RU2425832C2 - Heterocompound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or

, X denotes a single bond, -CH₂-, -NR³-, -O-, -S-, R¹ denotes a halogen; phenyl; pyridyl; (C₃-C₈)cycloalkyl; or (C₁-C₆) alkyl or (C₂-C₆) alkenyl, each of which can contain a halogen, -CONH₂, phenyl or (C₃-C₈)cycloalkyl as a substitute, R² denotes CN, -O-(C₁-C₆)alkyl, -C(=O)H, halogen; or (C₁-C₆)alkyl, which can be substituted with a halogen or -OH, R³ can form morpholino or 1-pyrrolidinyl together with R¹ and nitrogen, and when X denotes a single bond, R¹ and R² can jointly form a 5-member ring and additionally contain -(C₁-C₆)alkyl as a substitute, R⁴ denotes the following ring:

,

,

,

,

,

,

,

,

,

, or

, where any one of the bonds in the ring is linked to an oxazole ring, R⁵ denotes -H, (C₁-C₆)alkyl, which can be substituted by not less than one group selected from: -C(=O)NR^XR^Y, -NHR^X and -OR^X- (C₂-C₆)alkenyl-; -C(=O)H; -C(=O)NR^XR^Y, R^X and R^Y can be identical or different and denote -H; or (C₁-C₆)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP₁ agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

Description

FIELD OF THE INVENTION

The present invention relates to a new hetero compound and a medicament containing it as an active ingredient, namely, as a means for the treatment of immunological diseases.

BACKGROUND OF THE INVENTION

Sphingosine-1-phosphate is a metabolite of sphingolipid, which is a physiologically active substance released from an activated platelet (Non-Patent Document 1). The sphingosine-1-phosphate receptor is a protein-binding type G and belongs to the Edg family, which is an endothelial differentiation gene. To date, five receptors S1P ₁ (Edg1), S1P ₂ (Edg5), S1P ₃ (Edg3), S1P ₄ (Edg6) and S1P ₅ (Edg8) have been found. All of these receptors are widely present in cells and tissues throughout the body, however S1P ₁ , S1P ₃ and S1P ₄ are mainly expressed in the lymphocyte and endothelial cell, S1P ₂ are mainly expressed in the vascular smooth muscle cell and S1P ₅ are mainly expressed in the brain and spleen , and their amino acid sequences are well preserved in humans and rodents (Non-Patent Document 1). Many receptors are associated with G proteins by stimulating sphingosine-1-phosphate. S1P ₁ is associated with G _{i / 0} , S1P ₂ and S1P ₃ is associated with G _{i / 0} , G _q , G _12/13 and G _s , S1P ₄ is associated with G _{i / 0} , G _12/13 and G _s , S1P ₅ is a combination of G _{i / 0} and G _12/13 and cause cell growth? due to MAPK activation, a change in the cytoskeletal system and cell infiltration due to activation of Rac (and / or Rho), and cytokine and mediator generation due to PLC activation and calcium influx into the cell, etc. (Non-Patent Document 1). It was known that when S1P _{1 is} stimulated by sphingosine-1-phosphate, lymphocyte migration, inhibition of apoptosis, cytokine generation, lymphocyte sequestration in the thymus and other secondary lymphoid tissues, and angioplasty in vascular endothelial cells are induced (Non-Patent Document 2). On the other hand, S1P _{3 was} also found in cardiomyocytes and a random decrease in heart rate (bradyphysphgia) and blood pressure was detected upon stimulation of sphingosine-1-phosphate (Non-Patent Document 3), while bradyphyshgia was not detected upon stimulation of sphingosine-1-phosphate in knockout mouse in which S1P _{3 is} genetically removed (Non-Patent Document 4). It has been reported that FTY720 phosphate ester, which is the active substance FTY720, is currently undergoing clinical trials and has non-selective agonistic activity against S1P ₁ , S1P ₃ , S1P ₄ and S1P ₅ (Non-Patent Document 5), and especially bradyphysmia caused by the stimulation effect of S1P ₃ is often expressed as an undesirable side effect in clinical trials (Non-Patent Document 6). Thus, it is believed that stimulation of S1P ₁ (Non-Patent Document 7) is necessary for sequestration of a lymphocyte through the sphingosine-1-phosphate receptor, while S1P ₃ stimulation is not needed, and is more likely to be considered as the cause of an undesirable side effect. Therefore, to develop an immunosuppressive agent with fewer side effects, it is desirable to develop an agonist that has a weak effect on S1P ₃ and selectively affects S1P ₁ .

For example, as a compound having activity as an S1P ₁ agonist, a carboxylic acid derivative represented by the following formula was known (Patent Document 1):

[Chem. 1]

[for the symbol in the formula, refer to the publication]

As a compound having activity as an S1P ₁ agonist, an indane derivative is known, represented by the following formula (Patent Document 2):

[Chem. 2]

[for the symbol in the formula, refer to the publication]

As a compound having activity as an S1P ₁ agonist, an oxadiazole derivative represented by the following formula is known (the following figures, Patent Documents 3, 4, 5, and 6):

[Chem. 3]

[for the symbol in the formula, refer to the publication]

As a compound having activity as an S1P ₁ agonist, the derivative depicted by the following formula is known (following figure, Patent Document 7):

[Chem. 4]

[for the symbol in the formula, refer to the publication]

However, the compound of the present invention has not been described in any document.

Non-Patent Document 1: Annulan Review Biochemistry, 204, 73, 321-354

Non-Patent Document 2: Nature Review Immunology, 2005, 5, 560-570

Non-Patent Document 3: Japanese Journal of Pharmacology, 2000, 82, 328-342

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 Patent Application WO 2005/058848 Brochure

Patent Document 2: International Patent Application WO 2004/058149 Brochure

Patent Document 3: International Patent Application WO 2003/105771 Brochure

Patent Document 4: International Patent Application WO 2004/103279 Brochure

Patent Document 5: International Patent Application WO 2005/032465 Brochure

Patent Document 6: International Patent Application WO 2006/047195 Brochure

Patent Document 7: International Patent Application WO 2006/001463 Brochure

Description of the invention

The problem that the invention is intended to solve

The authors of the present invention conducted a study to detect a substance useful for the prevention and / or treatment of rejection during organ / bone marrow / tissue transplantation or autoimmune diseases based on agonistic activity with respect to S1P ₁ and, in the future, to provide a medicament containing this substance.

Means of solving the problem

The inventors of the present invention conducted extensive studies with respect to a substance having S1P ₁ agnostic activity, and as a result, they found that the new hetero compound could be used as an S1P ₁ agonist, thus completing the present invention. In other words, based on the present invention, it is possible to provide a new hetero compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof.

The compound represented by formula (I):

[Chem. 5]

or its pharmaceutically acceptable salt

[In the formula, the symbols mean as follows.]

The ring is:

[Chem. 6]

X is a single bond, —CH ₂ -, —NR ³ -, —O—, —S—, —S (= O) - or —S (= O ₂ ) -,

R ¹ represents —H, halogen, aryl, heteroaryl, (C ₃ -C ₈ ) cycloalkyl, C ₃ -C ₈ ) cycloalkenyl, (C ₃ -C ₈ ) heterocycloalkyl; or (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl, each of which may contain halogen, —CONH ₂ , aryl, or (C ₃ -C ₈ ) cycloalkyl as a substituent,

R ² represents —CN, —O— (C ₁ -C ₆ ) alkyl, —C (═O) H, halogen or (C ₁ -C ₆ ) alkyl, which may be substituted with halogen or —OH,

R ³ is —H, where R ³ can form morpholino, 1-pyrrolidinyl or 3,4-dehydropiperidin-1-yl together with R ¹ and nitrogen,

where when -X- is a single bond, R ¹ and R ² can in combination form a 5-membered ring and, in addition, contain (C ₁ -C ₆ ) alkyl as a substituent.

R ⁴ represents the following ring:

where any one of the bonds from the ring is connected to the oxadiazole ring,

[Chem. 7]

R ⁵ represents —H; (C ₁ -C ₆ ) alkyl, which may be substituted by at least one group selected from the series consisting of: —CN, —C (= O) NR ^X R ^Y , —NHR ^X , —SR ^X , —S (= O) ₂ R ^X and —OR ^X (this is defined as R ⁰ - (C ₁ -C ₆ ) alkyl); R ⁰ - (C ₁ -C ₆ ) alkyl-O-; R ⁰ - (C ₁ -C ₆ ) alkyl-C (= O) -; R ⁰ - (C ₁ -C ₆ ) alkyl-S (= O) ₂ -, R ⁰ -O- (C ₁ -C ₆ ) alkyl; R ⁰ -C (= O) (C ₁ -C ₆ ) alkyl-; R ⁰ —S (= O) ₂ - (C ₁ -C ₆ ) alkyl-; (C ₂ -C ₆ ) alkenyl-; -C (= O) H; -OR ^X ; -S (= O) ₂ R ^X ; halogen; = O; NR ^X R ^Y ; -C (= O) NR ^X R ^Y ;

R ^X and R ^Y may be the same or different with each other and represent —H; or (C ₁ -C ₆ ) alkyl, which may be substituted with —OH, NH ₂ , which may be protected by a protecting group, or heteroaryl, in which R ^X may form (C ₃ -C ₈ ) heterocycloalkyl together with R ^Y and nitrogen .

As for —X—, it in formula (I) is preferably a single bond or —O— and, more preferably, is —O—. As for R ¹ , it is preferably (C ₁ -C ₄ ) alkyl or (C ₂ -C ₄ ) alkenyl, each of which may be substituted with halogen or (C ₃ -C ₈ ) cycloalkyl and, in addition, more preferably represents (C ₁ -C ₄ ) alkyl, which may be substituted with F. With regard to ring A, it preferably represents:

[Chem. 8]

As for R ² , it is preferably halogen, —CN, (C ₁ –C ₄ ) alkyl, which may be substituted with halogen, and more preferably it is Cl, CF ₃ . As for R ⁴ , it preferably represents:

[Chem. 9]

and more preferably it is:

[Chem. 10]

As for R ⁵ , it is preferably —H, (C ₁ -C ₆ ) alkyl, which may be substituted with —C (= O) NR ^X R ^Y. As for R ^X , it is preferably —H, (C ₁ -C ₆ ) alkyl, which may be substituted with —OH. As for R ^Y , it is preferably —H; (C ₁ -C ₆ ) alkyl, which may be substituted with -OH.

The compound of the present invention depicted by formula (I) is characterized by a chemical structure in that a bicyclic nitrogen-containing unsaturated heterocycle or a bicyclic nitrogen-containing partially unsaturated heterocycle is linked to the 3-position of oxazole and has pharmacological characteristics in terms of the fact that the compound has S1P ₁ agonistic activity.

Effects of the invention

Since the compound of the invention has S1P ₁ agonistic activity, it can be used as an active ingredient in a treatment or as a prophylaxis for diseases caused by adverse lymphocytic infiltration, for example, transplant rejection during an organ, bone marrow or tissue transplant, or graft reaction against the host ", autoimmune diseases or inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotis syndrome, encephalomeningitis, bulbospinal paralysis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorders, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis or ischemic reperfusion injury, and, in addition, diseases caused by abnormal growth or accumulation of cells, such like cancer or leukemia.

The best embodiment of the invention

Hereinafter, the present invention will be described in more detail.

As used herein, “alkyl” means a linear or branched monovalent group. “C ₁ -C ₆ alkyl” means a C ₁ -C ₆ straight or branched group, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-propyl and n -hexyl, C ₁ -C ₄ alkyl is preferred, and methyl, ethyl, n-propyl and isopropyl are particularly preferred.

In the description, “halogen” means F, Cl, Br and I, and preferred examples include F and Cl.

In the description, “C ₂ -C ₆ alkenyl” means a C ₂ -C ₆ linear or branched group that has a double bond in this place, and specific examples thereof include: ethynyl (vinyl), 1-propenyl, 2-propenyl, 1- methylenin-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 1-methyl-1-propen-1-yl, 2-methyl-1-propen- 1-yl, 1-methyl-2-propen-1-yl and 2-methyl-2-propen-1-yl and preferably 1-methyl-2-propen-1-yl or 1-pentinyl.

In the specification, “C ₃ -C ₈ cycloalkyl” means a monovalent group of a non-aromatic carbon cycle having a reduction ratio of 3-8, which may partially have unsaturated bonds. Thus, specific examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the description, “C ₃ -C ₈ heterocycloalkyl” means a monovalent non-aromatic group having a reduction ratio of 4 to 9, containing one or more heteroatoms, identical or different from each other, selected from the series containing nitrogen, oxygen and, optionally, oxidized sulfur which may be partially unsaturated. Specific examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydropyranyl and tetrahydrothiopyranyl.

As used herein, “aryl” means an aromatic hydrocarbon group, but aryl groups having 6-14 carbon atoms are preferred. Specific examples thereof include phenyl, naphthyl and anthranyl, and phenyl is more preferred.

As used herein, “heteroaryl” means a 5- or 6-membered aromatic heterocycle cycle containing one or more heteroatoms that are different or different from each other, selected from the group consisting of nitrogen, oxygen and sulfur. Specific examples thereof include pyridyl, pyrazyl, pyrimidinyl, pyradisinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, axadiazolyl and thiadiazolyl. 6 membered heteroaryl is preferred and, in particular, pyridyl is preferred.

The compound of the present invention in some cases may exist as a geometric isomer or tautomer, depending on the type of substituent. Moreover, this compound may have asymmetric carbon. The present invention includes all isolated species of these isomers, as well as a mixture thereof. In addition, labeled compounds, i.e. compounds in which at least one element in the compound of the present invention is substituted by radioactive or non-radioactive isotopes are also included in the present invention.

Moreover, pharmaceutically applicable, so-called prodrugs containing a compound of the present invention are also included in the present invention. A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like of a compound of the present invention, by solvolysis or by physiological condition. Examples of a group capable of forming prodrugs include those 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.

