 60 min at 100,000xg, and suspended in a 10 mM Tris HC1 (pH 7.4) buffer solution containing 1 mM EDTA. The obtained membrane (0.13 mg/mL) and 50 pM GTP[y-35S] (NEN; inactive 1250 Ci/mmol) were reacted in a 20 mM HEPES (pH 7.0) buffer solution (total amount: 150 uL) containing 100 mM NaCl, 10 mM MgCl2, 0.1% fatty acid-free BSA, and 5 uM GDP for 1 hour together with the compound of the present invention (10'12 to 10"5 M), and then a membrane was recovered on a GF-C plate with a Cell Harvester (Packard, FilterMate). The FilterMate was dried at 50°C for 60 min, and Microscinti-o (Packard) was added thereto for measurement by a liquids scintillation counter for a microplate (Packard, TOP count). For evaluation of the human S1P i agonist activity of the compound of the present invention and the comparative compound, the percentages with the rate of a maximum reaction to make the GTP[y-35S] bonds saturated in the presence of the compound being set at 100%, and the rate of the reaction of the GTP[y-35S] bonds in the absence of the compound being set at 0% was used, a non-linear regression curve was plotted, and a concentration to cause an agonist activity operating 50% of the maximum reaction was defined as an EC50 value (nM). [0037] [Table 1] [0038] As a result, it can be confirmed that the compound of the present invention has an SIPi agonist activity. [0039] 2) Evaluation of peripheral blood lymphopenia in rat The peripheral blood lymphopenia in rat was measured at 24 hours after oral administration in the following manner. Six- to ten-week-old male Lewis rats (Japan Charles river laboratories) were randomly divided into the groups (n=3), and the compound of the present invention was suspended in 0.5% methyl cellulose-containing distilled water, and orally administered with a sonde. At 24 hours after administration, under ether anesthesia, 0.2 ml of blood was collected from ocular fundus. To the o A blood sample were immediately added EDTA/4K and heparin to prevent clotting, and the number of the lymphocytes in blood was measured with an automatic haematology analyzer (Sysmex Corp.; XT-2000i). For the reduction of the number of the lymphocytes in peripheral blood by the compound of the present invention, the percentage with the number of the lymphocytes in groups administered with 0.5% methyl cellulose-containing distilled water being set at 100%, as performed at the same time was used, and the dose to cause 50% reduction of the number of the lymphocytes in peripheral blood by administration of the compound of the present invention was defined an ED50 value (mg/kg). [0040] For the comparative compounds 1 and 2 as described in the pamphlet of International Publication No. WO2004/103279, the comparative compound 3 as pamphlet of International Publication No. WO2005/032465, and the compound of Example 119, the ED50 values at 24 hours after administration were compared for the reduction of the number of the lymphocytes in peripheral blood in rat. [0042] As a result, it was demonstrated that the compound of Example 119 shows a high ED50 value even after 24 hours, indicating persistence. [0043] Since the compound of the present invention has an SIPi agonist effect, it is useful as an active ingredient of an agent for treating or an agent for preventing a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or a tissue or a graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, or ischemia-reperfusion injury or an inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells, such as cancer and leukemia. Furthermore, the compound of the present invention is useful to treat and/or prevent the following diseases, based on the agonist activity against an SIPi. It is useful to treat and/or prevent inflammatory or hyperplastic skin diseases such as psoriasis, contact dermiatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, hives, vascular edema, obliterans, erythema, eosinophilia of skin, lupus erythematosus, acne, and alopecia areata, or expression of skin diseases through an immune system; autoimmune diseases or allergic diseases of eyes, such as keratoconjunctivitis, vernal conjunctitis, allergic conjunctivitis, uveitis associated with Behcet disease, keratitis, Herpesviral keratitis, Keratoconus keratitis, corneal epithelial dystrophies, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada disease, leratoconjunctivitis sicca (dry eye), vesicle, iridocyclitis, sarcoidosis, and - . ophthalmic diseases inendocrine glands; reversible obstructive lung diseases (asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dirt asthma), in particular, chronic or difficult asthma (for example, late-onset asthma, and airway diseases); mucous or angiitis (for example, gastric ulcers, ischemic or thrombotic Vascular Injuries, age-related maculopath, diabetic maculopath, ischemic bowel disease, bowel disease, necrotizing enteritis, intestinal tract lesion by heat burn, and diseases by a transmitter of a Leukotriene B4); inflammatory intestine or allergic diseases of intestine, including, for example, proctitis, eosinophilic enteritis, mastocytosis, celiac disease, Crohn's disease, and ulcerative colitis; food-related allergic diseases expressing the conditions on a site that is remote from the gastro-intestinal tract including, for example, migraine, rhinitis, and eczema; autoimmune diseases or inflammatory diseases including, for example, primary mucous edema, autoimmune atrophic gastritis, precocious climacteric period, juvenile diabetes, pemphigus vulgaris, pemphigoid, sympathetic ophtalmolima, lens-induced uveitis, paroxysmal Leukopenia, chronic active hepatitis, paroxysmal liver cirrhosis, discoid lupus erythematosus, Sjoegren syndrome, autoimmune orchitis, arthritis (for example, modified arthritis), and polychondritis; renal diseases including, for example, membranous nephrophathy, membranoproliferative nephritis, focal global glomerulosclerosis, crescent nephritis, glomerular nephritis, IgA nephropathy, tubulopathy interstitial nephritis, and diabetic nephropathy. Furthermore, the compound of the present invention is also useful to ( treat and/or prevent liver diseases (for example, immunogenic diseases (for example, autoimmune lever diseases, chronic autoimmune lever diseases such as primary biliary cirrhosis., sclerosing cholangitis, and the like), partial hepatic dissection, acute hepatic necrosis (for example, necrosis caused by toxin, viral hepatitis, shock, anoxia, or the like), Type B hepatitis, non-Type A hepatitis, cirrhosis, heptatic failure (for example, fulminant hepatitis, late-onset hepatitis, hepatic failure (acute hepatic failure or chronic hepatic disease)), and the like. In addition, compound of the present invention can be administered as an SI Pi agonist alone, or in combination with at least one agent, in the same dose or different doses, through the same or different administration routes. Examples of the agent that can-be combined include, but not limited thereto, cyclosporin A, tacrolimus, sirolimus, everolimus, mycophenolate, azathioprine, brequinar, Leflunomide, fingolimod, an anti-IL-2 receptor antibody (for example, daclizumab), an anti-CD3 antibody (for example, OKT3), anti-T cell immunoglobulin (for example, AtGam), belatacept, abatacept, cyclophosphamide, p-interferone, aspirine, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroid (for example, prednisolone, and dexamethasone). [0044] A preparation containing the compound represented by the formula (I), or one, or two or more kinds of the salts thereof as effective ingredients are prepared by using a carrier, an excipient or other additives that are usually used in the preparation of medicines. Administration may be made in any one form for either oral administration by tablets, pills, capsules, granules, powders, and solutions, or for parenteral administration by injections for intravenous injection, and intramuscular injection, suppositories, percutaneous preparations, transnasal preparations, inhalations or the like. The dose is appropriately decided in response to an individual case by taking the symptoms, age and sex of the subject and the like into consideration, but is usually from about 0.001 mg/kg to about 100 mg/kg per day per adult in the case of oral administration, and this is administered in one portion or dividing it into 2 to 4 portions. Also, in the case of intravenous administration according to the symptoms, it is administered usually within the range of from 0.0001 mg/kg to 10 mg/kg per day per adult, once a day or two or more times a day. In addition, in the case of inhalation, it is administered generally within the range of from 0.0001 mg/kg to 1 mg/kg per adult, once a day or two or more times a day. Regarding the solid composition of the present invention for oral administration, tablets, powders, granules, or the like are used. In such a solid composition, one or more active substances are mixed with at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and aluminum magnesium silicate. In a conventional method, the composition may contain inactive additives, for example, a lubricant such as magnesium stearate, a disintegrator such as carboxymethylstarch .,, .. sodium, or a solubilizing agent. As occasion demands, tablets or pills may be coated with a sugar coating, or a gastric or enteric coating agent. [0045] The liquid composition for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and contains generally used inert solvents such as purified water and ethanol. In addition to the inert solvent, this composition may contain an auxiliary agent such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a corrective, an aromatic, and an antiseptic. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Pharmacopeia). Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, and a solubilizing agent. These are sterilized, for example, by filtration through bacteria retaining filter, blending of bactericides, or irradiation. In addition, these can also be used by producing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use. Regarding a transmucosal agent such as an inhalations and a transnasal agent, those in a solid, liquid or semi-solid state are used, and may be produced in accordance with a conventionally known method. For example, an excipient such as lactose and starch, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be optionally added thereto. For their administration, an appropriate device for inhalation or blowing may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension by combining it with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule,may be used. ......,,. Alternatively, this may be in a form such as a high pressure aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, and carbon dioxide. The external agent includes ointments, plasters, creams, jellies, paps, sprays, lotions, eye drops, eye ointments, and the like. The external agent contains ointment bases, lotion bases, aqueous and non-aqueous liquids, suspensions, emulsions, and the like, for general use. Examples of the ointment or lotion bases include polyethylene glycol, propylene glycol, white Vaseline, white beeswax, polyoxyethylene hardened castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate. Example [0046] Hereinafter, the compounds of the present invention will be described in more detail with reference to Examples. The present invention is not limited to the inventions as described in the following Examples. The preparation methods of the starting material compounds are shown in Preparation Examples. [In the following tables, Pr represents Preparation Example No., and Structure represents a structural formula. As the abbreviation symbols in the structural formulae, Me represents a methyl group, and Et represents an ethyl group. Criss-cross double bond represents a cis/trans mixture, and if the section of Data describes only the numbers, it shows MS data. MS represents mass spectrometry data. In the tables, RT refers to a retention time in high performance liquid chromatography (HPLC), and M represents minutes. The condition for HPLC is as follows: column: Intertsil ODS-34.6x150 mm, eluent 0.01M KH2P04 aq./MeCN(3:7), flow rate: 1.0 ml/min, detection wavelength: 254 nm. If ^-NMR data are described in the tables, tetramethylsilane is used as an internal standard, and unless otherwise specifically mentioned, 8 (ppm) (integrated values, variation patterns) of the signals in ^-NMR using DMSO-d6 as a measurement solvent is shown. Abbreviation symbols have the same meanings as follows. S: singlet, d: doublet, t: triplet q: quartet dd: double doublet, ddd: double double doublet, dt: double triplet, dm: double multiplet, br: broad, brs: broad singlet, Hz: Hertz, CDCI3: deuterated chloroform, DMSO-d6: dimethylsulfoxide-d6, and in the present specification, NMR represents 'fl-NMR: proton nuclear magnetic resonance. The same shall apply hereinafter]. [0047] Preparation Example 1 Imidazo[l,2-a]pyridine-7-carbonitrile hydrochloride (1.50 g), hydroxylamine hydrochloride (301 mg), and Na2CC»3 (3.50 g) were stirred at 60°C for 6 hours in CH3OH (57 ml). The reaction solution was cooled and concentrated, and completion of the reaction was confirmed by LC-MS. To the residue was added water, followed by extraction twice with EtOAc. The organic layer was washed with water and saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated to obtain N'-hydroxyimidazo[l,2-a]pyridine-7-carboxamide (850 mg) as a white solid. [0048] The compounds shown in Pr 1-1 through Pr 1-17 were prepared in the same manner as in Preparation Example 1. [0050] Preparation Example 2 /- In a 50 ml reaction vessel, to a solution of lH-indole-4-carbonitril^ [0051] The compounds shown in Pr 2-1 through Pr 2-26 were prepared in the same manner as in Preparation Example 2. [0055] Preparation Example 3 A suspension of N -hydroxy-lH-indole-4-carboxamide (1.00 g), 4-fiuoro-3-(trifluoromethyl)benzoic acid (1.19 g), and EDCI/HC1 (1.32 g) in dioxane (30 ml) was stirred at room temperature for 1 hour, and further heated under reflux for 18 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added thereto, followed by stirring. The insolubles were collected by filtration. The organic layer of the mother liquor was washed with water, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The insolubles collected by filtration, together with the mother liquor, was purified by silica gel chromatography (n-hexane:EtGAc=80:20). To the objective substance was added acetone, followed by dissolving under heating, and addition with n-hexane, and the precipitated solid was collected by filtration to obtain 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (391 mg) as a white solid. [0056] i [0057] Preparation Example 4 5 N2- {[(5,6-Dichloropyridin-3 -yl)carbonyl] oxy} -1 H-indole-4-carboxamidine (1.91 g) was added to dioxane (40 ml), followed by heating under reflux for 5 hours. It was concentrated under reduced pressure, and then purified by silica gel column chromatography (EtOAc). To the obtained solid was added acetone, followed by suspension under heating. After being left to be cooled, the insolubles was collected by filtration to obtain 4-[5-(5,6-dichloropyridin-3-yl)-l,2,4-oxadiazol-3-ylplH-indole (1.44 g) as pale yellow powders. [0058] [0059] Preparation Example 5 A solution of N2-hydroxy-lH-indole-4-carboxamide (3.42 g) and 4-fluoro-3-(trifluoromethyl)benzoic acid (4.07 g) in THF (70 ml) was cooled to -10°C or lower, and added with DIC (3.7 ml). After stirring at -15 to -5°C for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in chloroform, and then the insolubles were collected by filtration. The obtained powders were purified by silica gel chromatography (n-hexane:EtOAc=50:50) to obtain N -{[4-fluoro-3-(Mfluoromethyl)benzoyl]oxy}-lH-indole-4-carboxamide (8.40 g) as a white solid. [0060] The compound shown in Pr 5-1 was prepared in the same manner as in Preparation Example 5. [0062] Preparation Example 6 To a solution of 6-amino-2-methylnicotinonitrile (960 mg) in ethanol (34 ml) was added a 40% aqueous chloroacetaldehyde solution (2.36 ml) at 60°C. The reaction mixture was refluxed for 8 hours. The resulting precipitates were collected by filtration to obtain 5-methylimidazo[l,2-a]pyridine-6-carbonitrile hydrochloride (580 mg) as a white solid. [0063] The compounds shown in Pr 6-1 through Pr 6-11 were prepared in the same manner as in Preparation Example 6. [0066] Preparation Example 7 To a solution of 3,4-diaminobenzonitrile (500 mg) in AcOH (10 ml) was added Ac20 (372 \|xt) at room temperature. The reaction mixture was refluxed for 15 hours (oil bath at 150°C). It was cooled to room temperature, and concentrated until the amount of AcOH was reduced to a half. It was neutralized with an aqueous Na2CC>3 solution, and extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCC>3 solution and saturated brine, dried over anhydrous MgSd, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 2-methyl-lH-benzimidazole-5-carbonitrile (390 mg) as a pale red one. [0067] [Table 12] [0068] Preparation Example 8 A reaction mixture of 4,5-diamino-2-methylbenzonitrile (20 mg) and formic acid (6 ml) was refluxed for 3 hours. The reaction solution was cooled and concentrated. To the residue was added a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSCU, and then filtered, and the filtrate was concentrated to obtain 5-methyl-lH-benzimidazole-6-carbonitrile as colorless powders. [0069] The compound shown in Pr 8-1 was prepared in the same manner as in Preparation Example 8. [0071] Preparation Example 9 A solution of 3,4-diaminobenzonitrile (400 mg) in ethyl orthoformate (6.48 ml) was added AcOH (238 mg), followed by stirring at 80°C for 2 hours. The reaction solution was cooled to room temperature, and partitioned between EtOAc and a 1M aqueous NaOH solution. The organic layer was washed with saturated brine, dried over anhydrous Na2S03, and then collected by filtration, and the filtrate was concentrated, and purified by silica gel chromatography to obtain 2-ethoxy-lH-benzimidazole-6-carbonitrile (164 mg) as colorless powders. [0072] [Table 14] [0073] Preparation Example 10 i To a suspension of 3,4-diaminobenzonitrile (400 mg) in CH3OH (4 ml) was added BrCN (477 mg), followed by stirring at 20°C for 14 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by concentration. To the residue was added chloroform:CH3OH=10:l (10 ml), and the resulting insolubles were removed by filtration. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 2-amino-lH-benzimidazole-6-carbonitrile (311 mg) as pale orange color powders. [0074] [Table 15] [0075] Preparation Example 11 To a solution of 3,4-diaminobenzonitrile (350 mg) in toluene (5.5 ml) was added CDI (554 mg), followed by stirring at 125°C for 2 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by extraction with EtOAc. The organic layer was dried over anhydrous Mgs04, and then filtered, and the filtrate was concentrated. It was powdered/washed with IPE/IPA to obtain 2-oxo-2,3-dihydro-lH-benzimidazole-5-carbonitrile (423 mg) as colorless powders. [0076] [Table 16] [0077] Preparation Example 12 To a mixed solution of N-(4-cyano-2-nitrophenyl)penta-4-enamide (1.0 g) in AcOH/ethanol (1:1,20 ml) was added iron powders (710 mg). The reaction solution was heated at 110°C for 3 hours, and then concentrated. To the residue was added chloroform, followed by neutralization with a saturated aqueous NaHCC>3 solution. The organic layer was dried over anhydrous MgSC>4, and then filtered to remove a desiccant, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-butenyl-lH-benzimidazole-5-carbonitrile (405 mg) as a colorless liquid. [0078] The compounds shown in Pr 12-1 through Pr 12-2 were prepared in the same manner as in Preparation Example 12. [0079] [Table 17] [0080] Preparation Example 13 To a solution of 2-fluoroterephthalonitrile (500 mg) and Et3N (572 ul) in EtOH (20 ml) was added hydrazine (monohydrate), followed by reaction at 60°C for 16 hours, and concentrated. The residue was washed with diethyl ether to obtain 3-amino- 1H-indazole-6-carbonitrile (488 mg) as a yellow solid. [0081] The compound shown in Pr 13-1 was prepared in the same manner as in Preparation Example 13. [0082] [Table 18] [0083] Preparation Example 14 To a suspension of 3-amino-lH-indazole-6-carbonitrile (345 mg) in AcOH was ( slowly added an aqueous NaN02 solution (301 mg) at 0°C. It was stirred at room temperature for 2.5 days, and the residue was collected by filtration, and washed with cool water. To the residue were added 0.1M HC1 and DME, followed by stirring at 80°C for 2 hours. The reaction mixture was neutralized with a saturated aqueous NaHCC>3 solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSC>4, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 50:50) to obtain lH-indazole-6-carbonitrile (175 mg) as a yellow solid. [0084] [Table 19] [0085] Preparation Example 15 Methyl (4-cyano-2-nitrophenyl)acetate (128 mg) was dissolved in AcOH (3.0 ml), followed by addition of iron powders (129 mg), and the reaction solution was ) stirred in an oil bath at 100°C for 1.5 hours. It was concentrated to remove AcOH, followed by addition of EtOAc. The brown solid was separated by filtration, and the organic layer was washed with a 1M HC1 solution and saturated brine, dried over anhydrous MgS04, and concentrated. The residue was purified by silica gel column chromatography (chloroform:CH30H=99:l to 95:5) to obtain to obtain 2-oxoindoline-6-j carbonitrile (52.0 mg) as a pale yellow solid. [0086] [Table 20] [0087] Preparation Example 16 To a solution of 6-bromo-2,2-dimethylindanemethylindan-l-one (124 mg) in TFA (4.44 g, 3.0 ml) was added triethylsilane (150 mg, 207 ul) at room temperature. After stirring at room temperature for 2.5 days, to the reaction solution was added water to stop the reaction, followed by washing with water and a saturated aqueous NaHC03 solution. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane only) to obtain 5-bromo-2,2-dimethylindane (114 mg) as a colorless oil. [0088] [Table 21] [0089] Preparation Example 17 In THF (30 ml), to a mixture of 6-bromo-l-indanone (300 mg) and diazomethane (504 mg, 221 ul) was added 60% NaH (125 mg) at 0°C. It was stirred at room temperature for 3.5 hours, and washed with a saturated NH4CI solution. The mixture was extracted with EtOAc, and the organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=100:0 to 80:20) to obtain 6-bromo-2,2-dimethyl-l-indanone (158 mg) as a pale yellow oil. [0090] [Table 22] [0091] Preparation Example 18 To a solution of 3-amino-4-hydroxybenzonitrile (730 mg) in DMF (10 ml) was added CDI (1.06 g) at 0°C, followed by stirring at room temperature for 3.5 hours. The reaction solution was diluted with water (10 ml), and extracted with EtOAc (200 ml). The organic layer was dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH30H-98:2 to 93.7) to obtain 2-oxo-2,3-dihydro-l,3-benzoxazole-5-carbonitrile (647 mg) as a pale yellow solid. [0092] The compound shown in Pr 18-1 was prepared in the same manner as in Preparation Example 18. [0093] [Table 23] [0094] Preparation Example 19 To a solution of 60% NaH (12.38 g) in DMF (480 ml) was added a solution o1 lH-indole-4-carbonitrile (40.0 g) in DMF (80 ml) at 0°C. After stirring at 0°C for 30 min, it was stirred at room temperature for 0.5 hour. Thereafter, a solution of 2-bromoacetamide (40.76 g) in DMF (80 ml) was added dropwise thereto at 0°C. The solution was warmed from 0°C to room temperature, and stirred for 12 hours. To the reaction solution was added water (1200 ml), and the precipitated white solid was collected by filtration. The solution was washed with hot water (300 ml) and diisopropyl ether (200 ml) to obtain 2-(4-cyano-lH-indol-l-yl)acetamide (52.1 g) as a white solid. [0095] [Table 24] [0096] Preparation Example 20 To a solution of 3-chloro-4-(2,2,2-trifluoro-l-methylethoxy)benzonitrile (430 mg) in IP A (3 ml) was added a 5M aqueous NaOH solution (1.37 ml), followed by stirring at 80°C for 24 hours, and a 5M aqueous NaOH solution (1.37 ml) was further added thereto, followed by stirring at 95°C for 24 hours. The reaction solution was concentrated until the amount was reduced to a half. To the residue was added 12M HC1, and the resulting precipitate was collected by filtration, and then dried to obtain 3-chloro-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid as a yellow solid. [0097] The compounds shown in Pr 20-1 through Pr 20-3 were prepared in the same manner as in Preparation Example 20. [0099] Preparation Example 21 To 3 [0100] The compounds shown in Pr 21-1 through Pr 21-6 were prepared in the same manner as in Preparation Example 21. [0102] Preparation Example 22 To 5-bromo-2-(2,2,2-trifluoro-l-methylethoxy)benzonitrile in a mixed solvent of toluene/THF (4:1) was added a solution of n-BuLi in n-hexane at -78°C. With passing a CO2 gas therethrough, the solution was stirred for 0.5 hour. To the reaction solution was added a 1M aqueous NaOH solution to complete the reaction, and followed by extraction with diethyl ether. The organic layer was acidified by adding 1M HC1, extracted with EtOAc, dried over anhydrous MgS04, and concentrated. The residue was purified by silica gel chromatography (chloroform:CH30H=97:3 to 90:10) to obtain 3-cyano-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid as a white solid. [0103] The compound shown in Pr 22-1 was prepared in the same manner as in Preparation Example 22. [0105] Preparation Example 23 To a mixed solution was added a 1M aqueous NaOH solution (4.1 ml) of methyl l-isobutyl-2-oxo-l,2-dihydropyridine-4-carboxylate (430 mg) in CH3OH-THF (4 ml - 3 ml). The solution was stirred at room temperature for 10 hours, and then > concentrated under reduced pressure, and water (10 ml) was added, and subsequently 1M HC1 was added thereto until pH becomes 3. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain l-isobutyl-2-oxo-l,2-dihydropyridine-4-carboxylic acid (325 mg) as white powders. [0106] [Table 28] [0107] Preparation Example 24 ) A solution of lH-benzimidazole-5-carboxylic acid (75.0 g) in dichloromethane (750 ml) was allowed to be reacted with oxalyl chloride (76.3 g, 52.4 ml) at room temperature for 1 hour, and then the reaction solution was concentrated. To a solution of the residue in THF (750 ml) was added a 28% aqueous NH3 solution (5 ml) under ice-cooling. This reaction mixture was stirred at the same temperature, and the A O reaction solution was concentrated. The purple residue was powdered/washed with IPE/IPA, and then collected by filtration to obtain lH-benzimidazole-6-carboxamide (129 g) (including inorganic salts). [0108] The compound shown in Pr 24-1 was prepared in the same manner as in Preparation Example 24. [0109] [Table 29] [0110] Preparation Example 25 Preparation Example 254 To a solution of lH-l,2,3-benzotriazole-5-carboxylic acid (2 g), EDCI/HC1 (2.82 g), and HOBt in DMF (70 ml) was added an aqueous NH3 solution (5.1 ml), followed by reaction at room temperature for 2 hours. It was concentrated, and the residue was washed with a saturated NaHC03 solution, collected by filtration, and dried to obtain 1H-1,2,3-benzotriazole-5-carboxamide (1.98 g) as a black solid. Preparation Example 25-3 In a 50 ml reaction vessel, to a solution of methyl 4-chloro-2-methyI-lH-benzimidazole-6-carboxylate ester (300 mg) in formamide (2.65 ml) was added NaOCH3 (288 mg) at room temperature. The solution was stirred at 80°C for 3 hours. Completion of the reaction was confirmed by TLC and LC, and then the reaction solution was concentrated, and added with water to complete the reaction. It was extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain 4-chloro-2-methyl-lH-benzimidazole-6-carboxamide (257 mg) as a white solid. ../ [0111] The compound shown in Pr 25-2 was prepared in the same manner as in Preparation Example 25-1. [0112] [Table 30] i [0113] Preparation Example 26 To a solution of 3-formyl-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid (490 mg) and K2C03 (387 mg) in acetone (10 ml) was added iodomethane (350 ul) at room temperature, followed by stirring for 2 hours. The reaction mixture was diluted with i water (15 ml), and extracted with EtOAc (30 ml). The organic layer was dried over anhydrous MgS04, and filtered to remove the desiccant, and the solvent was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain methyl 3-formyl-4-(2,2,2-trifluoro-l-methylethoxy)benzoate (122 mg) as a white solid. [0114] [Table 31] [0115] Preparation Example 27 Under ice-cooling, to DMF (30 ml) was slowly added dropwise POCI3 (6.68 g, 4.06 ml), followed by reaction at room temperature for 2 hours, and then a solution of lH-benzimidazole-6-carboxamide (2.38 g) in DMF (47.6 ml) was added thereto, followed by stirring at room temperature for 2 hours. To the solution was added a 1M aqueous NaOH solution (pH 6 to 7), followed by stirring at room temperature for 0.5 hour. The solution was extracted with EtOAc, and the organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, and powdered/washed with IPE to obtain lH-benzimidazole-6-carbonitrile (0.58 g) as a pale red crystal. [0116] The compounds shown in Pr 27-1 through Pr 27-2 were prepared in the same manner as in Preparation Example 27. [0118] Preparation Example 28 A solution of l,3-benzothiazole-6-carboxamide (1.96 g) in POCI3 (10 ml) was refluxed for 4 hours. The reaction solution was concentrated, and water was slowly added thereto at 0°C. It was extracted with EtOAc, and the organic layer was dried ! over anhydrous MgSCU, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 60:40) to obtain l,3-benzothiazole-6-carbonitrile as a pale yellow solid. [0119] The following Pr 28-1 was prepared in the same manner as in Preparation > Example 28. [0120] [0121] Preparation Example 29 [0122] To a solution of 6-bromo[l,2,4]triazolo[l,5-a]pyridine (400 mg) in DMF were added tris(dibenzylideneacetone)dipalladium (0), l'-bis(diphenylphosphino)ferrocene, and Zn(CN)2 under a nitrogen atmosphere, followed by stirring at 110°C for 23 hours. It was cooled to room temperature, and saturated NH4CI (12 ml), a saturated NH3 solution (6 ml), and H2O (12 ml) were added thereto. The reaction mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 to 5% CH30H/chloroform)[l,2,4]triazolo[l,5-a]pyridine-6-carbonitrile as a dark red solid. [0123] Preparation Example 30 In a 100 ml reaction vessel, to a solution of 6-bromo-7-methyl-lH-benzimidazole (500 mg) in DMF were added Zu(CN)2 (834 mg) and Pd (PPh)4 (547 mg) at room temperature, followed by stirring at 150°C for 5 hours. The reaction solution was poured into a 1:1 mixed solvent of a saturated NaHC03 solution and EtOAc, followed by stirring for 1 hour. The organic layer was washed with saturated brine, dried over anhydrous MgSCU, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (automatic purifier, chloroforrn:CH3OH=98:2 to 90:10) to obtain 7-memyl4H-benzimidazole-6-carbonitrile (161.8 mg) as a brown solid. [0124] The following Pr 30-1 through Pr 30-7 were prepared in the same manner as in Preparation Example 30. They were also prepared by the method as in Preparation Example 29. [0126] Preparation Example 31 To a mixed solution of 4-hydroxy-3-nitrobenzonitrile (1 g) andNH^Cl (163 mg) in ethanol (20 ml), THF (10 ml), and water (10 ml) were added Celite (5 g) and reduced iron (1.7 g), followed by heating under reflux at 70°C for 30 min. The i reaction solution was cooled to room temperature, diluted with EtOAc (200 ml), and then filtered through celite. The solution was washed with saturated brine, the organic layer was dried over anhydrous MgS04, and filtered, and the filtrate was concentrated under reduced pressure to obtain 3-amino-4-hydroxybenzonitrile (740 mg) as a pale brown solid. [0127] The following Pr 31-1 through Pr 31-3 were prepared in the same manner as Preparation Example 31. [0128] [Table 35] [0129] Preparation Example 32 To a mixed solution of 4-amino-3-nitrobenzonitrile (8 g) in EtOH/THF (40 ml/40 ml) was added Pd-C(50%wet) (0.8 g), followed by stirring under an H2 atmosphere for 12 hours. The reaction solution was filtered through celite, and concentrated. The residue was powdered/washed with a mixed solvent of IPE and IP A, and collected by filtration to obtain 3,4-diaminobenzonitrile (6.3 g) as orange powders. [0130] [Table 36] [0131] Preparation Example 33 To a solution of 2-amino-3-nitrobenzonitrile (2 g) in THF (30 ml) were added 4-pentenoyl chloride (2.90 g) and diisopropylethylamine (4.27 ml), followed by stirring at 80°C for 12 hours. The reaction solution was poured into water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH) to obtain N-(4-cyano-2-nitrophenyl)pent-4-enamide (174 mg) as a colorless liquid. [0132] The following Pr 33-1 through Pr 33-2 were prepared in the same manner as in Preparation Example 33. [0133] [Table 37] [0134] Preparation Example 34 To a solution of 3-chloro-4-fluorobenzonitrile (300 mg) and l,l,l-trifiuoro-2-propanol (263 mg) in THF (15 ml) was added 60% NaH (92.5 mg) at 5°C, followed by stirring at room temperature for 2 hours, addition of a saturated NH4CI solution to complete the reaction, and extraction with EtOAc. The obtained organic layer was dried over anhydrous MgS04, and concentrated. The residue was purified by silica gel chromatography (n-hexane:EtOAc=97:3 to 85:15) to obtain 3-chloro-4-(2,2,2-trifluoro-l-methylethoxy)benzonitrile (435 mg) as a colorless oily substance. [0135] The following Pr 34-1 through Pr 34-6 were prepared in the same manner as in Preparation Example 34. [0136] [Table 38] Preparation Example 35 In a 50 ml reaction vessel, to a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (100 mg) in DMF (1 ml) was added 60% NaH (10.9 mg) at 0°C. The solution was warmed to room temperature, followed by stirring for 0.5 hour. Further, tertiary-butyl (2-iodoethoxy)dimethylsilane was added thereto at 0°C, followed by stirring at room temperature for 15 hours. Completion of the reaction was confirmed by LC-MS, and then the reaction solution was added with water (30 ml). It was extracted three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and concentrated under reduced pressure. It was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=100:0 to 90:10) to obtain 1 -(2-{[tertiary-butyl (dimethyl)silyl]oxy}ethyl)-4-{5- [3-(trifiuoromethyl)-4-2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (86.4 mg) as a white solid. [0139] [Table 40] [0140] Preparation Example 36 LiH (78 mg) was suspended in DMF (5 ml), and a suspension of methyl-2-oxo-l,2-dihydropyridine-4-carboxylate (500 mg) in DMF (5 ml) was added dropwise thereto at room temperature. The suspension was stirred as it was, and a solution of l-iodo-2-methylpropane (506 ul) in DMF (5 ml) was added dropwise thereto over 10 min, followed by stirring at 50°C for 15 hours. To the reaction solution was added 1M HC1 at 0°C, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over anhydrous MgS04, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:EtOAc=90:10 to 50:50) to obtain methyl-1-isobutyl-2-oxo-l,2-dihydropyridine-4-carboxylate (440 mg) as white powders. [0141] [Table 41] [0142] Preparation Example 37 To a solution of 4-fluoro-3-nitrobenzonitrile (300 mg) and dimethyl malonate (286 mg) in DMF was added 60% NaH at 0°C, followed by reaction at room temperature to obtain dimethyl (4-cyano-2-nitrophenyl)malonate (T98 mg). [0143] [Table 42] [0144] Preparation Example 38 To a solution of dimethyl (4-cyano-2-nitrophenyl) malonate (198 mg) in DMSO (5 ml) were added LiCl (60.3 mg) and H20 (12 ul), followed by stirring at 100°C for 3 hours. The reaction solution was cooled to room temperature, and poured into EtOAc and saturated brine for partition. The organic layer was washed with saturated brine, dried over anhydrous MgSO, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n hexane:EtOAc=90:10 to 75:25) to obtain methyl (4-cyano-2-nitrophenyl)acetate ( mg) as a yellow oil. [0145] [Table 43] [0146] Preparation Example 39 To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1 g) and iron(3+) ris[(2Z)-4-oxopent-2-ene-2-oleate] (86 mg), and l-methylpyrrolidin-2-one (2.8 ml) in TfF (30 ml) was added a solution of 2M bromo(isobutyl)magnesium in diethyl ether 2.9 ml) under ice-cooling. The solution was stirred at room temperature for 30 ainutes, and diluted with diethyl ether (30 ml), and then IM HC1 was carefully added hereto to complete the reaction. The reaction solution was extracted with EtOAc (100 ril), and the organic layer was dried over anhydrous MgSC>4, and then filtered, and the iltrate was concentrated under reduced pressure. The residue was purified by silica ;el column chromatography (n-hexane:EtOAc=100:0 to 95:5) to obtain 4-isobutyl-3-trifluoromethyl)benzonitrile (320 mg) as a pale yellow liquid. [0147] The following Pr 39-1 was prepared in the same manner as in Preparation ixample 39. [0149] Preparation Example 40 To a solution of 4-fluoro-3-formylbenzonitrile (300 mg) in dichloromethane (7 ml) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-A-4-sulfanyI)ethanamine (757 mg) at room temperature, followed by stirring for 6 hours, and addition of a saturated aqueous NaHCCb solution (15 ml). After extraction with chloroform (30 ml), the organic layer was dried over anhydrous MgSCU, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain 3-(difluoromethyl)-4-fluorobenzonitrile (174 mg) as a colorless liquid. [0150] The following Pr 40-1 was prepared in the same manner as in Preparation Example 40. [0151] [0152] Preparation Example 41 The following Pr 41 -1 through Pr 41 -10 were prepared in the same manner as in Example 2. [0153] [Table 46] [0154] Preparation Example 42 The following Pr 42-1 through Pr 42-3 were prepared in the same manner as in Example 5. [0156] Preparation Example 43 The following Pr 43 was prepared in the same manner as in Example 6. [0157] [Table 48] [0158] Preparation Example 44 The following Pr 44-1 and Pr 44-2 were prepared in the same manner as in Example 12. [0160] Preparation Example 45 The following Pr 45 was prepared in the same manner as in Preparation nple 47. [0161] [Table 50] [0162] Preparation Example 46 The following Pr 46-1 through Pr 46-5 were prepared in the same manner as in riple 19. [0164] Preparation Example 47 To a solution of ethyl (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridin-2-yl)acetate(230 mg) in THF (2.0 ml) was added a 1M aqueous NaOH solution (1.0 ml), followed by 1 stirring at 80°C for 2 hours. After cooling to room temperature, a 1 M HC1 aqueous solution (1.0 ml) was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH30H=l 0:1 to 5:1) to obtain colorless powders. To a solution of this colorless powder in EtOAc was added a 4M HCl/EtOAc solution, followed by concentration. The resulting colorless powder was powdered/washed with IPE to obtain (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridin-2-yl)acetic acid hydrochloride (180.4 mg) as colorless powders. [0165] The following Pr 47-1 through Pr 47-13 were prepared in the same manner as l Preparation Example 47. [0168] Example 1 A solution of 3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)benzoic acid (810 mg), EDCI/HC1 (616 mg), and N'-hydroxy-7-methylimidazo[l,2-a]pyridine-6-carboxamide (510 mg) in dioxane was stirred at 115°C for 60 hours. The reaction solution was concentrated, and the residue was partitioned between water and chloroform. The organic layer was dried over anhydrous MgSO,, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (CH3OH/chloroform=0 to 5%), and recrystallized with EtOH to obtain 7-methyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (60 mg) as a white solid. [0169] Example 2 To a solution of 3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid (349 mg) in dichloromethane (6 ml) were added oxalyl chloride (333 mg) and a catalytic amount of DMF under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, and azeotroped with toluene. To a solution of the residue in THF were added N'-hydroxy-2-methyl-lH-benzimidazole-6-carboxyimidamide (200 mg) and N-ethyl-N-isopropyl-2-propaneamine (543 mg). The reaction mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, followed by three times extractions with EtOAc. The organic layer was combined, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was dissolved in dioxane, followed by stirring at 100°C for 3 hours. After cooling to room temperature, it was concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain a colorless oily substance. To a solution of this oily substance in EtOAc was added a 4M HCl/EtOAc solution, followed by stirring for a few minutes, and then the reaction mixture was concentrated to obtain 2-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3 -yl} -1 H-benzimidazole hydrochloride (239 mg) as a colorless crystal. [0170] Example 3 To a solution of 4-(2,2,2-trifluoro-l,l-dimethylethoxy)-3-(trifluoromethyl)benzoic acid (118 mg) and 2-{4-[amino(hydroxyimino)methyl]-lH-indol-l-yl}acetamide (104 mg) in dioxane (5 ml) was added DIC(69 ul), followed by stirring at room temperature for 3 hours, and then heating under reflux for 20 hours. The reaction solution was concentrated,-and then to the residue was added water (15 ml), followed by extraction with chloroform (15 ml). The organic layer was washed with a saturated aqueous NaHCC>3 solution and saturated brine, dried over anhydrous MgS04, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CAPCEL PAK, C18, MG, S-5, 30x50 mm; solvent: 50-90% acetonitrile/10 mM ammonium carbonate-ammonia (pH 9.2); 40 ml/min), and crystallized with diisopropyl ether to obtain 2-(4{5-[4-(2,2,2-trifluoro-l,l-dimethylethoxy)-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (40 mg) as a white solid. [0171] Example 4 To a suspension of 60% NaH (68.0 mg) in DMF was added cyclopropylmethanol (99 mg) at 0°C, followed by stirring at the same temperature for 15 min, and then 5-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole (120 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then added with water. It was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (CH3OH/chloroform=0 to 5%) to obtain an oily substance. A solution of the oily substance in chloroform-CH3OH was added with a 4M HCl/dioxane solution (0.5 ml), and concentrated to obtain 5-{5-[4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl]-l ,2,4-oxadiazol-3-yl}-lH-benzimidazole hydrochloride (20 mg) as a white solid. HPLC analysis: Condition (TSK-GEL (TOSOH) ODS-80TM 4.6x 150 mm, MeCN: 0.01M KH2P04(7:3), 1.0 ml/min, 254 nm)[RT: 7.90 min] [0172] Example 5 To a solution of 2-(4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol- 3-yl}-lH-indol-l-yl)acetamide (100 mg) and 2-propanol (35 ul) in DMF (3 ml) was added 60% NaH (12 mg) at 0°C, followed by stirring at room temperature for 9 hours. The reaction solution was added with water (5 ml) to complete the reaction, and extracted with as a mixed solvent of chloroform:CH30H (8:2). The organic layer was washed wim saturated brine, dried over anhydrous MgS04, and then filtered, and me . filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH30H=98:2 to 93:7), and crystallized with diethyl ether to obtain 2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (25 mg) as a pale yellow solid. [0173] Example 6 To a solution of 1,3-difluoropropanol (62 mg) in DMF (2.4 ml) was added 60% NaH (19 mg) at -10°C, followed by stirring at -10°C for 0.5 hour. To this reaction mixture was added 2-{4-[5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (120 mg) at -10°C, followed by stirring at -10°C for 3 hours. After adding water to the reaction solution, the reaction mixture was extracted with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5) to obtain 2-[4-(5-{3-chloro-4-[2-fluoro-l-(fluoromethyl)ethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (76.9 mg) as a white solid. [0174] Example 7 / To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (100 mg) and (2R)-l,l,l-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0°C, followed by stirring at 80°C for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chlorofornY.CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(lR)-2,2,2-trifluoro-l-methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (70 mg) as a pale yellow solid. [0175] Example 8 To a suspension of 60% NaH (43 mg) in DMF (4 ml) was added 2-propanol - (65 mg) at 0°C, followed by stirring at room-temperature for 20 min. After cooling to 0°C again, 2-{4-[5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl-acetamide (200 mg) was added thereto. The reaction mixture was radiated with a microwave at 60°C for 50 min. The reaction solution was added to an aqueous NH4CI solution, followed by stirring, and then the solvent was evaporated. After adding a mixed solvent (4:1) of chloroform-CHsOH, and suspending, the solid was removed, silica gel was added thereto, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 98:2; n-hexane:EtOAc=0:100) to obtain 2-{4-[5-(3-chloro-4-isopropylphenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (17.5 mg) as a white solid. [0176] Example 9 To a solution of 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (300 mg) in THF (1.5 ml) was added, propane-2-amine (0.75 ml), and after sealing the tube, the solution was stirred at 50 to 55°C for 40 hours. It was concentrated under reduced pressure, and then purified by silica gel chromatography (n-1 hexane:EtOAc). The obtained solid