JP5688918B2 - Pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition.

  Currently, it is said that there are more than 130 types of diseases called fibrosis, including rare diseases. Typical examples of such fibrosis include pulmonary fibrosis, liver fibrosis, glomerulosclerosis. Can be mentioned.

  Pulmonary fibrosis generally involves destruction of the alveolar structure by an inflammatory response, resulting in proliferation of fibroblasts and an excessive increase in the extracellular matrix, mainly collagen, causing the lung to harden. A group of diseases in which lung function is lost due to reconstructed lesions of the alveolar region.

  Hepatic fibrosis is an increase in extracellular matrix to replenish the site after necrosis of hepatocytes due to various liver disorders such as chronic viral hepatitis and alcoholic liver disorders, It refers to a pathological condition in which liver fibrosis occurs, and as an end image of this pathological condition, the entire liver fiber contracts and leads to cirrhosis that hardens.

  In order to suppress hepatic fibrosis, for example, penicillamine, which is known as a therapeutic agent for Wilkinson's disease in which copper accumulates in the liver due to abnormal copper metabolism and is studied as a proline hydroxylase inhibitor Drugs such as (Lufironil) are used.

  However, the above drugs are not sufficient as drugs for preventing liver fibrosis from the viewpoints of side effects and the like and effectiveness. Therefore, at present, there are currently no established therapeutic agents and fibrosis treatment methods that are effective for fibrosis such as liver fibrosis and how to specifically prevent the process of fibrosis. Research interests are on whether to do it.

  As described above, it is known that an excessive increase in the extracellular matrix mainly composed of collagen occurs in the process of causing fibrosis in lung tissue and hepatocytes. It is also known that the increase in extracellular matrix in hepatocytes occurs mainly in the sinusoidal Disse space, and Ito cells, which are mesenchymal cells in the liver, are the center of their production sources.

  Therefore, in order to suppress fibrosis in the liver, lung and the like, it is important to suppress an excessive increase in the extracellular matrix (that is, collagen).

  Patent Document 1 and Patent Document 2 have certain pyridine derivatives, and Patent Document 3 has certain benzene derivatives that have an effect of suppressing collagen production and are useful for fibrosis diseases. Is disclosed.

  However, there is still a strong demand for the development of a compound that is further excellent in the effect of suppressing the production of collagen, has few side effects, and is excellent in safety.

  On the other hand, in the field of cancer treatment, since the first use of nitrogen mustard as an antineoplastic agent in the world in the 1940s, many anticancer agents have been developed. For example, antimetabolite agents such as 5-fluorouracil, antitumor antibiotics such as adriamycin, platinum complexes such as cisplatin, and plant-derived anticancer agents such as vindesine are actually used clinically.

  However, since these anticancer agents are cytotoxic to normal cells, they often have serious side effects such as digestive disorders, bone marrow suppression, and hair loss. In most cases, the range that can be used for this side effect is limited, and the therapeutic effect itself is partial and short-term.

  Furthermore, many new anticancer agents have been developed to replace these anticancer agents, but no satisfactory results have been obtained at present.

Special Table 2002-507601 gazette JP 2001-89450 A JP 2001-89412 A

  An object of the present invention is to provide a pharmaceutical composition containing a novel compound that is remarkably excellent in suppressing the production of collagen and / or expresses an excellent tumor therapeutic effect particularly for malignant tumors.

  As a result of intensive studies to solve the above problems, the inventors of the present invention have a markedly excellent effect of suppressing the production of collagen by the heterocyclic compound represented by the following general formula (1) and a salt thereof, For example, the present inventors have found that it is useful as a preventive and therapeutic agent for fibrosis such as pulmonary fibrosis, liver fibrosis, and glomerulosclerosis. In addition, the present inventors have found that the compound represented by the following general formula (1) and a salt thereof have an excellent antitumor effect. The present invention has been completed based on such findings.

  The present invention provides a pharmaceutical composition comprising a heterocyclic compound represented by the following general formula (1) or a salt thereof.

  General formula (1)

[Wherein R ¹ is a group R ⁵ —Z ₁ —, a group R ⁵ —B—N (R ⁶ ) —, a group R ⁵ —N (R ⁶ ) —B—, a group R ⁵ —N (R ⁷ ) -, group ^{R 5 -N (R 8) -CO} -N (R 9) -, group ^{R 5 -N (R 10) -CS} -N (R 11) -, group ^R 5 _-SO 2 -N ( R ¹² ) —, group R ⁵ —CO—B ₁ —, group R ⁵ —B ₂ —CO—N (R ^12a ) —, group R ⁵ —B ₉ —SO ₂ —N (R ⁴⁷ ) —, group R ^5- O—B ₁₀ —SO ₂ —N (R ⁴⁸ ) — or a group

Indicates.
Z ₁ represents a lower alkylene group or a lower alkenylene group.
R ⁵ is a 5- to 15-membered monocyclic, binary or ternary saturated or unsaturated heterocyclic group having 1 to 4 nitrogen, oxygen or sulfur atoms (on the heterocyclic ring, oxo A lower alkoxy group having a halogen atom as a substituent; a lower alkyl group having a halogen atom as a substituent; a halogen atom; a lower alkylsulfonyl group; a lower alkyl group having a halogen atom on the phenyl ring; Phenyl group optionally substituted by alkyl group; lower alkylthio group; pyrrolyl group; benzoyl group; lower alkanoyl group; lower alkoxycarbonyl group; lower alkylenedioxy group; pyridyl group; and lower alkyl group and lower alkanoyl as substituents 1 to 3 groups selected from the group consisting of amino groups that may have a group selected from the group consisting of A group selected from the group consisting of a lower alkyl group, a cycloalkyl group, and a lower alkyl group on the naphthalene ring, a halogen atom and a lower alkyl group and a lower alkanoyl group as a substituent. A naphthyl group or group optionally substituted by 1 to 3 groups selected from the group of amino groups that may have

Indicates.
R ¹³ represents a hydrogen atom, a hydroxyl group, a carboxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom or a lower alkoxy group as a substituent, or a lower alkanoyloxy Group, lower alkoxycarbonyl group, lower alkoxycarbonyl group-substituted lower alkyl group, cyano group, phenyl group, nitro group, lower alkanoylamino group, lower alkylenedioxy group, phenoxy group, pyrazolyl group which may have a lower alkyl group, An oxazolyl group or a pyrrolyl group is shown.
m shows the integer of 1-5. If m represents 2-5, 2-5 of ^{R 13} may be the same or different.
R ⁴⁷ and R ⁴⁸ each represent a hydrogen atom or a lower alkyl group.
R ⁶ represents a hydrogen atom, a lower alkyl group which may have a lower alkoxy group as a substituent, a lower alkanoyl group, a lower alkylsulfonyl group or a phenyl lower alkyl group.
B represents a group —CO— or a lower alkylene group.
R ⁷ represents a hydrogen atom or a lower alkyl group.
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each represent a hydrogen atom or a lower alkyl group.
R ¹² and R ^12a each represent a hydrogen atom or a lower alkyl group.
B ₁ and B ₃ each represent a lower alkylene group.
n represents 0 or 1.
B ₂ represents a lower alkenylene group.
B ₉ represents a lower alkylene group or a lower alkenylene group.
B ₁₀ represents a lower alkylene group.
R ² represents a hydrogen atom or a lower alkyl group.
Y represents CH or N.
A ₁ represents a heterocyclic ring selected from the group consisting of an indolediyl group and an indolinediyl group. The heterocyclic ring may have one or more substituents.
T represents a group —N (R ¹⁴ ) —B ₄ —CO—, a group —B ₅ —CO— or a group —CO—.
R ¹⁴ represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, or a substituent. An amino-substituted lower alkanoyl group or lower alkylsulfonyl group which may have a lower alkyl group is shown.
B ₄ represents a lower alkylene group.
B ₅ represents a lower alkenylene group or a lower alkylene group which may have a hydroxyl group as a substituent.
R ³ represents a hydrogen atom or an alkyl group (on the alkyl group, a phenyl group or an amino group which may have a lower alkyl group may be substituted).
R ⁴ is (4-1) a lower alkyl group that may have a hydroxyl group as a substituent, and (4-2) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent. (4-3) a lower alkyl group on the phenyl ring; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; Alkyl group; phenyl lower alkyl group; lower alkynyl group; amino group which may have a lower alkyl group or lower alkylsulfonyl group as a substituent; lower alkylthio group; cycloalkyl group; phenylthio group; adamantyl group; Anilino group which may have a halogen atom as a group; a lower alkoxycarbonyl group; on the pyrrolidine ring A pyrrolidinyl group which may have an oxo group as a substituent; a phenyl group which may be substituted with 1 to 3 groups selected from the group consisting of a lower alkanoylamino group; a cyano group; and a phenoxy group, (4-4) From the group consisting of a halogen atom on the phenyl ring; a lower alkoxy group that may have a halogen atom as a substituent; a lower alkyl group; and a tetrazolyl group that may have a lower alkyl group or a lower alkoxy lower alkyl group as a substituent. 1 to 3 selected phenyl lower alkyl groups which may be substituted, (4-5) lower alkoxycarbonyl substituted lower alkyl group, (4-6) oxo group as a substituent on the tetrahydroquinoline ring, lower 1,2,3,4-tetrahydroquinolyl group which may have 1 to 3 groups selected from the group consisting of alkoxy groups and lower alkylenedioxy groups (4-7) a cycloalkyl lower alkyl group, (4-8) a pyridyl lower alkyl group, (4-9) an amino having a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent Group substituted lower alkyl group, (4-10) pyrrolidinyl lower alkyl group, (4-11) phenyl lower alkenyl group, (4-12) anilinocarbonyl lower which may have a lower alkyl group as a substituent on the phenyl ring A group consisting of an alkyl group, a (4-13) indolyl group, a (4-14) phenyl lower alkyl group which may have a lower alkyl group as a substituent on the piperazine ring and a lower alkylenedioxy group as a substituent on the phenyl ring A piperazinyl lower alkyl group which may have a group selected from: (4-15) an amidino lower alkyl group which may have a lower alkyl group as a substituent, (4-16) a fluorenyl group, (4-17) a carbazo A carbazolyl group which may have a lower alkyl group as a substituent on the ring, (4-18) cyano-substituted lower alkyl group or (4-19) 2,3-dihydrobenzo [d] imidazo [2,1-b ] Represents a thiazolyl group.
R ³ and R ⁴ , together with the nitrogen atom to which they are bonded, are bonded to each other via or not through another nitrogen atom or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring, or a group

May be formed. The saturated heterocyclic ring may have one or more substituents. ]

Examples of the substituent on the saturated heterocyclic ring formed by R ³ and R ⁴ include the groups shown in the following (1) to (32).
(1) A cyano group, a nitro group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group that may have a halogen atom or a lower alkoxy group as a substituent, and a halogen atom or a cycloalkyl group as a substituent. A lower alkoxy group, a hydroxyl group, an aminosulfonyl group which may have a lower alkyl group as a substituent, a lower alkylaminocarbonyl group, a tetrazolyl group which may have a lower alkyl group or a lower alkoxy lower alkyl group as a substituent, lower alkynyl Group, lower alkylsulfonyl group, lower alkylsulfonylamino group, 1,2,4-triazolyl group, imidazolyl group, piperidinyl group, thiadiazolyl group, and lower alkylenedioxy group which may have a halogen atom as a substituent. 1 to 3 Substituted a phenyl group optionally one or two with a lower alkyl group,
(2) The pyridine ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group as a substituent, a lower alkyl group that may have a hydroxyl group as a substituent, a halogen atom, a lower alkoxy group, and a cyano group. A pyridyl lower alkyl group,
(3) a pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring,
(4) a benzoyl group optionally selected from the group consisting of a cyano group, a lower alkoxy group and an amino group which may have a lower alkylsulfonyl group as a substituent on the phenyl ring;
(5) pyrimidinyl group,
(6) pyrazinyl group,
(7) a pyridyl group optionally having a lower alkyl group (which may be substituted with a halogen atom on the lower alkyl group);
(8) a lower alkoxycarbonyl group,
(9) a lower alkyl group which may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent,
(10) a phenyl group that may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom on the phenyl ring, a lower alkyl group that may have a halogen atom as a substituent, and a cyano group;
(11) A phenoxy group optionally having a lower alkoxy group (which may be substituted with a halogen atom on the lower alkoxy group),
(12) Group — (B ₆ CO) tN (R ¹⁵ ) R ¹⁶ (where B ₆ represents a lower alkylene group. T represents 0 or 1. R ¹⁵ and R ¹⁶ are the same. Or differently, a hydrogen atom; a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkyl group, a phenyl lower alkyl group that may have a lower alkoxy group on the phenyl ring, and a lower alkoxy group on the phenyl ring A phenyl group or a pyridyl group which may have, and R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are bonded are bonded to each other via or not through another nitrogen atom or oxygen atom to form a 6-membered A saturated heterocyclic ring may be formed, and 1 to 3 lower alkyl groups may be substituted on the heterocyclic ring).
(13) quinolyl lower alkyl group,
(14) a thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring (a lower alkyl group which may have a halogen atom as a substituent on the phenyl ring may be substituted),
(15) a benzimidazolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the benzimidazole ring,
(16) 1,2,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the 1,2,4-oxadiazole ring,
(17) a cycloalkyl lower alkyl group,
(18) tetrahydropyranyl group,
(19) a thienyl lower alkyl group which may have a lower alkyl group as a substituent on the thiophene ring,
(20) a hydroxyl group,
(21) an imidazolyl lower alkyl group optionally having 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom on the imidazole ring,
(22) benzothienyl group,
(23) 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring,
(24) isoxazolyl lower alkyl group optionally having 1 to 3 lower alkyl groups as substituents on the isoxazole ring,
(25) imidazo [2,1-b] thiazolyl lower alkyl group,
(26) 3,4-dihydro-2H-benzo [1,4] oxazinyl lower optionally having a lower alkyl group as a substituent on the 3,4-dihydro-2H-benzo [1,4] oxazine ring An alkyl group,
(27) A pyrazolyl lower alkyl group optionally having 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent on the pyrazole ring,
(28) a dihydropyridyl lower alkyl group which may have an oxo group as a substituent on the dihydropyridine ring,
(29) Morpholino lower alkyl group,
(30) a phenyl lower alkenyl group which may have a lower alkoxy group as a substituent on the phenyl ring,
(31) pyridylcarbonyl group, and
(32) N-oxide group Each of the substituents of the above (1) to (32) can be substituted on 1 to 3 on the heterocyclic ring. The substituents on the heterocycle may be the same or different.

R ³ and R ⁴ are 5- to 10-membered saturated or unsaturated heterocycles bonded to each other with or without other nitrogen or sulfur atoms, together with the nitrogen atom to which they are bonded,
The saturated heterocyclic ring is preferably a piperidine ring optionally having at least one substituent or a piperazine ring optionally having at least one substituent.

R ³ and R ⁴ are 5- to 10-membered saturated heterocycles bonded to each other together with or without other nitrogen atoms or sulfur atoms together with the nitrogen atom to which they are bonded, 1 benzyl group is substituted, and this benzyl group is substituted with a lower alkoxy group that may have a halogen atom; a benzyl group that may have a lower alkyl group that may have a halogen atom. It is preferable.

R ¹ is a group R ⁵ —SO ₂ —N (R ¹² ) — or a group R ⁵ —B—N (R ⁶ ) —.
(Wherein R ⁵ represents a group

Indicates.
m, B, R ¹³ , R ¹² and R ⁶ are the same as above)
It is preferable that

  Further, it is preferably used for suppressing the production of collagen.

  It is preferably used to treat and / or prevent diseases associated with fibrosis caused by excessive production of collagen.

  The disease involving fibrosis is preferably pulmonary fibrosis, liver fibrosis and / or glomerulosclerosis.