The compound represented by formula (I) can form salts with acids or bases. These may be any pharmaceutically acceptable salts, and specific examples thereof include inorganic acid addition salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and 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 a, 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, ornithine and ammonium salts.

Additionally, the present invention also includes various hydrates and solvates and polymorphic compounds of the compound represented by formula (I), and their salts.

The following abbreviations were used in the description.

Pr: production method, AcOH: acetic acid, n-BuLi: normal butyl lithium, t-BuOH: tertiary butanol, n-BuOH: normal butanol, BrCN: cyanide bromide, CDI: 1,1'-carbonylbis-1H-imidazole, DBU : diazobicyclo [5.4.0] undeca-7-ene, DMAP: 4 (N, N-dimethylamino) pyridine, DIC: N, N'-diisopropylcarbodiimide, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, DPPA: diphenylphosphorylazide, Et: ethyl, EDCI / HCl: N [3- (dimethylamino) propyl] -N'-ethylcarboxamide hydrochloride, EtOH: ethanol, Et ₃ N: triethylamine, EtOAc: ethyl acetate, HOBt: 1-hydroxy-1H-benzotriazole, HPLC: high performance liquid chromatography, IPE: diisopropyl ether ir, i-PrOH: 2-propanol, K ₂ CO ₃ : potassium carbonate, KSN: potassium cyanide, KHCO ₃ : potassium bicarbonate, KO ^t Bu: tertiary potassium butoxide, LC-MS: liquid chromatography-mass spectroscopy, LiH: lithium hydride, MeOH: methanol, NaH: sodium hydride, NaOH: sodium hydroxide, NaBH ₄ : sodium borohydride, NaCN: sodium cyanide, NaHCO ₃ : sodium bicarbonate, Na ₂ CO ₃ : sodium carbonate, NaOMe: sodium methoxide, NaOEt: ethoxide sodium, NCS: N-chlorosuccinimide, NH ₄ Cl: ammonium chloride, NMP: N-methylpyrrolidone, POCl ₃ : phosphorus oxochloride, P ₂ O ₅ : phosphorus pentoxide, THF: tetrahydrofuran, TLC: thin layer chromatography, TMEDA: N, N, N ', N'-tetra methylenediamine, Zn (CN) ₂ : zinc cyanide.

(Production Method)

The compound (I) of the present invention and its pharmaceutically acceptable salt can be obtained by applying various known synthetic methods, taking advantage of their basic framework or type of substituents. Here, depending on the type of functional groups, in some cases, from the point of view of the preparation procedure, it is effective to protect the functional group with a suitable protective group or replace it with a group that can be easily converted to a functional group, during the stages from the starting materials to the intermediate compounds. Examples of such functional groups include an amino group, a hydroxyl group, a carboxyl group, and examples of protective groups for them include protective groups as described in "Protective Groups in Organic Synthesis" edited TW Green and PGM Wuts, (USA) (3 ^rd edition, 1999) which can be selected at will, and their use is determined by the reaction conditions. Using such methods, the desired compound can be obtained by introducing a protective group to carry out the reaction, and then, if necessary, removing the protective group or converting to the desired group.

Additionally, the prodrug of compound (I) of the present invention can be prepared by introducing specific groups during the steps from the starting materials to intermediates similar to the above-described protecting groups, or by carrying out the reaction using the resulting compound (I) of the present invention. The reaction can be carried out using conventional methods of etherification, amination, dehydration or by a method well known to a person skilled in the art.

<First Intermediate Preparation Method>

[Chem. 11]

[where R or R 'means lower alkyl, which may be substituted by at least one substituent selected from the group consisting of —CN, —C (= O) OH, —C (= O) OR ^X , —C (= O ) NR ^X R ^Y , -C (= O) NHSO ₂ R ^X , -C (= O) - (C ₁ -C ₈ heterocycloalkyl), -NHR ^X , -OH, SR ^X , -S (= O ₂ ) R ^X , halogen and —OR ^X (which is defined as R ^Z lower alkyl); R ⁰ - (C ₁ -C ₆ ) alkyl-O-, R ⁰ - (C ₁ -C ₆ ) alkyl-C (= O) -; R ⁰ - (C ₁ -C ₆ ) alkyl-S (= O) ₂ -; R ⁰ —O— (C ₁ -C ₆ ) alkyl—; R ⁰ -C (= O) - (C ₁ -C ₆ ) alkyl; R ⁰ —S (= O) ₂ - (C ₁ -C ₆ ) alkyl-; (C ₂ -C ₆ ) alkenyl, -C (= O) H, -OR ^X ; -S (= O ₂ ) R ^X ; halogen; = O; -NR ^X R ^Y or -C (= O) NR ^X R ^Y ;

R ^X and R ^{Y are the} same or different from each other and each means —H; (C ₁ -C ₆ ) alkyl, which may be substituted with —OH or pyridyl. R ^X may also be bonded to R ^Y and a nitrogen atom to form (C ₃ -C ₈ ) heterocycloalkyl.

This production method is a method for producing a bezimidazole compound represented by the formula (1-c) by reacting an aldehyde compound with a 1,2-diaminobenzene compound represented by the formula (1-b), which can be obtained by reducing the compound represented by the formula (1-a).

The step depicted in Step 1-1 is the step of reducing the nitro group of the compound represented by formula (1-a) to an amino group that can be carried out under normal pressure or under elevated pressure in a reaction inert solvent.

In the step depicted in Step 1-2, where R 'is H, an imidazole ring can be created, for example, by reacting an orthoform ester such as ethyl orthoformate with a compound of the formula (1-b) in the presence of an acidic catalyst.

In addition, in the step depicted in Step 1-2, where R 'is not H, for example, a method in which the amino group of the compound represented by formula (1-a) is pre-acylated using carboxylic acid, carboxylic acid chloride, carboxylic anhydride or the like and cyclized by heating or in the presence of an acid, a method in which tetraalakyl orthocarbonate, CDI and BrCN is used instead of orthoformate, or other methods can be given as an example.

In addition, along with other methods, one can cite as an example the method in which the amine part of the nitrobenzene compound (1-a) is subjected to carbomylation, which leads to the acylamine compound (1-е), which undergoes reduction of its nitro group and cyclization upon heating (Stage 1-3, Stage 1-4).

All 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 boiling.

<Second Intermediate Preparation Method>

[Chem. 12]

[where R has the same meanings as defined above]

This production method is a method for producing imidazo [1,2-a] pyridine substituted with a nitrile group depicted using formula (2-b) using the 2-aminopyridine compound represented by formula (2-a) as the starting compound .

The step depicted in Step 2-1 is an assembly reaction of the imidazo [1,2-a] pyridine ring when chloroacetaldehyde or α-chloro ketone is reacted with the compound represented by formula (2-a).

It is preferably carried out in the presence of a base, and specific examples of the bases include alkali metal carbonates such as Na ₂ CO ₃ and K ₂ CO ₃ ; alkali metal hydrogen carbonates such as NaHCO ₃ and KHCO ₃ ; alkoxides such as NaOMe, NaOEt and KO ^t Bu; tertiary amines such as Et ₃ N and DIPEA; and organic amines such as DBU, pyridine and lutidine.

All these reactions can be carried out in a solvent inert to the reaction, or without solvent, from at room temperature to under heating or under heating with boiling.

<Third Intermediate Preparation Method>

[Chem. 13]

[where R has the same meanings as defined above]

This production method is a method for producing the imidazole compound depicted by the formula (3-c) by reacting hydrazine hydrate with the nitrile group of the cyanobenzene compound depicted by the formula (3-b) obtained by replacing the halogen of the compound depicted by the formula (3-a) )

The step depicted in Step 3-1 is a reaction of a halogen bonded by an aromatic ring to a nitrile group. An example of this is the reaction of Zn (CN) ₂ in the presence of palladium tetrakisphenylphosphine (0), the reaction of TMEDA and Pd catalyst in the presence of Na ₂ CO ₃ in DMA, and reactions in which KCN, NaCN or the like react instead of Zn (CN ) ₂ . Typically, the compound depicted by formula (3-b) can be prepared by reacting the compound depicted by formula (3-a) with tris (dibenzyl diacetone) dipalladium (0),

1'-bis (diphenylphosphino) ferrocene and Zn (CN) ₂ .

Here, examples of a leaving group include halogen, such as Br and Cl; methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluylsulfonyloxy and trifluoromethylisulfonyloxy.

The step depicted in Step 3-2 is a reaction for creating an imidazole ring from a cyanobenzaldehyde compound represented by the formula (3-b). Typically, hydrazine hydrate is used in this reaction, this reaction can be carried out without solvent or in a solvent inert to the reaction, such as MeOH and toluene, from at room temperature to under heating or under heating at boiling. Additionally, a method using copper cyanide can also be given as an example, and a base such as pyridine can be added. Also, this reaction is preferably carried out in a nitrogen atmosphere.

<Fourth Intermediate Preparation Method>

[Chem. 14]

[where R has the same meanings as defined above. Z is —CH = or —N =].

This production method is a method for producing a benzotriazole or benzimidazole compound represented by the formula (4-c) by dehydrating the amide compound shown in the formula (4-b) obtained using the carboxylic acid represented by the formula (4-a) as the starting compound .

The step depicted in step 4-1 is a condensation reaction of the carboxylic acid depicted in the formula (4-a) with ammonia and the creation of a carboxylic acid amide functional group depicted in the formula (4-b). The compound depicted by formula (4-a) can be used as the free acid, but its reactive derivatives can also be used. Examples of such reactive derivatives, starting from the compound represented by formula (4-b), include carboxylic acid halides such as acid chloride and acid bromide; ordinary esters such as methyl ether, ethyl ether and benzyl ether; carboxylic acid azides; activated esters, such as HOBt, p-nitrophenyl and N-hydroxysuccinimide; symmetric carboxylic acid anhydrides; mixed carboxylic acid anhydrides of alkyl esters of halocarboxylic acids, such as alkyl carbonic acid chloride, pivaloyl halide and p-toluenesulfonic acid chloride; mixed carboxylic acid anhydrides, such as mixed phosphoric anhydrides, such as those obtained by the reaction of diphenylphosphoryl chloride with N-methylmorpholine.

In the case where the compound represented by formula (4-a) is reacted as a free acid, either without isolating an activated ester, or the like, a condensing agent such as DCC, CDI, DPPA, diethyl phosphoryl cyanide and EDCI / HCl are preferably used. .

The solvent for the reaction varies depending on the reactivity of the derivative or condensing agent that is used, but the reaction is carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters such as EtOAc, acetonitrile, DMF and DMSO or in mixtures thereof. The reaction is also carried out under cooling, from under cooling to at room temperature or from at room temperature to under heating.

In addition, in the reaction, in order for the reaction to go well, it is desirable to carry out the reaction with an excess of ammonia or in the presence of a base such as N-methylmorpholine, trimethylamine, Et ₃ N, DIPEA, N, N-dimethylaniline, pyridine, DMAP, picoline and lutidine. Pyridine can be used in combination with a solvent.

The step depicted in Step 4-2 is dehydration for which the base may or may not be used and dehydrating agents such as trifluoroacetic anhydride, POCl ₃ and P ₂ O ₅ can be used.

In addition, in the case of the synthesis of condensed, intermediate heterocyclic compounds other than those described in the above methods for the preparation of intermediates, the methods described in the Reference Examples or in the Examples in this description, or equivalent methods, or in addition, should be used to obtain well Known methods or techniques obvious to those skilled in the art.

<First production method>

[Chem. 15]

[where A, X, R ¹ and R ⁴ as described above. Lv represents a leaving group. The carboxylic acid depicted by formulas (5-c), (5-d) and (5-g) can be purchased as a commercially available product, or prepared in the same way as a commercially available product].

This production method is a method for producing a compound of the present invention depicted by formula (I) by reacting a hydroxyamide depicted by formula (5-b) obtained by reacting hydroxylamine with aromatic nitrile depicted by formula (5-a), c carboxylic acid depicted by the formula (5-c).

In the step depicted in Step 5-1, the hydroxyamidine depicted by formula (5-b) can be prepared by reacting free hydroxylamine or hydroxylamine hydrochloride in the presence of a base.

This reaction should be carried out in a solvent inert to the reaction. Specific examples of solvents include alcohols such as MeOH, EtOH and i-PrOH; aromatic hydrocarbons such as toluene and xylene; ethers such as THF, dioxane and diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; acetonitriles; aprotic polar solvents such as DMF, 1,3-dimityl-2-imidazolidinone and DMSO; water or mixtures of such solvents. As a rule, alcohols are used in the reaction. As described above, when hydroxylamine hydrochloride is used, the reaction is preferably carried out in the presence of a base, and specific examples of bases include alkali metal carbonates such as Na ₂ CO ₃ and K ₂ CO ₃ ; alkali metal hydrogen carbonates such as NaHCO ₃ and KHCO ₃ ; alkoxides such as NaOMe, NaOEt and KO ^t Bu; tertiary amines such as Et ₃ N and DIPEA; organic amines such as DBU, pyridine and lutidine. The reaction temperature varies depending on the type of starting materials, reaction conditions, etc., but the reaction should be carried out, as a rule, from at room temperature to about the boiling point of the solvent. Typically, in the presence of warp, such as Na ₂ CO ₃ , the reaction should be carried out in an organic solvent inert to the reaction, such as MeOH, from at room temperature to under heating.

The stage depicted in Stage 5-2 consists of two stages, i.e. from the hydroxyamidine acylation step and the cyclization reaction step in the appropriate order. The acylation step can be carried out as follows. The compound represented by formula (5-c) can be used in the reaction as a free acid, but its reactive derivative can also be used in the reaction. Examples of such reactive derivatives include acid chloride and acid bromide; conventional ethers such as methyl ether, ethyl ether and benzyl ether; acid azides; activated esters such as HOBt, p-nitrophenyl, N-hydroxysuccinimide; symmetric acid anhydride; mixed acid anhydride with alkyl esters of halocarboxylic acids, such as alkyl halide, mixed phosphoric acid anhydride, such as those obtained by the reaction of diphenylphosphoryl chloride with N-methylmorpholine.