was dissolved in acetone under heating, and added with n-hexane, and the precipitate was filtered to obtain 4-[3-(lH-indol-4-yl)-l,2,4- oxadiazol-5-yl]-N-isopropyl-2-(trifluoromethyl)aniline (295 mg). ,. /" [0177] Example 10 To a mixed solution of 2-{4-[5-(5,6-dichloropyridin-3-yl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added isopropylamine (220 ul), followed by stirring at 150°C for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:EtOAc=40:60 to 0:100), and the obtained residue was suspended in diisopropyl ether under heating, and collected by filtration to obtain 2-(4-{5-[5-chloro-6-(isopropylamino)pyridin-3-yl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (62 mg) as white powders. [0178] Example 11 (11-1 and 11-2) To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole (105 mg) in DMF (3.15 ml) was added 60% NaH (31 mg) under ice-cooling, followed by stirring at the same temperature for 15 min, and methyl iodide (0.22 ml) was added thereto, followed by stirring at room temperature for 5 hours. To the reaction was added water, followed by extraction with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic producer, chloroform:CH3OH=10:1). The objective substance was dissolved in EtOAc (5 ml), added with a 4M HCl/EtOAc solution (5 ml), and concentrated to produce about 1:1 two regioisomers. The mixture was crystallized with acetonitrile to obtain l-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl} -1 H-benzimidazole hydrochloride (12.1 mg). The mother liquor was concentrated to obtain 1 -methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole hydrochloride and l-methyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole hydrochloride (70.2 mg) as colorless powders. [0179] Example 12 To a solution 4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indole (150 mg) in DMF (1.5 ml) was added 60% NaH (16 mg) at 0°C, followed by stirring at room temperature for 0.5 hour. Then, to the reaction mixture was added 2-bromoacetamide (70 mg) again at 0°C, followed by stirring at room temperature for 3 hours. To the reaction was added with water, followed by extraction with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 2-[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl}-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (145 mg) as a white solid. [0180] Example 13 To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy]phenyl]-l,2,4-oxadiazol-3-yl)indoline (100 mg) in acetonitrile (2.5 ml) was added K2CO3 (46 mg) and 3-iodopropanamide (124 mg) at room temperature, followed by stirring at 80°C for 15 hours. To the reaction solution was added an NaHCC>3 aqueous saturated solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSCU, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-2, 3-dihydro-lH-indol-l-yl)propanamide (23.6 mg) as a white solid. [0181] Example 14 To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole-3-carboaldehyde (150.0 mg) in CH3OH (1.5 ml) was added a 40% CH3OH solution of CH3NH2 (74.5 mg) at 0°C. After warming to room temperature, the solution was stirred at room temperature for 3 hours. After confirming the production of an iminium salt, the organic solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (L5 ml). To this was added NaBH4 (12.09 nig) at 0°C. After warming to room temperature, the solution was stirred at room temperature for 15 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain N-methyl-1 -(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-memylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-3-yl)methanamine (87.4 mg) as a white solid. [0182] Example 15 To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyi]-l ,2,4-oxadiazol-3-yl}indoline (100 mg) in DMF (1.0 ml) was added 60% NaH (10.9 mg) at 0°C, followed by stirring at room temperature for 0.5 hour. Acetyl chloride (24.1 ul) was added thereto at 0°C, followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=90:10 to 60:40) to obtain l-acetyl-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}indoline (56.8 mg) as a white crystal. [0183] Example 16 To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (80 mg) in DMF (0.80 ml) was added 60% NaH (8.7 mg) at 0°C, followed by stirring at room temperature for 0.5 hour. Methanesulfonyl chloride (21.1 ul) was added thereto at 0°C, followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then,.filtered, and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH==100:0 to 98:2) to obtain 1-(methylsulfonyl)-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (15.6 mg) as a white solid. [0184] Example 17 4- {5-[3-(Trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-l ,2,4- oxadiazol-3-yl}-lH-indole (100 mg) was dissolved in DMF (1.0 ml), followed by addition of 60% NaH (10.9 mg) at 0°C, and stirring at room temperature for 0.5 hour. Methyl chloride carbonate (26.3 ul) was added thereto at 0°C, followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml), the organic layer was ■ ........... combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 98:2) to obtain methyl 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole-l-carboxylate (98.6 mg) as a white solid. [0185] Example 18 To a solution of 3-(5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylemoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazol-2-yl)propanoicacid (23.5 mg) in dichloromethane (0.7 ml) were added oxalyl chloride (0.01 ml) and a few drops of DMF, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated to remove the solvent and the reagent. To a solution of the residue in THF was added NH4OH, followed by further stirring for 1 hour. To the reaction solution was added a saturated aqueous NH4C1 solution, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgS04, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform.-CHbOH^l 0:1) to obtain colorless powders. To a solution of the colorless powders in EtOAc was added a solution of 4N-HC1 in EtOAc. The reaction mixture was concentrated, and the residue was powdered and washed with' IPE to obtain 3-(5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazol-2-yl)propanamide hydrochloride as pale yellow powders. [0186] Example 19 To a solution of (4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetic acid (150 mg) and HOBt(65 mg) in DMF (1.5 ml) was added EDCI/HC1 (69 mg) at 0°C, followed by stirring at room temperature for 1 hour. After cooling to 0°C again, l-pyridin-2-ylmethanamine (39 mg) was added thereto, followed by stirring at room temperature for 15 hours. To the reaction solution was added a saturated aqueous NaHCC>3 solution to complete the reaction. It was extracted with EtO Ac, the organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chlorofornrCHsOH^lOOiO to 95:5) to obtain N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (157.8 mg) as a white solid. To a solution of N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (120 mg) in methylene chloride (2.4 ml) was added dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and powdered/washed with EPE. The obtained solid was collected by ■ filtration, and dried to obtain N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl] -1,2,4-oxadiazol-3-yl}-1 H-indol-1 -yl)acetamide hydrochloride (126 mg) as a white solid. [0187] Example 20 To a solution of [4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg), and after 30 min, methanesulfonamide (23 mg) and 2,3,4,6,7,8,9,10-octanydropyrimide[l,2-a]azepine (37 mg) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture, was added with water to complete the reaction. It was extracted with EtOAc, the obtained organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain N-(methylsulfonyl)-2-[4-(5- {3-(trifluoromethyl)-4-[(l S)-2,2,2-trifluoro-l -methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (56.4 mg) as a white solid. [0188] Example 21 POCl3 (158.4 ul) was added dropwise to a DMF solution (4 ml) at 0°C. After warming to room temperature, it was stirred for 0.5 hour. Then, a solution of 4-{5-[3- {trifluoromethyl)^-(2£ indole (500.0 mg) in DMF (1 ml) was added thereto at 0°C, followed by stirring at room temperature for 15 hours. After cooling to 0°C, to the reaction solution was added a 1M aqueous NaOH solution for adjustment of its pH to 9 to 10. This solution was stirred at 100°C for 1 hour. After being left to be cooled, to the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane, EtOAc=90:10 to 70:30) to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole-3-carboaldehyde (456.7 mg) as a white solid. [0189] Example 22 To a mixed solution of 5-[3-(lH-benzimidazol-6-yl)-l,2,4-oxadiazbl-5-yl]-2-(2,2,2-trifluoro-1 -methylethoxy)benzaldehyde (83 mg), potassium dihydrogen phosphate (421 mg), and 2-methyl-2-butene (0.5 ml) in tBuOH (2 ml) and water (0.5 ml) was added sodium chlorite (187 mg) at room temperature. The mixed reaction solution was stirred at room temperature for 3 hours, followed by dilution with water (10 ml), and extraction with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. To a solution of the residue in dioxane was added a 4 N HCl-dioxane solution, followed by concentration. The resulting powder was recrystallized with IPA (10 ml) to obtain 5-[3-(lH-benzimidazol-5-yl)-l,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-l-methylethoxy)benzoic acid hydrochloride (80 mg) as white powders. [0190] Example 23 To a solution of 2-[2-(methylthio)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole (400 mg) in dichloromethane (8.0 ml) was added mCPBA (534 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a Na2S2C>4 aqueous solution, followed by stirring for 1 hour. The reaction solution was extracted three times with EtOAc, and the organic layer was, combined, dried oyer anhydrous MgS04, filtered, and then concentrated. The residue was purified by silica gel chromatography (chloroform:CH3OH=10:1) to obtain a yellow oily substance. This was dissolved in EtOAc, and a 4M-HCl/EtOAc solution was added thereto, followed by concentration. The residue was washed with IPE to obtain 2-[2-(methylsulfonyl)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3 -yl} -1H-benzimidazole hydrochloride (146 mg) as pale yellow powders. [0191] Example 24 To a reaction mixture of 2-but-3-en4-yl-5-{543-(trifluoromemyl)-4-(2,2,2- trifluoro4-memylethoxy)phenylH,2,4-oxadiazol-3-ylHH-beIK^ (200 mg) in acetone (4 ml) and water (1 ml) were added tetraoxoosmium (51 mg) and 4- methylmorpholine 4-oxide (94 mg), followed by stirring overnight. The reaction mixture was filtered, and to the filtrate was added an aqueous sodium thiosulfate solution, followed by stirring for 1 hour. The solution was extracted with chloroform, and the organic layer was concentrated. The residue was purified by silica gel column \| chromatography (chloroform-CHsOH), and concentrated, and the obtained colorless powder was added with a solution of HC1 in ethanol, and dissolved therein, followed by concentration. The residue was powdered/washed with diisopropyl ether to obtain 4-(5- { 5-[3-(trifluoromethyl)-4-(2,2,2-triiluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-lH-benzimidazol-2-yl)butane-1,2-diol hydrochloride (102.3 mg). [0192] Example 25 To a solution of 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l- methylethoxy)phenyl] -1,2,4-oxadiazol-3 -yl} -2,3 -dihydro-1 H-indol-1 -yl)propanamide (100 mg) in chloroform (1 ml) was added manganese dioxide (67.6 mg), followed by reflux for 15 hours. The reaction solution was left to be cooled to room temperature, and filtered through Celite to remove manganese dioxide. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 3-(4-{5-[3- (trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH- indol-l-yl)-propanamide (46.3 mg)- [0193] Example 26 To a solution 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (100 mg) in AcOH (3 ml) was added portionwise sodium cyanoboroate (29 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, alkalified with a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSCU, and then filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25), and washed with n-hexane to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yljindoline (90 mg) as a pale yellow solid. [0194] Example 27 To a solution of 5-[3-(lH-benzimidazol-6-yl)-l,2,4-oxadiazol-5-yl]-2-(2,2,2- trifluoro-l-methylethoxy)benzaldehyde (80 mg) in ethanol (3 ml) was addedNaBH4(9 mg) at 0°C. After stirring at room temperature for 0.5 hour, a saturated NH4CI solution (10 ml) was added thereto, followed by extraction with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. To a solution of the residue (78 mg) in dioxane was added a 4M HCl/dioxane solution, followed by concentration. The resulting powder was recrystallized with IPA (10 ml) to obtain [5-[3-(lH-benzimidazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-1 -methylethoxy)phenyl]methanol hydrochloride (70 mg) as white powders. [0195] Example 28 A solution of 5-methyl-6-{5-[3-trifiuoro)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (120 mg) andNCS in THF/EtOH (1/1) was stirred at 80°C for overnight. It was concentrated, and the obtained residue was purified by silica gel column chromatography (GH3OH/chloroform 0 to 5%) to obtain 3-chloro-5-m«thyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (45 mg) as a pale yellow solid. [0196] Example 29 To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-memylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (150 mg) in ethanol was added NCS(67 mg) at room temperature, followed by stirring at 80°C for 15 hours. To the reaction solution was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25) to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl] -1,2,4-oxadiazol-3 -yl}imidazo[l,2-a]pyridine (110.4 mg) as a white solid. To asolution of 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (100 mg) in methylene chloride (2 ml) was added dropwise 10 equivalents of 4M HCl/dioxane at room temperature. After stirring at room temperature as it was for 1 hour, it was concentrated under reduced pressure. It was powdered/washed with diisopropyl ether, and then collected by filtration to obtain 3-chloro-5- {5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l -methyl ethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine hydrochloride (102.6 mg) as a white solid. [0197] Example 30 1 -(2- {[Tertiary-butyldimethylsilyl]oxy }ethyl)-4- {5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (60 mg) was dissolved in THF (1.2 ml), and TBAF (150 ]ul) was added thereto at 0°C, followed by stirring at room temperature for 3.0 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4- - ...- oxadiazol-3-yl/lH-indol-l-yl)ethanol (36.5 mg) as a white solid. [0198] Example 31 To a solution of tertiary-butyl 4-{[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2- trifluoro-1 -methylethoxy]phenyl} -1,2,4-oxadiazol-3-yl)-1 H-indol-1 - yl]acetyl}piperazine-l-carboxylate (70.7 mg) in methylene chloride (1 ml) was added dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring at room temperature for 3 hours. After 5 hours, the reaction solution was concentrated. With addition of diisopropyl ether, a white solid was precipitated. The white solid was washed with IPE to obtain l-(2-oxo-2-piperazin-l-ylethyl)-4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-1 -methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indole hydrochloride (58.9 mg) as a pale red solid. [0199] In following tables, the structural formulae of the Example compounds are shown. Ex: Example No. In following tables, the NMR data of the compounds of Examples are shown. Tetramethylsilane is used as an internal standard, and unless otherwise specifically mentioned, 8 (ppm) of the signals in ^-NMR using DMSO-d6 as a measurement solvent is shown. Ref-Ex represents Example No. (Ex), which can be referred to for the preparation. INDUSTRIAL APPLICABILITY [0231] The compound of the present invention is useful as a medicament, and in particular, for prevention and/or treatment of rejection in the transplantation of an organ, bone marrow, or tissue, an autoimmune disease, or the like, since it has SI Pi agonist activity. CLAIMS 1. A compound represented by the formula (I): [Chem. 16] or a pharmaceutically acceptable salt thereof, wherein the symbols mean as follows; the ring A is [Chem. 17] X is a single bond, -CH2-, -NR3-, -0-, -S-, -S(=0)-, or -S(=0)2-, R1 is -H; halogen; aryl; heteroaryl; (C3-Cg)cycloalkyl; (C3-Cs)cycloalkenyl; (C3.C8)heterocycloalkyl; or (C1-C6)alkyl or (C2-C8)alkenyl, each of which may contain halogen, -CONH2, aryl, or (C3-Cg)cycloalkyl, as a substituent, R2 is -CN, -0-(C1-C6)alkyl, -C(=0)H, halogen; or (C1-C6)alkyl which may be substituted with halogen or -OH, R is -H; wherein R may form morpholino, 1-pyrrolidinyl or 3,4- dehydropipelidin-1-yl, together with R1 and nitrogen, wherein, when -X- is a single bond, R1 and R2 may in combination form a 5-membered ring and further contain (C1-C6)alkyl, as a substituent, R4 is a following ring; wherein any one of bonds from the ring is bound to an oxadiazole ring, R5 is -H; (C1-Ce)alkyl which may be substituted with at least one group selected rom the group consisting of -CN, -C(=0)NRxRY, -NHRX, -SRx, -S(=0)2Rx, and -ORx, this is defined as R°-(C1-C6)alkyl); R0-(C1-C6)alkyl-O-; R°-(C1-C6)alkyl-C(=0)-; l0-(C1-C6)alkyl-S(=O)2-; R°-0-(C1-C6)alkyl-; R°-C(=0)-(C1-C6)alkyl-; l°-S(=0)2-(C1-C6)alkyl-; (C2-C6)alkenyl-; -C(=0)H; -ORx; -S(=0)2Rx; halogen; =0; -NRXRY; -C(=0)NRxRY; R and R may be the same with or different from each other, and is -H; or C1-C6)a]kyl which may be substituted with -OH, -NH2 which may be protected with a protecting group or heteroaryl, wherein Rx may form (C3-Cg)heterocycloalkyl, together with R1 or nitrogen. 2. The compound according to claim 1, which is represented by the formula II): [Chem. 19] or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is (C1-C6)alkyl which may contain halogen as a substituent. 4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -CN, halogen; or (C1-C6)alkyl which may be substituted with halogen or -OH. 5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R" is -H; or (C1-C6)alkyl which may be substituted with at least one -C(=0)NRxRY. 6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein X is a single bond, -CH2- or -0-. 7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is a following ring; [Chem. 20] wherein any one of bonds from the ring of R4 is bound to an oxadiazole ring. 8. A compound selected from the following: 5-(5-[3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl)-l,2,4- oxadiazol-3 -yl)-1 H-benzimidazole hydrochloride; 5-(5-[3-(trifluoromethyl)-4-[(lR)-2,2,2-trifluoro-l-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1 H-benzimidazole hydrochloride; 6-{5-[3-bromo-4-(2,2,2-trifluoro-l-methylethoxy]phenyl)-l,2,4-oxadiazol-3-yl}-lH-benzimidazole hydrochloride; 5-(5-[4-phenoxy-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-benzimidazole hydrochloride; 2-(4-{ 5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl} -1 H-indole-1 -yl)acetamide; 4- {5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy]phenyl)-l ,2,4-oxadiazol-3-yl)-l H-pyrrolo[2,3-b]pyridine hydrochloride; 6-{5-[3-(difluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-l ,2,4-oxadiazol-3-yl)-lH-benzimidazole hydrochloride; 2-(4- {5-[3-chloro-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide; 2-(4-{5-[4-cyclopentyl-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-indol-1 -yl)acetamide; 2-[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl)-12,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide; 2-[4-(5-{4-[2-fluoro-l-(fluoromethyl)ethoxy]-3-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide; 2-(4-{5-[3-cyano-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-1 H-indol-1 -yl)acetamide; N-(2-hydroxyethyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl} -1,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide; 2-[4-(5-{5-chloro-6-[(lS)-2,2,2-trifluoro-l-methylethoxy]pyridine-3-yl]-l,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide; 2-[4-(5-{5-chloro-6-[2-fluoro-l-(fluoromethyl)ethoxy]pyridin-3-yl}-l,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide; 2-[4-(5- {3-chloro-4-[2-fluoro-1 -(fluoromethyl)ethoxy]phenyl} -1,2,4-oxadiazol-3 -yi)-1 H-indol-1 -yl)acetamide; 2-[4-(5- {3-methyl-4-[( 1 S)-2,2,2-trifluoro-1 -methylethoxy]phenyl} -1,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide; 2-(4-{5-[4-isopropyl-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-indol-1 -yl)acetamide; 2- {4-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]- lH-indol-1 -yl)acetamide; N-(2-hydroxyethyl)-2-[4-(5-{3-methyl-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl} -1,2,4-oxadiazol-3-yl)-1 H-indol-1 -yl)acetamide; N-(2-hydroxyethyl)-2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl)acetamide; and 2-[4-(5-{3-chloro-4-[2-fluoro-l-(fluoromethyl)ethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-1 H-indol-1-yl]-N-(2-hydroxyethyl)acetamide. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, as an active ingredient. 10. The compound according to any one of claim 1 to 8, used for treatment and/or prevention of rej ection in transplantation of organ/tissue in human or animal, autoimmune disease, multiple sclerosis, rheumatism, psoriasis, asthma, atopy, Alzheimer's disease, tumor, or leukemia. 11. An agent comprising the compound according to any one of claims 1 to 8 as an active ingredient. 12. An agent comprising the compound according to any one of claims 1 to 8 as an active ingredient, and a pharmaceutically acceptable carrier or excipient. 13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, which is SIP1 agonist. 14. A method for treating and/or preventing rejection in transplantation of organ/ bone marrow / tissue in human or animal, graft-versus-host disease rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia, said method comprising administeration of the compound according to any one of claims 1 to 8, to a subject suffering from aforementioned disease. 15. Use of the compound according to any one of claims 1 to 8, for the manufacture of an agent for treating and/or preventing rejection in transplantation of organ/ bone marrow/tissue in human or animal, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia. 16. Use of the compound according to any one of claims 1 to 8, for treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in human or animal, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia. 17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, for the use for treating and/or preventing rejection in transplantation of an organ / bone marrow / tissue in human or animal, or graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.