  It is also preferably used for treating and / or preventing tumors.

  The tumor is preferably a malignant tumor.

  The malignant tumor is preferably a solid tumor, lymphoma or leukemia.

  At least one childhood brain tumor selected from the group consisting of astrocytoma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, and ependymoma; glioma, glioma, meningioma, pituitary gland At least one adult brain tumor selected from the group consisting of adenomas and schwannomas; at least one selected from the group consisting of maxillary sinus cancer, pharyngeal cancer, laryngeal cancer, oral cancer, lip cancer, tongue cancer, and parotid gland cancer Species head and neck cancer; at least one breast cancer and tumor selected from the group consisting of small cell lung cancer, non-small cell lung cancer, thymoma and mesothelioma; esophageal cancer, liver cancer, primary liver cancer, gallbladder cancer, bile duct Cancer, stomach cancer, colon cancer, colon cancer, rectal cancer, anal cancer, pancreatic cancer and pancreatic endocrine tumor, at least one digestive cancer and tumor selected from the group consisting of: penile cancer, renal pelvis / ureteral cancer, renal cell cancer, Testicular cancer, prostate cancer, bladder cancer, Wilms tumor and urinary tract At least one urological cancer and tumor selected from the group consisting of skin cancer; vulvar cancer, cervical cancer, endometrial cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, breast cancer, ovarian cancer and ovary At least one gynecological cancer and tumor selected from the group consisting of germ cell tumors; adult and pediatric soft tissue sarcomas; at least one bone tumor selected from the group consisting of osteosarcomas and Ewing tumors; adrenocortical carcinoma and thyroid Cancer and tumor of at least one endocrine tissue selected from the group consisting of cancer; malignant lymphoma, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, plasma cell tumor, acute myeloid leukemia, acute lymphocytic leukemia, adult T At least one malignant lymphoma and leukemia selected from the group consisting of cellular leukemia lymphoma, chronic myelogenous leukemia and chronic lymphocytic leukemia; chronic myeloproliferative disorder, malignant melanoma It is preferred that the tumor and metastases of cancer; the squamous cell carcinoma, at least one cancer and tumors of the skin selected from the group consisting of basal cell carcinoma and mycosis fungoides.

  The present invention relates to the above general formula (1)

And a salt thereof as a pharmaceutical composition.

  Specifically, each group shown in this specification is as follows.

  Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethylethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, Examples thereof include linear or branched alkylene groups having 1 to 6 carbon atoms such as pentamethylene and hexamethylene groups.

  Examples of the lower alkenylene group include vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-pentene-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4 -Double bonds such as -hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, 1,4-hexadienylene group Examples thereof include 1 to 3 linear or branched alkenylene groups having 2 to 6 carbon atoms.

  Examples of the 5- to 15-membered monocyclic, binomial or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen, oxygen or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Pyridyl, 1,2,5,6-tetrahydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 1,2,3,4-tetrazolyl, thienyl Quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, 2H-pyrrolyl, pyrrolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl, furazanyl, carbostyril, 3,4-dihydro Carbostyryl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetra Droisoquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazoyl, acridinyl, chromanyl, isoindolinyl, isochrominyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl , 3-dihydrobenzo [b] furyl, benzothienyl, phenoxathiinyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thiantenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, isoxa Zolidinyl, thiazolyl, isothiazolyl, pyranyl, 2-thiazolinyl 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4 -Benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl, 1,4-dithiaphthalenyl, dibenz [b , E] azepine, 6,11-dihydro-5H-dibenz [b, e] azepine, imidazo [2,1-b] thiazolyl group and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  Examples of the lower alkyl group include 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl, 1-ethylpropyl, butyl, isobutyl, tert-butyl, isopentyl, pentyl, and hexyl groups. A linear or branched alkyl group can be mentioned.

  As the lower alkyl group which may have a halogen atom as a substituent, in addition to the lower alkyl group, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, dichloromethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5 A straight chain having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as -chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl group, etc. A branched alkyl group can be exemplified.

  Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups and the like. it can.

  Examples of the lower alkoxy group which may have a halogen atom or a lower alkoxy group as a substituent include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, trifluoromethoxy, trichloromethoxy, Chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3 -Dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyloxy, meso Xoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, tert-butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy, 1-ethoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy, 1 -Methoxypropoxy, 2-methoxypropoxy, 3-ethoxypropoxy, 4-methoxybutoxy, 4-ethoxybutoxy, 5-methoxypentyloxy, 3-isopropoxypropoxy, 6-methoxyhexyloxy, 6-ethoxyhexyloxy group, etc. Examples of the substituent include a halogen atom or a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms.

  As the lower alkyl group which may have a lower alkoxy group as a substituent, for example, in addition to the lower alkyl group, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-propoxyethyl, 3-isopropoxypropyl Carbon number as a substituent such as 4-butoxybutyl, 5-pentyloxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl, 2-methyl-3-ethoxypropyl, 3-methoxypropyl Mention may be made of linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 6 linear or branched alkoxy groups.

  Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups.

  Examples of the lower alkylsulfonyl group include straight chain or branched chain having 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, and hexylsulfonyl groups. Mention may be made of alkylsulfonyl groups.

  Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenyl. Examples thereof include a phenylalkyl group in which an alkyl moiety such as ethyl or 2-methyl-3-phenylpropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the indolediyl group represented by A ₁ include indole- (1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 2,3- 2,4-, 2,5-, 2,6-, 2,7-, 3,4-, 3,5-, 3,6-, 3,7-, 4,5-, 4,6- 4,7-, 5,6-, 5,7- or 6,7-) diyl groups.

Examples of the indolinediyl group represented by A ₁ include indoline- (1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 2,3- 2,4-, 2,5-, 2,6-, 2,7-, 3,4-, 3,5-, 3,6-, 3,7-, 4,5-, 4,6- 4,7-, 5,6-, 5,7- or 6,7-) diyl groups.

Examples of the substituent on the heterocyclic ring represented by A _1, for example, methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl, 1-ethylpropyl, butyl, isobutyl, tert- butyl, isopentyl, pentyl, Hexyl, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl, 5-pentyloxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl-2 1 to 6 carbon atoms having 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms such as -methoxyethyl, 2-methyl-3-ethoxypropyl and 3-methoxypropyl groups A linear or branched alkyl group or an oxo group can be mentioned. One to four of these substituents may be present on the heterocyclic ring. Further, when two or more of these substituents are substituted, these substituents may be the same or different.

  Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, and cyclohexadecyl groups. Examples thereof include cycloalkyl groups having 3 to 16 carbon atoms.

  Examples of the cycloalkylcarbonyl group include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, cyclononylcarbonyl, cyclodecylcarbonyl, cycloundecylcarbonyl, cyclododecylcarbonyl, cyclotridecyl Examples thereof include cycloalkylcarbonyl groups in which the cycloalkyl moiety such as carbonyl, cyclotetradecylcarbonyl, cyclopentadecylcarbonyl, cyclohexadecylcarbonyl group and the like is a cycloalkyl group having 3 to 16 carbon atoms.

  1 to 3 groups selected from the group consisting of amino groups which may have a lower alkyl group, a halogen atom and a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent on the naphthalene ring. Examples of the naphthyl group that may be used include (1- or 2-) naphthyl, 1-methyl- (2-, 3-, 4-, 5-, 6-, 7- or 8-) naphthyl, and 2-ethyl. -(1-, 3-, 4-, 5-, 6-, 7- or 8-) naphthyl, 3-n-propyl- (1-, 2-, 4-, 5-, 6-, 7- or 8-) naphthyl, 4-n-butyl- (1-, 2-, 3-, 5-, 6-, 7- or 8-) naphthyl, 4-methyl- (1-, 2-, 3--5 -, 6-, 7- or 8-) naphthyl, 5-n-pentyl- (1-, 2-, 3-, 4-, 6-, 7- or 8-) naphthy. 6-n-hexyl- (1-, 2-, 3-, 4-, 5-, 7- or 8-) naphthyl, 1,7-dimethyl- (2-, 3-, 4-, 5-, 6- or 8-) naphthyl, 1,2,8-trimethyl- (3-, 4-, 5-, 6- or 7-) naphthyl, 1-dimethylamino- (2-, 3-, 4--5 -, 6-, 7- or 8-) naphthyl, 2-dimethylamino- (1-, 3-, 4-, 5-, 6-, 7- or 8-) naphthyl, 3-methylamino- (1- 2-, 4-, 5-, 6-, 7- or 8-) naphthyl, 5-amino- (1-, 2-, 3-, 4-, 6-, 7- or 8-) naphthyl, 5 -Dimethylamino- (1-, 2-, 3-, 4-, 6-, 7- or 8-) naphthyl, 4- (N-methyl-N-ethylamino)-(1-, 2-, 3- , 5-, 6-, 7- or 8- Naphthyl, 1-methyl-2-dimethylamino- (3-, 4-, 5-, 6-, 7- or 8-) naphthyl, 1-chloro- (2-, 3-, 4-, 5-, 6 Carbon number as a substituent on a naphthalene ring such as-, 7- or 8-) naphthyl, 1-acetylamino- (2-, 3-, 4-, 5-, 6-, 7- or 8-) naphthyl group 1 to 6 linear or branched alkyl group, halogen atom, and linear or branched alkyl group having 1 to 6 carbon atoms and linear or branched alkanoyl having 1 to 6 carbon atoms as substituents Examples thereof include a naphthyl group which may have 1 to 3 groups selected from the group consisting of amino groups which may have 1 to 2 groups selected from the group consisting of groups.

  Examples of the lower alkanoyl group that may have a halogen atom as a substituent include, in addition to the lower alkanoyl group, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, 2-chloroacetyl, 2 -Bromoacetyl, 2-fluoroacetyl, 2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloro Propionyl, 2,3-dichloropropionyl, 4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl, 5,6- Carbon number which may have 1 to 3 halogen atoms as substituents such as dibromohexanoyl group It can be exemplified 6 straight or branched chain alkanoyl group.

  Examples of the lower alkenyl group include vinyl, 1-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2- Pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl , 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, 1,4-hexadienyl group, etc. Examples thereof include C2-C6 straight or branched alkenyl groups having 1 to 3 bonds.

  Examples of the amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent include aminoacetyl, 2-aminopropionyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, methylaminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl, 5 -Pentylaminopentanoyl, 6-hexylaminohexanoyl, dimethylaminoacetyl, 3-diisopropylaminopropionyl, (N-ethyl-N-propylamino) acetyl, 2- (N-methyl-N-hexylamino) acetyl group, etc. Examples of the substituent include a linear or branched alkanoyl group having 2 to 6 carbon atoms substituted with an amino group having 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms. .

  Examples of the lower alkylene group that may have a hydroxyl group as a substituent include, in addition to the lower alkylene group, 1-hydroxymethylene, 1-hydroxyethylene, 2-hydroxytrimethylene, 1-hydroxytrimethylene, 1-hydroxy. 2-methyltrimethylene, 1-hydroxy-2,2-dimethyltrimethylene, 3-hydroxy-1-methyltrimethylene, 2-hydroxy-1-methyltrimethylene, 1-hydroxymethylmethylene, hydroxymethylmethylene, 2 -Hydroxymethyltrimethylene, 2-hydroxymethyl-2-methyltrimethylene, (2-hydroxyethyl) methylene, (1-hydroxyethyl) methylene, 2-hydroxytetramethylene, 1-hydroxytetramethylene, 3-hydroxypentamethylene 2 Hydroxypentamethylene, 1-hydroxypentamethylene, 3-hydroxyhexamethylene, 2-hydroxyhexamethylene, 1-hydroxyhexamethylene, 1,2-dihydroxytrimethylene, 2,2,4-trihydroxytetramethylene, 1,2 A linear or branched alkylene group having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents such as 1,6-trihydroxyhexamethylene, 3,4,5-trihydroxypentamethylene group, etc. It can be illustrated.

  As an alkyl group (on the alkyl group, a phenyl group or an amino group which may have a lower alkyl group may be substituted), 1 to 3 phenyl groups or amino groups as substituents, Preferable examples include the lower alkyl group exemplified above which may be present. Here, the amino group may have 1 to 2 lower alkyl groups exemplified above. Specifically, such an alkyl group (on the alkyl group, an amino group which may have a phenyl group or a lower alkyl group may be substituted) includes methyl, ethyl, propyl, Isopropyl, 2,2-dimethylpropyl, 1-ethylpropyl, butyl, isobutyl, tert-butyl, isopentyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, pentadecanyl, hexadecanyl, heptadecanyl, Octadecanyl, nonadecanyl, icosanyl, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 7-phenylheptyl, 8-phenyloctyl, 9- Fe Lunonyl, 10-phenyldecanyl, 11-phenylundecanyl, 12-phenyldodecanyl, 13-phenyltridecanyl, 14-phenyltetradecanyl, 15-phenylpentadecanyl, 16-phenylhexadecanyl, 17 -Phenylheptadecanyl, 18-phenyloctadecanyl, 19-phenylnonadecanyl, 20-phenylicosanyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, 2-amino Ethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 7-aminoheptyl, 8-aminooctyl, 9-aminononyl, 10-aminodecanyl, 11-aminoundeca Nyl, 12-aminododecanyl, 13-aminotridecanyl, 1 -Aminotetradecanyl, 15-aminopentadecanyl, 16-aminohexadecanyl, 17-aminoheptadecanyl, 18-aminooctadecanyl, 19-aminononadecanyl, 20-aminoicosanyl, 1,1-dimethyl 2-aminoethyl, 2-methyl-3-aminopropyl, N-methylaminomethyl, 2- (N-methylamino) ethyl, 3- (N-methylamino) propyl, 4- (N-ethylamino) Benzyl, 5- (N-methylamino) pentyl, 6- (N-propylamino) hexyl, 3- (N, N-dimethylamino) propyl, 3- (N, N-diethylamino) propyl and the like.

  Examples of the lower alkyl group that may have a hydroxyl group as a substituent include, in addition to the lower alkyl group, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl group Examples of such a substituent include a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups.

  Examples of the cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent include, in addition to the cycloalkyl group, 2-hydroxycyclopropyl, 3-hydroxycyclobutyl, 3- Hydroxycyclopentyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycycloheptyl, 4-hydroxycyclooctyl, 5-hydroxycyclononyl, 3-hydroxycyclodecyl, 4-hydroxycycloundecyl, 5-hydroxycyclododecyl, 6-hydroxycyclotridecyl, 7-hydroxycyclotetradecyl, 6-hydroxycyclopentadecyl, 8-hydroxycyclohexadecyl, 2,4-dihydroxycyclohexyl, 2,4,6-trihydroxycyclo Xyl, 1-methylcyclopentyl, 2-ethylcyclopropyl, 3-n-propylcyclobutyl, 2-n-butylcyclohexyl, 4-n-pentylcycloheptyl, 4-n-hexylcyclooctyl, 2,3-dimethylcyclohexyl , A group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent such as 2,3,4-trimethylcyclohexyl and 2-methyl-4-hydroxycyclohexyl group. The C3-C16 cycloalkyl group which may have 3 is mentioned.

  Examples of the amino lower alkoxy group that may have a lower alkyl group as a substituent include aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6 -Aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butyl Aminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, 2-diethylaminoethoxy, 2-diisopropylaminoethoxy, (N-ethyl-N-propylamino) methoxy, 2- (N-methyl) -N-hex A straight chain or branched chain having 1 to 6 carbon atoms substituted by an amino group having 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms as a substituent such as an ethoxy group. An example of an alkoxy group.

  Examples of the hydroxyl group-substituted lower alkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl. 1 having 1 to 3 hydroxyl groups as substituents such as 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl and 2-methyl-3-hydroxypropyl groups -6 linear or branched alkyl groups can be illustrated.