In the case where the compound represented by formula (5-c) is reacted as a free acid, either without isolating an activated ester or the like, a condensing agent such as DCC, CDI, DPPA, diethyl phosphoryl cyanide and EDCI / HCl are preferably used.

The solvent for the reaction varies depending on the reactivity of the derivative and the condensing agent that is used, but the reaction is carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, such as EtOAC, acetonitrile, DMF and DMSO, or a mixture of such solvents, upon cooling, from upon cooling to at room temperature, or from at room temperature to when heated.

In order to conduct the reaction well, in some cases it is preferable to carry out it in the presence of bases such as N-methylmorpholine, trimethylamine, Et ₃ N, DIPEA, N, N-dimethylaniline, pyridine, DMAP, picoline and lutidine. Pyridine can also be used in combination with a solvent. The acylated product as an intermediate can be purified by isolation and heated in an inert reaction solvent such as EtOH, dioxane, toluene and water. As a rule, this two-stage reaction should be carried out in one stage, by heating or microwave irradiation of the product in the form in which it is, or in the form of a reaction mixture after acylation.

Specific examples of solvents are off aromatic 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; aprotic polar solvents such as DMF, DMA, 1,3-dimethyl-2-imidazolidinone, NMP and DMSO; water or mixtures of these solvents. The reaction temperature varies depending on the type of starting materials, reaction conditions or the like, but the reaction should usually be carried out at room temperature to under heating.

In the case where X is —O— or —NH—, the synthesis can be carried out by the following preparation method.

The steps depicted in Step 5-3 and Step 5-5 can be carried out in the same manner as the step depicted in Step 5-2.

The steps depicted in Step 5-4 and Step 5-6 are the steps for preparing the compound of the present invention depicted by formula (I), carried out upon the reaction of phenol, aniline, alcohol or amine, represented by formula (5th) or formula (5-i), with a compound having a leaving group represented by the formula (5-f) or the formula (5-h). Here, examples of leaving groups include halogens such as chlorine or bromine; and sulfonyloxy, such as matanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfanyloxy and trifotrmethanesulfonyloxy.

The reaction is carried out at normal pressure or at elevated pressure, without a solvent or in a suitable solvent.

Specific examples of solvents include aromatic hydrocarbons such as toluene or xylene; ketones such as acetone and methyl ethyl ketone; 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-dichloethane, chloroform and carbon tetrachloride; acetonitriles; aprotic polar solvents such as DMF, 1,3-dimethyl-2-imidazolidinone, NMP and DMSO; water or mixtures of such solvents. A base is preferably used in this reaction, and specific examples of the bases include NaH; alkali metal carbonates such as Na ₂ CO ₃ and K ₂ CO ₃ ; alkali metal hydrogen carbonates such as NaHCO ₃ and KHCO ₃ ; alkoxides such as NaOMe, NaOEt and KO ^t Bu; tertiary amines such as Et ₃ N, tributylamine and DIPEA; organic amines such as DBU, pyridine and lutidine, but an excess can be combined with the amine depicted by formula (5th) or (5-i). The reaction temperature varies depending on the type of starting materials, reaction conditions, or the like, but as a rule, the reaction should be carried out from at room temperature to about the boiling point of the solvent. Typically, the reaction should be carried out in the presence of a base, such as NaH and Na ₂ CO ₃ , in an organic solvent inert to the reaction, such as DMF and DMA, from -10 ° C to with heating. Also, the amine depicted by the formula (5th) or the formula (5-i) can be represented as its salt. Additionally, microwave irradiation may be carried out by heating during cooking.

In addition, some of the compounds depicted by formula (I) can be prepared by combining well-known processes that can usually be used by qualified specialists in the field of technology, such as well-known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, deprotection groups and halogenation, starting from the compounds of the present invention, as prepared by the above method.

For example, with regard to alkylation, an alkylation reaction that is commonly used by those skilled in the art can be applied, which should be carried out in an organic solvent inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; DMF; acetonitriles; and polar aprotic solvents, upon cooling, from upon cooling to room temperature or from room temperature to upon heating, in the presence of a base such as NaH; alkali metal carbonates; alkali metal bicarbonates; alkoxides; tertiary amines and organic bases.

In addition, for example, regarding acylation, the acylation reaction, which is usually used by qualified specialists in the field of technology, can be used, in particular, that which can be carried out in the presence of HOBt, in a solvent that varies depending on the condensing agent, such as EDCI / HCl or CDI and diphenylphosphoryl cyanide, in a solvent that varies from the reaction conditions, but usually in an organic, inert solvent, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; esters such as EtOAc; acetonitriles; and aprotic solvents, when cooled, from when cooled to at room temperature or from at room temperature to when heated.

The compound thus prepared is purified by isolation, as if it is or in the form of its salt after salt formation using an appropriate method. Purification by isolation is carried out using well-known chemical operations such as extraction, concentration, stripping, crystallization, filtration, recrystallization and various chromatographic methods.

Different types of isomers can be isolated by appropriate methods using the difference in physicochemical properties between the isomers. For example, a racemic mixture can be converted into optically pure isomers, for example, using a conventional method for resolving racemic products, such as a method for resolving optical isomers in the form of diastereomeric salts with well-known optically active acids, such as tartaric acid. Also, the diastereomeric mixture can be separated, for example, by fractional crystallization or various chromatographic methods. In addition, optically active compounds can also be prepared using appropriate optically active starting materials.

The effect of the compounds of this invention was confirmed using the following pharmacological tests.

Experimental Example 1: Test to confirm agonistic S1P _one  activity

1) Evaluation of the activity of the receptor agonist by analyzing the binding of GTP [γ- ³⁵ S] using a human cell membrane expressing S1P _1.

In vitro S1P ₁ agonistic activity of the compounds of this invention was evaluated by increasing functional binding activity in GTP G-protein [γ- ³⁵ S] using a human S1P ₁ expressed cell membrane. The human S1P ₁ cDNA coding was cloned from the human colorectal cDNA library and introduced into the pcDNA3.1 expression vector to create S1P ₁ -pcDNA3.1. Then, Lipofectamine 2000 (GIBCO) S1P ₁ -pcDNA3.1 was transfected into CHO cell line and cultured in Ham's F-12 culture medium containing 10% fetal bovine serum, 100 U / ml penicillin, 100 μg / ml streptomycin and 1 mg / ml G418 disulfate, obtaining a G418-resistant strain. Cultured human S1P ₁ expressing cells were isolated in pure form in 1 mM mol EDTA / 2Na-containing FSB and destroyed under ice cooling in a glass homogenizer in 1 mM Tris-HCl (pH 7.4) buffer solution containing 0.1 mmol EDTA and protein inhibitor. It was centrifuged at 1400 × 10 min and the supernatant was subsequently centrifuged at 4 ° С for 60 min at 100000 × g and suspended in 10 mmol in 1 mmol Tris-HCl (pH 7.4) buffer solution containing 1 mmol EDTA. The resulting membranes (0.13 mg / ml) and 50 pM mol GTP [γ- ³⁵ S] (NEN; inactive 1250 Ci / mmol) were reacted in 20 mM HEPES (pH 7.0) buffer solution (total 150 μl) containing 100 mmol NaCl, 10 mmol MgCl ₂ , 0.1% fatty acid-free bovine serum albumin and 5 μmol cytindisphosphate for 1 hour together with the compound of the present invention (10 ^-12 to 10 ^-15 mol) and then the membranes were separated in GF-C tablet with cell halvester (Packard, FilterMate). FilterMate was dried at 50 ° C for 60 minutes and Microscinti-o (Packard) was added in addition to calculate using a microplate lipid scintillation detector (Packard, TOP count). In order to evaluate the agonistic activity with respect to human S1P _{1 of the} compound of the present invention and the comparative compound, the percentage with the maximum reaction value making the GTP [γ- ³⁵ S] bonds saturated in the presence of the compound was taken as 100% and the GTP [γ- ³⁵ reaction value S] bonds in the absence of compound was taken as 0%, a nonlinear regression curve was created, and the concentration causing the appearance of agonistic activity at the level of 50% of the maximum reaction was determined as the value of EC ₅₀ (nMol).

Table 1 Etc.
No. S1p _one
EC _fifty Etc.
No. S1p _one
EC _fifty Etc.
No. S1p _one
EC _fifty 2 13 60 2.1 151 eleven 5 5.5 64 5.7 152 7.6 6 1,2 65 4.0 158 1.8 8 5,4 67 3,7 163 1.9 12 4.7 81 5.9 164 2,8 fifteen 2.1 87 3,7 173 4.3 23 6.8 106 8.7 181 4.7 26 4.7 110 6.2 182 4.2 37 5,4 119 4.3 193 6.8 48 6.5 120 4.6 194 2.0 51 13 121 12 196 5.3 54 2,3 143 5,4 197 3.3 59 3.8 147 3.2

As a result, it was confirmed that the compounds of the present invention possess S1P ₁ agonistic activity.

2) Assessment of peripheral blood lymphocytopenia in rats

Peripheral blood lymphocytopenia in rats was determined 24 hours after oral administration as follows. Male Lewis rats six to ten weeks old (Japan Charles River Laboratory) were randomly assigned to groups (n = 3) and the compound of the present invention was suspended in distilled water containing 0.5% methylcellulose and orally administered with a probe. 24 hours after the administration, under ether anesthesia, 0.2 ml of blood was collected from the fundus. EDTA / 4K and heparin were immediately added to the blood sample to prevent clotting and the number of lymphocytes in the blood was counted using an automatic hematology analyzer (Sysmex Corp .; XT-2000i).

To reduce the number of lymphocytes in peripheral blood under the action of the compound of the present invention, the percentage with the number of lymphocytes in the groups that were prescribed distilled water containing 0.5% methylcellulose was taken as 100%, as was done last time, and the dose, which causes a decrease by 50% of the number of lymphocytes in peripheral blood when prescribing the compounds of the present invention, was determined as the value of ED ₅₀ (μg / kg).

For comparative compounds 1 and 2, which are described in the explanatory note of International Application No. WO2004 / 103279, comparative compound 3, which is believed to be accurately described in the explanatory note of International Application No. WO2005 / 032465, and the compound of Example 119, compared the value of ED ₅₀ later 24 hours after administration to reduce the number of peripheral blood lymphocytes in rats.

table 2 Compound Structure ED value _fifty  after 24 hours Note 119

0.071 m / kg Comparative Compound 1

1.4 mg / gk Comparative Compound 2

8.8 mg / gk Comparative Compound 3

3.7 mg / kg

As a result, it is seen that the compound of Example 119 shows a high ED ₅₀ value even after 24 hours, which indicates the preservation of the effect.

Due to the fact that the compound of the present invention has S1P ₁ agonistic activity, it is applicable as an active ingredient in a treatment or a prophylaxis for a disease caused by adverse lymphocytic infiltration, for example, an autoimmune disease such as transplant rejection during organ transplantation, bone marrow or tissue or graft versus host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalus nigit, myasthenia gravis, pancreatitis, hepatitis, pulmonary diseases, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury or an inflammatory disease, and in addition, diseases caused by the abnormal growth or accumulation of cells such as cancer or leukemia.

In addition, the compound of the present invention is applicable for the treatment and / or prophylaxis of the following diseases, based on agonistic activity with respect to S1P ₁ .

It is applicable for the treatment and / or prophylaxis of inflammatory or hyperplastic skin diseases such as psoriasis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus vulgaris, pemphigoid, bulerous epidermolysis, urticaria, edema, vascular edema, vascular occlusion, skin leukocytosis, lupus erythematosus, acne and circular alopecia or manifestations of skin diseases caused by the immune system; autoimmune diseases or allergic diseases of the eye, such as keratoconjunctivitis, spring conjunctivitis, allergic conjunctivitis, uheitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus keratitis, corneal epithelial dystrophy, corneous erythematosus, corneous erythroderma, corneous erythroderma, corneous erythroderma, corneal erythroderma, corneal erythroderma, corneo-corneous erythematosus, , Graves ophthalmopathy, Vogt-Koyanagi-Harada disease, dry keratoconjunctivitis (dry eyes), vesicles, iridocyclitis, sarcoidosis and ophthalmic disease glands tions; reversible obstructive pulmonary diseases (asthma, for example bronchial asthma, allergic asthma, endogenous bronchial asthma, exogenous bronchial asthma and asthma on the mud), in particular chronic or severe asthma (for example, late-onset asthma or respiratory diseases); mucosis or angina (for example, gastric ulcer, ischemic or thrombotic vascular damage, age-related macularopathy, diabetic muculopathy, coronary bowel disease, intestinal disease, necrotic enteritis, intestinal burn injury and diseases caused by the neurotransmitter lecotriene B4) intestinal inflammation or including, for example, proctitis, eosinophilic enteritis, mastocytosis, celiac disease, Crohn's disease and ulcerative colitis; food-related allergic diseases manifesting symptoms at a site remote from the gastrointestinal tract, including, for example, migraine, rhinitis and eczema; autoimmune diseases or inflammatory diseases, including, e.g., primary mucosal edema, autoimmune atrophic gastritis, precocious climacteric period, juvenile diabetes, pemphigus vulgaris, pemphigoid, sympathetic destruction eyeball fakoanafilaktichseky endophthalmitis, parkoksimzalnaya Leukopenia, chronic active hepatitis, prakosizmalny cirrhosis, discoid lupus erythematosus, Sjögren’s syndrome, autoimmune inflammation of the testicles, arthritis (e.g., modified arthritis) and polychander and I; renal diseases, such as membranous nephropathy, membranous proliferative nephritis, focal global glomerulosclerosis, sickle nephritis, glomerular nephritis, IgA-type primary nephropathy, interstitial nephritis tublopathy, and diabetic nephropathy. In addition, the compound of the present invention is also useful for the treatment and / or prophylaxis of liver diseases (e.g., immunogenic diseases (e.g., autoimmune liver diseases, chronic autoimmune liver diseases, such as biliary cirrhosis, sclerosing cholangitis and the like), partial stratification of the liver, acute necrotic hepatitis (e.g., necrosis due to toxin, viral hepatitis, shock, anoxia or the like), hepatitis B, non-type A hepatitis, cirrhosis, liver failure (e.g. m lnienosny hepatitis, hepatitis, late-onset hepatic failure (acute hepatic failure or chronic hepatic disease)) and the like.