Full Text

DESCRIPTION HETERO COMPOUND
Technical Field
[0001]
The present invention relates to a novel hetero compound and a medicine containing the same as an active ingredient, particularly an agent for treating immunological diseases.
Background Art
[0002]
Sphingosine-1 -phosphate is a metabolite of sphingolipid which is a physiologically active substance secreted from an activated platelet (Non-Patent Document 1). The sphingosine-1-phosphate receptor is a G protein-binding type, and belongs to an Edg-family which is the endothelial differentiation gene. Up to now, five receptors of SlPi(Edgl), SlP2(Edg5), SlP3(Edg3), SlP4(Edg6) and SlP5(Edg8) have been found. All of these receptors are broadly distributed in cells and tissues throughout the body, but SI Pi, SI P3 and S1P4 are predominantly expressed in lymphocyte and endothelial cell, SIP2 is predominantly expressed in vascular smooth muscle cell, and SIP5 is predominantly expressed in brain and spleen, and amino acid sequences thereof are well-conserved in human and rodent (Non-Patent Document 1). Many receptors bind to G proteins by stimulation of sphingosine-1-phosphate. SIPi bind to Gj/o, S1P2 and S1P3 bind to Gj/o, Gq, G12/13 and Gs, S1P4 binds to Gy0, G12/13 and Gs, SIP5 is coupled to G1/o and G12/13, and cell growth caused by activation of MAPK, change of cytoskeletal system and cell infiltration caused by activation of Rac (and/or Rho), and generation of cytokine and mediator caused by activation of PLC and calcium influx into cell, and the like (Non-Patent Document 1) are induced. It has been known that by the stimulating action of S1P1 of sphingosine-1 -phosphate, migration of lymphocyte, inhibition of apoptosis, generation of cytokine, sequestering lymphocyte in thymus and other secondary lymphoid tissues are induced, and angioplasty in vascular

endothelial cell is promoted (Non-Patent Document 2). On the other hand, expression
of S1P3 is also found on cardiomyocyte, and transiently-decrease in heart rate
(infrequent pulse) or in blood pressure by stimulation of sphingosine-1 -phosphate is
observed (Non-Patent Document 3) while infrequent pulse is not observed by
stimulation of sphingosine-1-phosphate in a knockout mouse wherein SIP3 is
genetically deleted (Non-Patent Document 4). It has been reported that FTY720
phosphate ester which is an active body of FTY720 currently in a clinical trial has non¬
selective agonist activity for SIPi, S1P3, S1P4 and S1P5 (Non-Patent Document 5), and
especially infrequent pulse induced by the stimulation effect through SIP3 is frequently
expressed as an undesirable side effect in clinical trial (Non-Patent Document 6).
Accordingly, it is considered that for sequestering lymphocyte through a sphingosine-1 -
phosphate receptor, the stimulation from SI Pi is essential (Non-Patent Document 7),
while the stimulation from SIP3 is not essential which is rather considered to be related
to the induction of undesirable side effect. Thus, for the development of .. . ,..-.„..,. :
immunosuppressive agent with few side effects, development of agonist having weak effect on SIP3 and selectively effecting on SIPi is desired.
[0003]
For example, as a compound having SIPi agonist activity, a carboxylic acid derivative represented by the following formula has been known (Patent Document 1).
[Chem. 1]

[For symbol in the formula, refer to the publication.]
As a compound having SI Pi agonist activity, an indane derivative represented by the following formula has been known (Patent Document 2).

[Chem. 2]

[For symbol in the formula, refer to the publication.]
As a compound having SIPi agonist activity, an oxadiazole derivative
represented as follows has been known (following figure, Patent Documents 3, 4, 5, and
6).
[Chem. 3]

(Patent Document 5) (Patent Document 6)
[For symbol in the formula, refer to the publication.] As a compound having SI Pi agonist activity, a derivative represented as follows has been known (following figure, Patent Document 7). [0004] [Chem. 4]

[For symbol in the formula, refer to the publication.]
[0005]
However, the compound of the present invention has not been disclosed in any
document.
[0006]
Non-Patent Document 1: Annual Review Biochemistry, 2004, 73, 321-354 Non-Patent Document 2: Nature Review Immunology, 2005, 5, 560-570 Non-Patent Document 3: Japanese Journal of Pharmacology, 2000, 82, 338-
342
Non-Patent Document 4: Journal of Pharmacology and Experimental
Therapeutics, 2004, 309, 758-768
Non-Patent Document 5: Science, 2002,296, 346-349
Non-Patent Document 6: Journal of American Society of Nephrology, 2002,
13,1073-1083
Non-Patent Document 7: Nature, 2004, 427, 355-360
Patent Document 1: International Publication WO 2005/058848 brochure
Patent Document 2: International Publication WO 2004/058149 brochure
Patent Document 3: International Publication WO 2003/105771 brochure
Patent Document 4: International Publication WO 2004/103279 brochure
i Patent Document 5: International Publication WO 2005/032465 brochure
Patent Document 6: International Publication WO 2006/047195 brochure Patent Document 7: International Publication WO 2006/001463 brochure
DISCLOSURE OF THE INVENTION > PROBLEM THAT THE INVENTION IS TO SOLVE [0007]
Inventors of the present inventors have carried out research in order to provide a compound useful for preventing and/or treating rejection in transplantation of organ/bone marrow/tissue or for autoimmune diseases, based on SIPi agonist activity, ) and furthermore to provide a medicine containing the same.

MEANS FOR SOLVING THE PROBLEM
[0008]
Inventors of the present invention have made extensive studies about a compound having SI Pi agonist activity, and as a result, they found that a novel hetero compound is useful as SI Pi agonist, thus completing the present invention. In the other words, according to the present invention, a novel hetero compound represented by following the general formula (I) or a pharmaceutically acceptable salt thereof can be provided.
[0009]
A compound represented by the formula (I):
[Chem. 5]

or a pharmaceutically acceptable salt thereof. [In the formula, the symbols mean as follows; the ring A is: [Chem. 6]

X is a single bond, -CH2-, -NR3-, -0-, -S-, -S(=0)-, or -S(=02>,
R1 is -H; halogen; aryl; heteroaryl; (C3.C8)cycloalkyl; (C3.C8)cycloalkenyl;
(C3.C8)heterocycloalkyl; or (Ci.C6)alkyl or (C2-C6)alkenyl, each of which may contain
halogen, -CONH2, aryl, or (C3.C8)cycloalkyl, as a substituent,
R2 is -CN, -0-(Ci.C6)alkyl, -C(=0)H, halogen; or (d.C6)alkyl which may be
substituted with halogen or -OH,

■7 >j
R is -H; wherein R may form morpholino, 1-pyrrolidinyl or 3,4-dehydropipelidin-1-yl, together with R1 and nitrogen,
wherein, when -X- is a single bond, R1 and R2 may in combination form a 5 membered ring and further contain (Ci_C6)alkyl, as a substituent,
R4 is a following ring:
wherein any one of a bond from the ring is bound to an oxadiazole ring,
[Chem. 7]

R5 is -H; (Ci.Ce)alkyl which may be substituted with at least one group selected from the group consisting of-CN, -C(=0)NRxRY, -NHRX, -SRx, -S(=0)2Rx, and -ORx, (this is defined as R°-(C1-C6)alkyl); R0-(CrC6)alkyl-O-; R0-(CrC6)alkyl-C(=O)-; R°-(C1-C6)alkyl-S(=0)2; R°-0-(Ci-C6)alkyl-; R0-C(=O)-(CrC6)alkyl-; R°-S(=0)2-(Ci-C6)alkyl-; (C2-C6)alkenyl-; -C(=0)H; -0RX; -S(=0)2RX; halogen; =0; -NRXRY; -C(=0)NRxRY;
Rx and RY may be the same with or different from each other, and is -H; or (Ci-C6)alkyl which may be substituted with -OH, -NH2 which may be protected with a protecting group, or heteroaryl, wherein Rx and RY may form (C3-Cg)heterocycloalkyl, together with nitrogen.

[0010]
As -X- in the formula (I), preferred is a single bond or -0-, and more preferred is -0-. As R1, preferred is (Ci-C4)alkyl or (C2.C4)alkenyl, each of which may be substituted with halogen or (C3-C6)cycloalkyl, and further more preferred is (Ci.C4)alkyl which may be substituted with F. As the ring A, preferred is:
[Chem. 8]

As R2, preferred is halogen, -CN, (Ci.C4)alkyl which may be substituted with halogen, and more preferred is -CI, -CF3. As R4, preferred is: [Chem. 9]

and more preferred is: [Chem. 10]
As R5, preferred is -H; (Ci.C6)alkyl which may be substituted with -C(=0)NRxRY As Rx, preferred is -H; (Ci.C6)alkyl which may be substituted with -OH. As RY, preferred is -H; (Ci.C6)alkyl which may be substituted with -OH.
[0011]
A compound of the present invention represented by the formula (I) is characterized in a chemical structure from the point that a bicyclic nitrogen-containing unsaturated hetero ring or a bicyclic nitrogen-containing partially unsaturated hetero

ring is bound to 3-position of oxadiazole, and has pharmacological characteristics from the point that the compound has SI Pi agonist activity.
EFFECTS OF THE INVENTION
[0012]
Since the compound of the invention has an SI Pi agonist activity, it is useful as an active ingredient of an agent for treating or an agent for preventing a disease caused by unfavorable lymphocytic infiltration, for example, graft rejection in the transplantation of an organ, bone marrow, or tissue or graft-versus-host disease, an autoimmune disease or an inflammatory disease such as rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, imTammatory bowel disease, atherosclerosis, or ischemia-reperfusion injury, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer or leukemia.
BEST MODE FOR CARRYING OUT THE INVENTION
[0013]
Hereinafter, the present invention will be described in more detail.
In the specification, "alkyl" means a linear or branched mono-valent group. "C1-C6 alkyl" means a C1-C6 linear or branched alkyl, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-propyl, and n-hexyl, preferably C1-C4 alkyl, and particularly preferably, methyl, ethyl, n-propyl, and isopropyl.
[0014]
In the specification, "halogen" represents F, CI, Br, and I, and preferable examples thereof include F or CI.
[0015]
In the specification, "C2-C6 alkenyl" means C2-C6 linear or branched alkenyl which has a double bond in a given site, and specific examples thereof include ethenyl (vinyl), 1-propenyl, 2-propenyl, 1-methylethen-l-yl, 1-buten-l-yl, 2-buten-l-yl, 3-

buten-1-yl, 1 -methyl- 1-propen-l-yl, 2-methyl-l-propen-l-yl, l-methyl-2-propen-l-yl, and2-methyl-2-propen-l-yl, and preferably, l-methyl-2-propen-l-yl or 1-pentenyl.
[0016]
In the specification, "C3-C8 cycloalkyl" means a mono-valent group of a non-aromatic carbon ring having a reduction number of 3 to 8, which may have partially unsaturated bonds. Thus, specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0017]
In the specification, "C3-Cg heterocycloalkyl" means a mono-valent group of a non-aromatic carbon ring having a reduction number of 4 to 9, containing one or more heteroatoms that are the same as or different from each other, selected from the group consisting of nitrogen, oxygen, and optionally oxidized sulfur, which may have partial unsaturations. Specific examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydropyranyl, and - , . tetrahydrothiopyranyl.
[0018]
In the specification, "aryl" means an aromatic hydrocarbon group, but preferred is an aryl group having 6 to 14 carbon atoms. Specific examples thereof include phenyl, naphthyl, and anthryl, and more preferred is phenyl.
[0019]
In the specification, "heteroaryl" means a 5- or 6-membered ring aromatic heterocycle, containing one or more heteroatoms that are the same as or different from each other, selected from the group consisting of nitrogen, oxygen, and sulfur. Specific examples thereof include pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazolyl, and thiadiazolyl. Preferred is a 6-membered heteroaryl, and particularly preferred is pyridyl.
[0020]
The compound of the present invention may exist in the form of a geometrical isomer or a tautomer in some cases depending on the kind of the substituents. Further the compound of the present invention may have asymmetric carbons. The present invention includes either of the isolated counterparts of these isomers, and a mixture

thereof. Also, the labeled compounds, that is, the compounds having at least one element in the compounds of the present invention substituted with radioactive isotopes or non-radioactive isotopes are also included in the present invention.
Furthermore, the pharmaceutically acceptable, so-called prodrugs of the compounds of the present invention are also included in the present invention. The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxylic group, or the like of the compound of the present invention, by solvolysis or under a physiological condition. Examples of the group capable of forming a prodrug include the groups as described in "Prog. Med., vol. 5,2157-2161 (1985), and "Iyakuhin no Kaihatsu (Development of Medicines) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198.
[0021]
The compound represented by the formula (I) may form salts with acids or bases. These salts can be any one that are pharmaceutically acceptable, and specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts.
In addition, of the present invention also includes various hydrates and solvates, and polymorphic substances of the compound represented by the formula (I) and a salt thereof.
[0022]
In the specification, the following abbreviations were used.
Pr: preparation method, AcOH: acetic acid, n-BuLi: normal butyl lithium, t-BuOH: tertiary butanol, n-BuOH: normal butanol, BrCN: cyanogen bromide, CDI: 1,1'-carbonyl bis-lH-imidazole, DBU: l,8-diazabicyc!o[5.4.0]undeca-7-ene, DMAP: 4-

(N,N-dimethylamino)pyridine, DIC: N,N'-diisopropylcarbodimide, DMF: N,N'- ..
dimethylformamide, DCC: dicyclohexylcarbodimide, DMA: N,N-dimethylacetamide,
DMSO: dimethylsulfoxide, DPPA: diphenylphosphorylazide, Et: ethyl, EDCI/HC1: N-
[3-(dimethylamino)propyl]-N'-ethylcarboxamide hydrochloride, EtOH: ethanol, Et3N:
triethylamine, EtOAc: ethyl acetate, HOBt: 1-hydroxy-lH-benzotriazole, HPLC: high
performance liquid chromatography, IPE: diisopropyl ether, i-PrOH: 2-propanol,
K2CO3: potassium carbonate, KCN: potassium cyanide, KHC03: potassium hydrogen
carbonate, KO^Bu: potassium tertiary butoxide, LC-MS: liquid chromatography-mass
spectroscopy, LiH: lithium hydride, MeOH: methanol, NaH: sodium hydride, NaOH:
sodium hydroxide, NaBU*: sodium borohydride, NaCN: sodium cyanide, NaHCC>3:
sodium hydrogen carbonate, Na2C03i sodium carbonate, NaOMe: sodium methoxide,
NaOEt: sodium ethoxide, NCS: N-chlorosuccinimide, NH4CI: ammonium chloride,
NMP: N-methylpyrrolidone, POCI3: phorphorous oxychloride, P2O5: phorphorous
pentaoxide, THF: tetrahydrofuranj TLC: thin layer chromatography, TMEDA: ,,..,.,,,
N,N,N'N'-tetramethylethylenediamine, Zn(CN)2: zinc cyanide
[0023]
(Preparation Method)
The compound (I) of the present invention and a pharmaceutically acceptable salt thereof may be prepared by applying various known synthetic methods, taking advantages of the characteristics based on their basic backbones or the kind of the substituents. Here, depending on the kind of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to protect the functional group with an appropriate protecting group, or to replace it by a group which may be easily converted into the functional group, during the steps of from starting materials to intermediates. Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group, and examples of a protecting group thereof include the protecting groups as described in "Protective Groups in Organic Synthesis", edited by T.W. Greene and P.G.M. Wuts, (USA) (3rd edition, 1999), which may be optionally selected and used in response to the reaction conditions. By such a method, the desired compound can be obtained bv introducing a protecting group to

carry out the reaction, and then, if desired, removing the protecting group or converting it into a desired group.
In addition, a prodrug of the compound (I) of the present invention can be prepared by introducing a specific group during the steps of from starting materials to intermediates, similar to the aforementioned protecting groups, or by carrying out the reaction using the obtained compound (I) of the present invention. The reaction may be carried out by employing common esterification, amidation, dehydration, or a method conventionally known to a person skilled in the art.

[Chem. 11]
[0024]

[wherein R or R' means lower alkyl which may be substituted with at least one substituent selected from the group consisting of-CN, -C(=0)OH, -C(=0)OR , -C(=0)NRxRY, -C(=0)NHS02Rx, -C(=0)-(Ci-C8 heterocycloalkyl), -NHRx, -OH, -SRX, -S(=02)Rx, halogen, and -ORx (which is defined as Rz-lower alkyl); R0-(CrC6)alkyl-O-; R°-(C1-C6)alkyl-C(=0)-; R°-(C1-C6)alkyl-S(=0)2-; R°-0-(Ci-C6)alkyl-; R0-C(=O)-(C1-C6)alkyl-; R°-S(=0)2-(Ci-C6)alkyl-; (C2-C6)alkenyl-; -C(=0)H; -ORx; -S(=0)2Rx; halogen; =0; -NRxRY; or -C(=0)NRxRY;
Rx and RY are the same as or different from each other, and each mean -H; (Ci-C6)alkyl that may be substituted with -OH or pyridyl. Also, Rx may be bonded with RY and a nitrogen atom to form (C3-Cg)heterocycloalkyl.

[0025]
This preparation method is a method for preparing a benzimidazole compound represented by the formula (1-c) by allowing an aldehyde compound to undergo the reaction with a 1,2-diaminobenzene compound represented by the formula (1 -b) that can be obtained by reduction of a compound represented by the formula (1 -a).
[0026]
The step represented by Step 1-1 is a step for reducing a nitro group of the compound represented by the formula (1-a) to an amino group, that can be carried out at normal pressure or under elevated pressure, in a solvent inert to the reaction.
In the step represented by Step 1-2 wherein R' is H, an imidazole ring can be constructed, for example, by allowing an orthoformic ester such as ethyl orthoformate to undergo the reaction with the compound represented by the formula (1-b) in the presence of an acid catalyst.
Furthermore, in the step represented by Step 1-2 wherein R'is not H, for example, a method in which an amino group of the compound represented by the formula (1-a) is preliminarily acylated using a carboxylic acid, an acid chloride, a carboxylic acid anhydride, or the like, and cyclized under heating or in the presence of an acid, a method in which tetraalkyl orthocarbonate, CDI, or BrCN is used instead of an orthoformic ester, or other methods can be exemplified.
Furthermore, as other methods, a method in which a nitrobenzene compound of the formula (1-a) is subject to carbamoylation of its amine moiety, induced into an acylamine compound (1-e), subject to reduction of its nitro group, and cyclized with heat can also be exemplified (Step 1-3, Step 1-4).
All of these reactions can be carried out in a solvent inert to the reaction, or without a solvent, from at room temperature to under heating, or from under heating or under reflux.