  Examples of the lower alkynyl group include straight chain or branched groups having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl group and the like. A branched alkynyl group can be exemplified.

  Examples of the amino group which may have a lower alkyl group or a lower alkylsulfonyl group as a substituent include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethyl Amino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N- Hexylamino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino Dimethylsulfonylamino, diethylsulfonylamino, dipropylsulfonylamino, dibutylsulfonylamino, dipentylsulfonylamino, dihexylsulfonylamino, N-methylsulfonyl-N-ethylsulfonylamino, N-ethylsulfonyl-N-propylsulfonylamino, N -As a substituent such as methylsulfonyl-N-butylsulfonylamino, N-methylsulfonyl-N-hexylsulfonylamino, etc., a linear or branched alkyl group having 1 to 6 carbon atoms or a linear chain having 1 to 6 carbon atoms Or the amino group which may have 1-2 branched alkylsulfonyl groups can be illustrated.

  Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, and hexylthio groups.

  Examples of the anilino group which may have a halogen atom as a substituent on the phenyl ring include anilino, 2-fluoroanilino, 3-fluoroanilino, 4-fluoroanilino, 2-bromoanilino, 3-bromoanilino, 4 -Bromoanilino, 2-iodoanilino, 3-iodoanilino, 4-iodoanilino, 2,3-dibromoanilino, 2,4-diiodoanilino, 2,5-difluoroanilino, 2,6-dichloroanilino, 2,4,6 -Trichloroanilino, 2,6-difluoroanilino, 3,5-difluoroanilino, 2,6-difluoroanilino, 2-chloroanilino, 3-chloroanilino, 4-chloroanilino, 2,3-dichloroanilino, 2 , 4-dichloroanilino, 2,5-dichloroanilino, 3,4-dichloroanilino, 1,6-dichloroanilino, 3,5-dichloroanilino, 2,4,6-trifluoroanilino, 2,4-difluoroanilino, substituents on the phenyl ring such as 3,4-difluoroanilino As an example, an anilino group having 1 to 3 halogen atoms can be exemplified.

  Examples of the lower alkoxycarbonyl group include linear or branched groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group and the like. Mention may be made of branched alkoxycarbonyl groups.

  Examples of the pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring include (1-, 2- or 3-) pyrrolidinyl, 2-oxo- (1-, 3-, 4- or 5-). Pyrrolidinyl, 3-oxo- (1-, 2-, 4- or 5-) pyrrolidinyl, 2,3-dioxo- (1-, 4- or 5-) pyrrolidinyl, 2,5-dioxo- (1--3 -Or 4-) The pyrrolidinyl group which may have 1-2 oxo groups as a substituent on pyrrolidine rings, such as a pyrrolidinyl group, can be illustrated.

  Examples of the lower alkanoylamino group include linear or branched alkanoylamino groups having 2 to 6 carbon atoms such as acetylamino, propionylamino, butyrylamino, pentanoylamino, 2-methylpropionylamino, and hexanoylamino groups. It can be illustrated.

  A lower alkyl group on the phenyl ring; a lower alkoxy group which may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group which may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl A lower alkynyl group; an amino group which may have a lower alkyl group or a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; A group selected from the group consisting of a lower alkoxycarbonyl group; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group. Phenyl optionally substituted As, for example, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 3-butyl Phenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4 , 5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyl Oxyphenyl, 4-hexyloxyphenyl, , 4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxy Phenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2- (bromomethoxy) phenyl, 3- (2-chloroethoxy) phenyl, 4- (2,3-dichloropropoxy) phenyl, 4- (4 -Fluorobutoxy) phenyl, 3- (5-chloropentyloxy) phenyl, 4- (5-bromohexyloxy) phenyl, 4- (5,6-dibromohexyloxy) phenyl, 3,4-di (trifluoromethoxy) ) Phenyl, 3,4-di (4,4,4-trichlorobutoxy) phenyl, 2,4-di ( 3-chloro-2-methoxypropyl) phenyl, 2,5-di (3-chloropropoxy) phenyl, 2,6-di (2,2,2-trifluoroethoxy) phenyl, 3,4,5-tri ( Trifluoromethoxy) phenyl, 4- (2,2,2-trichloroethoxy) phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxy Phenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2,3-diphenoxy Phenyl, 3,4-diphenoxyphenyl, 2,6-diphenoxyphenyl, 3,4 5-triphenoxyphenyl, 2-methyl-4-phenoxyphenyl, 3-ethyl-4-phenoxyphenyl, 2-methoxy-4-phenoxyphenyl, 3-ethoxy-4-phenoxyphenyl, 2-methyl-3-phenoxy- 4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3 , 5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, , 6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3- Dibromophenyl, 2,4-diiodophenyl, 4-methylthiophenyl, 4-cyclohexylphenyl, 4-chloro-2-anilinophenyl, 2- (4-chloroanilino) -5-ethoxycarbonylphenyl, 4- [2- (N, N-diethylamino) ethoxy] phenyl, 4- (2-oxo-1-pyrrolidinyl) phenyl, 4-methylaminophenyl, 4-methylsulfonylaminophenyl, 4- (2-hydroxyethyl) phenyl, 4-benzyl Phenyl, 4-ethynylphenyl, 4-phenylthiophenyl, 4- (1-adama) Nthyl) phenyl, 5-acetylamino-2-chlorophenyl, 2-propanoylaminophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-cyanophenyl, 3,4-dicyanophenyl, 3,4,5-tricyano A linear or branched alkyl group having 1 to 6 carbon atoms on a phenyl ring such as a phenyl group, or a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms , A halogen atom or an alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, and has 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms as a substituent. An aminoalkoxy group, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as a substituent, and a linear or branched alkyl group having 1 to 6 carbon atoms Alkyl A phenylalkyl group, a linear or branched alkynyl group having 2 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms or a linear chain having 1 to 6 carbon atoms as a substituent, Amino group having 1 to 2 branched alkylsulfonyl groups, linear or branched alkylthio group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 16 carbon atoms, phenylthio group, adamantyl group , An anilino group having 1 to 3 halogen atoms as substituents on the phenyl ring, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, and an oxo group as a substituent on the pyrrolidine ring. 1 to 3 groups selected from the group consisting of a pyrrolidinyl group that may have 2 or 2 amino groups, an amino group that has 1 to 2 linear or branched alkanoyl groups having 2 to 6 carbon atoms, a cyano group, and a phenoxy group Replace The phenyl group which may be exemplified.

  Examples of the lower alkoxy lower alkyl group include methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl, 5-pentyloxypentyl, and 6-hexyloxyhexyl. , 1,1-dimethyl-2-methoxyethyl, 2-methyl-3-ethoxypropyl, a carbon number having a straight or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as 3-methoxypropyl group Mention may be made of 1 to 6 linear or branched alkyl groups.

  Examples of the tetrazolyl group optionally having a lower alkyl group or a lower alkoxy lower alkyl group as a substituent include (1- or 5-) tetrazolyl, 1-methyltetrazol-5-yl, 5-methyltetrazol-1 -Yl, 1-ethyltetrazol-5-yl, 5-ethyltetrazol-1-yl, 1-propyltetrazol-5-yl, 5-propyltetrazol-1-yl, 1-isopropyltetrazol-5-yl, 5- Isopropyltetrazol-1-yl, 1- (2,2-dimethylpropyl) tetrazol-5-yl, 5- (2,2-dimethylpropyl) tetrazol-1-yl, 1- (1-ethylpropyl) tetrazole-5 -Yl, 5- (1-ethylpropyl) tetrazol-1-yl, 1-butyltetrazol-5- 5-butyltetrazol-1-yl, 1-isobutyltetrazol-5-yl, 5-isobutyltetrazol-1-yl, 1-tert-butyltetrazol-5-yl, 5-tert-butyltetrazol-1-yl 1-isopentyltetrazol-5-yl, 5-isopentyltetrazol-1-yl, 1-pentyltetrazol-5-yl, 5-pentyltetrazol-1-yl, 1-hexyltetrazol-5-yl, 5- Hexyltetrazol-1-yl, 1-methoxymethyltetrazol-5-yl, 5-methoxymethyltetrazol-1-yl, 1- (1-ethoxyethyl) tetrazol-5-yl, 5- (1-ethoxyethyl) tetrazole -1-yl, 1- (2-methoxyethyl) tetrazol-5-yl, 5- 2-methoxyethyl) tetrazol-1-yl, 1- (2-propoxyethyl) tetrazol-5-yl, 5- (2-propoxyethyl) tetrazol-1-yl, 1- (3-isopropoxypropyl) tetrazole- 5-yl, 5- (3-isopropoxypropyl) tetrazol-1-yl, 1- (4-butoxybutyl) tetrazol-5-yl, 5- (4-butoxybutyl) tetrazol-1-yl, 1- ( 5-pentyloxypentyl) tetrazol-5-yl, 5- (5-pentyloxypentyl) tetrazol-1-yl, 1- (6-hexyloxyhexyl) tetrazol-5-yl, 5- (6-hexyloxyhexyl) ) Tetrazol-1-yl, 1- (1,1-dimethyl-2-methoxyethyl) tetrazol-5-yl, 5 -(1,1-dimethyl-2-methoxyethyl) tetrazol-1-yl, 1- (2-methyl-3-ethoxypropyl) tetrazol-5-yl, 5- (2-methyl-3-ethoxypropyl) tetrazole The exemplified lower alkyl group or the exemplified lower alkoxy lower alkyl group such as -1-yl, 1- (3-methoxypropyl) tetrazol-5-yl, 5- (3-methoxypropyl) tetrazol-1-yl group, etc. The tetrazolyl group which may have one is mentioned.

  From the group consisting of a halogen atom on the phenyl ring; a lower alkoxy group optionally having a halogen atom as a substituent; a lower alkyl group; and a tetrazolyl group optionally having a lower alkyl group or a lower alkoxy lower alkyl group as a substituent Examples of the phenyl lower alkyl group which may be substituted by 1 to 3 selected groups include, in addition to the phenyl lower alkyl group, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4- Chlorobenzyl, 2- (2-fluorophenyl) ethyl, 2- (4-fluorophenyl) ethyl, 2- (4-chlorophenyl) ethyl, 3,4-dibromobenzyl, 3,4-diiodobenzyl, 2,4 -Difluorobenzyl, 2,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4,5-trifluoro Benzyl, 3- (4-chlorophenyl) propyl, 1- (2-bromophenyl) ethyl, 4- (3-fluorophenyl) butyl, 5- (4-iodophenyl) pentyl, 6- (4-chlorophenyl) hexyl, 1,1-dimethyl-2- (3-fluorophenyl) ethyl, 2-methyl-3- (4-chlorophenyl) propyl, 2-methylbenzyl, 2- (3-methylphenyl) ethyl, 3- (4-methyl Phenyl) propyl, 1- (2-ethylphenyl) ethyl, 4- (3-ethylphenyl) butyl, 5- (4-ethylphenyl) pentyl, 6- (4-isopropylphenyl) hexyl, 1,1-dimethyl- 2- (3-butylphenyl) ethyl, 2-methyl-3- (4-pentylphenyl) propyl, 4-hexylbenzyl, 3,4-dimethyl Benzyl, 3,4-diethylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2,6-dimethylbenzyl, 3,4,5-trimethylbenzyl, 2-methoxybenzyl, 2- (2-methoxy Phenyl) ethyl, 2- (3-methoxyphenyl) ethyl, 2- (4-methoxyphenyl) ethyl, 4-methoxybenzyl, 1- (2-ethoxyphenyl) ethyl, 3- (3-ethoxyphenyl) propyl, 4 -(4-Ethoxyphenyl) butyl, 5- (4-isopropoxyphenyl) pentyl, 6- (3-butoxyphenyl) hexyl, 1,1-dimethyl-2- (4-pentyloxyphenyl) ethyl, 2-methyl -3- (4-hexyloxyphenyl) propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4 -Dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2 -[2- (bromomethoxy) phenyl] ethyl, 1- [3- (2-chloroethoxy) phenyl] ethyl, 3- [4- (2,3-dichloropropoxy) phenyl] propyl, 4- [4- ( 4-fluorobutoxy) phenyl] butyl, 5- [3- (5-chloropentyloxy) phenyl] pentyl, 6- [4- (5-bromohexyloxy) phenyl] hexyl, 1,1-dimethyl-2- [ 4- (5,6-dibromohexyloxy) phenyl] ethyl, 3,4-di (trifluoromethoxy) benzyl, 3, -Di (4,4,4-trichlorobutoxy) benzyl, 2,4-di (3-chloro-2-methoxypropyl) benzyl, 2,5-di (3-chloropropoxy) benzyl, 2,6-di ( 2,2,2-trifluoroethoxy) benzyl, 3,4,5-tri (trifluoromethoxy) benzyl, 4- (2,2,2-trichloroethoxy) benzyl, 2-methyl-4-trifluoromethoxybenzyl 3-ethyl-4-trichloromethoxybenzyl, 2-methoxy-4-trifluoromethoxybenzyl, 3-ethoxy-4-trichloromethoxybenzyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxybenzyl, 2 -Chloro-3-methylbenzyl, 4-fluoro-2-trifluoromethoxybenzyl, 3-chloro-2-methyl-4 Methoxybenzyl, (1- or 5-) tetrazolylbenzyl, 1-methyltetrazol-5-ylbenzyl, 5-methyltetrazol-1-ylbenzyl, 1-ethyltetrazol-5-ylbenzyl, 5-ethyltetrazol-1-ylbenzyl Halogen on the phenyl ring such as 5-pentyltetrazol-1-ylbenzyl, 1-hexyltetrazol-5-ylbenzyl, 5-methoxymethyltetrazol-1-ylbenzyl, 1- (1-ethoxyethyl) tetrazol-5-ylbenzyl group C1-C6 linear or branched alkoxy group having 1 to 3 halogen atoms as atoms and substituents, C1-C6 linear or branched alkyl group and substituent As a linear or branched alkyl group having 1 to 6 carbon atoms, 1 to 3 groups selected from the group consisting of tetrazolyl groups which may have a branched alkoxy group may be substituted, and the alkyl moiety is a straight chain or branched chain having 1 to 6 carbon atoms And a phenylalkyl group which is an alkyl group.

  Examples of the lower alkoxycarbonyl-substituted lower alkyl group include methoxycarbonylmethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-propoxycarbonylethyl, 3-isopropoxycarbonylpropyl, 4-butoxycarbonylbutyl, 5-pentyl. Oxycarbonylpentyl, 6-hexyloxycarbonylhexyl, 1,1-dimethyl-2-methoxycarbonylethyl, 2-methyl-3-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 6,6,6-trimethoxycarbonylhexyl group As examples of the substituent, the linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 carbonyl groups having a linear or branched alkoxy group having 1 to 6 carbon atoms may be mentioned. Can do.

  As a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent on the tetrahydroquinoline ring Is, for example, (1,2,3,4,5,6,7 or 8-) 1,2,3,4-tetrahydroquinolyl, 2-oxo- (1,3,4,5,6,7 Or 8-) 1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-methylenedioxy- (1,3,4,5 or 8-) 1,2,3,4-tetrahydroquino Lyl, 4-oxo- (1,2,3,5,6,7 or 8-) 1,2,3,4-tetrahydroquinolyl, 2,4-dioxo- (1,3,5,6,7 Or 8-) 1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-6,7-methylenedio Ci- (1,3,5 or 8-) 1,2,3,4-tetrahydroquinolyl, 5,6-ethylenedioxy- (1,2,3,4,7 or 8-) 1,2, 3,4-tetrahydroquinolyl, 7,8-trimethylenedioxy- (1,2,3,4,5 or 6-) 1,2,3,4-tetrahydroquinolyl, 6,7-tetramethylenedi Oxy- (1,2,3,4,5 or 8-) 1,2,3,4-tetrahydroquinolyl, 5-methoxy-2-oxo- (1,3,4,6,7 or 8-) 1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-ethylenedioxy- (1,3,4,5 or 8-) 1,2,3,4-tetrahydroquinolyl group, etc. An oxo group as a substituent on the tetrahydroquinoline ring, a linear or branched alkoxy group having 1 to 6 carbon atoms, and 1 to 4 carbon atoms The chain or branched alkylenedioxy group consisting group selected from the group which may have 1 to 3 1,2,3,4-tetrahydroquinolyl group may be exemplified.