Additionally, the compound of the present invention can be administered as an S1P ₁ agonist alone, in combination with at least one agent, in the same dose or in different doses, by the same or different route of administration. Examples of agents that can be combined include, but are not limited to, cyclosporin A, tarcolimus, sirolimus, everolimus, mycophenolate, azathiophene, brequinar, leflunomide, fingolimod, and anti-IL-2 receptor antibodies (e.g., daclizumab) and anti-CD3 antibodies (e.g., OCT3), and atni-T cell immunoglobulin (e.g., AtGam), belatacept, abatacept, cyclophosamide, β-interferon, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and an anti-inflammatory steroid (e.g. prednisolone) and dexase.

A preparation containing a compound depicted by formula (I), or one, two or more of its salts as active ingredients, is prepared using a carrier, excipient or other additives commonly used in the manufacture of medicines.

Reception can be carried out in any form, both in the form of tablets, granules, powders and solutions, and in the form of parenteral injections, both intravenous and intramuscular, suppositories, subcutaneous preparations, transnasal preparations, inhalations, etc. The dose is calculated in each individual case, taking into account the symptoms, age, gender, etc. of the patient, but usually it varies from 0.001 mg / kg to 100 mg / kg per day for an adult in case of oral administration and can be taken in one portion or divided into 2-4 servings. Also, in the case of intravenous administration, in accordance with the symptoms, the drug is taken at a rate of from 0.0001 mg / kg to 10 mg / kg per day for an adult, one or two or more times a day. Additionally, in case of inhalation, administration is carried out at the rate of 0.0001-1 mg / kg for an adult, one or two or more times a day.

As for the solid compositions of the present invention for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are mixed with at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and aluminum-magnesium silicate. In a standard method, the composition may contain inactive additives, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium as carboxymethyl starch or a solubilizing component. If necessary, tablets or pills may be coated with a sugar coating, or soluble in the stomach, or enteric coated.

A liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like. and contains commonly used inert solvents such as purified water and ethanol. In addition to an inert solvent, the composition may contain an adjuvant, such as a solubilizing agent, a moisturizing agent or a suspending agent, a sweetener, a neutralizing agent, a flavoring agent and an antiseptic.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of aqueous solvents include distilled water for injection and saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive, alcohols such as ethanol, and Polysorbate 80 (Pharmacopeia). Such a composition may also contain an agent for maintaining muscle tone, an antiseptic, a moisturizing agent, an emulsifying agent, a dispersing agent, a stabilizing agent, and a solubilizing agent. These substances are sterilized, for example, by filtration through a filter that traps bacteria, mixing bactericides or by irradiation. In addition, they can be used in the manufacture of a sterile solid composition and its dissolution or suspension in sterile water or a sterile solvent for injection immediately before administration.

As for the transmucosal agent, such as, for example, inhalation or transnasal agent, solid, liquid or semi-liquid forms are used, which can be made in accordance with a generally known known method. For example, fillers, such as lactose or starch, pH control agents, antiseptics, surfactants, lubricants, stabilizers, thickeners can be added if necessary. To receive them, appropriate devices for inhalation or injection can be used. For example, the compound may be taken by a conventional device or atomizer, such as a metered-dose inhalation device, in pure form, either as a prescription powder or as a solution or suspension in which it is combined with a pharmaceutically acceptable carrier. The inhaler for inhalation of dry powder can be either disposable or reusable, using a dry powder or a capsule containing the powder. Alternatively, a high-pressure aerosol dispenser may be used in which a suitable propellant is used, for example chlorofluoroalkane, hydrofluoroalkane and carbon dioxide.

The external agent includes ointments, patches, creams, jellies, pastes, sprayers, lotions, eye drops, eye ointments, and the like. The external agent may contain ointment bases, lotion bases, aqueous and non-aqueous liquids, suspensions, emulsions, etc., used in such cases. Examples of ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, clarified beeswax, polyethoxyethylene solid castor oil, glycerol monostearate, stearyl alcohol, cetyl alcohol, lauryl macrogol, and sorbitansexvioleate.

Example

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 invention as described in the following examples. Methods for preparing the starting materials are shown in Production Examples.

[In the following tables, Pr means Production Example No., and Structure means a structural formula. As the abbreviated symbols in the structural formula, Me represents a methyl group and Et represents an ethyl group. The crossed double bond denotes a cis / trans mixture, and if only numbers are described in the Data section, it shows the MS data. MS stands for mass spectrometric data. In the tables, RT stands for retention time in high performance liquid chromatography (HPLC) and M stands for minutes. The HPLC conditions are as follows: column: Intertsil ODS-34.6 × 150 mm, eluent 0.01M KH ₂ PO ₄ aq / MeCN (3: 7), eluent flow 1.0 ml / min, detection wavelength: 254 nm . If ¹ H-NMR data are described in the tables, tetramethylsilane was used as the internal standard, and unless otherwise stated, δ (ppm) (integrated value, measurement scheme) of the ¹ H-NMR signals is shown in DMSO-d ₆ as in the solvent used for registration. The abbreviated characters have the same meanings as in the following: s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet of doublets, ddd: doublet of doublet of doublets, dt: doublet of triplet, dm: doublet of doublet, br : broadened, brs: broadened singlet, Hz: Hertz, CDCl ₃ : deuterated chloroform, DMSO-d ₆ : dimethyl sulfoxide-d ₆ , and in this description NMR stands for ¹ H-NMR: proton nuclear magnetic resonance. Similar will apply here in this document].

Production Example 1

Imidazo [1,2-a] pyridin-7-carbonitrile hydrochloride (1.5 g), hydroxylamine hydrochloride (301 mg) and Na ₂ CO ₃ (3.5 g) were stirred at 60 ° C. for 6 hours in CH ₃ OH (57 ml). The reaction solution was cooled and concentrated, and completion of the reaction was determined by LC-MS. Water was added to the residue, then extracted with EtOAC. The organic layer was washed with water and brine, dried over anhydrous MgSO _4, and then filtered off and the filtrate was concentrated to obtain N'-hydroxyimidazo [1,2-a] pyridine-7-carboxamide (850 mg) as a solid.

The compounds shown in Pr 1-1 to Pr 1-17 were obtained in the same manner as in Production Example 1.

Table 3 Pr Structure Ms Pr Structure Data one

177 1-1

191 1-2

191 1-3

205 1-4

263 1-5

177 1-6

191 1-7

RT:
1.79
M 1-8

191 1-9

177 1-10

191 1-11

RT:
1.64M 1-12

RT:
1,60
M 1-13

192 1-14

233 1-15

231 1-16

391 1-17

Production Example 2

In a 50 ml reaction vessel, hydroxylamine (50% aqueous solution) was added to a solution of 1H-indole-4-carbonitlir (5.00 g) in CH ₃ OH (100 ml) at room temperature, then boiled for 15 hours (completion of the reaction) confirmed by TLC). The reaction solution was concentrated under reduced pressure and dried by azeotropic distillation with toluene three times. The resulting solid was washed with IPE. N'-hydroxy-1H-indole-4-carboxyldiamide (6.12 g) was obtained as a white solid.

The compounds shown in Pr 2-1 to Pr 2-26 were obtained in the same manner as in Production Example 2.

Table 4 Pr Structure Ms Pr Structure Data 2

176 2-1

191 2-2

205 2-3

263 2-4

177 2-5

191 2-6

191 2-7

221 2-8

192 2-9

193 2-10

191 2-11

188

Table 5 Pr Structure Ms Pr Structure Data 2-12

202 2-13

2-14

RT:
1.68
M 2-15

177 2-16

NMR
below 2-17

2-18

RT:
1,62
M 2-19

200 2-20

RT:
1,69
M 2-21

RT:
1.62M 2-22

RT:
1.62M 2-23

177 2-24

225 2-25

177 2-26

177

Table 6 Pr NMR 2-16 5.71 (2H, s), 6.47 (1H, d), 7.50 (1H, d), 7.61 (1H, d), 7.93 (1H, d), 9.78 (1H , s), 11.70 (1H, s)

Production Example 3

Suspension of N ² -hydroxy-1H-indole-4-carboxamide (1.00 g), 4-fluoro-3- (trifluoromethyl) benzoic acid (1.19 g) and EDCI / HCl (1.32 g) in dioxane ( 30 ml) was stirred at room temperature for 1 hour, and then heated at the boil for 18 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added, then stirred. The insoluble portion was separated by filtration. The organic layer of the mother liquor was washed with water, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated under reduced pressure. Insoluble impurities were separated by filtration, together with the mother liquor, was purified by silica gel chromatography (n-hexane: EtOAc = 80:20). Acetone was added to the target substance, then dissolved by heating and n-hexane was added, the precipitate was separated by filtration to obtain 4- {5- [4-fluoro-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazole-3- silt} -1H-indole (391 mg) as a white solid.

Table 7 Pr Structure Ms 3

346

Production Example 4

N ² - {[(5,6-Dichloropyridin-3-yl) carbonyl] oxy} -1H-indole-4-carboxamide (1.91 g) was added to dioxane (40 ml), then heated at the boil for 5 hours . The reaction mixture was concentrated under reduced pressure and then purified by silica gel column chromatography (EtOAc). Acetone was added to the resulting solid, then suspended by heating. After the solution was allowed to cool, insoluble particles were removed by filtration to obtain 4- [5- (5,6-dichloropyridin-3-yl) -1,2,4-oxadiazol-3-yl] -1H-indole (1.44 g) in the form of a pale yellow powder.

Table 8 Pr Structure Ms four

331,
329

Production Example 5

A solution of N ² -hydroxy-1H-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 below and DIC (3.7 ml) was added. After stirring from -15 to -5 ° C for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in chloroform, and then the insoluble portion was separated by filtration. The resulting powder was purified by silica gel chromatography (n-hexane: EtOAc = 50:50) to obtain N ² - {[4-fluoro-3- (trifluoromethyl) benzoyl] oxy} -1H-indole-4-carboxamide (8, 40 g) as a white solid.

The compound shown in Pr 5-1 was obtained in the same manner as in Production Example 5.

Table 9 Pr Structure Ms Pr Structure Ms 5

388,
366 5-1

-

Production Example 6

To a solution of 6-amino-2-methylnicotinonitrile (960 mg) in ethanol (34 ml) was added a 40% aqueous solution of chloroacetaldehyde (2.36 ml) at 60 ° C. The reaction mixture was boiled for 8 hours. The precipitate formed was filtered off to obtain 5-methylimidazo [1,2-a] pyridin-6-carbonitrile hydrochloride (580 mg) as a white solid.

The compounds shown in Pr 6-1 to Pr 6-11 were obtained in the same manner as in Production Example 6.

Table 10 Pr Structure Ms Pr Structure Ms 6

158 6-1

158 6-2

158 6-3

252 6-4

144 6-5

172 6-6

NMR
below 6-7

252 6-8

172 6-9

NMR
below 6-10

158 6-11

158

Table 11 Pr NMR 6-6 2.39 (3H, s), 7.14 (2H, m), 7.92 (1H, s), 8.18 (1H, s), 8.62 (1H, d) 6-9 7.48 (1H, dd, J = 1.6, 9.3Hz), 7.74 (1H, d, J = 9.3Hz), 7.76 (1H, d, J = 1.6Hz), 8 06 (1H, s), 9.37 (1H, s)

Production Example 7

To a solution of 3,4-diaminobenzonitrile (500 mg) in AcOH (10 ml) was added Ac ₂ O (372 μl) at room temperature. The reaction mixture was boiled for 15 hours (oil bath at 150 ° C). The reaction mixture was cooled to room temperature and concentrated until the amount of AcOH was reduced to half. The reaction mixture was neutralized with an aqueous solution of Na ₂ CO ₃ and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 2-methyl-1H-benzimidazole-5-carbonitrile (390 mg) as a pale red substance.

Table 12 Pr Structure Ms 7

158

Production Example 8

The reaction mixture of 4,5-diamino-2-methylbenzonitrile (20 mg) and formic acid (6 ml) was boiled 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 MgSO _4, then filtered, and the filtrate was concentrated to obtain 5-methyl-1H-benzimidazole-6-carbonitrile as a colored powder.

The compounds shown in Pr 8-1 were obtained in the same manner as in Production Example 8.

Table 13 Pr Structure Ms Pr Structure Ms 8

158 8-1

211,
213

Production Example 9

To a solution of 3,4-diaminobenzonitrile (400 mg) in ethyl orthoformate (6.48 g) was added AcOn (238 mg), then stirred at 80 ° C for 2 hours. The reaction solution was cooled to room temperature and partitioned between EtOAc and 1M aqueous NaOH. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₃ and then filtered off and the filtrate was concentrated and purified by silica gel column chromatography to obtain 2-ethoxy-1H-benzimidazole-6-carbonitrile (164 mg) as a colored powder .

Table 14 Pr Structure Ms 9

210

Production Example 10

To a suspension of 3,4-diaminobenzonitrile (400 mg) in CH ₃ OH (4 ml) was added BrCN (477 mg), then stirred at 20 ° C. for 14 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), then concentrated. Chloroform: CH ₃ OH = 10: 1 (10 ml) was added to the residue, and the resulting insoluble impurities were removed by filtration. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography to obtain 2-amino-1H-benzimidazole-6-carbonitrile (311 mg) as a light orange powder.

Table 15 Pr Structure Ms 10

159

Production Example 11

To a solution of 3,4-diaminobenzonitrile (350 mg) in toluene (5.5 ml) was added CDI (554 mg), then stirred at 125 ° C. for 2 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was triturated / washed with IPE / IPA to give 2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (423 mg) as a colored powder.