[0027]

[Chem. 12]

[wherein R has the same meanings as defined above].
This preparation method is a method for preparing an imidazo[l,2-a]pyridine substituted with a nitrile group represented by the formula (2-b), by using a 2-aminopyridine compound represented by the formula (2-a) as a starting material.
The step represented by Step 2-1 is a reaction for constructing an imidazo[l,2-a]pyridine ring by allowing a chloroacetaldehyde or a-chloroketone to undergo the reaction with the compound represented by the formula (2-a).
It is preferably carried out in the presence of a base, and specific examples of the base include alkali carbonates such as Na2CC>3 and K2CO3; alkali hydrogen carbonates such as NaHC03 and KHCO3; alkoxides such as NaOMe, NaOEt, and KOlBu; tertiary amines such as Et3N and DIPEA; and organic amines such as DBU, pyridine, and lutidine.
All of these reactions can be carried out in a solvent inert to the reaction, or without a solvent, from at room temperature to under heating, or under heating with reflux.
[0028]

[Chem. 13]

[wherein R has the same meanings as defined above.]

This preparation method is a method for preparing an indazole compound represented by the formula (3-c) by allowing a hydrazine hydrate with a nitrile group to undergo the reaction with a cyanobenzene compound represented by the formula (3-b) obtained by substituting a halogen group of a compound represented by the formula (3-a).
The step represented by Step 3-1 is a reaction for substituting a halogen bonding with an aromatic ring with a nitrile group. It is exemplified by a method for reaction of Zn (CN)2 in the presence of tetrakistriphenylphosphine palladium (0), a method for allowing TMEDA and Pd catalysts to undergo the reaction in the presence of Na2CC>3 in DMA, and a method for allowing KCN, NaCN, or the like to undergo the reaction instead of Zn(CN)2. Usually, the compound represented by the formula (3-b) can be obtained by reacting the compound represented by the formula (3-a) with tris(dibenzylideneacetone)dipalladium (0), l'-bis(diphenylphosphino)ferrocene, and Zn(CN)2.
Here, examples of the leaving group include halogen such as Br and CI; methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.
[0029]
The step represented by Step 3-2 is a reaction for constructing an indazole ring from a cyanobenzaldehyde compound represented by the formula (3-b). Usually, a hydrazine hydrate is used in this reaction, which can be carried out without a solvent, or in a solvent inert to the reaction such as MeOH and toluene, from at room temperature to under heating, or under heating with reflux. In addition, a method using copper cyanide can also be exemplified, and a base such as pyridine may be added. Also, this > reaction is preferably carried out under a nitrogen atmosphere.

[0030]

[Chem. 14]

[wherein R has the same meanings as defined above. Z represents -CH= or-N=].
This preparation method is a method for preparing a benzotriazole or benzimidazole compound represented by the formula (4-c) by dehydrating an acid amide compound represented by the formula (4-b), obtained using a carboxylic acid compound represented by the formula (4-a) as a starting material.
The step represented by Step 4-1 is a reaction for condensing a carboxylic acid compound with ammonia represented by the formula (4-a), and constructing an acid amide group represented by the formula (4-b). The compound represented by the formula (4-a) can be used in the reaction as free acid, but a reactive derivative thereof may also be used in the reaction. Examples of the reactive derivative induced from the compound represented by the formula (4-b) include acid halides such as acid chloride and acid bromide; common esters such as methyl ester, ethyl ester, and benzyl ester; acid azides; active esters such as HOBt, p-nitrophenol, and N-hydroxysuccinirnide; symmetrical acid anhydrates; a mixed acid anhydrate of a halocarboxylic acid alkyl ester such as an alkyl carbonic acid halide, a pivaloyl halide, and p-toluene sulfonic acid chloride; and a mixed acid anhydrate such as a mixed phosphoric mixed acid anhydrate, such as those obtained by the reaction of diphenylphosphoryl chloride with N-methyl morpholine.
In a case where the compound represented by the formula (4-a) is reacted as a free acid, or without isolation to an active ester, or the like, a condensing agent such as DCC, CDI, DPP A, diethylphosphoryl cyanide, and EDCI/HC1 is preferably used.

The reaction solvent varies depending on a reactive derivative or a condensing agent to be used, but the reaction is carried out in an organic solvent inert to the reaction such as hydrocarbon halides, aromatic hydrocarbons, ethers, esters such as EtOAc, acetonitrile, DMF, and DMSO, or a mixed solvent thereof. Also, the reaction is carried out under cooling, from under cooling to at room temperature, or from at room temperature to under heating.
Furthermore, in the reaction, it is in some cases advantageous in advancing the reaction smoothly to carry out the reaction with an excessive amount of ammonia or in the presence of a base such as N-methylmorpholine, trimemylamine, Et3N, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline, and lutidine. Pyridine may be used in combination with the solvent.
The step represented by Step 4-2 is dehydration, for which a base may or may not exist, and a dehydrating agent such as trifluoroacetic anhydrate, POCI3, and P2O5 may be used.
Furthermore, in a case for synthesizing a condensed, intermediate heterocycle other than those described in the above-described intermediate preparation methods, the methods described in Reference Examples or Examples in the present specification, or equivalent methods may be employed, or additionally, well-known methods or methods apparent to a person skilled in the art can also be used for the preparation.

[wherein A, X, R1, and R4 are as described above. Lv represents a leaving group. A carboxylic acid represented by the formula (5-c), (5-d), and (5-g) can be purchased as a commercially available product, or prepared to a commercially available product].
This preparation method is a method for preparing the compound of the present invention represented by the formula (I) by reacting a hydroxyamidine represented by the formula (5-b) obtained by allowing hydroxylamine to undergo the reaction with an aromatic nitrile compound represented by the formula (5-a), with a carboxylic acid represented by the formula (5-c).
In a step represented by Step 5-1, the hydroxyamidine represented by the formula (5-b) can be prepared by allowing a free hydroxylamine or hydroxylamine hydrochloride to undergo the reaction in the presence of a base.
This reaction can be carried out in a solvent inert to the reaction. Specific examples of the solvent include alcohols such as MeOH, EtOH, and i-PrOH; aromatic hydrocarbons such as toluene and xylene; ethers such as ether, THF, dioxane, and diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; acetonitriles; aprotic polar solvents such as DMF, l,3-dimethyl-2-imidazolidinone, and DMSO; water; or a mixed

solvent thereof. Usually, alcohols are used in the reaction. As described above, in a
case where hydroxylamine hydrochloride is used in this reaction, the reaction is
preferably used in the presence of a base, and specific examples of the base include
alkali carbonates such as Na2C03 and K2CO3; alkali hydrogen carbonates such as (
NaHCC>3 and KHCO3; alkoxides such as NaOMe, NaOEt, and KOlBu; tertiary amines such as Et3N and DIPEA; and organic amines such as DBU, pyridine, and lutidine. The reaction temperature varies depending on the kinds of the starting material compounds, the reaction conditions, or the like, but the reaction can be carried out usually from at room temperature to at about a reflux temperature of the solvent. Typically, in the presence of a base such as Na2C(>3, the reaction can be carried out in an organic solvent inert to the reaction, such as MeOH, from at room temperature to under heating.
The step represented by Step 5-2 consists of two steps, i.e., a step of acylation of a hydroxyamidine product, and a step of a cyclization reaction in this order. The acylation step can be carried out in the following manner. The compound represented by the formula (5-c) can be used in the reaction as a free acid, but a reactive derivative thereof may also be used in the reaction. Examples of the reactive derivative include acid halides such as acid chloride and acid bromide; common esters such as methyl ester, ethyl ester, and benzyl ester; acid azides; active esters such as HOBt, p-nitrophenol, and N-hydroxysuccinimide; symmetrical acid anhydrates; a mixed acid anhydrate of a halocarboxylic acid alkyl ester such as an alkyl carbonic acid halide, a pivaloyl halide, and p-toluene sulfonic acid chloride; and a mixed acid anhydrate such as a mixed phosphoric mixed acid anhydrate, such as those obtained by the reaction of diphenylphosphoryl chloride with N-methyl morpholine.
1 In a case where the compound represented by the formula (5-c) is reacted as a
free acid, or without isolation to an active ester, or the like, a condensing agent such as DCC, CDI, DPP A, diethylphosphoryl cyanide, and EDCI/HC1 is preferably used.
The reaction solvent varies depending on a reactive derivative or a condensing agent to be used, but the reaction is carried out in an organic solvent inert to the reaction
) such as hydrocarbon halides, aromatic hydrocarbons, ethers, esters such as EtOAc,

acetonitrile, DMF, and DMSO, or a mixed solvent thereof, under cooling, from under cooling to at room temperature, or from at room temperature to under heating.
In the reaction, the reaction may be smoothly advanced in some cases to parry out the reaction in the presence of a base such as N-methylmorpholine, trimethylamine Et3N, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline, and lutidine. Also, pyridine may be used in combination with the solvent. An acylated product as an intermediate can be purified by isolation, and heated in an organic solvent inert to the reaction, such as EtOH, dioxane, toluene, and water. Usually, this two-step reaction can be carried out in one operation, by heating or microwave-radiating the product as it is or as a reaction mixture, after acylation.
Specific examples of the solvent include aromatics such as toluene, xylene, and pyridine; ethers such as diethyl ether, THF, dioxane, and diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; acetonitriles; aprotie polar solvents such as DMF, DMA, l,3-dimethyl-2-imidazolidinone, NMP, and DMSO; water; or a mixed solvent thereof. The reaction temperature varies depending on the kinds of the starting material compounds, the reaction conditions, or the like, but the reaction can be carried out usually from at room temperature to under heating.
[0031]
In a case where X represents -O- or -NH-, synthesis can be made by the following preparation method.
The steps represented by Step 5-3 and Step 5-5 can be carried out in the same manner as the step represented by Step 5-2.
The steps represented by Step 5-4 and Step 5-6 are steps for preparing the compound of the present invention represented by the formula (I) by allowing phenol, aniline, alcohol, or amine represented by the formula (5-e) or the formula (5-i) to undergo the reaction with a compound having a leaving group, represented by the formula (5-f) or the formula (5-h). Here, examples of the leaving group include halogens such as chlorine and bromine; and sulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and trifluoromethanesulfonyloxy.

The reaction is carried out at normal pressure or under elevated pressure, without a solvent or in an appropriate solvent.
Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and methylethylketone; ethers such as ether, THF, dioxane, and diethoxyethane; alcohols such as MeOH, EtOH, i-PrOH, and n-BuOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; acetonitriles; aprotic polar solvents such as DMF, [,3-dimethyl-2-imidazolidinone, NMP, and DMSO; water; or a mixed solvent thereof. This reaction is preferably used in the presence of a base, and specific examples of the >ase include NaH; alkali carbonates such as Na2CC>3 and K2CO3; alkali hydrogen carbonates such as NaHCC>3 and KHCO3; alkoxides such as NaOMe, NaOEt, and iCOlBu; tertiary amines such as Et3N, tributylamine, and DIPEA; and organic amines iuch as DBU, pyridine, and lutidine, but an excessive amount can be combined in an unine represented by -the formula (5-e) or the formula (5-i). The reaction temperature, varies depending on the kinds of the starting material compounds, the reaction conditions, or the like, but the reaction can be carried out usually from at room emperature to at about a reflux temperature of the solvent. Usually, the reaction can 5e carried out in the presence of a base such as NaH and Na2CC>3, in an organic solvent nert to the reaction, such as DMF and DMA, from at -10°C to under heating. Also, :he amine represented by the formula (5-e) or the formula (5-i) can be provided for the ■eaction as a salt thereof. In addition, a microwave may be radiated under heating for he preparation.
[0032]
Moreover, several compounds represented by the formula (I) can be prepared oy any combination of well-known processes that can be usually employed by a person skilled in the art, such as well-known alkylation, acylation, substitution reaction, Dxidation, reduction, hydrolysis, deprotection, and halogenation from the compound of the present invention as prepared in the above-described manner.
For example, for alkylation, the alkylation reaction that can be usually used by a person skilled in the art can be employed, which can be carried out in an organic solvent inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated

hydrocarbons such as dichloroethane, dichloroethane, and chloroform; DMF, acetonitriles; and aprotic polar solvents, under cooling, from under cooling to at room temperature, or from at room temperature to under heating, in the presence of a base such as NaH; alkali carbonates; alkali hydrogen carbonates; alkoxides; tertiary amines; and organic bases.
Furthermore, for example, for acylation, the acylation reaction that can be usually used by a person skilled in the art can be employed, which can be particularly carried out in the presence of HOBt, in a solvent varying depending on a condensing agent such as EDCI/HC1 or CDI, and diphenylphosphorylcyanide, in a solvent varying depending on the reaction condition, but usually in an organic, inert solvent such as ethers; aromatic hydrocarbons; halogenated hydrogen such as dichloromethane, dichloroethane, and chloroform; esters such as EtOAc; acetonitriles; and aprotic solvents, under cooling, from under cooling to at room temperature, or from at room temperature to under heating.
[0033]
Thus prepared compound is purified by isolation, as it is, or as a salt thereof after a salt-forming treatment by a conventional method. The purification by isolation is carried out by applying common chemical operations such as extraction, concentration, removal by distillation, crystallization, filtration, recrystallization, and various types of chromatography.
Various types of the isomers can be isolated by a conventional method, taking advantage of the difference in the physiochemical properties among the isomers. For example, a racemic mixture can be induced into optically pure isomers, for example, by a general resolution method for racemic products, such as an optical resolution method for inducing diastereomer salts with general, optically active acids such as tartaric acid. Also, the diastereomer mixture can be separated, for example, by fractional crystallization, or various types of chromatography. Furthermore, the optically active compounds can also be prepared by using the corresponding, optically active starting materials.

[0034]
The actions of the compounds of the present invention were confirmed by the following pharmacological tests.
[0035]
Experimental Example 1: Test for confirming an SI Pi agonist activity
[0036]
1) Evaluation of a receptor agonist activity by a GTP[y-35S] bond assay using the membrane of a human SI Pi expressing cell
The in vitro SI Pi agonist activity of the compound of the present invention was evaluated by the increase in the functional bonding activity into the G-Protein of a GTP[y-35S] using the membrane of a human SIPi expressing cell. A cDNA encoding a human SIPi was cloned from a human colorectal cDNA library, and introduced to an expression vector pcDNA3.1 to construct a SlPi-pcDNA3.1. Then, by Lipofectamine 2000 (GIBCO), the SIPrpcDNA3.1 was transfected into a CHO cell, and cultured in a Ham's F-12 culture medium containing 10% fetal bovine serum, 100 U/mL Penicillin, 100 ug/mL Streptomycin, and 1 mg/mL G418 disulfate, to obtain a stable, G418-resistant strain. The cultured human SI Pi expressing cells were isolated in a 1 mM EDTA/2Na-containing PBS, and disrupted under ice-cooling by a homogenizer made of glass in a 1 mM Tris HC1 (pH 7.4) buffer solution containing 0.1 mM EDTA and a protein inhibitor. It was centrifuged at 1,400x 10 min, and a supernatant was further centrifuged at 4°C for 60 min at 100,000xg, and suspended in a 10 mM Tris HC1 (pH 7.4) buffer solution containing 1 mM EDTA. The obtained membrane (0.13 mg/mL) and 50 pM GTP[y-35S] (NEN; inactive 1250 Ci/mmol) were reacted in a 20 mM HEPES (pH 7.0) buffer solution (total amount: 150 uL) containing 100 mM NaCl, 10 mM MgCl2, 0.1% fatty acid-free BSA, and 5 uM GDP for 1 hour together with the compound of the present invention (10'12 to 10"5 M), and then a membrane was recovered on a GF-C plate with a Cell Harvester (Packard, FilterMate). The FilterMate was dried at 50°C for 60 min, and Microscinti-o (Packard) was added thereto for measurement by a liquids scintillation counter for a microplate (Packard, TOP count). For evaluation of the human S1P i agonist activity of the compound of the present invention and the comparative compound, the percentages with the rate of a

maximum reaction to make the GTP[y-35S] bonds saturated in the presence of the compound being set at 100%, and the rate of the reaction of the GTP[y-35S] bonds in the absence of the compound being set at 0% was used, a non-linear regression curve was plotted, and a concentration to cause an agonist activity operating 50% of the maximum reaction was defined as an EC50 value (nM).
[0037]
[Table 1]

[0038]
As a result, it can be confirmed that the compound of the present invention has an SIPi agonist activity.
[0039]
2) Evaluation of peripheral blood lymphopenia in rat
The peripheral blood lymphopenia in rat was measured at 24 hours after oral administration in the following manner. Six- to ten-week-old male Lewis rats (Japan Charles river laboratories) were randomly divided into the groups (n=3), and the compound of the present invention was suspended in 0.5% methyl cellulose-containing distilled water, and orally administered with a sonde. At 24 hours after administration, under ether anesthesia, 0.2 ml of blood was collected from ocular fundus. To the
o A

blood sample were immediately added EDTA/4K and heparin to prevent clotting, and the number of the lymphocytes in blood was measured with an automatic haematology analyzer (Sysmex Corp.; XT-2000i). For the reduction of the number of the lymphocytes in peripheral blood by the compound of the present invention, the percentage with the number of the lymphocytes in groups administered with 0.5% methyl cellulose-containing distilled water being set at 100%, as performed at the same time was used, and the dose to cause 50% reduction of the number of the lymphocytes in peripheral blood by administration of the compound of the present invention was defined an ED50 value (mg/kg).
[0040]
For the comparative compounds 1 and 2 as described in the pamphlet of International Publication No. WO2004/103279, the comparative compound 3 as
pamphlet of International Publication No. WO2005/032465, and the compound of Example 119, the ED50 values at 24 hours after administration were compared for the reduction of the number of the lymphocytes in peripheral blood in rat.