  Examples of the cycloalkyl lower alkyl group include cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, and 6-cyclooctylhexyl. 1,1-dimethyl-2-cyclononylethyl, 2-methyl-3-cyclodecylpropyl, cycloundecylmethyl, 2-cyclododecylethyl, 1-cyclotridecylethyl, 3-cyclotetradecylpropyl, 4- Examples thereof include a cycloalkylalkyl group having 3 to 16 carbon atoms in which an alkyl moiety such as cyclopentadecylbutyl and 5-cyclohexadecylpentyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the pyridyl lower alkyl group include (2,3 or 4-) pyridylmethyl, 2-[(2,3 or 4-) pyridyl] ethyl, 1-[(2,3 or 4-) pyridyl] ethyl, 3-[(2,3 or 4-) pyridyl] propyl, 4-[(2,3 or 4-) pyridyl] butyl, 1,1-dimethyl-2-[(2,3 or 4-) pyridyl] ethyl , 5-[(2,3 or 4-) pyridyl] pentyl, 6-[(2,3 or 4-) pyridyl] hexyl, 1-[(2,3 or 4-) pyridyl] isopropyl, 2-methyl- Examples include a pyridylalkyl group in which an alkyl moiety such as a 3-[(2,3 or 4-) pyridyl] propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the amino group-substituted lower alkyl group which may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent include, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylamino Ethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino) methyl, 2- (N, N-dimethylamino) ethyl, 2- (N-methyl-N-he Silamino) ethyl, formylaminomethyl, acetylaminomethyl, 1-propionylaminoethyl, 2-acetylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylaminobutyl, 5-hexanoylaminopentyl, 6-acetylaminohexyl , N-methyl-N-acetylaminomethyl, 2- (N-ethyl-N-propanoylamino) ethyl, (N-ethyl-N-butyrylamino) methyl, 2- (N-methyl-N-hexanoylamino) C1-C6 linear or branched alkyl group and C1-C6 linear or branched alkanoyl group as substituents such as ethyl and 3- (N, N-dimethylamino) propyl group A linear or branched alkyl group having 1 to 6 carbon atoms and having an amino group which may have 1 to 2 groups selected from the group consisting of It can be exemplified.

  Examples of the pyrrolidinyl lower alkyl group include (1-, 2- or 3-) pyrrolidinylmethyl, 2-[(1-, 2- or 3-) pyrrolidinyl] ethyl, 1-[(1-, 2- Or 3-) pyrrolidinyl] ethyl, 3-[(1-, 2- or 3-) pyrrolidinyl] propyl, 4-[(1-, 2- or 3-) pyrrolidinyl] butyl, 5-[(1-2, -Or 3-) pyrrolidinyl] pentyl, 6-[(1-, 2- or 3-) pyrrolidinyl] hexyl, 1,1-dimethyl-2-[(1-, 2- or 3-) pyrrolidinyl] ethyl, 2 Mentioning a pyrrolidinylalkyl group in which the alkyl moiety such as -methyl-3-[(1-, 2- or 3-) pyrrolidinyl] propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. Can do.

  Examples of the phenyl lower alkenyl group include styryl, 3-phenyl-2-propenyl group (common name: cinnamyl group), 4-phenyl-2-butenyl group, 4-phenyl-3-butenyl group, and 5-phenyl-4. -Pentenyl group, 5-phenyl-3-pentenyl group, 6-phenyl-5-hexenyl group, 6-phenyl-4-hexenyl group, 6-phenyl-3-hexenyl group, 4-phenyl-1,3-butadienyl group Phenylalkenyl having an alkenyl moiety such as a 6-phenyl-1,3,5-hexatrienyl group, which is a linear or branched alkenyl group having 2 to 6 carbon atoms and having 1 to 3 double bonds A group can be exemplified.

  Examples of the anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring include anilinocarbonylmethyl, 2-anilinocarbonylethyl, 1-anilinocarbonylethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl, 5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, 2-methyl-3-anilinocarbonylpropyl, (4-methylani Linocarbonyl) methyl, 2- (3-methylanilinocarbonyl) ethyl, 3- (4-methylanilinocarbonyl) propyl, 1- (2-ethylanilinocarbonyl) ethyl, 4- (3-ethylanilinocarbonyl) ) Butyl, 5- (4-ethylanilinocarbonyl) pentyl 6- (4-Isopropylanilinocarbonyl) hexyl, 1,1-dimethyl-2- (3-butylanilinocarbonyl) ethyl, 2-methyl-3- (4-pentylanilinocarbonyl) propyl, 4-hexylani Linocarbonylmethyl, 3,4-dimethylanilinocarbonylmethyl, 3,4-diethylanilinocarbonylmethyl, 2,4-dimethylanilinocarbonylmethyl, 2,5-dimethylanilinocarbonylmethyl, 2,6-dimethylani The alkyl moiety such as linocarbonylmethyl, 3,4,5-trimethylanilinocarbonylmethyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and has 1 to 1 carbon atoms as a substituent on the phenyl ring. Illustrative of an anilinocarbonylalkyl group, which may have 1 to 3 linear or branched alkyl groups of 6 That.

  As a piperazinyl lower alkyl group which may have a group selected from the group consisting of a lower alkyl group as a substituent on the piperazine ring and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, For example, [(1-, 2- or 3-) piperazinyl] methyl, 2-[(1-, 2- or 3-) piperazinyl] ethyl, 1-[(1-, 2- or 3-) piperazinyl] Ethyl, 3-[(1-, 2- or 3-) piperazinyl] propyl, 4-[(1-, 2- or 3-) piperazinyl] butyl, 5-[(1-, 2- or 3-) piperazinyl ] Pentyl, 6-[(1-, 2- or 3-) piperazinyl] hexyl, 1,1-dimethyl-2-[(1-, 2- or 3-) piperazinyl] ethyl, 2-methyl-3- [ (1-2 Or 3-) piperazinyl] propyl, [1-methyl- (2-, 3- or 4-) piperazinyl] methyl, 2- [1-ethyl- (2-, 3- or 4-) piperazinyl] ethyl, 1- [4-propyl- (1-, 2-, or 3-) piperazinyl] ethyl, 3- [3-isopropyl- (1-, 2-, 4-, 5- or 6-) piperazinyl] propyl, 4- [ 2-butyl- (1-, 3-, 4-, 5- or 6-) piperazinyl] butyl, 5- [1-isobutyl- (2-, 3- or 4-) piperazinyl] pentyl, 3- [4- Methyl- (1-, 2-, or 3-) piperazinyl] propyl, 6- [1-tert-butyl- (2-, 3- or 4-) piperazinyl] hexyl, 1,1-dimethyl-2- [4 -Pentyl- (1-, 2- or 3-) piperazinyl] ethyl [1,2-dimethyl- (3-, 4-, 5- or 6-) piperazinyl] methyl, [1,2,6-trimethyl- (3-, 4- or 5-) piperazinyl] methyl, 2- [ An alkyl moiety such as 4- (3,4-methylenedioxybenzyl)-(1-, 2- or 3-) piperazinyl] ethyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, It has a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the piperazine ring and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring. And a piperazinylalkyl group having 1 to 3 groups selected from the group consisting of phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms. .

  Examples of the amidino lower alkyl group which may have a lower alkyl group as a substituent include amidinomethyl, 2-amidinoethyl, 1-amidinoethyl, 3-amidinopropyl, 4-amidinobutyl, 5-amidinopentyl and 6-amidino. Hexyl, 1,1-dimethyl-2-amidinoethyl, 2-methyl-3-amidinopropyl, N, N-dimethylamidinomethyl, 2- (N, N-dimethylamidino) ethyl, 1- (N-methylamidino) Ethyl, 3- (N-ethylamidino) propyl, 4- (Nn-propylamidino) propyl, 5- (Nn-pentylamidino) pentyl, 6- (Nn-hexylamidino) hexyl, (N -Methyl-N-ethylamidino) An alkyl moiety such as a methyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. Ri, can be exemplified amidino alkyl group which may have one or two straight-chain or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the carbazolyl group which may have a lower alkyl group as a substituent on the carbazole ring include (1-, 2-, 3- or 4-) carbazolyl, 9-methyl- (1-, 2-, 3- Or 4-) carbazolyl, 9-ethyl- (1-, 2-, 3- or 4-) carbazolyl, 1-ethyl- (2-, 3-, 4-, 5-, 6-, 7-, 8- Or 9-) carbazolyl, 2-n-propyl- (1-, 3-, 4-, 5-, 6-, 8- or 9-) carbazolyl, 3-n-butyl- (1-, 2-, 4 -, 5-, 6-, 7-, 8- or 9-) carbazolyl, 4-n-pentyl- (1-, 2-, 3-, 5-, 6-, 7-, 8- or 9-) Carbazolyl, 5-n-hexyl- (1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-) carbazolyl, 6,9-dimethyl (1-, 2-, 3-, 4-, 5-, 7- or 8-) carbazolyl, 1,7,8-trityl- (2-, 3-, 4-, 5-, 6-, 7- An carbazolyl group that may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on a carbazole ring such as a carbazolyl group.

  The cyano-substituted lower alkyl group includes cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl, 2-methyl. A cyanoalkyl group in which an alkyl moiety such as a -3-cyanopropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms can be given.

The 5- to 10-membered saturated heterocyclic group formed by bonding to each other with or without a nitrogen atom or a sulfur atom together with the nitrogen atom to which R ³ and R ⁴ are bonded is, for example, 1, 2, 3,4,5,6-hexahydropyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, thiomorpholino, homopiperazinyl, homopiperidinyl, 6-azabicyclo [3,2,1] octyl, 3-aza-spiro [5,5] undecyl, thiazolidinyl Examples include groups.