Table 16 Pr Structure NMR eleven

7.07 (1H, d, J = 8.2Hz), 7.31 (1H, d, J = 1.6Hz), 7.39 (1H, dd, J = 1.6,
8.2Hz), 11.12 (2H, broad)

Production Example 12

To a mixed solution of N- (4-cyano-2-nitrphenyl) penta-4-enamide (1.0 g) in AcOH) / ethanol (1: 1.20 ml) was added iron powder (710 mg). The reaction solution was heated at 110 ° C for 3 hours and then concentrated. Chloroform was added to the residue, then neutralized with saturated aqueous NaHCO ₃ . The organic layer was dried with anhydrous MgSO 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-1H-benzimidazole-5-carbonitrile (405 mg) as a colored liquid.

The compounds shown in Pr 12-1 to Pr 12-2 were obtained in the same manner as in Production Example 12.

Table 17 Pr Structure Ms Pr Structure Ms 12

220 12-1

266 12-2

218

Production Example 13

To a solution of 2-fluoroterephthalphthalonitrile (500 mg) and Et ₃ N (572 μl) in EtOH (20 ml) was added hydrazine (monohydrate), then the mixture was allowed to react at 60 ° C for 16 hours and concentrated. The residue was washed with diethyl ether to give 3-amino-1H-imidazole-6-carbonitrile (488 mg) as a yellow solid.

The compound shown in Pr 13-1 was obtained in the same manner as in Production Example 13.

Table 18 Pr Structure Ms Pr Structure Ms 13

157 13-1

Production Example 14

An aqueous solution of NaNO ₂ (301 mg) was slowly added to a suspension of 3-amino-1H-imidazole-6-carbonitrile (345 mg) in AcOH at 0 ° C. The reaction mixture was stirred at room temperature for 2.5 days and the residue was separated by filtration and washed with cold water. To the residue was added 0.1 M HCl and DME, then stirred at 80 ° C for 2 hours. The reaction mixture was neutralized with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 80:20 to 50:50) to give 1H-indazole-6-carbonitrile (175 mg) as a yellow solid.

Table 19 Pr Structure Ms fourteen

142

Production Example 15

Methyl (4-cyano-2-nitrophenyl) acetate (128 mg) was dissolved in AcOH (3.0 ml), then iron powder (129 mg) was added and the reaction solution was stirred in an oil bath at 100 ° C for 1.5 hours . The reaction solution was concentrated to remove AcOn, then EtOAc was added. The brown solid was separated by filtration and the organic layer was washed with 1M HCl and brine, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 99: 1 to 95: 5) to obtain 2-oxoindoline-6-carbonitrile (52.0 mg) as a light yellow solid.

Table 20 Pr Structure Ms fifteen

157

Production Example 16

To a solution of 6-bromo-2,2-dimethylindanmethylindan-1-one (124 mg) in TFA (4.44 g, 3.0 ml) was added triethylsilane (150 mg, 207 μl) at room temperature. After stirring at room temperature for 2.5 days, water was added to the reaction solution to stop the reaction, then washed with water and a saturated solution of NaHCO ₃ . The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was purified by column chromatography (n-hexane only) to give 5-bromo-2,2-dimethylindane (114 mg) as a colored oil.

Table 21 Rf Structure NMR 16

1.09 (6H, s), 2.63 (2H, s), 2.68 (2H, s), 7.13 (1H, d), 7.27 (1H, dm), 7.36 (1H , m)

Production Example 17

In THF (30 ml), 60% NaH (125 mg) was added to a mixture of 6-bromo-1-indanone (300 mg) and diazomethane (504 mg, 221 μl) at 0 ° C. The mixture was stirred at room temperature for 3.5 hours and washed with a saturated solution of NH ₄ Cl. The mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO ₄ 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-1-indanone (158 mg) as a light yellow oil.

Table 22 Pr Structure Ms 17

261,
263

Production 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., then stirred 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 MgSO ₄ and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 98: 2 to 97: 3) to obtain 2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile (647 mg) as light yellow solid.

Compounds Pr 18-1 were obtained in the same manner as in Production Example 18.

Table 23 Pr Structure Ms Pr Structure Ms eighteen

159 18-1

183

Production Example 19

To a solution of 60% NaH (12.38 g) in DMF (480 ml) was added a solution of 1H-indole-4-carbonitrile (40.0 g) in DMF (80 ml) at 0 ° C. After stirring at 0 ° C. for 30 minutes, the solution was stirred at room temperature for 0.5 hours. Subsequently, a solution of 2-bromoacetamide (40.76 g) in DMF (80 ml) was added dropwise at 0 ° C. The solution was warmed from 0 ° C to room temperature and stirred for 12 hours. Water (1200 ml) was added to the reaction solution, and the precipitated solid was separated by filtration. The solution was washed with hot water (300 ml) and diisopropyl ether (200 ml) to obtain 2- (4-cyano-1H-indol-1-yl) acetamide (5.21 g) as a white solid.

Table 24 Pr Structure Ms 19

222

Production Example 20

To a solution of 3-chloro-4- (2,2,2-trifluoro-1-methylethoxy) benzonitrile (430 mg) in IPA (3 ml) was added a 5M aqueous NaOH solution (1.37 ml), then stirred at 80 ° C. a 5M aqueous NaOH solution (1.37 ml) was added over 24 hours, and then stirred at 95 ° C. for 24 hours. The reaction solution was concentrated until its amount was reduced to half. 12M HCl was added to the residue, and the resulting precipitate was filtered off and then dried, yielding 3-chloro-4- (2,2,2-trifluoro-1-methylethoxy) benzoic acid as a yellow solid.

The compound shown in Pr 20-1 to Pr 20-3 was obtained in the same manner as in Production Example 20.

Table 25 Pr Structure Ms Pr Structure Ms twenty

267 20-1

251 20-2

247 20-3

263

Production Example 21

Water (2 ml) and sulfuric acid (2 ml) were added to 3- (difluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) benzonitrile (234 mg), then boiled for 24 hours. After cooling to room temperature, the reaction solution was made basic with a 5M aqueous NaOH solution and extracted with diethyl ether (30 ml). The aqueous layer was acidified with 1M HCl and extracted with EtOAc. The organic layer was dried with anhydrous MgSO ₄ and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: CH ₃ OH = 97: 3 to 90:10) to give 3-formyl-4- (2,2,2-trifluoro-1-methylethoxy) benzoic acid (151 mg) as white solid.

The compounds shown in Pr 21-1 to Pr 21-6 were obtained in the same manner as in Production Example 21.

Table 26 Pr Structure Ms Pr Structure Ms 21

261 21-1

315 21-2

245 21-3

257 21-4

301 21-5

261 21-6

311,
313

Production Example 22

To 5-bromo-2- (2,2,2-trifluoro-1-methylethoxy) benzonitrile in a toluene / THF (4: 1) solvent mixture was added a solution of n-BuLi in n-hexane at -78 ° C. The solution was stirred for 0.5 hours, passing through it gaseous CO ₂ . A 1 M aqueous NaOH solution was added to the reaction solution to complete the reaction, and then was extracted with diethyl ether. The organic layer was acidified by adding 1M HCl, extracted with EtOAc, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 97: 3 to 90:10) to obtain 3-cyano-4- (2,2,2-trifluoro-1-methylethoxy) benzoic acid as a white solid substances.

The compound shown in Pr 22-1 was obtained in the same manner as in Production Example 22.

Table 27 Pr Structure Ms Pr Structure Ms 22

258 22-1

189

Production Example 23

To a stirred solution of methyl 1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (430 mg) in CH ₃ OH-THF (4 ml-3 ml) was added an aqueous solution of 1M NaOH. The solution was stirred at room temperature for 10 hours and then concentrated under reduced pressure and water (10 ml) was added and then 1M HCl was added until the pH reached 3. The resulting solid was filtered off, washed with water and dried under reduced pressure. pressure to obtain 1-isobutyl-2-oxo-1,2-dihydroxypyridine-4-carboxylic acid (235 mg) as a white powder.

Table 28 Pr Structure Ms 23

194

Production Example 24

A solution of 1H-benzimidazole-5-carboxylic acid (75.0 g) in dichloromethane (750 ml) was 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 solution of NH ₃ (5 ml) under ice-cooling. This reaction mixture was stirred at the same temperature and the reaction solution was concentrated. The purple residue was triturated / washed with IPE / IPA and separated by filtration to give 1H-benzimidazole-6-carboxamide (129 g) (including inorganic salts).

The compound shown in Pr 24-1 was obtained in the same manner as in Production Example 24.

Table 29 Pr Structure Ms Pr Structure Ms 24

162 24-1

184

Production Example 25

Production Example 25-1

To a solution of 1H-1,2,3-benzotriazole-5-carboxylic acid (2 g), EDCI / HCl (2.82 g) and HOBt in DMF (70 ml) was added an aqueous solution of NH ₃ (5.1 ml), then the mixture was reacted at room temperature for 2 hours. The mixture was concentrated and the residue was washed with a saturated aqueous NaHCO ₃ solution, separated by filtration and dried, yielding 1H-1,2,3-benzotriazole-5-carboxamide (1.98 g) as a black solid.

Production Example 25-2

In a 50 ml reaction vessel, NaOHCH ₃ (288 mg) was added at room temperature to a solution of methyl 4-chloro-2-methyl-1H-benzimidazole-6-carboxylate ether (300 mg) in formamide (2.65 ml). The solution was stirred at 80 ° C for 3 hours. The completion of the reaction was determined by TLC and LC, and then the reaction solution was concentrated and water was added to complete the reaction. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform: CH ₃ OH = 100: 0 to 90:10) to obtain 4-chloro-2-methyl-1H-benzimidazole-6-carboxamide (257 mg) as white solid matter.

The compounds shown in Pr 25-2 were obtained in the same manner as in Production Example 25-1.

Table 30 Pr Structure Ms Pr Structure Ms 25-1

185 25-2

201 25-3

232,
234

Production Example 26

To a solution of 3-formyl-4- (2,2,2-trifluoro-1-methietoxy) benzoic acid (490 mg) and K ₂ CO ₃ (387 mg) in acetone (10 ml) was added iodomethane (350 μl) at room temperature and then stirred for 2 hours. The reaction mixture was diluted with water (15 ml) and extracted with EtOAc (30 ml). The organic layer was dried over anhydrous MgSO ₄ and filtered to remove a desiccant, and the solvent was concentrated. The residue was purified by silica gel column chromatography (n-hexane: EtOAC = 95: 5 to 80:20) to give methyl 3-formyl-4- (2,2,2-trifluoro-1-methylethoxy) benzoate (122 mg) in the form of a solid.

Table 31 Pr Structure Ms 26

275

Production Example 27

Under ice-cooling, DMF (30 ml) was slowly added dropwise with POCl ₃ (6.68 g, 4.06 ml), then the mixture was reacted at room temperature for 2 hours, and then a solution of 1H-benzimdazole-6-carboxamide (2 , 38 g) in DMF (47.6 ml) and then the mixture was stirred at room temperature for 2 hours. To the solution was added a 1M aqueous NaOH solution (pH 6-7), then was stirred at room temperature for 0.5 hours. The solution was extracted with EtOAc and the organic layers were combined and washed with brine, dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was purified by column chromatography and triturated / washed with IPE to give 1H-benzimidazole-6-carbonitrile (0.58 g) as pale red crystals.

Compounds shown in Pr 27-1 to Pr 27-2 were obtained in the same manner as in Production Example 27.

Table 32 Pr Structure Ms Pr Structure Ms 27

144 27-1

192 27-2

144

Production Example 28

A solution of 1,3-benzothiazole-6-carboxamide (1.96 g) in POCl ₃ (10 ml) was boiled for 4 hours. The reaction solution was concentrated and water was slowly added at 0 ° C. The mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was purified by column chromatography (n-hexane: EtOAc = 80:20 to 60:40) to give 1,3-benzothiazole-6-carbonitrile as a pale yellow solid.

The following Pr 28-1 was obtained in the same manner as in Production Example 28

Table 33 Pr Structure Ms Pr Structure Ms 28

183 28-1

143

Production Example 29

To a solution of 6-bromo [1,2,4] triazolo [1,5-a] pyridine (400 mg) in DMF were added tris (dibenzyl diacetno) dipalladium (0), 1'-bis (diphenylphosphino) ferrocene and Zn (CN) ₂ in a nitrogen atmosphere, then was stirred at 110 ° C for 23 hours. The mixture was cooled to room temperature and saturated NH ₄ Cl (2 ml), saturated NH ₃ solution (6 ml) and H ₂ O (12 ml) were added. The reaction mixture was extracted three times with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-5% CH ₃ OH / chloroform) to give [1,2,4] triazolo [1,5-a] pyridin-6-carbonitrile as a dark red solid.

Production Example 30

In a 100 ml reaction vessel, Zn (CN) ₂ (834 mg) and Pd (PPh) ₄ (547 mg) were added at room temperature to a solution of 6-bromo-7-methyl-1H-benzimidazole (500 mg) in DMF, then stirred at 150 ° C for 5 hours. The reaction solution was poured into a 1: 1 mixture of saturated NaHCO ₃ and EtOAc and stirred for 1 hour. The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography (automatic purifier, chloroform: CH ₃ OH = 98: 2 to 90:10) to obtain 7-methyl-1H-benzimidazole-6-carbonitrile (161.8 mg) as a brown solid.

The following Pr 30-1 to Pr 30-7 were obtained in the same manner as in Production Example 30. They were also obtained using the method of Production Example 29.

Table 34 Pr Structure Data Pr Structure Data 29th

NMR: 7.98
(1H, d), 8.04
(1H, d), 8.74
(1H, s), 9.90-
9.87 (1H, m) thirty

MS: 158 30-1

NMR: 7.67
(1H, dd), 8.25
(1H, ddd)
8.34 (1H, dd), 10.17 (1H, s) 30-2

MS: 158 30-3

MS: 144 30-4

MS: 176 30-5

NMR: 10.17
(1H, s), 8.34
(1H, dd), 8.25
(1H, ddd)
7.67 (1H, dd) 30-6

NMR:
7.95 (1H,
dd), 8.19
(1H, dd),
8.23 (1H, dd) 30-7

MS: 157

Production Example 31

To a mixed solution of 4-hydroxy-3-nitrobenzonitrile (1 g) and NH ₄ 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) were further heated at the boil at 70 ° C for 30 minutes. The reaction solution was cooled to room temperature, diluted with EtOAc (200 ml) and then filtered through celite. The solution was washed with brine, the organic layer was dried over anhydrous MgSO ₄ and filtered, and the filtrate was evaporated under reduced pressure to give 3-amino-4-hydroxybenzonitrile (740 mg) as a light brown solid.