[0042]
As a result, it was demonstrated that the compound of Example 119 shows a high ED50 value even after 24 hours, indicating persistence.
[0043]
Since the compound of the present invention has an SIPi agonist effect, it is useful as an active ingredient of an agent for treating or an agent for preventing a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or a tissue or a graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, or ischemia-reperfusion injury or an

inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells, such as cancer and leukemia.
Furthermore, the compound of the present invention is useful to treat and/or prevent the following diseases, based on the agonist activity against an SIPi.
It is useful to treat and/or prevent inflammatory or hyperplastic skin diseases
such as psoriasis, contact dermiatitis, eczematoid dermatitis, seborrheic dermatitis,
lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, hives, vascular edema,
obliterans, erythema, eosinophilia of skin, lupus erythematosus, acne, and alopecia
areata, or expression of skin diseases through an immune system; autoimmune diseases
or allergic diseases of eyes, such as keratoconjunctivitis, vernal conjunctitis, allergic
conjunctivitis, uveitis associated with Behcet disease, keratitis, Herpesviral keratitis,
Keratoconus keratitis, corneal epithelial dystrophies, corneal leukoma, ocular
pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada
disease, leratoconjunctivitis sicca (dry eye), vesicle, iridocyclitis, sarcoidosis, and - .
ophthalmic diseases inendocrine glands; reversible obstructive lung diseases (asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dirt asthma), in particular, chronic or difficult asthma (for example, late-onset asthma, and airway diseases); mucous or angiitis (for example, gastric ulcers, ischemic or thrombotic Vascular Injuries, age-related maculopath, diabetic maculopath, ischemic bowel disease, bowel disease, necrotizing enteritis, intestinal tract lesion by heat burn, and diseases by a transmitter of a Leukotriene B4); inflammatory intestine or allergic diseases of intestine, including, for example, proctitis, eosinophilic enteritis, mastocytosis, celiac disease, Crohn's disease, and ulcerative colitis; food-related allergic diseases expressing the conditions on a site that is remote from the gastro-intestinal tract including, for example, migraine, rhinitis, and eczema; autoimmune diseases or inflammatory diseases including, for example, primary mucous edema, autoimmune atrophic gastritis, precocious climacteric period, juvenile diabetes, pemphigus vulgaris, pemphigoid, sympathetic ophtalmolima, lens-induced uveitis, paroxysmal Leukopenia, chronic active hepatitis, paroxysmal liver cirrhosis, discoid lupus erythematosus, Sjoegren syndrome, autoimmune orchitis, arthritis (for example, modified arthritis), and polychondritis; renal diseases including, for example, membranous nephrophathy,

membranoproliferative nephritis, focal global glomerulosclerosis, crescent nephritis, glomerular nephritis, IgA nephropathy, tubulopathy interstitial nephritis, and diabetic
nephropathy. Furthermore, the compound of the present invention is also useful to
(
treat and/or prevent liver diseases (for example, immunogenic diseases (for example,
autoimmune lever diseases, chronic autoimmune lever diseases such as primary biliary cirrhosis., sclerosing cholangitis, and the like), partial hepatic dissection, acute hepatic necrosis (for example, necrosis caused by toxin, viral hepatitis, shock, anoxia, or the like), Type B hepatitis, non-Type A hepatitis, cirrhosis, heptatic failure (for example, fulminant hepatitis, late-onset hepatitis, hepatic failure (acute hepatic failure or chronic hepatic disease)), and the like.
In addition, compound of the present invention can be administered as an SI Pi agonist alone, or in combination with at least one agent, in the same dose or different doses, through the same or different administration routes. Examples of the agent that
can-be combined include, but not limited thereto, cyclosporin A, tacrolimus, sirolimus,
everolimus, mycophenolate, azathioprine, brequinar, Leflunomide, fingolimod, an anti-IL-2 receptor antibody (for example, daclizumab), an anti-CD3 antibody (for example, OKT3), anti-T cell immunoglobulin (for example, AtGam), belatacept, abatacept, cyclophosphamide, p-interferone, aspirine, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroid (for example, prednisolone, and dexamethasone).
[0044]
A preparation containing the compound represented by the formula (I), or one, or two or more kinds of the salts thereof as effective ingredients are prepared by using a carrier, an excipient or other additives that are usually used in the preparation of medicines.
Administration may be made in any one form for either oral administration by tablets, pills, capsules, granules, powders, and solutions, or for parenteral administration by injections for intravenous injection, and intramuscular injection, suppositories, percutaneous preparations, transnasal preparations, inhalations or the like. The dose is appropriately decided in response to an individual case by taking the symptoms, age and sex of the subject and the like into consideration, but is usually from about 0.001 mg/kg

to about 100 mg/kg per day per adult in the case of oral administration, and this is administered in one portion or dividing it into 2 to 4 portions. Also, in the case of intravenous administration according to the symptoms, it is administered usually within the range of from 0.0001 mg/kg to 10 mg/kg per day per adult, once a day or two or more times a day. In addition, in the case of inhalation, it is administered generally within the range of from 0.0001 mg/kg to 1 mg/kg per adult, once a day or two or more times a day.
Regarding the solid composition of the present invention for oral
administration, tablets, powders, granules, or the like are used. In such a solid
composition, one or more active substances are mixed with at least one inactive
excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline
cellulose, starch, polyvinyl pyrrolidone, and aluminum magnesium silicate. In a
conventional method, the composition may contain inactive additives, for example, a
lubricant such as magnesium stearate, a disintegrator such as carboxymethylstarch .,, ..
sodium, or a solubilizing agent. As occasion demands, tablets or pills may be coated with a sugar coating, or a gastric or enteric coating agent.
[0045]
The liquid composition for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and contains generally used inert solvents such as purified water and ethanol. In addition to the inert solvent, this composition may contain an auxiliary agent such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a corrective, an aromatic, and an antiseptic.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Pharmacopeia). Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, and a solubilizing agent. These are sterilized, for example, by filtration through bacteria retaining filter, blending of

bactericides, or irradiation. In addition, these can also be used by producing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.
Regarding a transmucosal agent such as an inhalations and a transnasal agent, those in a solid, liquid or semi-solid state are used, and may be produced in accordance with a conventionally known method. For example, an excipient such as lactose and starch, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be optionally added thereto. For their administration, an appropriate device for inhalation or blowing may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension by combining it with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule,may be used. ......,,.
Alternatively, this may be in a form such as a high pressure aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, and carbon dioxide.
The external agent includes ointments, plasters, creams, jellies, paps, sprays, lotions, eye drops, eye ointments, and the like. The external agent contains ointment bases, lotion bases, aqueous and non-aqueous liquids, suspensions, emulsions, and the like, for general use. Examples of the ointment or lotion bases include polyethylene glycol, propylene glycol, white Vaseline, white beeswax, polyoxyethylene hardened castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.
Example
[0046]
Hereinafter, the compounds of the present invention will be described in more detail with reference to Examples. The present invention is not limited to the inventions as described in the following Examples. The preparation methods of the starting material compounds are shown in Preparation Examples.

[In the following tables, Pr represents Preparation Example No., and Structure represents a structural formula. As the abbreviation symbols in the structural formulae, Me represents a methyl group, and Et represents an ethyl group. Criss-cross double bond represents a cis/trans mixture, and if the section of Data describes only the numbers, it shows MS data. MS represents mass spectrometry data. In the tables, RT refers to a retention time in high performance liquid chromatography (HPLC), and M represents minutes. The condition for HPLC is as follows: column: Intertsil ODS-34.6x150 mm, eluent 0.01M KH2P04 aq./MeCN(3:7), flow rate: 1.0 ml/min, detection wavelength: 254 nm. If ^-NMR data are described in the tables, tetramethylsilane is used as an internal standard, and unless otherwise specifically mentioned, 8 (ppm) (integrated values, variation patterns) of the signals in ^-NMR using DMSO-d6 as a measurement solvent is shown. Abbreviation symbols have the same meanings as follows. S: singlet, d: doublet, t: triplet q: quartet dd: double doublet, ddd: double double doublet, dt: double triplet, dm: double multiplet, br: broad, brs: broad singlet, Hz: Hertz, CDCI3: deuterated chloroform, DMSO-d6: dimethylsulfoxide-d6, and in the present specification, NMR represents 'fl-NMR: proton nuclear magnetic resonance. The same shall apply hereinafter].
[0047]
Preparation Example 1
Imidazo[l,2-a]pyridine-7-carbonitrile hydrochloride (1.50 g), hydroxylamine hydrochloride (301 mg), and Na2CC»3 (3.50 g) were stirred at 60°C for 6 hours in CH3OH (57 ml). The reaction solution was cooled and concentrated, and completion of the reaction was confirmed by LC-MS. To the residue was added water, followed by extraction twice with EtOAc. The organic layer was washed with water and saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated to obtain N'-hydroxyimidazo[l,2-a]pyridine-7-carboxamide (850 mg) as a white solid.
[0048]
The compounds shown in Pr 1-1 through Pr 1-17 were prepared in the same manner as in Preparation Example 1.

[0050]
Preparation Example 2 /-
In a 50 ml reaction vessel, to a solution of lH-indole-4-carbonitril^ [0051]
The compounds shown in Pr 2-1 through Pr 2-26 were prepared in the same manner as in Preparation Example 2.

[0055]
Preparation Example 3
A suspension of N -hydroxy-lH-indole-4-carboxamide (1.00 g), 4-fiuoro-3-(trifluoromethyl)benzoic acid (1.19 g), and EDCI/HC1 (1.32 g) in dioxane (30 ml) was stirred at room temperature for 1 hour, and further heated under reflux for 18 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added thereto, followed by stirring. The insolubles were collected by filtration. The organic layer of the mother liquor was washed with water, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The insolubles collected by filtration, together with the mother liquor, was purified by silica gel chromatography (n-hexane:EtGAc=80:20). To the objective substance was added acetone, followed by dissolving under heating, and addition with n-hexane, and the precipitated solid was collected by filtration to obtain 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (391 mg) as a white solid.
[0056] i
[0057]
Preparation Example 4
5 N2- {[(5,6-Dichloropyridin-3 -yl)carbonyl] oxy} -1 H-indole-4-carboxamidine
(1.91 g) was added to dioxane (40 ml), followed by heating under reflux for 5 hours.

It was concentrated under reduced pressure, and then purified by silica gel column chromatography (EtOAc). To the obtained solid was added acetone, followed by suspension under heating. After being left to be cooled, the insolubles was collected by filtration to obtain 4-[5-(5,6-dichloropyridin-3-yl)-l,2,4-oxadiazol-3-ylplH-indole (1.44 g) as pale yellow powders. [0058]

[0059]
Preparation Example 5
A solution of N2-hydroxy-lH-indole-4-carboxamide (3.42 g) and 4-fluoro-3-(trifluoromethyl)benzoic acid (4.07 g) in THF (70 ml) was cooled to -10°C or lower, and added with DIC (3.7 ml). After stirring at -15 to -5°C for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in chloroform, and then the insolubles were collected by filtration. The obtained powders were purified by silica gel chromatography (n-hexane:EtOAc=50:50) to obtain N -{[4-fluoro-3-(Mfluoromethyl)benzoyl]oxy}-lH-indole-4-carboxamide (8.40 g) as a white solid.
[0060]
The compound shown in Pr 5-1 was prepared in the same manner as in Preparation Example 5.

[0062]
Preparation Example 6
To a solution of 6-amino-2-methylnicotinonitrile (960 mg) in ethanol (34 ml) was added a 40% aqueous chloroacetaldehyde solution (2.36 ml) at 60°C. The reaction mixture was refluxed for 8 hours. The resulting precipitates were collected by filtration to obtain 5-methylimidazo[l,2-a]pyridine-6-carbonitrile hydrochloride (580 mg) as a white solid.
[0063]
The compounds shown in Pr 6-1 through Pr 6-11 were prepared in the same manner as in Preparation Example 6.

[0066]
Preparation Example 7
To a solution of 3,4-diaminobenzonitrile (500 mg) in AcOH (10 ml) was added Ac20 (372 |xt) at room temperature. The reaction mixture was refluxed for 15 hours

(oil bath at 150°C). It was cooled to room temperature, and concentrated until the amount of AcOH was reduced to a half. It was neutralized with an aqueous Na2CC>3 solution, and extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCC>3 solution and saturated brine, dried over anhydrous MgSd, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 2-methyl-lH-benzimidazole-5-carbonitrile (390 mg) as a pale red one.
[0067]
[Table 12]

[0068]
Preparation Example 8
A reaction mixture of 4,5-diamino-2-methylbenzonitrile (20 mg) and formic acid (6 ml) was refluxed for 3 hours. The reaction solution was cooled and concentrated. To the residue was added a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSCU, and then filtered, and the filtrate was concentrated to obtain 5-methyl-lH-benzimidazole-6-carbonitrile as colorless powders.
[0069]
The compound shown in Pr 8-1 was prepared in the same manner as in Preparation Example 8.

[0071]
Preparation Example 9
A solution of 3,4-diaminobenzonitrile (400 mg) in ethyl orthoformate (6.48 ml) was added AcOH (238 mg), followed by stirring at 80°C for 2 hours. The reaction solution was cooled to room temperature, and partitioned between EtOAc and a 1M aqueous NaOH solution. The organic layer was washed with saturated brine, dried over anhydrous Na2S03, and then collected by filtration, and the filtrate was concentrated, and purified by silica gel chromatography to obtain 2-ethoxy-lH-benzimidazole-6-carbonitrile (164 mg) as colorless powders.
[0072]
[Table 14]

[0073]
Preparation Example 10
i To a suspension of 3,4-diaminobenzonitrile (400 mg) in CH3OH (4 ml) was
added BrCN (477 mg), followed by stirring at 20°C for 14 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by concentration. To the residue was added chloroform:CH3OH=10:l (10 ml), and the resulting insolubles were removed by filtration. The filtrate was concentrated, and the

obtained residue was purified by silica gel column chromatography to obtain 2-amino-lH-benzimidazole-6-carbonitrile (311 mg) as pale orange color powders.
[0074]
[Table 15]
[0075]
Preparation Example 11
To a solution of 3,4-diaminobenzonitrile (350 mg) in toluene (5.5 ml) was added CDI (554 mg), followed by stirring at 125°C for 2 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by extraction with EtOAc. The organic layer was dried over anhydrous Mgs04, and then filtered, and the filtrate was concentrated. It was powdered/washed with IPE/IPA to obtain 2-oxo-2,3-dihydro-lH-benzimidazole-5-carbonitrile (423 mg) as colorless powders.
[0076]
[Table 16]

[0077]
Preparation Example 12
To a mixed solution of N-(4-cyano-2-nitrophenyl)penta-4-enamide (1.0 g) in AcOH/ethanol (1:1,20 ml) was added iron powders (710 mg). The reaction solution was heated at 110°C for 3 hours, and then concentrated. To the residue was added chloroform, followed by neutralization with a saturated aqueous NaHCC>3 solution. The organic layer was dried over anhydrous MgSC>4, and then filtered to remove a desiccant, and the solvent was concentrated under reduced pressure. The residue was

purified by silica gel column chromatography to obtain 3-butenyl-lH-benzimidazole-5-carbonitrile (405 mg) as a colorless liquid.
[0078]
The compounds shown in Pr 12-1 through Pr 12-2 were prepared in the same manner as in Preparation Example 12.
[0079]
[Table 17]

[0080]
Preparation Example 13
To a solution of 2-fluoroterephthalonitrile (500 mg) and Et3N (572 ul) in EtOH (20 ml) was added hydrazine (monohydrate), followed by reaction at 60°C for 16 hours, and concentrated. The residue was washed with diethyl ether to obtain 3-amino- 1H-indazole-6-carbonitrile (488 mg) as a yellow solid.
[0081]
The compound shown in Pr 13-1 was prepared in the same manner as in Preparation Example 13.
[0082]
[Table 18]

[0083]
Preparation Example 14
To a suspension of 3-amino-lH-indazole-6-carbonitrile (345 mg) in AcOH was ( slowly added an aqueous NaN02 solution (301 mg) at 0°C. It was stirred at room temperature for 2.5 days, and the residue was collected by filtration, and washed with cool water. To the residue were added 0.1M HC1 and DME, followed by stirring at 80°C for 2 hours. The reaction mixture was neutralized with a saturated aqueous NaHCC>3 solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSC>4, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 50:50) to obtain lH-indazole-6-carbonitrile (175 mg) as a yellow solid.
[0084]
[Table 19]

[0085]
Preparation Example 15
Methyl (4-cyano-2-nitrophenyl)acetate (128 mg) was dissolved in AcOH (3.0 ml), followed by addition of iron powders (129 mg), and the reaction solution was ) stirred in an oil bath at 100°C for 1.5 hours. It was concentrated to remove AcOH, followed by addition of EtOAc. The brown solid was separated by filtration, and the organic layer was washed with a 1M HC1 solution and saturated brine, dried over anhydrous MgS04, and concentrated. The residue was purified by silica gel column chromatography (chloroform:CH30H=99:l to 95:5) to obtain to obtain 2-oxoindoline-6-j carbonitrile (52.0 mg) as a pale yellow solid.

[0086] [Table 20]
[0087]
Preparation Example 16
To a solution of 6-bromo-2,2-dimethylindanemethylindan-l-one (124 mg) in TFA (4.44 g, 3.0 ml) was added triethylsilane (150 mg, 207 ul) at room temperature. After stirring at room temperature for 2.5 days, to the reaction solution was added water to stop the reaction, followed by washing with water and a saturated aqueous NaHC03 solution. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane only) to obtain 5-bromo-2,2-dimethylindane (114 mg) as a colorless oil.
[0088]
[Table 21]

[0089]
Preparation Example 17
In THF (30 ml), to a mixture of 6-bromo-l-indanone (300 mg) and diazomethane (504 mg, 221 ul) was added 60% NaH (125 mg) at 0°C. It was stirred at room temperature for 3.5 hours, and washed with a saturated NH4CI solution. The mixture was extracted with EtOAc, and the organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified

by silica gel column chromatography (n-hexane:EtOAc=100:0 to 80:20) to obtain 6-bromo-2,2-dimethyl-l-indanone (158 mg) as a pale yellow oil.
[0090]
[Table 22]
[0091]
Preparation Example 18
To a solution of 3-amino-4-hydroxybenzonitrile (730 mg) in DMF (10 ml) was added CDI (1.06 g) at 0°C, followed by stirring at room temperature for 3.5 hours. The reaction solution was diluted with water (10 ml), and extracted with EtOAc (200 ml). The organic layer was dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH30H-98:2 to 93.7) to obtain 2-oxo-2,3-dihydro-l,3-benzoxazole-5-carbonitrile (647 mg) as a pale yellow solid.
[0092]
The compound shown in Pr 18-1 was prepared in the same manner as in Preparation Example 18.
[0093]
[Table 23]

[0094]
Preparation Example 19
To a solution of 60% NaH (12.38 g) in DMF (480 ml) was added a solution o1 lH-indole-4-carbonitrile (40.0 g) in DMF (80 ml) at 0°C. After stirring at 0°C for 30 min, it was stirred at room temperature for 0.5 hour. Thereafter, a solution of 2-bromoacetamide (40.76 g) in DMF (80 ml) was added dropwise thereto at 0°C. The solution was warmed from 0°C to room temperature, and stirred for 12 hours. To the reaction solution was added water (1200 ml), and the precipitated white solid was collected by filtration. The solution was washed with hot water (300 ml) and diisopropyl ether (200 ml) to obtain 2-(4-cyano-lH-indol-l-yl)acetamide (52.1 g) as a white solid.
[0095]
[Table 24]

[0096]
Preparation Example 20
To a solution of 3-chloro-4-(2,2,2-trifluoro-l-methylethoxy)benzonitrile (430 mg) in IP A (3 ml) was added a 5M aqueous NaOH solution (1.37 ml), followed by stirring at 80°C for 24 hours, and a 5M aqueous NaOH solution (1.37 ml) was further added thereto, followed by stirring at 95°C for 24 hours. The reaction solution was concentrated until the amount was reduced to a half. To the residue was added 12M HC1, and the resulting precipitate was collected by filtration, and then dried to obtain 3-chloro-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid as a yellow solid.
[0097]
The compounds shown in Pr 20-1 through Pr 20-3 were prepared in the same manner as in Preparation Example 20.

[0099]
Preparation Example 21
To 3 [0100]
The compounds shown in Pr 21-1 through Pr 21-6 were prepared in the same manner as in Preparation Example 21.

[0102]
Preparation Example 22
To 5-bromo-2-(2,2,2-trifluoro-l-methylethoxy)benzonitrile in a mixed solvent of toluene/THF (4:1) was added a solution of n-BuLi in n-hexane at -78°C. With passing a CO2 gas therethrough, the solution was stirred for 0.5 hour. To the reaction solution was added a 1M aqueous NaOH solution to complete the reaction, and followed by extraction with diethyl ether. The organic layer was acidified by adding 1M HC1, extracted with EtOAc, dried over anhydrous MgS04, and concentrated. The residue was purified by silica gel chromatography (chloroform:CH30H=97:3 to 90:10) to obtain 3-cyano-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid as a white solid.
[0103]
The compound shown in Pr 22-1 was prepared in the same manner as in Preparation Example 22.

[0105]
Preparation Example 23
To a mixed solution was added a 1M aqueous NaOH solution (4.1 ml) of methyl l-isobutyl-2-oxo-l,2-dihydropyridine-4-carboxylate (430 mg) in CH3OH-THF (4 ml - 3 ml). The solution was stirred at room temperature for 10 hours, and then > concentrated under reduced pressure, and water (10 ml) was added, and subsequently 1M HC1 was added thereto until pH becomes 3. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain l-isobutyl-2-oxo-l,2-dihydropyridine-4-carboxylic acid (325 mg) as white powders.
[0106]
[Table 28]

[0107]
Preparation Example 24
) A solution of lH-benzimidazole-5-carboxylic acid (75.0 g) in dichloromethane
(750 ml) was allowed to be reacted with oxalyl chloride (76.3 g, 52.4 ml) at room temperature for 1 hour, and then the reaction solution was concentrated. To a solution of the residue in THF (750 ml) was added a 28% aqueous NH3 solution (5 ml) under ice-cooling. This reaction mixture was stirred at the same temperature, and the
A O

reaction solution was concentrated. The purple residue was powdered/washed with IPE/IPA, and then collected by filtration to obtain lH-benzimidazole-6-carboxamide (129 g) (including inorganic salts).
[0108]
The compound shown in Pr 24-1 was prepared in the same manner as in Preparation Example 24.
[0109]
[Table 29]

[0110]
Preparation Example 25
Preparation Example 254
To a solution of lH-l,2,3-benzotriazole-5-carboxylic acid (2 g), EDCI/HC1 (2.82 g), and HOBt in DMF (70 ml) was added an aqueous NH3 solution (5.1 ml), followed by reaction at room temperature for 2 hours. It was concentrated, and the residue was washed with a saturated NaHC03 solution, collected by filtration, and dried to obtain 1H-1,2,3-benzotriazole-5-carboxamide (1.98 g) as a black solid.
Preparation Example 25-3
In a 50 ml reaction vessel, to a solution of methyl 4-chloro-2-methyI-lH-benzimidazole-6-carboxylate ester (300 mg) in formamide (2.65 ml) was added NaOCH3 (288 mg) at room temperature. The solution was stirred at 80°C for 3 hours. Completion of the reaction was confirmed by TLC and LC, and then the reaction solution was concentrated, and added with water to complete the reaction. It was extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to

90:10) to obtain 4-chloro-2-methyl-lH-benzimidazole-6-carboxamide (257 mg) as a
white solid. ../
[0111]
The compound shown in Pr 25-2 was prepared in the same manner as in Preparation Example 25-1.
[0112]
[Table 30]

i [0113]
Preparation Example 26
To a solution of 3-formyl-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid (490 mg) and K2C03 (387 mg) in acetone (10 ml) was added iodomethane (350 ul) at room temperature, followed by stirring for 2 hours. The reaction mixture was diluted with
i water (15 ml), and extracted with EtOAc (30 ml). The organic layer was dried over anhydrous MgS04, and filtered to remove the desiccant, and the solvent was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain methyl 3-formyl-4-(2,2,2-trifluoro-l-methylethoxy)benzoate (122 mg) as a white solid.