On the phenyl ring, selected from the group consisting of a cyano group, a nitro group, a halogen atom as a substituent, a lower alkyl group that may have a halogen atom or a lower alkoxy group as a substituent, and a halogen atom and a cycloalkyl group as a substituent. A lower alkoxy group which may have a group, a hydroxyl group, an aminosulfonyl group which may have a lower alkyl group as a substituent, a lower alkylaminocarbonyl group, a lower alkyl group or a lower alkoxy lower alkyl group which may have a substituent Tetrazolyl group, lower alkynyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, 1,2,4-triazolyl group, imidazolyl group, piperidinyl group, thiadiazolyl group and lower alkylenedioxy which may have a halogen atom as a substituent Is it an underlying group Examples of the phenyl-substituted lower alkyl group having 1 to 2 phenyl groups optionally substituted by 1 to 3 groups include, for example, 1,1-diphenylmethyl, 1,1 in addition to the phenyl lower alkyl group. -Di (4-fluorophenyl) methyl, 1-phenyl-1- (4-methoxyphenyl) methyl, 3,4-methylenedioxybenzyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxy Benzyl, (2,2-difluorobenzo [1,3] dioxol-5-yl) methyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, (2 -, 3- or 4-) methoxymethylbenzyl, 3- (1-ethoxyethyl) benzyl, 4- (2-methoxyethyl) benzyl, 2- (2-propoxyethyl) benzyl, 3- (3-isopropoxypropyl) ) Benzyl, 4- (4-butoxybutyl) benzyl, 2- (5-pentyloxypentyl) benzyl, 3- (6-hexyloxyhexyl) benzyl, 4- (1,1-dimethyl-2-methoxyethyl) benzyl 2- (2-methyl-3-ethoxypropyl) benzyl, 3- (3-methoxypropyl) benzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4 -Chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, (2-, 3- or 4-) isobu Rubenzyl, (2-, 3- or 4-) octylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, (2-, 3- or 4-) ethoxy Benzyl, (2-, 3- or 4-) propoxybenzyl, (2-, 3- or 4-) isopropoxybenzyl, (2-, 3- or 4-) (3-methylbutoxy) benzyl, (2- , 3- or 4-) cyclopropylmethoxybenzyl, (2-, 3- or 4-) 2-fluoroethoxybenzyl, (2-, 3- or 4-) 2,2,2-trifluoroethoxybenzyl, ( 2-, 3- or 4-) difluoromethoxybenzyl, (2-, 3- or 4-) 2,2-difluoroethoxybenzyl, (2-, 3- or 4-) (2-fluoro-1-fluoromethyl) Toxi) benzyl, (2-, 3- or 4-) 1,1,2,2-tetrafluoroethoxybenzyl, 3-methoxy-4- (2,2-difluoroethoxy) benzyl, (2-, 3- or 4-) propylbenzyl, (2-, 3- or 4-) [1,2,3] thiadiazol-4-ylbenzyl, 2-fluoro-4-isopropoxybenzyl, 3-fluoro-4-isopropoxybenzyl, 4 -Cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6 -Dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl , 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, (2-, 3- or 4-) isopropylbenzyl, 4-methoxy -3-chlorobenzyl, 2- (4-methoxyphenyl) ethyl, 2- (4-fluorophenyl) ethyl, 2- (4-chlorophenyl) ethyl, 2- (3-methoxyphenyl) ethyl, 2- (4- Methylphenyl) ethyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4- (4-methoxyphenyl) butyl, 2- (4-methylphenyl) ethyl, 3-chloro-6-methoxybenzyl, 4-nitro-3-methylbenzyl, 4-hydroxybenzyl, 3-hydroxybenzyl, 2-hydroxy Benzyl, 2- (2-cyanophenyl) ethyl, 1- (3-cyanophenyl) ethyl, 3- (4-cyanophenyl) propyl, 4- (2-cyanophenyl) butyl, 5- (3-cyanophenyl) Pentyl, 6- (4-cyanophenyl) hexyl, 1,1-dimethyl-2- (2,4-dicyanophenyl) ethyl, 2-methyl-3- (2,4,6-tricyanophenyl) propyl, 2 -(2-nitrophenyl) ethyl, 1- (3-nitrophenyl) ethyl, 3- (4-nitrophenyl) propyl, 4- (2-nitrophenyl) butyl, 5- (3-nitrophenyl) pentyl, 6 -(4-nitrophenyl) hexyl, 1,1-dimethyl-2- (2,4-dinitrophenyl) ethyl, 2-methyl-3- (2,4,6-trinitrophenyl) propyl, -(2-fluorophenyl) ethyl, 1- (3-bromophenyl) ethyl, 3- (4-iodophenyl) propyl, 4- (2-bromophenyl) butyl, 5- (3-chlorophenyl) pentyl, 6- (4-bromophenyl) hexyl, 1,1-dimethyl-2- (2,4-dichlorophenyl) ethyl, 2-methyl-3- (2,4,6-trifluorophenyl) propyl, 2- (2-ethyl) Phenyl) ethyl, 1- (3-propylphenyl) ethyl, 3- (4-butylphenyl) propyl,
4- (2-pentylphenyl) butyl, 5- (3-hexylphenyl) pentyl, 6- (4-trifluoromethylphenyl) hexyl, 1,1-dimethyl-2- (2,4-dimethylphenyl) ethyl, 2-methyl-3- [2,4,6-tri (trifluoromethyl) phenyl] propyl, 2- (2-ethylphenyl) ethyl, 1- (3-propylphenyl) ethyl, 3- (4-butylphenyl) ) Propyl, 4- (2-pentylphenyl) butyl, 5- (3-hexylphenyl) pentyl, 6- (4-trifluoromethylphenyl) hexyl, 1,1-dimethyl-2- (2,4-dimethylphenyl) ) Ethyl, 2-methyl-3- [2,4,6-tri (trifluoromethyl) phenyl] propyl, 2- (2-ethoxyphenyl) ethyl, 1- (3-propyl) Poxyphenyl) ethyl, 3- (4-butoxyphenyl) propyl, 4- (2-pentyloxyphenyl) butyl, 5- (3-hexyloxyphenyl) pentyl, 6- (4-trifluoromethoxyphenyl) hexyl, 1 , 1-dimethyl-2- (2,4-dimethoxyphenyl) ethyl, 2-methyl-3- [2,4,6-tri (trifluoromethoxy) phenyl] propyl, 2- (2-hydroxyphenyl) ethyl, 1- (3-hydroxyphenyl) ethyl, 3- (4-hydroxyphenyl) propyl, 4- (2-hydroxyphenyl) butyl, 5- (3-hydroxyphenyl) pentyl, 6- (4-hydroxyphenyl) hexyl, 1,1-dimethyl-2- (2,4-dihydroxyphenyl) ethyl, 2-methyl-3- (2,4,6-to Hydroxyphenyl) propyl, 2-aminosulfonylbenzyl, 2- (3-methylaminosulfonylphenyl) ethyl, 3- (4-ethylaminosulfonylphenyl) propyl, 4- (2-propylaminosulfonylphenyl) butyl, 5- ( 3-isopropylaminosulfonylphenyl) pentyl, 6- [4- (2,2-dimethylpropylaminosulfonyl) phenyl] hexyl, 2- (1-ethylpropylaminosulfonyl) benzyl, 2- (3-butylaminosulfonylphenyl) Ethyl, 3- (4-isobutylaminosulfonylphenyl) propyl, 4- (2-tert-butylaminosulfonylphenyl) butyl, 5- (3-isopentylaminosulfonylphenyl) pentyl, 6- (4-pentylaminosulfonylphenyl) ) Hexyl, 3-hexylaminosulfonylbenzyl, 2- (4-N, N-dimethylaminosulfonylphenyl) ethyl, 3- (2-N-methyl-N-ethylaminosulfonylphenyl) propyl, 4- (3-N, N-diethylaminosulfonylphenyl) butyl, 5- (4-aminocarbonylphenyl) pentyl, 6- (2-methylaminocarbonylphenyl) hexyl, 3-ethylaminocarbonylbenzyl, 2- (4-propylaminocarbonylphenyl) ethyl, 3- (2-isopropylaminocarbonylphenyl) propyl, 4- [3- (2,2-dimethylpropylaminocarbonyl) phenyl] butyl, 5- [4- (1-ethylpropylaminocarbonyl) phenyl] pentyl, 6- (2-Butylaminocarbonylphenyl) hex 4-isobutylaminocarbonylbenzyl, 2- (2-tert-butylaminocarbonylphenyl) ethyl, 3- (3-isopentylaminocarbonylphenyl) propyl, 4- (2-pentylaminocarbonylphenyl) butyl, 5- (3-hexylaminocarbonylphenyl) pentyl, 6- (4-N, N-dimethylaminocarbonylphenyl) hexyl, 2-N-methyl-N-ethylaminocarbonylbenzyl, 2- (3-N, N-diethylaminocarbonyl) Phenyl) ethyl, 3- [4- (1H-tetrazolyl) phenyl] propyl, 4- [2- (2H-tetrazolyl) phenyl] butyl, 5- [3- (5H-tetrazolyl) phenyl] pentyl, 6- [4 -(5-Methyl-1H-tetrazol-1-yl) phenyl] hex , 3- (5-methyl-2H-tetrazol-2-yl) benzyl, 2- [4- (5-methyl-5H-tetrazol-5-yl) phenyl] ethyl, 3- [2- (5-ethyl) -1H-tetrazol-1-yl) phenyl] propyl, 4- [3- (5-ethyl-1H-tetrazol-1-yl) phenyl] butyl, 5- [4- (5-propyl-1H-tetrazole-1) -Yl) phenyl] pentyl, 6- [2- (5-isopropyl-1H-tetrazol-1-yl) phenyl] hexyl, 4- [5- (2,2-dimethylpropyl) -1H-tetrazol-1-yl ] Benzyl, 2- {2- [5- (1-ethylpropyl) -1H-tetrazol-1-yl] phenyl} ethyl, 3- [3- (5-butyl-1H-tetrazol-1-yl) phenyl ] Propyl, 4- [4- (5-isobutyl-1H-tetrazol-1-yl) phenyl] butyl, 5- [2- (5-tert-butyl-1H-tetrazol-1-yl) phenyl] pentyl, 6 -[3- (5-Isopentyl-1H-tetrazol-1-yl) phenyl] hexyl, 2- (5-pentyl-1H-tetrazol-1-yl) benzyl, 2- [3- (5-hexyl-1H- Tetrazol-1-yl) phenyl] ethyl, 3- [4- (5-methoxy-1H-tetrazol-1-yl) phenyl] propyl, 4- [2- (5-ethoxy-1H-tetrazol-1-yl) Phenyl] butyl, 5- [3- (5-propoxy-1H-tetrazol-1-yl) phenyl] pentyl, 6- [4- (5-isopropoxy-1H-tetrazole-) -Yl) phenyl] hexyl, 3- (5-butoxy-1H-tetrazol-1-yl) benzyl, 2- [4- (5-tert-butoxy-1H-tetrazol-1-yl) phenyl] ethyl, 3- [2- (5-pentyloxy-1H-tetrazol-1-yl) phenyl] propyl, 4- [3- (5-hexyloxy-1H-tetrazol-1-yl) phenyl] butyl, 5- (4-ethynyl) Phenyl) pentyl, 6- [2- (2-propynyl) phenyl] hexyl, 4- (2-butynyl) benzyl, 2- [3- (3-butynyl) phenyl] ethyl, 3- [4- (1-methyl) -2-propynyl) phenyl] propyl, 4- [2- (2-pentynyl) phenyl] butyl, 5- [3- (2-hexynyl) phenyl] pentyl, 6- (4-methyl) Sulfonylphenyl) hexyl, 3-ethylsulfonylbenzyl, 2- (4-propylsulfonylphenyl) ethyl, 3- (2-isopropylsulfonylphenyl) propyl, 4- [3- (2,2-dimethylpropylsulfonyl) phenyl] butyl, 5- [4- (1-ethylpropylsulfonyl) phenyl] pentyl, 6- (2-butylsulfonylphenyl) hexyl, 4-isobutylsulfonylbenzyl, 2- (2-tert-butylsulfonylphenyl) ethyl, 3- (3 -Isopentylsulfonylphenyl) propyl, 4- (4-pentylsulfonylphenyl) butyl, 5- (2-hexylsulfonylphenyl) pentyl, 6- (3-methylsulfonylaminophenyl) hexyl, 2-ethylsulfonylaminobenzyl, 2 -(3-Pro Pyrsulfonylsulfonylaminophenyl) ethyl, 3- (4-isopropylsulfonylaminophenyl) propyl, 4- (2-butylsulfonylaminophenyl) butyl, 5- (3-tert-butylsulfonylaminophenyl) pentyl, 6- (4- Pentylsulfonylaminophenyl) hexyl, 3-hexylsulfonylaminobenzyl, 2- (4-N, N-dimethylsulfonylaminophenyl) ethyl, 3- (2-N, N-diethylsulfonylaminophenyl) propyl, 4- (3 -N-methylsulfonyl-N-ethylsulfonylaminophenyl) butyl, 2- (3,4-methylenedioxyphenyl) ethyl, 1- (2,3-ethylenedioxyphenyl) ethyl, 3- (3,4- Trimethylenedioxyphenyl) propyl, 4- (3,4-teto Methylenedioxyphenyl) butyl, 5- (3,4-methylenedioxyphenyl) pentyl, 6- (3,4-ethylenedioxyphenyl) hexyl, 1,1-dimethyl-2- (3,4-methylenedi) A cyano group, a nitro group, a halogen atom as a substituent on a phenyl ring such as oxyphenyl) ethyl, 2-methyl-3- (3,4-methylenedioxyphenyl) propyl group, a halogen atom or a carbon number of 1 as a substituent A linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 linear or branched alkoxy groups of ˜6, a halogen atom as a substituent and a cyclohexane having 3 to 16 carbon atoms. A linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of alkyl groups, a hydroxyl group, and a linear or branched group having 1 to 6 carbon atoms as a substituent. Chain An aminosulfonyl group that may have an alkyl group, an alkylaminocarbonyl group in which the alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms, or a linear or branched chain having 1 to 6 carbon atoms as a substituent A linear alkyl group or a linear or branched alkoxy group having 1 to 6 carbon atoms, a tetrazolyl group that may have a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear chain having 1 to 6 carbon atoms Or a branched alkynyl group, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, a linear or branched alkylsulfonylamino group having 1 to 6 carbon atoms, 1,2,4-triazolyl 1 to 3 groups selected from the group consisting of a group, an imidazolyl group, a piperidinyl group, a thiadiazolyl group, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms which may have a halogen atom as a substituent Replace Examples thereof include a phenyl-substituted alkyl group having 1 to 2 phenyl groups which may be substituted.

  A pyridyl lower alkyl having 1 to 3 groups selected from the group consisting of a hydroxyl group as a substituent, a lower alkyl group having a hydroxyl group as a substituent, a halogen atom, a lower alkoxy group and a cyano group on the pyridine ring. Examples of the group include, in addition to the pyridyl lower alkyl group, [2-methyl- (3,4,5 or 6-) pyridyl] methyl, [2-methyl-3-hydroxy-5-hydroxymethyl- (4 Or 6-) pyridyl] methyl, 2- [3-ethyl- (2,4,5 or 6) pyridyl] ethyl, 1- [4-propyl- (2,3,5 or 6) pyridyl] ethyl, 3- [2-butyl- (3,4,5 or 6) pyridyl] propyl, 4- [3-pentyl- (2,4,5 or 6) pyridyl] butyl, 1,1-dimethyl-2- [4-hexyl- ( , 3,5 or 6) pyridyl] ethyl, 5- [2,3-dimethyl- (4,5 or 6) pyridyl] pentyl, 6- [2,4,6-trimethyl- (3 or 5-) Pyridyl] hexyl, 1- [2-hydroxy- (2,3,5 or 6) pyridyl] isopropyl, 2-methyl-3- [3-hydroxy- (2,4,5 or 6) pyridyl] propyl, [2-hydroxy- (3,4,5 or 6-) pyridyl] methyl, 2- [3-hydroxy- (2,4,5 or 6-) pyridyl] ethyl, 1- [4-hydroxy- (2, 3,5 or 6) pyridyl] ethyl, 3- [2-hydroxy- (3,4,5 or 6) pyridyl] propyl, 4- [3-hydroxy- (2,4,5 or 6) pyridyl ] Butyl, 1,1-dimethyl-2- [4-hydroxy- (2,3, Or 6-) pyridyl] ethyl, 5- [2,3-dihydroxy- (4,5 or 6) pyridyl] pentyl, 6- [2,4,6-trihydroxy- (3 or 5-) pyridyl] hexyl [2-hydroxymethyl- (3,4,5 or 6) pyridyl] methyl, 2- [3- (2-hydroxyethyl)-(2,4,5 or 6-) pyridyl] ethyl, 1- [ 4- (3-hydroxypropyl)-(2,3,5 or 6) pyridyl] ethyl, 3- [2- (4-hydroxybutyl)-(3,4,5 or 6) pyridyl] propyl, 4 -[3- (5-hydroxypentyl)-(2,4,5 or 6-) pyridyl] butyl, 1,1-dimethyl-2- [4- (6-hydroxyhexyl)-(2,3,5 or 6-) Pyridyl] ethyl, 5- [2,3-di (hydroxymethyl) )-(4,5 or 6) pyridyl] pentyl, 6- [2,4,6-tri (hydroxymethyl)-(3 or 5-) pyridyl] hexyl, 1- [2-hydroxymethyl- (2, 3,5 or 6-) pyridyl] isopropyl, 2-methyl-3- [3- (2,3-dihydroxypropyl)-(2,4,5 or 6) pyridyl] propyl, [2-methyl-3- (2,2,4-trihydroxybutyl)-(4,5 or 6) pyridyl] methyl, [2-methyl-5-hydroxymethyl- (3,4,6-) pyridyl] methyl, [2-chloro -(3-, 4-, 5- or 6-) pyridyl] methyl, [3-fluoro- (2-, 4-, 5- or 6-) pyridyl] methyl, [2-bromo- (3-, 4 -, 5- or 6-) pyridyl] methyl, [2-methoxy- (3-, 4- 5- or 6-) pyridyl] methyl, [3-methoxy- (2-, 4-, 5- or 6-) pyridyl] methyl, [4-methoxy- (2- or 3-) pyridyl] methyl, [2 -Ethoxy- (3,4-, 5- or 6-) pyridyl] methyl, [3-ethoxy- (2-, 4-, 5- or 6-) pyridyl] methyl, [2-isopropoxy- (3- , 4-, 5- or 6-) pyridyl] methyl, [3-methoxymethoxy- (2-, 4-, 5- or 6-) pyridyl] methyl, [3-cyano- (2-, 4-, 5) -Or 6-) pyridyl] methyl, [3,5-dichloro- (2- or 4-) pyridyl] methyl, [2,6-dichloro- (3- or 4-) pyridyl] methyl, [2-cyano- As a substituent on a pyridine ring such as (3-, 4-, 5- or 6-) pyridyl] methyl group, a hydroxyl group as a substituent A group consisting of 1 to 6 carbon groups having 1 to 3 acid groups, a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms, and a cyano group There may be 1 to 3 groups selected from the following, and examples thereof include a pyridylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring include [(1,2 or 3-) pyrrolyl] methyl, 2-[(1,2 or 3). -) Pyrrolyl] ethyl, 1-[(1,2 or 3-) pyrrolyl] ethyl, 3-[(1,2 or 3-) pyrrolyl] propyl, 4-[(1,2 or 3-) pyrrolyl] butyl , 5-[(1,2 or 3-) pyrrolyl] pentyl, 6-[(1,2 or 3-) pyrrolyl] hexyl, 1,1-dimethyl-2-[(1,2 or 3-) pyrrolyl] Ethyl, 2-methyl-3-[(1,2 or 3-) pyrrolyl] propyl, [1-methyl- (2 or 3-) pyrrolyl] methyl, 2- [2-ethyl- (1,3,4, or 5-) pyrrolyl] ethyl, 1- [3-propyl- (1,2,4 or 5-) pi Ryl] ethyl, 3- [1-butyl- (2,3 or 4-) pyrrolyl] propyl, 4- [2-pentyl- (1,3,4,5-) pyrrolyl] butyl, 5- [3-hexyl -(1,2,4 or 5-) pyrrolyl] pentyl, 6- [1,2-dimethyl- (3,4,5-) pyrrolyl] hexyl, 1,1-dimethyl-2- [1,2,3 Carbon as a substituent on a pyrrole ring such as -trimethyl- (4 or 5-) pyrrolyl] ethyl, 2-methyl-3- [1-ethyl-2-methyl- (3,4,5-) pyrrolyl] propyl group A pyrrolylalkyl group having 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms, wherein the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms; It can be illustrated.