The following Pr 31-1 to Pr 31-3 were prepared in the same manner as in Preparation Example 31.

Table 35 Pr Structure Ms Pr Structure Ms 31

133 31-1

157 31-2

225,
227 31-3

170

Production Example 32

To a solution of 4-amino-3-nitrobenzontryl (8 g) in a mixture of solvents EtOH / THF (40 ml / 40 ml) was added Pd-C (50% by weight) (0.8 g), then stirred in an atmosphere of H ₂ in within 12 hours. The reaction solution was filtered through celite and concentrated. The residue was triturated / washed with a mixture of IPE and IPA solvents and separated by filtration to obtain 3,4-diaminobenzonitrile (6.3 g) as an orange powder.

Table 36 Pr Structure Ms 32

156

Production Example 33

To a solution of 2-amino-3-nitrobenzonitrile (2 g) in THF (30 ml) was added 4-petinoyl chloride (2.90 g) and diisopropylethylamine (4.27 g) was further stirred at 80 ° C. for 12 hours. The reaction solution was poured into water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH) to obtain N- (4-cyano-2-nitrophenyl) pent-4-enamide (174 mg) as a colored liquid.

The following Pr 33-1 to Pr 33-2 were obtained in the same manner as in Production Example 33.

Table 37 Pr Structure Ms Pr Structure Ms 33

244 33-1

290 33-2

264

Production Example 34

To a solution of 3-chloro-4-fluorobenzonitrile (300 mg) and 1,1,1-trifluoro-2-propanol in THF (15 ml) was added 60% NaH (92.5 mg) at 5 ° C, then stirred at room temperature for 2 hours, a saturated solution of NH ₄ Cl was added to complete the reaction and extracted with EtOAc. The resulting organic layer was dried over anhydrous MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 97: 3 to 85:15 to obtain 3-chloro-4- (2,2,2-trifluoro-1-methylethoxy) benzonitrile (435 mg) as colored oily substance.

The following Pr 34-1 to Pr 34-6 were obtained in the same manner as in Production Example 34.

Table 38 Pr Structure Data Pr Structure Data 34

NMR below 34-1

NMR below 34-2

MS:
252 34-3

MS:
268 34-4

NMR below 34-5

MS:
316,
318 34-6

MS:
242

Table 39 Pr NMR 34 1.48 (3H, d), 5.53 (1H, m), 7.57 (1H, d), 7.87 (1H, dd), 8.09 (1H, d) 34-1 1.47 (3H, d), 5.50 (1H, m), 7.59 (1H, t), 7.74 (1H, dm), 7.95 (1H, dd) 34-4 1.47 (3H, d), 5.48 (1H, m), 7.46 (1H, d), 7.90 (1H, dd), 8.08 (1H, d)

Production Example 35

In a 50 ml reaction vessel to a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (100 mg) in DMF (1 ml) was added 60% NaH (10.9 mg) at 0 ° C. Next, tert-butyl (2-iodoethoxy) dimethylsilane was added to the mixture at 0 ° C, then stirred at room temperature for 15 hours. The completion of the reaction was confirmed by CJ-MS and then water (30 ml) was added to the reaction solution. The mixture was extracted three times with EtOAC (20 ml). The organic layer was washed with brine, dried over anhydrous MgSO _4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purifier, (n-hexane: EtOAC = 100: 0 to 90:10) to obtain 1- (2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) -4 - {5- [3- (trifluoromethyl) -4-2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (86.4 mg) in the form of a white solid.

Table 40 Pr Structure Ms 35

622

Production Example 36

LiH was suspended in DMF (5 ml) and a suspension of methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (500 mg) in DMF (5 ml) was added dropwise to that suspension at room temperature. The suspension was stirred and a solution of 1-iodine-2-methylpropane (506 μl) in DMF (5 ml) was added dropwise over 10 minutes, then stirred at 50 ° C for 15 hours. 1M HCl was added to the reaction solution at 0 ° C and then EtOAc was extracted and the organic layer was washed with brine, dried over anhydrous MgSO ₄ and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 90: 10 to 50:50) to give methyl 1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (440 mg) as white powder.

Table 41 Pr Structure Ms 36

210

Production Example 37

To a solution of 4-fluoro-3-nitrobenonitrile (300 mg) and dimethyl malonate (286 mg) in DMF was added 60% NaH at 0 ° C, then the mixture was reacted at room temperature to form dimethyl (4-cyano-2-nitrophenyl) malonate ( 198 mg).

Table 42 Pr Structure Ms 37

301

Production Example 38

To a solution of dimethyl (4-cyano-2-nitrophenyl) malonate (198 mg) in DMSO (5 ml) was added LiCl (60.3 mg) and H ₂ O (12 μl), then stirred at 100 ° C for 3 hours . The reaction solution was cooled to room temperature and poured into EtOAc and brine in portions. The organic layer was washed with brine, dried over anhydrous MgSO _4, 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 give methyl (4-cyano-2-nitrophenyl) acetate (128 mg) as a yellow solid.

Table 43 Pr Structure Ms 38

219

Production Example 39

To a solution of 4-chloro-3- (trifluoromethyl) benonitrile (1 g) and iron (3+) tris [(2Z) -4-oxcopent-2-en-2-oleate] (86 mg) and 1-methylpyrrolidin-2 -one (2.8 ml) in THF (30 ml) was added a solution of 3M bromine (isobutyl) magnesium in diethyl ether (2.9 ml) under ice-cooling. The solution was stirred at room temperature for 30 minutes and diluted with diethyl ether (30 ml) and then 1M HCl was carefully added to complete the reaction. The reaction solution was extracted with EtOAc (100 ml) and the organic layer was dried over anhydrous MgSO ₄ and then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 100: 5 to 95: 5) to obtain 4-isobutyl-3- (trifluoromethyl) benzonitrile (320 mg) as a pale yellow liquid.

The following Pr 39-1 was obtained in the same manner as in Production Example 39.

Table 44 Pr Structure Data 39

NMR: 0.89 (6H, d), 1.91-2.03 (1H, m), 2.70 (2H, dm), 7.70 (1H, d), 8.09 (1H, dd) 8.21 (1H, d) 39-1

MS: 262

Production 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-λ ⁴ -sulfanyl) ethanamine (757 mg) at room temperature , then stirred for 6 hours and saturated aqueous NaHCO ₃ solution (15 ml) was added. After extraction with chloroform (30 ml), the organic layer was dried over anhydrous MgSO ₄ , 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 colored liquid.

The following Pr 40-1 was obtained in the same manner as in Production Example 40.

Table 45 Pr Structure Data Pr Structure Data 40

NMR: 7.25 (1H,
t), 7.66 (1H, dd), 8.14-8.20 (1H, m), 8.22 (1H, dm) 40-1

MS:
321

Production Example 41

The following Pr 41-1 to Pr 41-10 were obtained in the same manner as in Example 2.

Table 46 Pr Structure Ms Pr Structure Ms 41-1

427 41-2

393 41-3

373 41-4

585 41-5

349 41-6

437 41-7

362 41-8

551 41-9

405 41-10

410

Production Example 42

The following Pr 42-1 to Pr 42-3 were obtained in the same manner as in Example 5.

Table 47 Pr Structure Data 42-1

NMR: 1.67 (6H, s), 7.71 (1H, d), 8.12 (1H, dd), 8.26 (1H, d)

42-2

MS: 282 42-3

NMR: 1.67 (6H, s), 7.71 (1H, d), 8.12 (1H, dd), 8.26 (1H, d)
MS: 288

Production Example 43

The following Pr 43 was obtained in the same manner as in Example 6.

Table 48 Pr Structure Ms 43

627

Production Example 44

The following Pr 44-1 to Pr 44-3 were obtained in the same manner as in Example 12.

Table 49 Pr Structure Ms 44-1

536 44-2

222

Production Example 45

The following Pr 45 was obtained in the same manner as in Production Example 47.

Table 50 Pr Structure NMR 45

1.47 (3H, d), 5.49-5.60 (1H, m), 7.09 (1H, t), 7.50 (1H, d),
8.07-8.13 (2H, m)

Production Example 46

The following Pr 46-1 to Pr 46-5 were obtained in the same manner as in Example 19.

Table 51 Etc. Structure Ms 46-1

625 46-2

661 46-3

657 46-4

751 46-5

380

Production Example 47

To a solution of ethyl (7- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxiazol-3-yl} imidazo [1, 2-a] pyridin-2-yl) acetate (230 mg) in THF (2.0 ml) was added an aqueous solution of NaOH (1 ml), then stirred at 80 ° C for 2 hours. After cooling to room temperature, 1M HCl was added, then extracted with chloroform. The organic layer was dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 10: 1 to 5: 1) to obtain a colored powder. To a solution of this colored powder in EtOAc was added a solution of 4M HCl / EtOAc, then concentrated. The resulting colored powder was triturated / washed with IPE to give (7- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxaiazole- 3-yl} imidazo [1,2-a] pyridin-2-yl) acetic acid hydrochloride (180.4 mg) as a colored powder.

The following Pr 47-1 to Pr 46-13 were obtained in the same manner as in Production Example 47.

Table 52 Pr Structure Pr Structure 47

47-1

47-2

47-3

47-4

47-5

47-6

47-7

47-8

47-9

47-10

47-11

47-12

47-13

Table 53 Pr Ms Pr Ms Pr Ms Pr Ms 47 501 47-1 515 47-2 501 47-3 499 47-4 522 47-5 514 47-6 499 47-7 530 47-8 500 47-9 468 47-10 504 47-11 555 47-12 498 47-13 585

Example 1

A solution of 3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methosimethyl) benzoic acid (810 mg), EDCI / HCl (616 mg) and N'-hydroxy-7-methylimidazo [1,2- 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 ₄ and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (CH ₃ OH / chloroform = 0 to 5%) and recrystallized from EtOH to give 7-methyl-6- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro -1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} imidazo [1,2-a] pyridine (60 mg) as a white solid.

Example 2

To a solution of 3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methosimethyl) benzoic acid (349 mg) in dichloromethane (6 ml) was added oxalyl chloride (333 mg) and a catalytic amount of DMF under ice cooling, further stirred at room temperature for 1 hour. The reaction solution was concentrated and dried by azeotropic distillation with toluene. To a solution of the residue in THF was added N'-hydroxy-2-methyl-1H-benzimidazole-6-carboxyimidamide (200 mg), N-ethyl-N-isopropyl-2-propanenamine (543 mg). The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, then extracted with EtOAc three times. The organic layers were combined, dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was dissolved in dioxane, then stirred at 100 ° C for 3 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain a colored oily substance. A solution of 4M HCl / EtOAc was added to a solution of this oily substance in EtOAc, then it was stirred for several minutes and concentrated to obtain 2-methyl-5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro -1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole hydrochloride (239 mg) as colored crystals.

Example 3

To a solution of 4- (2,2,2-trifluoro-1,1-dimethylethoxy) -3- (trifluoromethyl) benzoic acid (118 mg) and 2- {4- [amino (hydroxyimino) methyl] -1H-indole-1 -yl} acetamide (104 mg) in dioxane (5 ml) was added DIC (69 μl), then stirred at room temperature for 3 hours and then heated to boiling for 20 hours. The reaction solution was concentrated, and then water (15 ml) was added to the residue, then extracted with chloroform (15 ml). The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using preparative HPLC (column: CAPCEL PAK, C18, MG, S-5, 30 × 50 mm; solvent: 50-90% acetonitrile / 10 mmol ammonium carbonate-ammonia (pH 9.2); 40 ml / min ) and recrystallized from diisopropyl ether to give 2- (4 {5- [4- (2,2,2-trifluoro-1,1-dimethylethoxy) -3- (trifluoromethyl) phenyl] -1,2,4-oxadiazole- 3-yl} -1H-indol-1-yl) acetamide (40 mg) as a white solid.

Example 4

To a suspension of 60% NaH (68.0 mg) in DMF, cyclopropylmethanol (99 mg) was added at 0 ° C, then stirred at the same temperature, then 5- {5- [4-fluoro-3- (trifluoromethyl) phenyl] - 1,2,4-oxadiazol-3-yl} -1H-benzimidazole (120 mg). The reaction mixture was stirred at room temperature for 2 hours and then water was added. The mixture was extracted with EtOAc and the organic layer was concentrated. The residue was purified by silica gel column chromatography (CH ₃ OH / chloroform = 0 to 5%) to obtain an oily substance. A solution of 4M HCl / dioxane (0.5 ml) was added to a solution of an oily substance in chloroform-CH ₃ OH and concentrated to give 5- {5- [4- (cyclopropylmethoxy) -3- (trifluoromethyl) phenyl] -1,2,4 -oxadiazol-3-yl} -1H-benzimidazole hydrochloride (20 mg) as a white substance.

HPLC analysis: Conditions (TSK-GEL (TOSOH) ODS-80TM 4.6 × 150 mm, MeCN: 0.01M KH ₂ PO ₄ (7: 3), 1.0 ml / min, 254 nm) [RT: 7 , 90 min]

Example 5

To a solution of 2- (4- {5- [4-fluoro-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indol-1-yl) acetamide (100 mg) and 2-propanol (35 μl) in DMF (3 ml) was added 60% NaH (12 mg) at 0 ° C. It was further stirred at room temperature for 9 hours. Water (5 ml) was added to the reaction solution to complete the reaction, and extracted with a solvent mixture of chloroform: CH ₃ OH (8: 2). The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 98: 2 to 93: 7) and crystallized from diethyl ether to give 2- (4- {5- [4-isopropoxy-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indol-1-yl) acetamide (25 mg) as a pale yellow solid.