[0114] [Table 31]

[0115]
Preparation Example 27
Under ice-cooling, to DMF (30 ml) was slowly added dropwise POCI3 (6.68 g, 4.06 ml), followed by reaction at room temperature for 2 hours, and then a solution of lH-benzimidazole-6-carboxamide (2.38 g) in DMF (47.6 ml) was added thereto, followed by stirring at room temperature for 2 hours. To the solution was added a 1M aqueous NaOH solution (pH 6 to 7), followed by stirring at room temperature for 0.5 hour. The solution was extracted with EtOAc, and the organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, and powdered/washed with IPE to obtain lH-benzimidazole-6-carbonitrile (0.58 g) as a pale red crystal.
[0116]
The compounds shown in Pr 27-1 through Pr 27-2 were prepared in the same
manner as in Preparation Example 27.

[0118]
Preparation Example 28
A solution of l,3-benzothiazole-6-carboxamide (1.96 g) in POCI3 (10 ml) was refluxed for 4 hours. The reaction solution was concentrated, and water was slowly added thereto at 0°C. It was extracted with EtOAc, and the organic layer was dried ! over anhydrous MgSCU, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 60:40) to obtain l,3-benzothiazole-6-carbonitrile as a pale yellow solid.
[0119]
The following Pr 28-1 was prepared in the same manner as in Preparation > Example 28.
[0120]

[0121]
Preparation Example 29
[0122]
To a solution of 6-bromo[l,2,4]triazolo[l,5-a]pyridine (400 mg) in DMF were added tris(dibenzylideneacetone)dipalladium (0), l'-bis(diphenylphosphino)ferrocene, and Zn(CN)2 under a nitrogen atmosphere, followed by stirring at 110°C for 23 hours. It was cooled to room temperature, and saturated NH4CI (12 ml), a saturated NH3 solution (6 ml), and H2O (12 ml) were added thereto. The reaction mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 to 5% CH30H/chloroform)[l,2,4]triazolo[l,5-a]pyridine-6-carbonitrile as a dark red solid.
[0123]
Preparation Example 30
In a 100 ml reaction vessel, to a solution of 6-bromo-7-methyl-lH-benzimidazole (500 mg) in DMF were added Zu(CN)2 (834 mg) and Pd (PPh)4 (547 mg) at room temperature, followed by stirring at 150°C for 5 hours. The reaction solution was poured into a 1:1 mixed solvent of a saturated NaHC03 solution and EtOAc, followed by stirring for 1 hour. The organic layer was washed with saturated brine, dried over anhydrous MgSCU, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (automatic purifier, chloroforrn:CH3OH=98:2 to 90:10) to obtain 7-memyl4H-benzimidazole-6-carbonitrile (161.8 mg) as a brown solid.
[0124]
The following Pr 30-1 through Pr 30-7 were prepared in the same manner as in Preparation Example 30. They were also prepared by the method as in Preparation Example 29.

[0126]
Preparation Example 31
To a mixed solution of 4-hydroxy-3-nitrobenzonitrile (1 g) andNH^Cl (163 mg) in ethanol (20 ml), THF (10 ml), and water (10 ml) were added Celite (5 g) and reduced iron (1.7 g), followed by heating under reflux at 70°C for 30 min. The i reaction solution was cooled to room temperature, diluted with EtOAc (200 ml), and then filtered through celite. The solution was washed with saturated brine, the organic layer was dried over anhydrous MgS04, and filtered, and the filtrate was concentrated under reduced pressure to obtain 3-amino-4-hydroxybenzonitrile (740 mg) as a pale brown solid.

[0127]
The following Pr 31-1 through Pr 31-3 were prepared in the same manner as Preparation Example 31. [0128] [Table 35]

[0129]
Preparation Example 32
To a mixed solution of 4-amino-3-nitrobenzonitrile (8 g) in EtOH/THF (40 ml/40 ml) was added Pd-C(50%wet) (0.8 g), followed by stirring under an H2 atmosphere for 12 hours. The reaction solution was filtered through celite, and concentrated. The residue was powdered/washed with a mixed solvent of IPE and IP A, and collected by filtration to obtain 3,4-diaminobenzonitrile (6.3 g) as orange powders.
[0130]
[Table 36]

[0131]
Preparation Example 33
To a solution of 2-amino-3-nitrobenzonitrile (2 g) in THF (30 ml) were added 4-pentenoyl chloride (2.90 g) and diisopropylethylamine (4.27 ml), followed by stirring at 80°C for 12 hours. The reaction solution was poured into water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH) to obtain N-(4-cyano-2-nitrophenyl)pent-4-enamide (174 mg) as a colorless liquid.
[0132]
The following Pr 33-1 through Pr 33-2 were prepared in the same manner as in Preparation Example 33.
[0133]
[Table 37]

[0134]
Preparation Example 34
To a solution of 3-chloro-4-fluorobenzonitrile (300 mg) and l,l,l-trifiuoro-2-propanol (263 mg) in THF (15 ml) was added 60% NaH (92.5 mg) at 5°C, followed by stirring at room temperature for 2 hours, addition of a saturated NH4CI solution to complete the reaction, and extraction with EtOAc. The obtained organic layer was dried over anhydrous MgS04, and concentrated. The residue was purified by silica gel

chromatography (n-hexane:EtOAc=97:3 to 85:15) to obtain 3-chloro-4-(2,2,2-trifluoro-l-methylethoxy)benzonitrile (435 mg) as a colorless oily substance.
[0135]
The following Pr 34-1 through Pr 34-6 were prepared in the same manner as in Preparation Example 34.
[0136]
[Table 38]

Preparation Example 35
In a 50 ml reaction vessel, to a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (100 mg) in DMF (1 ml) was added 60% NaH (10.9 mg) at 0°C. The solution was warmed to room temperature, followed by stirring for 0.5 hour. Further, tertiary-butyl (2-iodoethoxy)dimethylsilane was added thereto at 0°C, followed by stirring at room temperature for 15 hours. Completion of the reaction was confirmed by LC-MS, and then the reaction solution was added with water (30 ml). It was extracted three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and concentrated under reduced pressure. It was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=100:0 to 90:10) to obtain 1 -(2-{[tertiary-butyl (dimethyl)silyl]oxy}ethyl)-4-{5- [3-(trifiuoromethyl)-4-2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (86.4 mg) as a white solid.
[0139]
[Table 40]

[0140]
Preparation Example 36
*LiH (78 mg) was suspended in DMF (5 ml), and a suspension of methyl-2-oxo-l,2-dihydropyridine-4-carboxylate (500 mg) in DMF (5 ml) was added dropwise thereto at room temperature. The suspension was stirred as it was, and a solution of l-iodo-2-methylpropane (506 ul) in DMF (5 ml) was added dropwise thereto over 10 min, followed by stirring at 50°C for 15 hours. To the reaction solution was added 1M HC1 at 0°C, followed by extraction with EtOAc, and the organic layer was washed with
saturated brine, dried over anhydrous MgS04, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:EtOAc=90:10 to 50:50) to obtain methyl-1-isobutyl-2-oxo-l,2-dihydropyridine-4-carboxylate (440 mg) as white powders.
[0141]
[Table 41]
[0142]
Preparation Example 37
To a solution of 4-fluoro-3-nitrobenzonitrile (300 mg) and dimethyl malonate (286 mg) in DMF was added 60% NaH at 0°C, followed by reaction at room temperature to obtain dimethyl (4-cyano-2-nitrophenyl)malonate (T98 mg).
[0143]
[Table 42]
[0144]
Preparation Example 38
To a solution of dimethyl (4-cyano-2-nitrophenyl) malonate (198 mg) in DMSO (5 ml) were added LiCl (60.3 mg) and H20 (12 ul), followed by stirring at 100°C for 3 hours. The reaction solution was cooled to room temperature, and poured into EtOAc and saturated brine for partition. The organic layer was washed with saturated brine, dried over anhydrous MgSO*, and then filtered, and the filtrate was

concentrated. The residue was purified by silica gel column chromatography (n hexane:EtOAc=90:10 to 75:25) to obtain methyl (4-cyano-2-nitrophenyl)acetate ( mg) as a yellow oil.
[0145]
[Table 43]

[0146]
Preparation Example 39
To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1 g) and iron(3+) ris[(2Z)-4-oxopent-2-ene-2-oleate] (86 mg), and l-methylpyrrolidin-2-one (2.8 ml) in TfF (30 ml) was added a solution of 2M bromo(isobutyl)magnesium in diethyl ether 2.9 ml) under ice-cooling. The solution was stirred at room temperature for 30 ainutes, and diluted with diethyl ether (30 ml), and then IM HC1 was carefully added hereto to complete the reaction. The reaction solution was extracted with EtOAc (100 ril), and the organic layer was dried over anhydrous MgSC>4, and then filtered, and the iltrate was concentrated under reduced pressure. The residue was purified by silica ;el column chromatography (n-hexane:EtOAc=100:0 to 95:5) to obtain 4-isobutyl-3-trifluoromethyl)benzonitrile (320 mg) as a pale yellow liquid.
[0147]
The following Pr 39-1 was prepared in the same manner as in Preparation ixample 39.

[0149]
Preparation Example 40
To a solution of 4-fluoro-3-formylbenzonitrile (300 mg) in dichloromethane (7 ml) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-A-4-sulfanyI)ethanamine (757 mg) at room temperature, followed by stirring for 6 hours, and addition of a saturated aqueous NaHCCb solution (15 ml). After extraction with chloroform (30 ml), the organic layer was dried over anhydrous MgSCU, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain 3-(difluoromethyl)-4-fluorobenzonitrile (174 mg) as a colorless liquid.
[0150]
The following Pr 40-1 was prepared in the same manner as in Preparation Example 40.
[0151]

[0152]
Preparation Example 41
The following Pr 41 -1 through Pr 41 -10 were prepared in the same manner as in Example 2. [0153] [Table 46]

[0154]
Preparation Example 42
The following Pr 42-1 through Pr 42-3 were prepared in the same manner as in Example 5.

[0156]
Preparation Example 43
The following Pr 43 was prepared in the same manner as in Example 6.
[0157]
[Table 48]

[0158]
Preparation Example 44
The following Pr 44-1 and Pr 44-2 were prepared in the same manner as in Example 12.

[0160]
Preparation Example 45
The following Pr 45 was prepared in the same manner as in Preparation nple 47. [0161] [Table 50]

[0162]
Preparation Example 46
The following Pr 46-1 through Pr 46-5 were prepared in the same manner as in riple 19.

[0164]
Preparation Example 47
To a solution of ethyl (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridin-2-yl)acetate(230 mg) in THF (2.0 ml) was added a 1M aqueous NaOH solution (1.0 ml), followed by 1 stirring at 80°C for 2 hours. After cooling to room temperature, a 1 M HC1 aqueous solution (1.0 ml) was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH30H=l 0:1 to 5:1) to obtain colorless powders. To a solution of this

colorless powder in EtOAc was added a 4M HCl/EtOAc solution, followed by concentration. The resulting colorless powder was powdered/washed with IPE to obtain (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridin-2-yl)acetic acid hydrochloride (180.4 mg) as colorless powders. [0165]
The following Pr 47-1 through Pr 47-13 were prepared in the same manner as l Preparation Example 47.

[0168]
Example 1
A solution of 3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)benzoic acid (810 mg), EDCI/HC1 (616 mg), and N'-hydroxy-7-methylimidazo[l,2-a]pyridine-6-carboxamide (510 mg) in dioxane was stirred at 115°C for 60 hours. The reaction solution was concentrated, and the residue was partitioned between water and chloroform. The organic layer was dried over anhydrous MgSO,*, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (CH3OH/chloroform=0 to 5%), and recrystallized with EtOH to obtain 7-methyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (60 mg) as a white solid.
[0169]
Example 2
To a solution of 3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)benzoic acid (349 mg) in dichloromethane (6 ml) were added oxalyl chloride (333 mg) and a catalytic amount of DMF under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, and azeotroped with toluene. To a solution of the residue in THF were added N'-hydroxy-2-methyl-lH-benzimidazole-6-carboxyimidamide (200 mg) and N-ethyl-N-isopropyl-2-propaneamine (543 mg). The reaction mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, followed by three times extractions with EtOAc. The organic layer was combined, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was dissolved in dioxane, followed by stirring at 100°C for

3 hours. After cooling to room temperature, it was concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain a colorless oily substance. To a solution of this oily substance in EtOAc was added a 4M HCl/EtOAc solution, followed by stirring for a few minutes, and then the reaction mixture was concentrated to obtain 2-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3 -yl} -1 H-benzimidazole hydrochloride (239 mg) as a colorless crystal.
[0170]
Example 3
To a solution of 4-(2,2,2-trifluoro-l,l-dimethylethoxy)-3-(trifluoromethyl)benzoic acid (118 mg) and 2-{4-[amino(hydroxyimino)methyl]-lH-indol-l-yl}acetamide (104 mg) in dioxane (5 ml) was added DIC(69 ul), followed by stirring at room temperature for 3 hours, and then heating under reflux for 20 hours. The reaction solution was concentrated,-and then to the residue was added water (15 ml), followed by extraction with chloroform (15 ml). The organic layer was washed with a saturated aqueous NaHCC>3 solution and saturated brine, dried over anhydrous MgS04, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CAPCEL PAK, C18, MG, S-5, 30x50 mm; solvent: 50-90% acetonitrile/10 mM ammonium carbonate-ammonia (pH 9.2); 40 ml/min), and crystallized with diisopropyl ether to obtain 2-(4{5-[4-(2,2,2-trifluoro-l,l-dimethylethoxy)-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (40 mg) as a white solid.
[0171]
Example 4
To a suspension of 60% NaH (68.0 mg) in DMF was added cyclopropylmethanol (99 mg) at 0°C, followed by stirring at the same temperature for 15 min, and then 5-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole (120 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then added with water. It was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (CH3OH/chloroform=0 to 5%) to obtain an oily substance. A

solution of the oily substance in chloroform-CH3OH was added with a 4M HCl/dioxane solution (0.5 ml), and concentrated to obtain 5-{5-[4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl]-l ,2,4-oxadiazol-3-yl}-lH-benzimidazole hydrochloride (20 mg) as a white solid.
HPLC analysis: Condition (TSK-GEL (TOSOH) ODS-80TM 4.6x 150 mm, MeCN: 0.01M KH2P04(7:3), 1.0 ml/min, 254 nm)[RT: 7.90 min]
[0172]
Example 5
To a solution of 2-(4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-
3-yl}-lH-indol-l-yl)acetamide (100 mg) and 2-propanol (35 ul) in DMF (3 ml) was
added 60% NaH (12 mg) at 0°C, followed by stirring at room temperature for 9 hours.
The reaction solution was added with water (5 ml) to complete the reaction, and
extracted with as a mixed solvent of chloroform:CH30H (8:2). The organic layer was
washed wim saturated brine, dried over anhydrous MgS04, and then filtered, and me .
filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH30H=98:2 to 93:7), and crystallized with diethyl ether to obtain 2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (25 mg) as a pale yellow solid.
[0173]
Example 6
To a solution of 1,3-difluoropropanol (62 mg) in DMF (2.4 ml) was added 60% NaH (19 mg) at -10°C, followed by stirring at -10°C for 0.5 hour. To this reaction mixture was added 2-{4-[5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (120 mg) at -10°C, followed by stirring at -10°C for 3 hours. After adding water to the reaction solution, the reaction mixture was extracted with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5) to obtain 2-[4-(5-{3-chloro-4-[2-fluoro-l-(fluoromethyl)ethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (76.9 mg) as a white solid.

[0174]
Example 7 /
To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (100 mg) and (2R)-l,l,l-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0°C, followed by stirring at 80°C for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chlorofornY.CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(lR)-2,2,2-trifluoro-l-methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (70 mg) as a pale yellow solid.
[0175]
Example 8
To a suspension of 60% NaH (43 mg) in DMF (4 ml) was added 2-propanol - (65 mg) at 0°C, followed by stirring at room-temperature for 20 min. After cooling to 0°C again, 2-{4-[5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl-acetamide (200 mg) was added thereto. The reaction mixture was radiated with a microwave at 60°C for 50 min. The reaction solution was added to an aqueous NH4CI solution, followed by stirring, and then the solvent was evaporated. After adding a mixed solvent (4:1) of chloroform-CHsOH, and suspending, the solid was removed, silica gel was added thereto, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 98:2; n-hexane:EtOAc=0:100) to obtain 2-{4-[5-(3-chloro-4-isopropylphenyl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (17.5 mg) as a white solid.
[0176]
Example 9
To a solution of 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (300 mg) in THF (1.5 ml) was added, propane-2-amine (0.75 ml), and after sealing the tube, the solution was stirred at 50 to 55°C for 40 hours. It was concentrated under reduced pressure, and then purified by silica gel chromatography (n-1 hexane:EtOAc). The obtained solid was dissolved in acetone under heating, and added

with n-hexane, and the precipitate was filtered to obtain 4-[3-(lH-indol-4-yl)-l,2,4-
oxadiazol-5-yl]-N-isopropyl-2-(trifluoromethyl)aniline (295 mg). ,. /"
[0177]
Example 10
To a mixed solution of 2-{4-[5-(5,6-dichloropyridin-3-yl)-l,2,4-oxadiazol-3-yl]-lH-indol-l-yl}acetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added isopropylamine (220 ul), followed by stirring at 150°C for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:EtOAc=40:60 to 0:100), and the obtained residue was suspended in diisopropyl ether under heating, and collected by filtration to obtain 2-(4-{5-[5-chloro-6-(isopropylamino)pyridin-3-yl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (62 mg) as white powders.
[0178]
Example 11 (11-1 and 11-2)
To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole (105 mg) in DMF (3.15 ml) was added 60% NaH (31 mg) under ice-cooling, followed by stirring at the same temperature for 15 min, and methyl iodide (0.22 ml) was added thereto, followed by stirring at room temperature for 5 hours. To the reaction was added water, followed by extraction with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic producer, chloroform:CH3OH=10:1). The objective substance was dissolved in EtOAc (5 ml), added with a 4M HCl/EtOAc solution (5 ml), and concentrated to produce about 1:1 two regioisomers. The mixture was crystallized with acetonitrile to obtain l-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl} -1 H-benzimidazole hydrochloride (12.1 mg). The mother liquor was concentrated to obtain 1 -methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole hydrochloride and l-methyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole hydrochloride (70.2 mg) as colorless powders.