  Examples of the benzoyl group which may be substituted by a group selected from the group consisting of a cyano group, a lower alkoxy group and an amino group which may have a lower alkylsulfonyl group as a substituent on the phenyl ring include, for example, benzoyl, 4- Cyanobenzoyl, 2-aminobenzoyl, 3-aminobenzoyl, 4-aminobenzoyl, 3,4-diaminobenzoyl, 2,4,6-triaminobenzoyl, 3-cyanobenzoyl, 2-cyanobenzoyl, 2,3-dicyano Benzoyl, 3,4,5-tricyanobenzoyl, (2-, 3- or 4-) methoxybenzoyl, 2-methylsulfonylaminobenzoyl, 3-methylsulfonylaminobenzoyl, 4-ethylsulfonylaminobenzoyl, 2-propylsulfonyl Aminobenzoyl, 3-isopropylsulfonyl Minobenzoyl, 4- (2,2-dimethylpropylsulfonylamino) benzoyl, 2- (1-ethylpropylsulfonylamino) benzoyl, 3-butylsulfonylaminobenzoyl, 4-isobutylsulfonylaminobenzoyl, 2-tert-butylsulfonylamino A cyano group on a phenyl ring such as benzoyl, 3-isopentylsulfonylaminobenzoyl, 4-pentylsulfonylaminobenzoyl, 2-hexylsulfonylaminobenzoyl, 2-N, N-dimethylsulfonylaminobenzoyl, etc., having 1 carbon as a substituent A group selected from the group consisting of -6 linear or branched alkoxy groups and an amino group which may have 1 to 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents 1 to 3 may be substituted Yl group can be exemplified.

  The pyridyl group which may have a lower alkyl group (a halogen atom may be substituted on the lower alkyl group) as a substituent is pyridyl which may have 1 to 3 lower alkyl groups as exemplified above The group can be mentioned. Here, on the lower alkyl group, 1 to 5 halogen atoms as exemplified above may be contained as a substituent. Specifically, the pyridyl group which may have a lower alkyl group (which may be substituted with a halogen atom on the lower alkyl group) as such a substituent includes, for example, (2-, 3- Or 4-) pyridyl, 2-methyl- (3-, 4-, 5- or 6-) pyridyl, 3-ethyl- (2-, 4-, 5- or 6-) pyridyl, 4-propyl- (2 -Or 3-) pyridyl, 2-butyl- (2-, 3-, 5- or 6-) pyridyl, 3-tert-butyl- (2-, 4-, 5- or 6-) pyridyl, 4-pentyl -(2- or 3-) pyridyl, 2-hexyl- (3-, 4-, 5- or 6-) pyridyl, 3-trifluoromethyl- (2-, 4-, 5- or 6-) pyridyl group Etc. are included.

  Examples of the lower alkyl group which may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent include, in addition to the lower alkyl group, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3- Hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2 , 2-Trichloroethyl 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromo 1 carbon atom having 1 to 3 groups selected from the group consisting of a hydroxyl group and a halogen atom as a substituent such as hexyl, 2-hydroxy-3-fluoropropyl, 2,2-dichloro-3-hydroxybutyl group, etc. -6 linear or branched alkyl groups can be illustrated.

  Examples of the phenyl group on which 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group having a halogen atom as a substituent and a cyano group may be substituted on the phenyl ring include, for example, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2, 4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluoropheny 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2-trifluoro Methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- (bromomethyl) phenyl, 3- (2-chloroethyl) phenyl, 4- (2,3-dichloropropyl) phenyl, 4- (4- Fluorobutyl) phenyl, 3- (5-chloropentyl) phenyl, 4- (5-bromohexyl) phenyl, 4- (5,6-dibromohexyl) phenyl, 3,4-di (trifluoromethyl) phenyl, 3 , 4-Di (4,4,4-trichlorobutyl) phenyl, 2,4-di (3-chloro-2-methylpropyl) Enyl, 2,5-di (3-chloropropyl) phenyl, 2,6-di (2,2,2-trifluoroethyl) phenyl, 3,4,5-tri (trifluoromethyl) phenyl, 4- ( 2,2,2-trichloroethyl) phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4 A halogen atom on the phenyl ring such as dicyanophenyl, 3,5-dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4,5-tricyanophenyl, etc. A group selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, which may have 1 to 3 halogen atoms as a substituent, and a cyano group; Examples of the phenyl group which may be substituted by 3 may be mentioned.

  Examples of the phenoxy group which may have a lower alkoxy group as a substituent on the phenyl ring (a halogen atom may be substituted on the lower alkoxy group) include, for example, phenoxy, 2-methoxyphenoxy, 3-methoxy Phenoxy, 4-methoxyphenoxy, 2-ethoxyphenoxy, 3-ethoxyphenoxy, 4-ethoxyphenoxy, 4-isopropoxyphenoxy, 3-butoxyphenoxy, 4-pentyloxyphenoxy, 4-hexyloxyphenoxy, 3,4-dimethoxy Phenoxy, 3,4-diethoxyphenoxy, 2,4-dimethoxyphenoxy, 2,5-dimethoxyphenoxy, 2,6-dimethoxyphenoxy, 3,4,5-trimethoxyphenoxy, 2-trifluoromethoxyphenoxy, 3- Trifluoromethoxyfe Xy, 4-trifluoromethoxyphenoxy, 2- (bromomethoxy) phenoxy, 3- (2-chloroethoxy) phenoxy, 4- (2,3-dichloropropoxy) phenoxy, 4- (4-fluorobutoxy) phenoxy, 3 -(5-chloropentyloxy) phenoxy, 4- (5-bromohexyloxy) phenoxy, 4- (5,6-dibromohexyloxy) phenoxy, 3,4-di (trifluoromethoxy) phenoxy, 3,4- Di (4,4,4-trichlorobutoxy) phenoxy, 2,4-di (3-chloro-2-methoxypropyl) phenoxy, 2,5-di (3-chloropropoxy) phenoxy, 2,6-di (2 , 2,2-trifluoroethoxy) phenoxy, 3,4,5-tri (trifluoromethoxy) phenoxy, 4- (2, , 2-trichloroethoxy) phenoxy, 2-methoxy-4-trifluoromethoxyphenoxy, 3-ethoxy-4-trichloromethoxyphenoxy, etc., carbons having 1 to 3 halogen atoms as substituents on the phenyl ring Examples thereof include phenoxy groups which may be substituted by 1 to 3 linear or branched alkoxy groups of 1 to 6.

Examples of the 6-membered saturated heterocyclic ring bonded to each other with or without another nitrogen atom or oxygen atom together with the nitrogen atom to which R ¹⁵ and R ¹⁶ are bonded include piperidinyl, piperazinyl, and morpholinyl groups. Can do.

  Examples of the quinolyl lower alkyl group include (2,3,4,5,6,7 or 8-) quinolylmethyl, 2-[(2,3,4,5,6,7 or 8-) quinolyl] ethyl, 1-[(2,3,4,5,6,7 or 8-) quinolyl] ethyl, 3-[(2,3,4,5,6,7 or 8-) quinolyl] propyl, 4-[( 2,3,4,5,6,7 or 8-) quinolyl] butyl, 5-[(2,3,4,5,6,7 or 8-) quinolyl] pentyl, 6-[(2,3,3) And a quinolylalkyl group in which the alkyl moiety such as a 4,5,6,7, or 8-) quinolyl] hexyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

  As a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring (a lower alkyl group that may have a halogen atom as a substituent on the phenyl ring may be substituted), for example, [ (2,4 or 5-) thiazolyl] methyl, 2-[(2,4 or 5-) thiazolyl] ethyl, 1-[(2,4 or 5-) thiazolyl] ethyl, 3-[(2,4 or 5-) thiazolyl] propyl, 4-[(2,4 or 5-) thiazolyl] butyl, 5-[(2,4 or 5-) thiazolyl] pentyl, 6-[(2,4 or 5-) thiazolyl] Hexyl, 1,1-dimethyl-2-[(2,4 or 5-) thiazolyl] ethyl, 2-methyl-3-[(2,4 or 5-) thiazolyl] propyl, [2-phenyl- (4 or 5-) thiazolyl] 2- [4-phenyl- (2 or 5-) thiazolyl] ethyl, 1- [5-phenyl- (2 or 4-) thiazolyl] ethyl, 3- [2-phenyl- (2 or 5-) thiazolyl ] Propyl, 4- (2,4-diphenyl-5-thiazolyl) butyl, 5- (2,5-diphenyl-4-thiazolyl) pentyl, 6- (4,5-diphenyl-2-thiazolyl) hexyl, 1, 1-dimethyl-2- [2-phenyl- (4 or 5-) thiazolyl] ethyl, 2-methyl-3- [4-phenyl- (2 or 5-) thiazolyl] propyl, [4-phenyl- (2 or 5-) thiazolyl] methyl, [5-phenyl- (2 or 4-) thiazolyl] methyl, (2,4-diphenyl-5-thiazolyl) methyl, (2,5-diphenyl-4-thiazolyl) methyl, (4 , 5- A phenyl group as a substituent on a thiazole ring such as phenyl-2-thiazolyl) methyl, [2- (4-toluoromethylphenyl) -thiazol-5-yl] methyl group (a halogen atom as a substituent on the phenyl ring) 1 to 2 carbon atoms having 1 to 3 carbon atoms which may have 1 to 3 carbon atoms may be substituted), and the alkyl moiety is 1 to 6 carbon atoms. Examples thereof include thiazolylalkyl groups which are linear or branched alkyl groups.

  Examples of the benzimidazolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the benzimidazole ring include, for example, (1-, 2-, 4-, 5-, 6- or 7-) benz. Imidazolylmethyl, 1-methyl- (2-, 4-, 5-, 6- or 7-) benzimidazolylmethyl, 2- [1-methyl- (2-, 4-, 5-, 6- or 7-) Benzimidazolylmethyl] ethyl, 3- [1-methyl- (2-, 4-, 5-, 6- or 7-) benzimidazolylmethyl] propyl, 4- [1-methyl- (2-, 4--5 -, 6- or 7-) benzimidazolylmethyl] butyl, 5- [1-methyl- (2-, 4-, 5-, 6- or 7-) benzimidazolylmethyl] pentyl, 6- [1-methyl- (2-, 4-, 5-, 6- or 7-) Imidazolylmethyl] hexyl, 2- [2-ethyl- (1-, 4-, 5-, 6- or 7-) benzimidazolyl] ethyl, 4-propyl- (1-, 2-, 5-, 6- Or 7-) benzimidazolylmethyl, 5-butyl- (1-, 2-, 4-, 6- or 7-) benzimidazolylmethyl, 2- [6-pentyl- (1-, 2-, 4-, 5) -Or 7-) benzimidazolyl] ethyl, 3- [7-hexyl- (1-, 2-, 4-, 5- or 6-) benzimidazolyl] propyl, 1-ethyl- (2-, 4-, 5) -, 6- or 7-) benzimidazolylmethyl, 1-butyl- (2-, 4-, 5-, 6- or 7-) benzimidazolylmethyl, 1-isopropyl- (2-, 4-, 5-, 6- or 7-) benzimidazolylmethyl, 1,2-dimethyl- 4-, 5-, 6- or 7-) benzimidazolylmethyl, 1-methyl-4-ethyl- (2-, 5-, 6- or 7-) benzimidazolylmethyl, 1-propyl-5-methyl- ( Alkyl moieties such as 2-, 4-, 6- or 7-) benzimidazolylmethyl, 1,2,5-trimethyl- (4-, 6- or 7-) benzimidazolylmethyl are straight chain having 1 to 6 carbon atoms Or it is a branched alkyl group and can illustrate the benzimidazolyl alkyl group which may have 1 to 3 C1-C6 linear or branched alkyl groups as a substituent on a benzimidazole ring.

  Examples of the 1,2,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,2,4-oxadiazole ring include, for example, (2 or 5-) 1,2,4-oxa Diazolylmethyl, 2-[(2 or 5-) 1,2,4-oxadiazolyl] ethyl, 1-[(2 or 5-) 1,2,4-oxadiazolyl] ethyl, 3-[(2 or 5- ) 1,2,4-oxadiazolyl] propyl, 4-[(2 or 5-) 1,2,4-oxadiazolyl] butyl, 5-[(2 or 5-) 1,2,4-oxadiazolyl] pentyl, 6 -[(2 or 5-) 1,2,4-oxadiazolyl] hexyl, 1,1-dimethyl-2-[(2 or 5-) 1,2,4-oxadiazolyl] ethyl, 2-methyl-3- [ (2 or 5-) 1,2,4-oxadia Yl] propyl, 2-oxo-[(3 or 5-) 1,2,4-oxadiazolyl] methyl, 5-oxo-[(2 or 3-) 1,2,4-oxadiazolyl] methyl, 2- [2 -Oxo- (3 or 5-) (1,2,4-oxadiazolyl)] ethyl, 1- [5-oxo- (2 or 3-) 1,2,4-oxadiazolyl] ethyl, 3-[(2 or 5-) 1,2,4-oxadiazolyl] propyl, 4- [2-oxo (3 or 5-) 1,2,4-oxadiazolyl] butyl, 5- [5-oxo (2 or 3-) 1,2 , 4-oxadiazolyl] pentyl, 6- [2-oxo (3 or 5-) 1,2,4-oxadiazolyl] hexyl, 1,1-dimethyl-2- [5-oxo (2 or 3-) 1,2 , 4-Oxadiazolyl] ethyl, 2-methyl-3- [ -Oxo (3 or 5-) 1,2,4-oxadiazolyl] propyl group or other 1,2,4-oxadiazole ring may have an oxo group as a substituent, and the alkyl moiety has 1 to An example is a 1,2,4-oxadiazolylalkyl group which is 6 straight-chain or branched alkyl groups.

  Examples of the thienyl lower alkyl group that may have a lower alkyl group as a substituent on the thiophene ring include (2- or 3-) thienylmethyl, 2-[(2- or 3-) thienyl] ethyl, 1- [(2- or 3-) thienyl] ethyl, 3-[(2- or 3-) thienyl] propyl, 4-[(2- or 3-) thienyl] butyl, 5-[(2- or 3-) Thienyl] pentyl, 6-[(2- or 3-) thienyl] hexyl, 1,1-dimethyl-2-[(2- or 3-) thienyl] ethyl, 2-methyl-3-[(2- or 3 -) Thienyl] propyl, [5-methyl- (2-, 3- or 4-) thienyl] methyl, 2- [5-methyl- (2-, 3- or 4-) thienyl] ethyl, 1- [4 -Methyl- (2-, 3- or 5-) thienyl] ethyl, 3- [ -Methyl- (2-, 3- or 4-) thienyl] propyl, 4- [4-ethyl- (2-, 3- or 5-) thienyl] butyl, 5- [5-propyl- (2-, 3 -Or 4-) thienyl] pentyl, 6- [4-butyl- (2-, 3- or 5-) thienyl] hexyl, 1,1-dimethyl-2- [4,5-dimethyl- (2- or 3) -) Thienyl] ethyl, 2-methyl-3- [4-methyl- (2-, 3-, or 5-) thienyl] propyl group or the like on a thiophene ring as a substituent, Examples thereof include a thienylalkyl group that may have a branched alkyl group, and the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the imidazolyl lower alkyl group optionally having 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom on the imidazole ring include (1-, 2-, 4- or 5-) imidazolylmethyl, 2-[(1-, 2-, 4- or 5-) imidazolyl] ethyl, 1-[(1-, 2-, 4- or 5-) imidazolyl] ethyl, 3-[( 1-, 2-, 4- or 5-) imidazolyl] propyl, 4-[(1-, 2-, 4- or 5-) imidazolyl] butyl, 5-[(1-, 2-, 4- or 5 -) Imidazolyl] pentyl, 6-[(1-, 2-, 4- or 5-) imidazolyl] hexyl, 1,1-dimethyl-2-[(1-, 2-, 4- or 5-) imidazolyl] Ethyl, 2-methyl-3-[(1-, 2-, 4- or 5-) imida Ryl] propyl, 1-methyl- (2-, 4- or 5-) imidazolylmethyl, 2-methyl- (1-, 4- or 5-) imidazolylmethyl, 4-methyl- (1-, 2- or 5 -) Imidazolylmethyl, 5-methyl- (1-, 2- or 4-) imidazolylmethyl, 2- [1-methyl- (2-, 4- or 5-) imidazolyl] ethyl, 2- [2-methyl- (1-, 4- or 5-) imidazolyl] ethyl, 2- [4-methyl- (1-, 2- or 5-) imidazolyl] ethyl, 2- [5-methyl- (1-, 2- or 4) -) Imidazolyl] ethyl, 1- [1-methyl- (2-, 4- or 5-) imidazolyl] ethyl, 3- [2-methyl- (1-, 4- or 5-) imidazolyl] propyl, 4- [4-Methyl- (1-, 2- or 5-) imidazolyl] buty 5- [5-methyl- (1-, 2- or 4-) imidazolyl] pentyl, 6- [1-methyl- (2-, 4- or 5-) imidazolyl] hexyl, 1,1-dimethyl-2 -[2-methyl- (1-, 4- or 5-) imidazolyl] ethyl, 2-methyl-3- [4-methyl- (1-, 2- or 5-) imidazolyl] propyl, 1-chloro- ( 2-, 4- or 5-) imidazolylmethyl, 2-chloro- (1-, 4- or 5-) imidazolylmethyl, 4-chloro- (1-, 2- or 5-) imidazolylmethyl, 5-chloro- (1-, 2- or 4-) imidazolylmethyl, 1-fluoro- (2-, 4- or 5-) imidazolylmethyl, 2-bromo- (1-, 4- or 5-) imidazolylmethyl, 4-iodo -(1-, 2- or 5-) imidazolylmethyl, A straight or branched chain having 1 to 6 carbon atoms as a substituent on an imidazole ring such as 5-fluoro- (1-, 2- or 4-) imidazolylmethyl, 1,2,4-trichloro-5-imidazolylmethyl Mention may be made of an imidazolylalkyl group which may have 1 to 3 groups selected from the group consisting of a chain alkyl group and a halogen atom, and wherein the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Can do.