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, then stirred at -10 ° C for 0.5 hours. To this reaction mixture was added 2- {4- [5- (3-chloro-4-fluorophenyl) -1,2,4-oxadiazol-3-yl] -1H-indol-1-yl} acetamide (120 mg) at −10 ° C. and further stirred 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 brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 100: 0 to 95: 5) to obtain 2- [4- (5- {3-chloro-4- [2-fluoro-1- (fluoromethyl) ethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl] acetamide (76.9 mg) as a white substance.

Example 7

To a solution of 2- {4- [5- (4-fluoro-3-methylphenyl) -1,2,4-oxadiazol-3-yl] -1H-indol-1-yl} acetamide (100 mg) and (2R) -1,1,1-trifluoropropan-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0 ° C. It was further stirred at 80 ° C for 4 hours. Water (15 ml) was added to the reaction solution to complete the reaction, filtered and then dried. The resulting powder was purified by column chromatography (chloroform: CH ₃ OH = 100: 0 to 95: 5) and crystallized from diisopropyl ether to give 2- [4- (5- {3-methyl-4 - [(1R) -2 , 2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl] acetamide (70 mg) as a pale yellow solid.

Example 8

To a suspension of 60% NaH (43 mg) in DMF (4 ml) was added 2-propanol (65 mg) at 0 ° C, then it was stirred at room temperature for 20 min. After cooling to 0 ° C., 2- {4- [5- (3-chloro-4-fluorophenyl) -1,2,4-oxadiazol-3-yl] -1H-indol-1-yl-acetamide (200 mg ) The reaction mixture was irradiated with microwave at 60 ° C for 50 minutes. The reaction mixture was added to an aqueous solution of NH ₄ Cl, then stirred and then the solvent was evaporated. After adding a solvent mixture (4: 1) of chloroform-CH ₃ OH and suspending, the solids were separated, silica gel was added and the solvent was evaporated. The residue was purified by column chromatography (chloroform: CH ₃ OH = 100: 0 to 98: 2; n-hexane: EtOAc = 0: 100) to obtain 2- {4- [5- (3-chloro-4-isopropylphenyl) -1,2,4-oxadiazol-3-yl] -1H-indol-1-yl} acetamide (17.5 mg) as a white solid.

Example 9

To a solution of 4- {5- [4-fluoro-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (300 mg) in THF (1.5 ml) was added propane -2-amine (0.75 ml) and after plugging into a tube, the solution was stirred at 50 ° -55 ° C for 40 hours. The solution was concentrated under reduced pressure and then purified by column chromatography (n-hexane: EtOAc). The resulting solid was dissolved in acetone with heating and n-hexane was added and the precipitate was filtered off to obtain 4- [3- (1H-indol-4-yl) -1,2,4-oxadiazol-5-yl] -N-isopropyl- 2- (trifluoromethyl) aniline (295 mg).

Example 10

To a mixed solution of 2- {4- [5- (5,6-dichloropyridin-3-yl) -1,2,4-oxadiazol-3-yl] -1H-indol-1-yl} acetamide (100 mg) in isopropylamine (220 μl) was added to dioxane (2 ml) and NMP (2 ml), then stirred 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 column chromatography (n-hescan: EtOAc = 40: 60 to 0: 100), and the obtained residue was suspended in diisopropyl ether under heating and separated by filtration to obtain 2- (4- {5- [5-chloro-6- (isopropylamino) pyridin-3-yl] -1,2,4-oxadiazol-3-yl} -1H-indol-1-yl) acetamide (62 mg) as a white powder .

Example 11 (11-1 and 11-2)

To a solution of 5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole (105 mg) in DMF (3.15 ml) was added 60% NaH (31 mg) under ice-cooling, then stirred at the same temperature for 15 minutes and methyl iodide (0.22 ml) was added, then stirred at room temperature for 5 o'clock. Water was added to the reaction mixture, then extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by column chromatography (automatic processor, chloroform: CH ₃ OH = 10: 1). The target compound was dissolved in EtOAc (5 ml), a 4M HCl / EtOAc solution (5 ml) was added and concentrated to obtain approximately 1: 1 two regioisomers. The mixture was crystallized from acetonitrile to give 1-methyl-5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazole-3- il} -1H-benzimidazole hydrochloride (12.1 mg). The mother liquor was concentrated to give 1-methyl-5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl } -1H-benzimidazole hydrochloride and 1-methyl-6- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazole-3 -yl} -1H-benzimidazole hydrochloride (70.2 mg) as a colored powder.

Example 12

To a solution of 4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4-oxazol-3-yl) -1H -indole (150 mg) in DMF (1.5 ml) was added 60% NaH (16 mg) at 0 ° C and then stirred at room temperature for 0.5 hours. Then, 2-bromoacetamide (70 mg) was also added to the reaction mixture at 0 ° C, and then stirred at room temperature for 3 hours. Water was added to the reaction mixture, then extracted with EtOAc, the organic layer was separated, washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: CH ₃ OH = 100: 0 to 90:10) to give 2- [4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2 trifluoro-1-methylphenoxy] phenyl} -oxadiazol-3-yl) -1H-indol-1-yl] acetamide (145 mg) as a white solid.

Example 13

To a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy] phenyl] -1,2,4-oxadiazol-3-yl) indoline (100 mg) in acetonitrile (2.5 ml) was added K ₂ CO ₃ (46 mg) and 3-iodopropanamide (124 mg) at room temperature, then stirred at 80 ° C for 15 hours. A saturated aqueous solution of NaHCO _{3 was} added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: CH ₃ OH = 100: 0 to 90:10) to obtain 3- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1 -methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2,3-dihydro-1H-indol-1-yl) propanamide (23.6 mg) as a white solid.

Example 14

To a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indol-3 -carbaldehyde (150.0 mg) in CH ₃ OH (1.5 ml) was added a 40% solution of CH ₃ OH in CH ₃ NH ₂ (74.5 mg) at 0 ° C. After warming to room temperature, the solution was stirred at room temperature for 4 hours. After confirming the formation of the iminium salt, the organic solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (1.5 ml). To this solution was added NaBH ₄ (12.09 mg). After warming to room temperature, the solution was stirred at room temperature for 15 hours. Water (30 ml) was added to the reaction solution, then it was extracted three times with EtOAc (20 ml). The organic layer was combined, washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform: CH ₃ OH = 100: 0 to 90:10) to obtain N-methyl-1- (4- {5- [3- (trifluoromethyl) -4- ( 2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indol-3-yl) methanamine (87.4 mg) as a white substance.

Example 15

To a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} indlin (100 mg) in DMF (1.0 ml) was added 69% NaH (10.9 mg) at 0 ° C, then was stirred at room temperature for 0.5 hours. Alkyl chloride (24.1 μl) was added at 0 ° C, then stirred at room temperature for 3 hours. Water (30 ml) was added to the reaction solution, then it was extracted three times with EtOAc (20 ml). The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hesane: EtOAc = 90: 10 to 60:40) to obtain 1-acetyl-4- {5- [3- (trifluoromethyl) -4- (2,2 , 2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} indoline (56.8 mg) as white crystals.

Example 16

To a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (80 mg) in DMF (0.80 ml) was added 60% NaH (8.7 mg) at 0 ° C, then stirred at room temperature for 0.5 hours. Methanesulfonyl chloride (21.1 μl) was added at 0 ° C, then stirred at room temperature for 3 hours. Water (30 ml) was added to the reaction solution, then it was extracted three times with EtOAc (20 ml). The organic layer was combined, washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (automatic purifier, chloroform: CH ₃ OH = 100: 0 to 98: 2) to obtain 1- (methylsulfonyl) -4- {5- [3- (trifluoromethyl) -4- (2 , 2,2-trifluoro-1-methethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (15.6 mg) as a white solid.

Example 17

4- {5- [3- (Trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (100 mg) dissolved in DMF (1.0 ml), then 60% NaH (10.9 mg) was added at 0 ° C and stirred at room temperature for 0.5 hours. Methyl chloride carbonate (26.3 μl) was added at 0 ° C, then stirred at room temperature for 3 hours. Water (30 ml) was added to the reaction solution, then extracted three times with EtOAc (20 ml), the organic layer was combined, washed with brine, dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform: CH ₃ OH = 100: 0 to 98: 2) to obtain methyl 4- {5- [3- (trifluoromethyl) -4- (2,2,2- trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole-1-carboxylate (98.6 mg) as a white solid.

Example 18

To a solution of 3- (5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H- benzimidazol-2-yl) propanoic acid (23.5 mg) in dichloromethane was added oxalyl chloride (0.01 ml) and a few drops of DMF, then stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove solvent and reagent. To a solution of the residue in THF was added NH ₄ OH, then stirred for 1 hour. A saturated aqueous solution of NH ₄ Cl was added to the reaction solution, then EtOAc was extracted. The organic layer was dried over anhydrous MgSO ₄ and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 10: 1) to obtain a colored powder. To a solution of the colored powder in EtOAc was added a solution of 4N-HCl in EtOAc. The reaction mixture was concentrated and the residue was triturated and washed with IPE to give 3- (5- {5- [3- (triftomethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2, 4-oxadiazol-3-yl} -1H-benzimidazol-2-yl) propanamide hydrochloride as a pale yellow powder.

Example 19

To a solution of (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole- 1-yl) acetic acid (150 mg) and HOBt (65 mg) in DMF (1.5 ml) were added EDCI / HCl (69 mg) at 0 ° C, then stirred at room temperature for 1 hour. After cooling to 0 ° C., 1-pyridin-2-ylmethanamine (39 mg) was added, then it was stirred at room temperature for 15 hours. Saturated aqueous NaHCO ₃ solution was added to the reaction solution to complete the reaction. The reaction solution was extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous MgSO ₄ and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 100: 0 to 95: 5) 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} -1H-indol-1-yl) acetamide (157.8 mg) as a solid white substances. To a solution of N- (pyridin-2-ylmethyl) -2- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4 -oxadiazol-3-yl} -1H-indol-1-yl) acetamide (120 mg) in methylene chloride (2.2 ml) was added dropwise 10 equivalents of 4M HC / dioxane, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure and triturated / washed in IPE. The resulting solid was separated by filtration and dried, yielding N- (pyridin-2-ylmethyl) -2- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl ] -1,2,4-oxadiazol-3-yl} -1H-indol-1-yl) acetamide hydrochloride (126 mg) as a white solid.

Example 20

To a solution of [4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro-1-methietoxy] phenyl} -1,2,4-oxadiazol-3-yl) - 1H-indol-1-yl] acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg) and after 30 minutes methanesulfonamide (23 mg) and 2,3,4,6,7,8,9 were added. , 10-octahydropyrimide [1,2-a] azepine (37 mg), then stirred at room temperature for 15 hours. Water was added to the reaction mixture to complete the reaction. The reaction solution was extracted with EtOAc, the resulting organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 100: 0 to 90:10) to obtain N- (methylsulfonyl) -2- [4- (5- {3- (trifluoromethyl) -4 - [( 1S) -2,2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl] acetamide (56.4 mg) as a white solid substances.

Example 21

POCl ₃ (158.4 μl) was added dropwise to a DMF solution (4 ml) at 0 ° C. After warming to room temperature, the solution was stirred for 0.5 hours. Then a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (500 , 0 mg) in DMF (1 ml) was added at 0 ° C, then stirred at room temperature for 15 hours. After cooling to 0 ° C, a 1M aqueous NaOH solution was added to the reaction solution to adjust the pH to 9-10. This solution was stirred at 100 ° C for 1 hour. Then it was left to cool, water (30 ml) was added to the reaction solution, then EtOAc (20 ml) was extracted three times. The organic layer was combined, washed with brine, dried over anhydrous MgSO _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 70:30) to give 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro -1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole-3-carbaldehyde (456.7 mg) as a white solid.

Example 22

To a mixture of a solution of 5- [3- (1H-benzimidazol-6-yl) -1,2,4-oxadiazol-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) were added sodium chloride (187 mg) at room temperature. The mixed reaction solution was stirred at room temperature for 3 hours, then diluted with water (10 ml) and extracted with EtOAc (20 ml). The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. To a solution of the residue in dioxane was added 4 N. HCl-dioxane solution, then concentrated. The resulting residue was recrystallized from IPA (10 ml) to give 5- [3- (1H-benzimidazol-5-yl) -1,2,4-oxadiazol-5-yl] -2- (2,2,2-trifluoro- 1-methylethoxy) benzoic acid hydrochloride (80 mg) as a white powder.

Example 23

To a solution of 2- [2- (methylthio) ethyl] -5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazole -3-yl} -1H-benzimidazole (400 mg) in dichloromethane (8.0 ml) was added mCBA (534 mg), then stirred at room temperature for 3 hours. An aqueous solution of Na ₂ S ₂ O _{4 was} added to the reaction mixture, followed by stirring for 1 hour. The reaction solution was extracted three times with EtOAc and the organic layer was combined, dried over anhydrous MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 10: 1) to obtain a yellow oily substance. This material was dissolved in EtOAc and 4M-HCl / EtOAc was added then concentrated. The residue was washed with IPE to give 2- [2- (methylsulfanyl) 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 a light yellow powder.

Example 24

To the reaction mixture 2-but-3-en-1-yl-5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4 -oxadiazol-3-yl} -1H-benzimidazole (200 mg) in acetone and water (1 ml) was added tetraoxosmium (51 mg) and 4-methylmorpholine-4-oxide (94 mg), then stirred overnight. The reaction mixture was filtered and an aqueous solution of sodium thiosulfate was added to the filtrate, then stirred for 1 hour. The solution was extracted with chloroform and the organic layers were concentrated. The residue was purified by silica gel column chromatography (chloroform-CH ₃ OH) and concentrated, and the resulting colored powder was added to a solution of HCl in ethanol and dissolved in it, and then concentrated. The residue was triturated / washed with diisopropyl ether to give 4- (5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazole -3-yl} -1H-benzimidazol-2-yl) butan-1,2-diol hydrochloride (102.3 mg).