[0179]
Example 12
To a solution 4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indole (150 mg) in DMF (1.5 ml) was added 60% NaH (16 mg) at 0°C, followed by stirring at room temperature for 0.5 hour. Then, to the reaction mixture was added 2-bromoacetamide (70 mg) again at 0°C, followed by stirring at room temperature for 3 hours. To the reaction was added with water, followed by extraction with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 2-[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl}-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (145 mg) as a white solid.
[0180]
Example 13
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy]phenyl]-l,2,4-oxadiazol-3-yl)indoline (100 mg) in acetonitrile (2.5 ml) was added K2CO3 (46 mg) and 3-iodopropanamide (124 mg) at room temperature, followed by stirring at 80°C for 15 hours. To the reaction solution was added an NaHCC>3 aqueous saturated solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSCU, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-2, 3-dihydro-lH-indol-l-yl)propanamide (23.6 mg) as a white solid.
[0181]
Example 14
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole-3-carboaldehyde (150.0 mg) in CH3OH (1.5 ml) was added a 40% CH3OH solution of CH3NH2 (74.5 mg) at 0°C. After warming to room temperature, the solution was stirred at room temperature for 3

hours. After confirming the production of an iminium salt, the organic solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (L5 ml). To this was added NaBH4 (12.09 nig) at 0°C. After warming to room temperature, the solution was stirred at room temperature for 15 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain N-methyl-1 -(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-memylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-3-yl)methanamine (87.4 mg) as a white solid.
[0182]
Example 15
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyi]-l ,2,4-oxadiazol-3-yl}indoline (100 mg) in DMF (1.0 ml) was added 60% NaH (10.9 mg) at 0°C, followed by stirring at room temperature for 0.5 hour. Acetyl chloride (24.1 ul) was added thereto at 0°C, followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=90:10 to 60:40) to obtain l-acetyl-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}indoline (56.8 mg) as a white crystal.
[0183]
Example 16
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (80 mg) in DMF (0.80 ml) was added 60% NaH (8.7 mg) at 0°C, followed by stirring at room temperature for 0.5 hour. Methanesulfonyl chloride (21.1 ul) was added thereto at 0°C, followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml),

followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then,.filtered, and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH==100:0 to 98:2) to obtain 1-(methylsulfonyl)-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (15.6 mg) as a white solid.
[0184]
Example 17
4- {5-[3-(Trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-l ,2,4-
oxadiazol-3-yl}-lH-indole (100 mg) was dissolved in DMF (1.0 ml), followed by
addition of 60% NaH (10.9 mg) at 0°C, and stirring at room temperature for 0.5 hour.
Methyl chloride carbonate (26.3 ul) was added thereto at 0°C, followed by stirring at
room temperature for 3 hours. To the reaction solution was added water (30 ml),
followed by extraction three times with EtOAc (20 ml), the organic layer was ■ ...........
combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 98:2) to obtain methyl 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole-l-carboxylate (98.6 mg) as a white solid.
[0185]
Example 18
To a solution of 3-(5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylemoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazol-2-yl)propanoicacid (23.5 mg) in dichloromethane (0.7 ml) were added oxalyl chloride (0.01 ml) and a few drops of DMF, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated to remove the solvent and the reagent. To a solution of the residue in THF was added NH4OH, followed by further stirring for 1 hour. To the reaction solution was added a saturated aqueous NH4C1 solution, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgS04, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform.-CHbOH^l 0:1) to obtain colorless powders. To a solution of the colorless

powders in EtOAc was added a solution of 4N-HC1 in EtOAc. The reaction mixture was concentrated, and the residue was powdered and washed with' IPE to obtain 3-(5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazol-2-yl)propanamide hydrochloride as pale yellow powders.
[0186]
Example 19
To a solution of (4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetic acid (150 mg) and HOBt(65 mg) in DMF (1.5 ml) was added EDCI/HC1 (69 mg) at 0°C, followed by stirring at room temperature for 1 hour. After cooling to 0°C again, l-pyridin-2-ylmethanamine (39 mg) was added thereto, followed by stirring at room temperature for 15 hours. To the reaction solution was added a saturated aqueous NaHCC>3 solution to complete the reaction. It was extracted with EtO Ac, the organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chlorofornrCHsOH^lOOiO to 95:5) to obtain N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (157.8 mg) as a white solid. To a solution of N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide (120 mg) in methylene chloride (2.4 ml) was added dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and powdered/washed with EPE. The obtained solid was collected by ■ filtration, and dried to obtain N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl] -1,2,4-oxadiazol-3-yl}-1 H-indol-1 -yl)acetamide hydrochloride (126 mg) as a white solid.
[0187]
Example 20
To a solution of [4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg), and after 30 min, methanesulfonamide (23 mg)

and 2,3,4,6,7,8,9,10-octanydropyrimide[l,2-a]azepine (37 mg) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture, was added with water to complete the reaction. It was extracted with EtOAc, the obtained organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain N-(methylsulfonyl)-2-[4-(5- {3-(trifluoromethyl)-4-[(l S)-2,2,2-trifluoro-l -methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl]acetamide (56.4 mg) as a white solid.
[0188]
Example 21
POCl3 (158.4 ul) was added dropwise to a DMF solution (4 ml) at 0°C. After
warming to room temperature, it was stirred for 0.5 hour. Then, a solution of 4-{5-[3-
{trifluoromethyl)^-(2£
indole (500.0 mg) in DMF (1 ml) was added thereto at 0°C, followed by stirring at room temperature for 15 hours. After cooling to 0°C, to the reaction solution was added a 1M aqueous NaOH solution for adjustment of its pH to 9 to 10. This solution was stirred at 100°C for 1 hour. After being left to be cooled, to the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane, EtOAc=90:10 to 70:30) to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole-3-carboaldehyde (456.7 mg) as a white solid.
[0189]
Example 22
To a mixed solution of 5-[3-(lH-benzimidazol-6-yl)-l,2,4-oxadiazbl-5-yl]-2-(2,2,2-trifluoro-1 -methylethoxy)benzaldehyde (83 mg), potassium dihydrogen phosphate (421 mg), and 2-methyl-2-butene (0.5 ml) in tBuOH (2 ml) and water (0.5 ml) was added sodium chlorite (187 mg) at room temperature. The mixed reaction solution was stirred at room temperature for 3 hours, followed by dilution with water

(10 ml), and extraction with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. To a solution of the residue in dioxane was added a 4 N HCl-dioxane solution, followed by concentration. The resulting powder was recrystallized with IPA (10 ml) to obtain 5-[3-(lH-benzimidazol-5-yl)-l,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-l-methylethoxy)benzoic acid hydrochloride (80 mg) as white powders.
[0190]
Example 23
To a solution of 2-[2-(methylthio)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-benzimidazole (400 mg) in dichloromethane (8.0 ml) was added mCPBA (534 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a Na2S2C>4 aqueous solution, followed by stirring for 1 hour. The reaction solution was extracted three times with EtOAc, and the organic layer was, combined, dried oyer anhydrous MgS04, filtered, and then concentrated. The residue was purified by silica gel chromatography (chloroform:CH3OH=10:1) to obtain a yellow oily substance. This was dissolved in EtOAc, and a 4M-HCl/EtOAc solution was added thereto, followed by concentration. The residue was washed with IPE to obtain 2-[2-(methylsulfonyl)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3 -yl} -1H-benzimidazole hydrochloride (146 mg) as pale yellow powders.
[0191]
Example 24
To a reaction mixture of 2-but-3-en4-yl-5-{543-(trifluoromemyl)-4-(2,2,2-
trifluoro4-memylethoxy)phenylH,2,4-oxadiazol-3-ylHH-beIK^ (200 mg) in
acetone (4 ml) and water (1 ml) were added tetraoxoosmium (51 mg) and 4-
methylmorpholine 4-oxide (94 mg), followed by stirring overnight. The reaction
mixture was filtered, and to the filtrate was added an aqueous sodium thiosulfate
solution, followed by stirring for 1 hour. The solution was extracted with chloroform,
and the organic layer was concentrated. The residue was purified by silica gel column
| chromatography (chloroform-CHsOH), and concentrated, and the obtained colorless
powder was added with a solution of HC1 in ethanol, and dissolved therein, followed by

concentration. The residue was powdered/washed with diisopropyl ether to obtain 4-(5- { 5-[3-(trifluoromethyl)-4-(2,2,2-triiluoro-1 -methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-lH-benzimidazol-2-yl)butane-1,2-diol hydrochloride (102.3 mg).
[0192]
Example 25
To a solution of 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-
methylethoxy)phenyl] -1,2,4-oxadiazol-3 -yl} -2,3 -dihydro-1 H-indol-1 -yl)propanamide
(100 mg) in chloroform (1 ml) was added manganese dioxide (67.6 mg), followed by
reflux for 15 hours. The reaction solution was left to be cooled to room temperature,
and filtered through Celite to remove manganese dioxide. The filtrate was
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 3-(4-{5-[3-
(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-
indol-l-yl)-propanamide (46.3 mg)-
[0193]
Example 26
To a solution 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (100 mg) in AcOH (3 ml) was added portionwise sodium cyanoboroate (29 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, alkalified with a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSCU, and then filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25), and washed with n-hexane to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yljindoline (90 mg) as a pale yellow solid.
[0194]
Example 27
To a solution of 5-[3-(lH-benzimidazol-6-yl)-l,2,4-oxadiazol-5-yl]-2-(2,2,2-
trifluoro-l-methylethoxy)benzaldehyde (80 mg) in ethanol (3 ml) was addedNaBH4(9 mg) at 0°C. After stirring at room temperature for 0.5 hour, a saturated NH4CI

solution (10 ml) was added thereto, followed by extraction with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. To a solution of the residue (78 mg) in dioxane was added a 4M HCl/dioxane solution, followed by concentration. The resulting powder was recrystallized with IPA (10 ml) to obtain [5-[3-(lH-benzimidazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-1 -methylethoxy)phenyl]methanol hydrochloride (70 mg) as white powders.
[0195]
Example 28
A solution of 5-methyl-6-{5-[3-trifiuoro)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (120 mg) andNCS in THF/EtOH (1/1) was stirred at 80°C for overnight. It was concentrated, and the obtained residue was purified by silica gel column chromatography (GH3OH/chloroform 0 to 5%) to obtain 3-chloro-5-m«thyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (45 mg) as a pale yellow solid.
[0196]
Example 29
To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-memylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (150 mg) in ethanol was added NCS(67 mg) at room temperature, followed by stirring at 80°C for 15 hours. To the reaction solution was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSC>4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25) to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl] -1,2,4-oxadiazol-3 -yl}imidazo[l,2-a]pyridine (110.4 mg) as a white solid. To asolution of 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine (100 mg) in methylene chloride (2 ml) was added dropwise 10 equivalents of 4M HCl/dioxane at room temperature. After stirring at room temperature as it was for 1 hour, it was concentrated under reduced pressure. It was

powdered/washed with diisopropyl ether, and then collected by filtration to obtain 3-chloro-5- {5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l -methyl ethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[l,2-a]pyridine hydrochloride (102.6 mg) as a white solid.
[0197]
Example 30
1 -(2- {[Tertiary-butyldimethylsilyl]oxy }ethyl)-4- {5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-lH-indole (60 mg) was dissolved in THF (1.2 ml), and TBAF (150 ]ul) was added thereto at 0°C, followed by stirring at room temperature for 3.0 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgS04, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4- - ...- oxadiazol-3-yl/lH-indol-l-yl)ethanol (36.5 mg) as a white solid.
[0198]
Example 31
To a solution of tertiary-butyl 4-{[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-
trifluoro-1 -methylethoxy]phenyl} -1,2,4-oxadiazol-3-yl)-1 H-indol-1 -
yl]acetyl}piperazine-l-carboxylate (70.7 mg) in methylene chloride (1 ml) was added
dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring at room temperature
for 3 hours. After 5 hours, the reaction solution was concentrated. With addition of
diisopropyl ether, a white solid was precipitated. The white solid was washed with IPE to obtain l-(2-oxo-2-piperazin-l-ylethyl)-4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-1 -methylethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-lH-indole hydrochloride (58.9 mg) as a pale red solid.
[0199]
In following tables, the structural formulae of the Example compounds are shown. Ex: Example No.

In following tables, the NMR data of the compounds of Examples are shown. Tetramethylsilane is used as an internal standard, and unless otherwise specifically mentioned, 8 (ppm) of the signals in ^-NMR using DMSO-d6 as a measurement solvent is shown. Ref-Ex represents Example No. (Ex), which can be referred to for the preparation.

INDUSTRIAL APPLICABILITY
[0231]
The compound of the present invention is useful as a medicament, and in particular, for prevention and/or treatment of rejection in the transplantation of an organ, bone marrow, or tissue, an autoimmune disease, or the like, since it has SI Pi agonist activity.

CLAIMS
1. A compound represented by the formula (I): [Chem. 16]
or a pharmaceutically acceptable salt thereof,
wherein the symbols mean as follows;
the ring A is
[Chem. 17]

X is a single bond, -CH2-, -NR3-, -0-, -S-, -S(=0)-, or -S(=0)2-,
R1 is -H; halogen; aryl; heteroaryl; (C3-Cg)cycloalkyl; (C3-Cs)cycloalkenyl; (C3.C8)heterocycloalkyl; or (C1-C6)alkyl or (C2-C8)alkenyl, each of which may contain halogen, -CONH2, aryl, or (C3-Cg)cycloalkyl, as a substituent,
R2 is -CN, -0-(C1-C6)alkyl, -C(=0)H, halogen; or (C1-C6)alkyl which may be substituted with halogen or -OH,
R is -H; wherein R may form morpholino, 1-pyrrolidinyl or 3,4- dehydropipelidin-1-yl, together with R1 and nitrogen,
wherein, when -X- is a single bond, R1 and R2 may in combination form a 5-membered ring and further contain (C1-C6)alkyl, as a substituent,
R4 is a following ring;

wherein any one of bonds from the ring is bound to an oxadiazole ring,
R5 is -H; (C1-Ce)alkyl which may be substituted with at least one group selected
rom the group consisting of -CN, -C(=0)NRxRY, -NHRX, -SRx, -S(=0)2Rx, and -ORx,
this is defined as R°-(C1-C6)alkyl); R0-(C1-C6)alkyl-O-; R°-(C1-C6)alkyl-C(=0)-;
l0-(C1-C6)alkyl-S(=O)2-; R°-0-(C1-C6)alkyl-; R°-C(=0)-(C1-C6)alkyl-;
l°-S(=0)2-(C1-C6)alkyl-; (C2-C6)alkenyl-; -C(=0)H; -ORx; -S(=0)2Rx; halogen;
=0; -NRXRY; -C(=0)NRxRY;
R and R may be the same with or different from each other, and is -H; or
C1-C6)a]kyl which may be substituted with -OH, -NH2 which may be protected with a
protecting group or heteroaryl, wherein Rx may form (C3-Cg)heterocycloalkyl, together
with R1 or nitrogen.
2. The compound according to claim 1, which is represented by the formula II):

[Chem. 19]

or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is (C1-C6)alkyl which may contain halogen as a substituent.
4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -CN, halogen; or (C1-C6)alkyl which may be substituted with halogen or -OH.
5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R" is -H; or (C1-C6)alkyl which may be substituted with at least
one -C(=0)NRxRY.
6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein X is a single bond, -CH2- or -0-.
7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is a following ring;
[Chem. 20]

wherein any one of bonds from the ring of R4 is bound to an oxadiazole ring.

8. A compound selected from the following:
5-(5-[3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl)-l,2,4- oxadiazol-3 -yl)-1 H-benzimidazole hydrochloride;
5-(5-[3-(trifluoromethyl)-4-[(lR)-2,2,2-trifluoro-l-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1 H-benzimidazole hydrochloride;
6-{5-[3-bromo-4-(2,2,2-trifluoro-l-methylethoxy]phenyl)-l,2,4-oxadiazol-3-yl}-lH-benzimidazole hydrochloride;
5-(5-[4-phenoxy-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-benzimidazole hydrochloride;
2-(4-{ 5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl} -1 H-indole-1 -yl)acetamide;
4- {5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1 -methylethoxy]phenyl)-l ,2,4-oxadiazol-3-yl)-l H-pyrrolo[2,3-b]pyridine hydrochloride;
6-{5-[3-(difluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-l ,2,4-oxadiazol-3-yl)-lH-benzimidazole hydrochloride;
2-(4- {5-[3-chloro-4-(2,2,2-trifluoro-1 -methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-lH-indol-l-yl)acetamide;
2-(4-{5-[4-cyclopentyl-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-indol-1 -yl)acetamide;
2-[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl)-12,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide;
2-[4-(5-{4-[2-fluoro-l-(fluoromethyl)ethoxy]-3-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide;
2-(4-{5-[3-cyano-4-(2,2,2-trifluoro-l-methylethoxy)phenyl]-l,2,4-oxadiazol-3-yl}-1 H-indol-1 -yl)acetamide;
N-(2-hydroxyethyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl} -1,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide;
2-[4-(5-{5-chloro-6-[(lS)-2,2,2-trifluoro-l-methylethoxy]pyridine-3-yl]-l,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide;
2-[4-(5-{5-chloro-6-[2-fluoro-l-(fluoromethyl)ethoxy]pyridin-3-yl}-l,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide;

2-[4-(5- {3-chloro-4-[2-fluoro-1 -(fluoromethyl)ethoxy]phenyl} -1,2,4-oxadiazol-3 -yi)-1 H-indol-1 -yl)acetamide;
2-[4-(5- {3-methyl-4-[( 1 S)-2,2,2-trifluoro-1 -methylethoxy]phenyl} -1,2,4-oxadiazol-3 -yl)-1 H-indol-1 -yl)acetamide;
2-(4-{5-[4-isopropyl-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-indol-1 -yl)acetamide;
2- {4-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]- lH-indol-1 -yl)acetamide;
N-(2-hydroxyethyl)-2-[4-(5-{3-methyl-4-[(lS)-2,2,2-trifluoro-l-methylethoxy]phenyl} -1,2,4-oxadiazol-3-yl)-1 H-indol-1 -yl)acetamide;
N-(2-hydroxyethyl)-2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-yl)-lH-indol-l-yl)acetamide; and
2-[4-(5-{3-chloro-4-[2-fluoro-l-(fluoromethyl)ethoxy]phenyl}-l,2,4-oxadiazol-3-yl)-1 H-indol-1-yl]-N-(2-hydroxyethyl)acetamide.
9. A pharmaceutical composition comprising a compound according to any
one of claims 1 to 8, as an active ingredient.
10. The compound according to any one of claim 1 to 8, used for treatment and/or prevention of rej ection in transplantation of organ/tissue in human or animal, autoimmune disease, multiple sclerosis, rheumatism, psoriasis, asthma, atopy, Alzheimer's disease, tumor, or leukemia.
11. An agent comprising the compound according to any one of claims 1 to 8 as an active ingredient.
12. An agent comprising the compound according to any one of claims 1 to 8 as an active ingredient, and a pharmaceutically acceptable carrier or excipient.
13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, which is SIP1 agonist.

14. A method for treating and/or preventing rejection in transplantation of organ/ bone marrow / tissue in human or animal, graft-versus-host disease rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia, said method comprising administeration of the compound according to any one of claims 1 to 8, to a subject suffering from aforementioned disease.
15. Use of the compound according to any one of claims 1 to 8, for the manufacture of an agent for treating and/or preventing rejection in transplantation of organ/ bone marrow/tissue in human or animal, graft-versus-host disease, rheumatoid
arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome,
encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.
16. Use of the compound according to any one of claims 1 to 8, for treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in human or animal, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.
17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, for the use for treating and/or preventing rejection in transplantation of an organ / bone marrow / tissue in human or animal, or graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis,

nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, cancer, or leukemia.

Documents:

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Patent Number

280006

Indian Patent Application Number

5303/CHENP/2008

PG Journal Number

06/2017

Publication Date

10-Feb-2017

Grant Date

07-Feb-2017

Date of Filing

03-Oct-2008

Name of Patentee

ASTELLAS PHARMA INC.

Applicant Address

3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411

Inventors:

#	Inventor's Name	Inventor's Address
1	HARADA, HIRONORI	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
2	FUJITA, KAZUYA	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
3	ABE, YOSHITO	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
4	HATTORI, KAZUYUKI	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
5	MORITA, MASATAKA	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
6	IMADA, SUNAO	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
7	ITANI,HIROMICHI	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
8	MOROKATA, TATSUAKI	C/O ASTELLAS PHARMA INC., 3-11,NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411
9	TSUTSUMI, HIDEO	2-21, YUHIGAOKA 2-CHOME, TOYONAKA-SHI, OSAKA 561-0864

PCT International Classification Number

C07D413/04

PCT International Application Number

PCT/JP07/57414

PCT International Filing date

2007-04-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2006-276693	2006-10-10	Japan
2	2006-102544	2006-04-03	Japan
3	2006-279227	2006-10-12	Japan