  Examples of the 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring include (1,3,4,5,6,7 or 8-) 1, 2,3,4-tetrahydroquinolyl, 2-oxo- (1,3,4,5,6,7 or 8-) 1,2,3,4-tetrahydroquinolyl, 4-oxo- (1,2 , 3,5,6,7 or 8-) 1,2,3,4-tetrahydroquinolyl, 2,4-dioxo- (1,3,5,6,7 or 8-) 1,2,3 Examples thereof include 1,2,3,4-tetrahydroquinolyl group which may have 1 to 2 oxo groups as substituents on a tetrahydroquinoline ring such as 4-tetrahydroquinolyl group.

  Examples of the isoxazolyl lower alkyl group optionally having 1 to 3 lower alkyl groups as a substituent on the isoxazole ring include (3-, 4- or 5-) isoxazolylmethyl, 2-[( 3-, 4- or 5-) isoxazolyl] ethyl, 1-[(3-, 4- or 5-) isoxazolyl] ethyl, 3-[(3-, 4- or 5-) isoxazolyl] propyl, 4- [ (3-, 4- or 5-) isoxazolyl] butyl, 5-[(3-, 4- or 5-) isoxazolyl] pentyl, 6-[(3-, 4- or 5-) isoxazolyl] hexyl, 1, 1-dimethyl-2-[(3-, 4- or 5-) isoxazolyl] ethyl, 2-methyl-3-[(3-, 4- or 5-) isoxazolyl] propyl, 5-methyl- (3- or 4-) Isoxazolylmethyl, , Can be exemplified isoxazolyl alkyl group which may have 1-2 the exemplary lower alkyl groups as substituents on the isoxazole ring and 5-dimethyl-4-isoxazolylmethyl groups.

  Examples of imidazo [2,1-b] thiazolyl lower alkyl groups include, for example, imidazo [2,1-b] thiazol- (2-, 3-, 5- or 6-) ylmethyl, 2- [imidazo [2,1 -B] thiazol- (2-, 3-, 5- or 6-) yl] ethyl, 1- [imidazo [2,1-b] thiazol- (2-, 3-, 5- or 6-) yl] Ethyl, 3- [imidazo [2,1-b] thiazole- (2-, 3-, 5- or 6-) yl] propyl, 4- [imidazo [2,1-b] thiazole- (2-, 3 -, 5- or 6-) yl] butyl, 5- [imidazo [2,1-b] thiazole- (2-, 3-, 5- or 6-) yl] pentyl, 6- [imidazo [2,1 -B] thiazole- (2-, 3-, 5- or 6-) yl] hexyl, 1,1-dimethyl-2- [imida [2,1-b] thiazol- (2-, 3-, 5- or 6-) yl] ethyl, 2-methyl-3- [imidazo [2,1-b] thiazole- (2-, 3-, An imidazo [2,1-b] thiazolylalkyl group in which an alkyl moiety such as 5- or 6-) yl] propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms can be mentioned. .

  As a 3,4-dihydro-2H-1,4-benzoxazinyl lower alkyl group optionally having a lower alkyl group as a substituent on the 3,4-dihydro-2H-1,4-benzoxazine ring Is, for example, 3,4-dihydro-2H-1,4-benzoxazine- (2-, 3-, 4-, 5-, 6-, 7- or 8-) ylmethyl, 2- [3,4- Dihydro-2H-1,4-benzoxazine- (2-, 3-, 4-, 5-, 6-, 7- or 8-) yl] ethyl, 1- [3,4-dihydro-2H-1, 4-Benzoxazine- (2-, 3-, 4-, 5-, 6-, 7- or 8-) yl] ethyl, 3- [3,4-dihydro-2H-1,4-benzoxazine- ( 2-, 3-, 4-, 5-, 6-, 7- or 8-) yl] propyl, 4- [3,4-dihydro-2H 1,4-benzoxazine- (2-, 3-, 4-, 5-, 6-, 7- or 8-) yl] butyl, 5- [3,4-dihydro-2H-1,4-benzoxazine -(2-, 3-, 4-, 5-, 6-, 7- or 8-) yl] pentyl, 6- [3,4-dihydro-2H-1,4-benzoxazine- (2-, 3 -, 4-, 5-, 6-, 7- or 8-) yl] hexyl, 1,1-dimethyl-2- [3,4-dihydro-2H-1,4-benzoxazine- (2-, 3 -, 4-, 5-, 6-, 7- or 8-) yl] ethyl, 2-methyl-3- [3,4-dihydro-2H-1,4-benzoxazine- (2-, 3-, 4-, 5-, 6-, 7- or 8-) yl] propyl, [4-methyl-3,4-dihydro-2H-1,4-benzoxazine- (2-, 3-, -, 5-, 6-, 7- or 8-) yl] methyl group or the like on a 3,4-dihydro-2H-1,4-benzoxazine ring as a substituent, straight or branched having 1 to 6 carbon atoms 3,4-dihydro-2H-1,4-benzoxazinylalkyl, which may have 1 to 3 chain alkyl groups and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms The group can be mentioned.

  Examples of the pyrazolyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent on the pyrazole ring include, for example, an alkyl moiety directly having 1 to 6 carbon atoms. Mention may be made of pyrazolylalkyl groups which are chain or branched alkyl groups. Here, the pyrazole ring may have 1 to 3 groups selected from the group of the lower alkyl group exemplified above and the halogen atom exemplified above. Specifically, the pyrazolyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent on such a pyrazole ring includes, for example, pyrazole ( 1-, 3-, 4- or 5-) ylmethyl, 2- [pyrazole- (1-, 3-, 4- or 5-) yl] ethyl, 1- [pyrazole- (1-, 3-, 4- Or 5-) yl] ethyl, 3- [pyrazol- (1-, 3-, 4- or 5-) yl] propyl, 4- [pyrazol- (1-, 3-, 4- or 5-) yl] Butyl, 5- [pyrazol- (1-, 3-, 4- or 5-) yl] pentyl, 6- [pyrazol- (1-, 3-, 4- or 5-) yl] hexyl, 1,1- Dimethyl-2- [pyrazole- (1-, 3-, 4- or 5-) yl] ethyl, 2-methyl -3- [pyrazol- (1-, 3-, 4- or 5-) yl] propyl, [(1,3-, 1,4- or 3,4-) dimethylpyrazol-5-yl] methyl, 2 -[(1,3-, 1,4- or 3,4-) dimethylpyrazol-5-yl] ethyl, [1-methyl-4-chloropyrazol- (3- or 5-) yl] methyl, 2- [1-Methyl-4-chloropyrazol- (3- or 5-) yl] ethyl group and the like are included.

  Examples of the dihydropyridyl lower alkyl group that may have an oxo group as a substituent on the dihydropyridine ring include a dihydropyridylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. be able to. Here, the dihydropyridine ring may have one oxo group as a substituent. Specifically, the dihydropyridyl lower alkyl group which may have an oxo group as a substituent on such a dihydropyridine ring includes, for example, 1,2-dihydropyridine- (1-, 2-, 3-, 4- , 5- or 6-) ylmethyl, 2-oxo-1,2-dihydropyridine- (1-, 3-, 4-, 5- or 6-) ylmethyl, 2- [1,2-dihydropyridine- (1-, 2-, 3-, 4-, 5- or 6-) yl] ethyl, 1- [1,2-dihydropyridin- (1-, 2-, 3-, 4-, 5- or 6-) yl] ethyl , 3- [1,2-dihydropyridin- (1-, 2-, 3-, 4-, 5- or 6-) yl] propyl, 4- [1,2-dihydropyridine- (1-, 2-, 3 -, 4-, 5- or 6-) yl] butyl, 5- [1,2-dihydropyridine- 1-, 2-, 3-, 4-, 5- or 6-) yl] pentyl, 6- [1,2-dihydropyridine- (1-, 2-, 3-, 4-, 5- or 6-) Yl] hexyl, 1,1-dimethyl-2- [1,2-dihydropyridine- (1-, 2-, 3-, 4-, 5- or 6-) yl] ethyl, 2-methyl-3- [1 , 2-dihydropyridine- (1-, 2-, 3-, 4-, 5- or 6-) yl] propyl group and the like.

  Examples of the morpholino lower alkyl group include morpholinomethyl, 2-morpholinoethyl, 1-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 5-morpholinopentyl, 6-morpholinohexyl, 1,1-dimethyl-2- Examples thereof include a morpholinoalkyl group in which the alkyl moiety such as morpholinoethyl and 2-methyl-3-morpholinopropyl groups is a linear or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the phenyl lower alkenyl group that may have a lower alkoxy group as a substituent on the phenyl ring include, for example, a linear or branched alkenyl group having 2 to 6 carbon atoms and a double bond. Examples thereof include 1 to 3 phenylalkenyl groups. Here, the phenyl ring of the phenylalkenyl group may have 1 to 3 lower alkoxy groups exemplified above. Specifically, the phenyl lower alkenyl group which may have a lower alkoxy group as a substituent on such a phenyl ring includes, for example, styryl, 3-phenyl-2-propenyl (common name: cinnamyl), 4- Phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl- 3-hexenyl, 4-phenyl-1,3-butadienyl, 6-phenyl-1,3,5-hexatrienyl, 2-[(2-, 3- or 4-) methoxyphenyl] vinyl, 2-[( 2-, 3- or 4-) ethoxyphenyl] vinyl, 3-[(2-, 3- or 4-) methoxyphenyl] -2-propenyl, 3-[(2-, 3- or 4- Ethoxyphenyl] -2-propenyl, 3-[(2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-) dimethoxyphenyl] -2-propenyl, 4-[(2,3,4-, 2,3,5-, 2,3,6-, 2,4,5- or 2,4,6-) triethoxyphenyl] -2-butenyl group and the like included.

  Examples of the lower alkanoyl group include a linear or branched alkanoyloxy group having 1 to 6 carbon atoms.

  The production method of the compound of the present invention will be described below.

The compound of the present invention is produced, for example, as shown in the following reaction formula-1 to reaction formula-13.
[Reaction Formula-1]

[Wherein, R ¹ , R ² , R ³ , R ⁴ , Y, T and A ₁ are the same as above. X ₁ represents a halogen atom. ]

  The reaction between the compound (2) and the compound (3) is generally performed in a suitable solvent or without a solvent, in the presence or absence of a basic compound.

  Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, and halogens such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Hydrocarbons, methanol, ethanol, isopropanol, butanol, tert-butanol, lower alcohols such as ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, Examples thereof include pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, and mixed solvents thereof.

  Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, and the like. , Potassium hydride, potassium, sodium, sodium amide, sodium methylate, sodium ethylate, sodium alcoholate such as sodium-n-butoxide, pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethyl Aniline, N-methylmorpholine, 1,5-diazabicyclo [4.3,0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2. ] Can be exemplified organic bases or mixtures thereof, such as octane (DABCO).

  When the reaction is carried out in the presence of a basic compound, the basic compound is usually used in an amount of at least equimolar amount, preferably equimolar to 10-fold molar amount relative to the compound (2).

  Compound (3) is usually used in an amount of at least equimolar amount, preferably equimolar to 10-fold molar amount relative to compound (2).

  The reaction is usually carried out at about -30 to 200 ° C, preferably about -30 to 150 ° C, and the reaction is generally completed in about 5 minutes to 80 hours.

  In the reaction system of this reaction, an alkali metal halide such as sodium iodide or potassium iodide may be added, or a phase transfer catalyst may be added.

  Examples of the phase transfer catalyst include tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfite, tributylmethylammonium chloride, tributylbenzylammonium. Chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzyldimethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, Benzyltrier Linear or branched alkyl groups having 1 to 18 carbon atoms, such as ruammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride, linear or branched alkyl groups having 1 to 6 carbon atoms in the alkyl moiety. A linear or branched alkyl group having 1 to 18 carbon atoms such as a quaternary ammonium salt substituted by a group selected from the group consisting of a phenylalkyl group and a phenyl group, which is a branched alkyl group, and tetrabutylphosphonium chloride Can be exemplified by phosphonium salts substituted with 1-dodecanylpyridinium chloride and pyridinium salts substituted with a linear or branched alkyl group having 1 to 18 carbon atoms. These phase transfer catalysts are used singly or in combination of two or more.

The phase transfer catalyst is generally used in an amount of 0.1-fold mol to equimolar amount, preferably 0.1-0.5 mol amount, relative to compound (2).
[Reaction Formula-2]

[Wherein R ¹ , R ² , R ³ , R ⁴ , Y and A ₁ are the same as defined above. T ₁ represents a group —N (R ¹⁴ ) —B ₄ —, a group —B ₅ —, or a direct bond. Here, R ¹⁴ , B ₄ and B ₅ are the same as described above. ]

  A wide variety of known amide bond forming reactions can be applied to the reaction between the compound (4) and the compound (5). Specifically, (b) a mixed acid anhydride method, that is, a method in which a carboxylic acid (4) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with an amine (5), (b) activity Ester method, ie, carboxylic acid (4) as an active ester such as phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or active amide with benzoxazoline-2-thione , A method of reacting this with amine (5), (c) a carbodiimide method, ie, carboxylic acid (4) with amine (5) dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC) , Condensation reaction in the presence of an activator such as carbonyldiimidazole, (d) others For example, a method in which a carboxylic acid (4) is converted into a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and this is reacted with an amine (5). Examples thereof include a method of reacting at a high temperature and a method of reacting an acid halide of carboxylic acid (4), that is, a carboxylic acid halide with amine (5).

  The mixed acid anhydride used in the mixed anhydride method (ii) is obtained by a normal Schotten-Baumann reaction, and is usually reacted with an amine (5) without isolation, by the general formula (1). The compound of the present invention is produced.

  The Schotten-Baumann reaction is performed in the presence of a basic compound.

  The basic compound used is a compound conventionally used for the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo [4]. .3.0] Nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) Bases, carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium, Sodium amide, sodium methylate, sodium Inorganic bases such as metal alcoholates such as Chirato like. These basic compounds are used singly or in combination of two or more. The reaction is usually performed at about -20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours.