Example 25

To a solution of 3- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -2, Manganese dioxide (67.7 mg) was added in 3-dihydro-1H-indol-1-yl) propanamide (100 mg) in chloroform (1 ml) and then boiled for 15 hours. The reaction solution was allowed to cool 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: CH ₃ OH = 100: 0 to 90:10) to obtain 3- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro -1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indol-1-yl) propanamide (46.3 mg).

Example 26

To a solution of 4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indole (100 mg) in AcOH (3 ml) was added portionwise sodium cyanoborate (29 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, made basic with a 1M aqueous NaOH solution and extracted with EtOAc.

The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated and the residue was purified by silica gel column chromatography (n-hezane: EtOAc = 90: 10 to 75:25) and washed with n-hexane, giving 4 - {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} indoline (90 mg) as a light yellow solid.

Example 27

To a solution of 5- [3- (1H-benzimidazol-6-yl) -1,2,4-oxadiazol-5-yl] -2- (2,2,2-trifluoro-1-methylethoxy) benzaldehyde (80 mg) in ethanol (3 ml) was added NaBH ₄ (9 mg) at 0 ° C. After stirring at room temperature for 0.5 hours, a saturated solution of NH ₄ Cl (10 ml) was added, followed by extraction with EtOAc (20 ml). The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. 4M HCl / dioxane was added to a solution of the residue in dioxane, and then concentrated. The resulting powder was recrystallized from IPA (10 ml) to give [5- [3- (1H-benzimidazol-5-yl) -1,2,4-oxadiazol-5-yl] -2- (2,2,2-trifluoro -1-methylethoxy) phenyl] methanol hydrochloride (70 mg) as a white powder.

Example 28

A solution of 5-methyl-6- {5- [3-trifluoro) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} imidazo [1, 2-a] pyridine (120 mg) and NCS in THF / EtOH (1/1) were stirred at 80 ° C. overnight. The solution was concentrated and the obtained residue was purified by silica gel column chromatography (CH ₃ OH / chloroform 0-5%) to obtain 3-chloro-5-methyl-6- {5- [3- (trifluoro) -4- (2, 2,2-trifluoro-1-methoxyethyl) phenyl] -1,2,4-oxadiazol-3-yl} imidazo [1,2-a] pyridine (45 mg) as a pale yellow solid.

Example 29

To a solution of 5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} imidazo [1,2- a] pyridine (150 mg) in ethanol was added NCS (67 mg) at room temperature, after which it was stirred at 80 ° C for 15 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hesane: EtOAc = 90: 10 to 75:25) to give 3-chloro-5- {5- [3- (trifluoromethyl) -4- (2,2,2- trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} imidazo [1,2-a] pyridine (110.4 mg) as a white solid. To a solution of 3-chloro-5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} imidazo [ 1,2-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 is for 1 hour, the mixture was concentrated under reduced pressure. The residue was triturated / washed with diisopropyl ether and then filtered off to obtain 3-chloro-5- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1, 2,4-oxadiazol-3-yl} imidazo [1,2-a] pyridine hydrochloride (102.6 mg) as a white solid.

Example 30

1- (2 - {[Tert-butyldimethylsilyl] oxy} ethyl) -4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2, 4-oxadiazol-3-yl} -1H-indole (60 mg) was dissolved in THF (1.2 ml), and TBAF (150 μl) was added thereto at 0 ° C, after which it was stirred at room temperature for 3, 0 hours Water (30 ml) was added to the reaction mixture, after which it was extracted three times with EtOAc (20 ml). The organic layer was combined, washed with brine, dried over anhydrous MgSO _4, and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform: CH ₃ OH = 100: 0 to 90:10) to obtain 2- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro -1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl-1H-indol-1-yl) ethanol (36.5 mg) as a white solid.

Example 31

To a solution of tert-butyl 4 - {[4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4-oxadiazole -3-yl) -1H-indol-1-yl] acetyl} piperazine-1-carboxylate (70.7 mg) in methylene chloride (1 ml) was added dropwise 10 equivalents of 4M HCl / dioxane, followed by stirring at room temperature in within 3 hours. After 5 hours, the reaction solution was concentrated. When diisopropyl ether was added, a white solid precipitated. The white solid was washed with IPE to give 1- (2-oxo-2-piperazin-1-yl-ethyl) -4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro- 1-methylethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H-indole hydrochloride (58.9 mg) as a light red solid.

The following tables show the structural formulas of the compounds of Examples. Ex: Example No.

Table 54 Etc.
No. Structure Etc.
No. Structure one

2

3

four

5

6

7

8

9

10

11/1

11/2

12

13

fourteen

fifteen

Table 55 Etc.
No. Structure Project No. Structure 16

17

eighteen

19

twenty

21

22

23

24

25

26

27

Table 56 Etc.
No. Structure Etc.
No. Structure 28

29th

thirty

31

32

33

34

35

36

37

38

39

40

41

Table 57 Etc.
No. Structure Etc.
No. Structure 42

43

44

45

46

47

48

49

fifty

51

52

53

54

55

Table 58 Etc.
No. Structure Etc.
No. Structure 56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

Table 59 Etc.
No. Structure Etc.
No. Structure 72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

Table 60 Etc.
No. Structure Etc.
No. Structure 88

89

90

91

92

93

94

95

96

97

98

99

one hundred

101

102

103

Table 61 Etc.
No. Structure Etc.
No. Structure 104

105

106

107

108

109

110

111

112

113

114

115

116

117

Table 62 Etc.
No. Structure Etc.
No. Structure 118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

Table 63 Etc.
No. Structure Etc.
No. Structure 134

135

136

137

138

139

140

141

142

143

144

145

146

147

Table 64 Etc.
No. Structure Etc.
No. Structure 148

149

150

151

152

153

154

155

156

157

158

159

160

161

Table 65 Etc.
No. Structure Etc.
No. Structure 162

163

164

165

166

167

168

169

170

171

172

173

174

175

Table 66 Etc.
No. Structure Project No. Structure 176

177

178

179

180

181

182

183

184

185

186

187

188

189

Table 67 Etc.
No. Structure Etc.
No. Structure 190

191

192

193

194

195

196

197

198

The following tables show the NMR data of the compounds of Examples. Tetramethylsilane was used as the internal standard and, unless stated otherwise, δ (ppm) of ¹ H-NMR signal is shown as measured in DMSO-d ₆ used as a solvent. Ref-Ex refers to Example No., which should be related to receipt.

Industrial use

The compound of the present invention is applicable as a medicine and, in particular, for the prevention and / or treatment of organ rejection during transplantation, bone marrow or tissue, autoimmune diseases, etc., since it has S1P ₁ agonistic activity.

Claims (16)

1. The compound of formula (I)
[Chem. 16]

or a pharmaceutically acceptable salt thereof,
where the characters have the following meanings:
ring a represents
[Chem. 17]

or

X is a single bond, —CH ₂ -, —NR ³ -, —O—, —S—,
R ¹ represents halogen, phenyl, pyridyl, (C ₃ -C ₈ ) cycloalkyl, or (C ₁ -C ₆ ) alkyl, or (C ₂ -C ₆ ) alkenyl, each of which may contain halogen, -CONH ₂ , phenyl or (C ₃ -C ₈ ) cycloalkyl as a substituent,
R ² represents —CN, —O— (C ₁ -C ₆ ) alkyl, —C (═O) H, halogen, or (C ₁ -C ₆ ) alkyl, which may be substituted with halogen or —OH,
R ³ can form morpholino or 1-pyrrolidinyl together with R ¹ and nitrogen, and when -X- is a single bond, R ¹ and R ² can in combination form a 5-membered ring and additionally contain (C ₁ -C ₆ ) alkyl as a substituent,
R ⁴ represents the following ring:
[Chem. eighteen]

,

,

,

,

,

,

,

,

,

or

where any one of the bonds from the ring is connected to the oxazole ring
R ⁵ represents —H, (C ₁ -C ₆ ) alkyl, which may be substituted by at least one group selected from the group consisting of —C (= O) NR ^X R ^Y , —NHR ^X and —OR ^X - ( C ₂ -C ₆ ) alkenyl-, -C (= O) H, -C (= O) NR ^X R ^Y ,
R ^X and R ^Y may be the same or different from each other and represent —H or (C ₁ –C ₆ ) alkyl. 2. The compound according to claim 1, which is depicted using the formula (II):
[Chem. 19]

or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R ¹ represents (C ₁ -C ₆ ) alkyl, which may contain halogen as a substituent. 4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, in which R ² is —CN, halogen or (C ₁ -C ₆ ) alkyl, which may be substituted with halogen or —OH. 5. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R ⁵ represents -H; or (C ₁ -C ₆ ) alkyl, which may be substituted with at least one —C (= O) NR ^X R ^Y. 6. The compound according to claim 2 or its pharmaceutically acceptable salt, in which X is a single bond, —CH ₂ - or —O—. 7. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R ⁴ represents the following ring:
[Chem. 20]

or

where any one of the bonds from the ring R ⁴ is connected to the oxadiazole ring. 8. The compound of formula (I)
[Chem. 16]

or its pharmaceutically acceptable salt, where the symbols have the following meanings:
ring a represents

X represents —O—,
R ¹ represents (C ₁ -C ₄ ) alkyl optionally substituted with F,
R ² represents halogen, —CN, or (C ₁ -C ₆ ) alkyl optionally substituted with halogen,
R ⁴ represents the following ring:
[Chem. eighteen]

where any one of the bonds from the ring is connected to the oxazole ring,
R ⁵ represents —H; (C ₁ -C ₆ ) alkyl optionally substituted with -C (= O) NR ^X R ^Y ,
R ^X represents —H; (C ₁ -C ₆ ) alkyl,
R ^Y represents —H. 9. A compound selected from the following:
5- (5- [3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl) -1,2,4-oxadiazol-3-yl) -1H-benzimidazole hydrochloride;
5- (5- [3- (trifluoromethyl) -4 - [(1R) -2,2,2-trifluoro-1-methylethoxy] phenyl) -1,2,4-oxadiazol-3-yl) -1H-benzimidazole hydrochloride;
6- {5- [3-bromo-4- (2,2,2-trifluoro-1-methylethoxy] phenyl) -1,2,4-oxadiazol-3-yl} -1H-benzimidazole hydrochloride;
5- (5- [4-phenoxy-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl) -1H-benzimidazole hydrochloride;
2- (4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy) phenyl) -1,2,4-oxadiazol-3-yl} -1H-indole- 1-yl) acetamide;
4- {5- [3- (trifluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy] phenyl) -1,2,4-oxadiazol-3-yl) -1H-pyrrolo [2,3 -b] pyridine hydrochloride;
6- {5- [3- (difluoromethyl) -4- (2,2,2-trifluoro-1-methylethoxy] phenyl) -1,2,4-oxadiazol-3-yl) -1H-benzimidazole hydrochloride;
2- (4- {5- [3-chloro-4- (2,2,2-trifluoro-1-methylethoxy) phenyl) -1,2,4-oxadiazol-3-yl} -1H-indole-1- sludge) acetamide;
2- (4- {5- [4-cyclopentyl-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl) acetamide;
2- [4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl) -1,2,4-oxadiazol-3-yl) - 1H-indol-1-yl) acetamide;
2- [4- (5- {4- [2-fluoro-1- (fluoromethyl) ethoxy] -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-3-yl) -1H-indol-1 -yl) acetamide;
2- (4- {5- [3-cyano-4- (2,2,2-trifluoro-1-methylethoxy) phenyl] -1,2,4-oxadiazol-3-yl} -1H-indol-1- sludge) acetamide;
N- (2-hydroxyethyl) -2- [4- (5- {3- (trifluoromethyl) -4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4 -oxadiazol-3-yl) -1H-indol-1-yl) acetamide;
2- [4- (5- {5-chloro-6 - [(1S) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl] -1,2,4-oxadiazol-3-yl ) -1H-indol-1-yl) acetamide;
2- [4- (5- {5-chloro-6- [2-fluoro-1- (fluoromethyl) ethoxy] pyridin-3-yl} -1,2,4-oxadiazol-3-yl) -1H-indole -1-yl) acetamide;
2- [4- (5- {3-chloro-4- [2-fluoro-1- (fluoromethyl) ethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl ) acetamide;
2- [4- (5- {3-methyl-4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H- indol-1-yl) acetamide;
2- (4- {5- [4-isopropyl-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl) acetamide;
2- {4- [5- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl] -1H-indol-1-yl) acetamide;
N- (2-hydroxyethyl) -2- [4- (5- {3-methyl-4 - [(1S) -2,2,2-trifluoro-1-methylethoxy] phenyl} -1,2,4-oxadiazole -3-yl) -1H-indol-1-yl) acetamide;
N- (2-hydroxyethyl) -2- (4- {5- [4-isopropoxy-3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl) acetamide; and
2- [4- (5- {3-chloro-4- [2-fluoro-1- (fluoromethyl) ethoxy] phenyl} -1,2,4-oxadiazol-3-yl) -1H-indol-1-yl ] -N- (2-hydroxyethyl) acetamide. 10. A pharmaceutical composition having an S1P ₁ agonist activity, comprising an effective amount of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier or excipient. 11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of rejection during organ / tissue transplantation in humans or animals, autoimmune diseases or multiple sclerosis. 12. An agent having S1P ₁ agonist activity, comprising a compound according to any one of claims _{1 to 9} , or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier or excipient. 13. A method for the treatment and / or prevention of rejection during transplantation of an organ / bone marrow / tissue in a human or animal, a graft versus host reaction or multiple sclerosis, said method comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -9 to a patient suffering from the aforementioned disease. 14. The use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and / or prevention of rejection during organ / bone marrow / tissue transplantation in humans or animals, graft versus host disease, or multiple sclerosis. 15. The use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of rejection during organ / bone marrow / tissue transplantation in humans or animals, graft versus host disease, or multiple sclerosis. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing rejection during transplantation of an organ / bone marrow / tissue in a human or animal, a graft versus host reaction, or multiple sclerosis.