  The reaction between the obtained mixed acid anhydride and amine (5) is usually performed at about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 About minutes to 5 hours.

  The mixed acid anhydride method is generally performed in a solvent. As the solvent to be used, any solvent commonly used in the mixed acid anhydride method can be used. Specifically, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride, benzene, toluene, Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate, ethyl acetate, isopropyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphate triamide And aprotic polar solvents such as these or a mixed solvent thereof.

  Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.

  The ratio of the carboxylic acid (4), the alkylhalocarboxylic acid and the amine (5) used in the mixed acid anhydride method should normally be equimolar, but the alkylhalocarboxylic acid and the amine (5) Carboxylic acid (4) can be used in the range of about equimolar to 1.5 times molar amount.

  In the method (c) in which the condensation reaction is carried out in the presence of the activator, the reaction is carried out in a suitable solvent in the presence or absence of a basic compound. As the solvent and the basic compound used here, any of the solvent and the basic compound used in the method of reacting the amine (5) with the carboxylic acid halide of the other method (d) can be used. The amount of activator used is usually at least equimolar, preferably equimolar to 5-fold molar relative to compound (5). When using WSC as an activator, the reaction can be advantageously advanced by adding an acid such as 1-hydroxybenzotriazole and / or hydrochloric acid to the reaction system. The reaction is usually performed at about -20 to 180 ° C, preferably about 0 to 150 ° C, and the reaction is generally completed in about 5 minutes to 90 hours.

  Of the other methods (d), when the method of reacting a carboxylic acid halide with an amine (5) is employed, the reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound used, known compounds can be widely used. For example, any of the basic compounds used in the Schotten-Baumann reaction can be used. Examples of the solvent include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, acetonitrile, pyridine, in addition to the solvent used in the mixed acid anhydride method. , Acetone, water and the like. The proportion of amine (5) and carboxylic acid halide used is not particularly limited and may be appropriately selected within a wide range. Usually, the latter is at least about the equimolar amount, preferably equimolar to 5 times the former. The molar amount is good. The reaction is usually carried out at about -20 to 180 ° C, preferably about 0 to 150 ° C, and the reaction is generally completed in about 5 minutes to 50 hours.

  Further, the amide bond formation reaction shown in the above reaction formula-2 is carried out by converting carboxylic acid (4) and amine (5) into triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloride, diethyl chlorophosphate. It can also be carried out by a method of reacting in the presence of a condensing agent of a phosphorus compound such as diethyl cyanophosphate, diphenyl phosphate azide, and bis (2-oxo-3-oxazolidinyl) phosphinic chloride. The condensing agent may be used alone or in combination of two or more.

The reaction is usually performed at about −20 to 150 ° C., preferably about 0 to 100 ° C. in the presence of a solvent and a basic compound used in the method for reacting the amine (5) with the carboxylic acid halide. In general, the reaction is completed in about 5 minutes to 30 hours. The condensing agent and the carboxylic acid (4) are used in an amount of at least about equimolar amount, preferably about equimolar to 2-fold molar amount with respect to the amine (5).
[Reaction Formula-3]

[Wherein, R ¹ , R ² , Y, T and A ₁ are the same as above.
R ^3a and R ^4a are the same as the 5- to 10-membered saturated heterocyclic group defined by R ³ and R ⁴ except that they have at least one secondary amine on the heterocyclic group. is there.
R ^3ba and R ^4ba are defined as R ³ and R ⁴ except that they have at least one tertiary amine substituted with a group R ¹⁷ (R ^18a ) CH— on the heterocyclic group. It is the same as a 10-membered saturated heterocyclic group.
R ¹⁷ represents a hydrogen atom or a lower alkyl group.
R ^18a is a hydrogen atom; a cyano group, a nitro group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group that may have a halogen atom or a lower alkoxy group as a substituent, and a halogen atom as a substituent. A lower alkoxy group, a hydroxyl group, an aminosulfonyl group which may have a lower alkyl group as a substituent, a lower alkylaminocarbonyl group, a tetrazolyl group which may have a lower alkyl group or a lower alkoxy lower alkyl group as a substituent, lower alkynyl 1 to 3 groups selected from the group consisting of a group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a 1,2,4-triazolyl group, an imidazolyl group, a piperidinyl group and a lower alkylenedioxy group may be substituted. Lower alkyl group having 1 to 2 good phenyl groups A cyano group, a nitro group, a halogen atom as a substituent on the phenyl ring, a lower alkyl group that may have a halogen atom or a lower alkoxy group as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a hydroxyl group An aminosulfonyl group which may have a lower alkyl group as a substituent, a lower alkylaminocarbonyl group, a tetrazolyl group which may have a lower alkyl group or a lower alkoxy lower alkyl group as a substituent, a lower alkynyl group and a lower alkylsulfonyl group A phenyl group optionally substituted by 1 to 3 groups selected from the group consisting of lower alkylsulfonylamino group, 1,2,4-triazolyl group, imidazolyl group, piperidinyl group and lower alkylenedioxy group; Above, hydroxyl as a substituent, water as a substituent A pyridyl lower alkyl group having 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkyl group and a cyano group, which may have a group; a hydroxyl group and a substituent as a substituent on the pyridine ring A pyridyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group which may have a hydroxyl group, a halogen atom, a lower alkoxy group and a cyano group; a lower alkyl group as a substituent on the pyrrole ring; A pyrrolyl lower alkyl group which may have 3 to 3; a pyrrolyl group which may have 1 to 3 lower alkyl groups as a substituent on the pyrrole ring; a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent lower alkyl group with it; group ^{_{- (B 6 CO) t-}} N (R 15) R 16; quinolyl lower alkyl group; a quinolyl group; A thiazolyl lower alkyl group that may have a phenyl group as a substituent on the azole ring, a thiazolyl group that may have a phenyl group as a substituent on the thiazole ring; a lower alkyl group as a substituent on the benzimidazole ring; A benzimidazolyl lower alkyl group which may have 3; a benzimidazolyl group which may have 1 to 3 lower alkyl groups as substituents on the benzimidazole ring; a substituent on the 1,2,4-oxadiazole ring 1,2,4-oxadiazolyl lower alkyl group which may have an oxo group as 1, 2,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,2,4-oxadiazole ring; Cycloalkyl lower alkyl group; cycloalkyl group; lower alkyl as substituent on thiophene ring A thienyl lower alkyl group which may have a group; a thienyl group which may have a lower alkyl group as a substituent on the thiophene ring; a group selected from the group consisting of a lower alkyl group and a halogen atom as a substituent on the imidazole ring; An imidazolyl lower alkyl group which may have 1 to 3 groups; an imidazolyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent on the imidazole ring; isoxazole Isoxazolyl lower alkyl group optionally having 1 to 3 lower alkyl groups as substituents on the ring; isoxazolyl group optionally having 1 to 3 lower alkyl groups as substituents on the isoxazole ring; imidazo [2,1-b] thiazolyl lower alkyl group; imidazo [2,1-b] thiazolyl group; 3,4-dihydro- 3,4-dihydro-2H-1,4-benzoxazinyl lower alkyl group optionally having a lower alkyl group as a substituent on the H-1,4-benzoxazine ring; 3,4-dihydro- 3,4-dihydro-2H-1,4-benzoxazinyl group optionally having a lower alkyl group as a substituent on the 2H-1,4-benzoxazine ring; lower as a substituent on the pyrazole ring A pyrazolyl lower alkyl group optionally having 1 to 3 groups selected from the group consisting of an alkyl group and a halogen atom; a group selected from the group consisting of a lower alkyl group and a halogen atom as a substituent on the pyrazole ring; An optionally substituted pyrazolyl group; a dihydropyridyl lower alkyl group which may have an oxo group as a substituent on the dihydropyridine ring; a substituent on the dihydropyridine ring; It illustrates one phenyl-lower alkenyl group which may have a or a lower alkoxy group as a substituent on the phenyl ring; a morpholino lower alkyl group; a morpholino group and dihydropyridyl group which may have an oxo group.
R ¹⁷ and R ^18a may form a cycloalkyl group or a tetrahydro-4H-pyranyl group together with the carbon atom to which they are bonded.
Carbon number of the alkyl part of group R < ¹⁷ > (R <^18a> ) CH- in a compound (1ba) shall be less than six.
X ₂ represents a halogen atom, a lower alkanesulfonyloxy group such as a methanesulfonyloxy group, or an arylsulfonyloxy group such as a p-toluenesulfonyloxy group.
R ^3bb and R ^4bb are saturated 5- to 10-membered rings as defined for R ³ and R ⁴ except that they have at least one tertiary amine substituted with a group R ^18b on a heterocyclic group. Same as heterocyclic group.
R ^{3b c} and R ^{4b c} are 5- to 10-membered rings as defined for R ³ and R ⁴ except that they have at least one tertiary amine substituted with a group R ^18c on a heterocyclic group. The same as the saturated heterocyclic group of
R ^18b is a substituent of a heterocyclic group formed by combining R ³ and R ⁴ (1), (2), (3), (5), (6), (7), ( 9), (10), (12) (where t is 1), (13), (14), (15), (16), (17), (18), (19), (21) , (22), (23), (24), (25), (26), (27), (28), (29), or (30)
Is the same group.
R ^18c is the same group as the above (4), (8) or (31) which is a substituent of the heterocyclic group formed by combining R ³ and R ⁴ . ]

  The reaction between compound (1a) and compound (6a) is carried out, for example, in the absence of a reducing agent in the absence of a solvent or in a suitable solvent. This method is hereinafter referred to as “Method A”.

  Examples of the solvent used here include water, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetonitrile, formic acid, and acetic acid, diethyl ether, tetrahydrofuran, dioxane, and monoglyme. And ethers such as diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, or a mixed solvent thereof.

  Examples of the reducing agent include, for example, fatty acids such as formic acid, sodium formate and sodium acetate or alkali metal salts thereof, sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, lithium aluminum hydride and the like. Examples thereof include a reducing agent or a mixture of these hydrogenation reducing agents, a catalytic hydrogen reducing agent such as palladium-black, palladium-carbon, platinum oxide, platinum black, and Raney nickel.

  When a fatty acid such as formic acid, sodium formate, sodium acetate or the like, or an alkali metal salt thereof is used as the reducing agent, the reaction temperature is usually from room temperature to about 200 ° C., preferably from about 50 to 150 ° C. Generally, the process is completed in about 10 minutes to 10 hours. Fatty acid or its alkali metal salt is preferably used in a large excess amount relative to compound (1a).

  When a hydrogenation reducing agent is used, the reaction temperature is usually about −80 to 100 ° C., preferably about −80 to 70 ° C., and the reaction is generally completed in about 30 minutes to 60 hours. The hydrogenation reducing agent is generally used in an amount of about equimolar to 20-fold molar amount, preferably about equimolar to 6-fold molar amount relative to compound (1a). In particular, when lithium aluminum hydride is used as the hydrogenation reducing agent, it is preferable to use ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, and aromatic hydrocarbons such as benzene, toluene and xylene. . In the reaction system of the reaction, amines such as trimethylamine, triethylamine, N-ethyl-N, N-diisopropylamine, or molecular sieves such as molecular sieve 3A (MS-3A), molecular sieve 4A (MS-4A), etc. It may be added.

  When a catalytic hydrogen reducing agent is used, it is usually used in a hydrogen atmosphere at normal pressure to 20 atmospheres, preferably normal pressure to 10 atmospheres, or a hydrogen donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc. In the presence, the reaction is usually carried out at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C. The reaction is generally completed in about 1 to 12 hours. The catalytic hydrogen reducing agent is usually used in an amount of 0.1 to 40% by weight, preferably about 1 to 20% by weight, based on the compound (1a).

  In the reaction of compound (1a) with compound (6a), compound (6a) is usually used in an amount of at least equimolar amount, preferably equimolar to large excess, relative to compound (1a).

In the compound (6a), R ¹⁷ and R ^18a are used under the conditions using a hydrogenation reducing agent, starting from a compound that forms a cycloalkyl ring or a tetrahydro-4H-pyran ring together with the carbon atom to which they are bonded. When the reaction is carried out in place of the compound (6a), a cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl) oxy] trimethylsilane is used as a starting material instead of the compound (6a), and the compound (6a) described above is used in the reaction system. May be generated.

  The reaction between the compound (1a) and the compound (6b) is performed under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction between the compound (1a) and the compound (6c) is performed under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the above Reaction Scheme-2.
[Scheme-4]

[Wherein, R ¹ , R ² , Y, T and A ₁ are the same as above.
R ^3c and R ^4c are 5- to 10-membered rings defined by R ³ and R ⁴ except that they have at least one tertiary amine substituted with a lower alkoxycarbonyl group on the heterocyclic group. Same as the saturated heterocyclic group.
R ^3d and R ^4d are the same as the 5- to 10-membered saturated heterocyclic group defined by R ³ and R ⁴ except that they have at least one secondary amine on the heterocyclic group. is there. ]
The reaction for converting the compound (1c) to the compound (1d) is a hydrolysis reaction (this hydrolysis reaction is hereinafter referred to as “hydrolysis B”). For example, in a suitable solvent or without a solvent, acid or basic This can be done in the presence of the compound.

  Examples of the solvent used include water, lower alcohols such as methanol, ethanol, isopropanol and tert-butanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme, acetic acid, Aliphatic acids such as formic acid, esters such as methyl acetate and ethyl acetate, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide or these A mixed solvent etc. can be mentioned.

  Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as sulfonic acid such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, boron tribromide, boron trichloride, and the like. And Lewis acid. These acids are used singly or in combination of two or more.

  Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. be able to. These basic compounds are used singly or in combination of two or more.

The hydrolysis reaction proceeds normally at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 10 minutes to 50 hours.
[Reaction Formula-5]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, T and A ₁ are the same as above. ]

The reaction between the compound (7) and the compound (8) is carried out under the same reaction conditions as the reaction between the compound (5) and the compound (4) in the above Reaction Scheme-2.
[Reaction Formula-6]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , Y, T and A ₁ are the same as above. R ^6a represents a lower alkyl group, a lower alkylsulfonyl group or a phenyl lower alkyl group which may have a lower alkoxy group as a substituent. X ₂ represents a halogen atom, a lower alkanesulfonyloxy group such as a methanesulfonyloxy group, or an arylsulfonyloxy group such as a p-toluenesulfonyloxy group. B ₇ represents B, a group —SO ₂ — or a direct bond. ]

The reaction between the compound (1f) and the compound (9) is performed under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.
[Reaction Formula-7]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , Y, T, A ₁ and X ₂ are the same as above. ]

The reaction between the compound (10) and the compound (11) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above reaction formula-1.
[Reaction Formula-8]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , Y, T and A ₁ are the same as above. ]

  The reaction between the compound (12) and the compound (13) is carried out in the presence or absence of a basic compound, preferably in the absence of a suitable inert solvent or no solvent.

  As for the inert solvent and the basic compound, the amine (5) is added to the carboxylic acid halide of the method (d) in the reaction (amide bond formation reaction) between the compound (4) and the compound (5) in the reaction formula-2. Any solvent and basic compound used in the reaction can be used.

  The amount of compound (13) to be used is generally about equimolar to 5-fold molar amount, preferably about equimolar to 3-fold molar amount with respect to compound (12).

  The reaction proceeds suitably at about 0 to 200 ° C., preferably about room temperature to about 150 ° C., and is usually completed in about 5 minutes to 50 hours.

Boron compounds such as boron trifluoride diethyl ether complex may be added to the reaction system of the reaction.
[Reaction Formula-9]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ¹¹ , Y, T and A ₁ are the same as above. ]

The reaction between the compound (14) and the compound (15) is performed under the same reaction conditions as the reaction between the compound (12) and the compound (13) in the above Reaction Scheme-8.
[Reaction Formula-10]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, T and A ₁ are the same as above. R ¹⁹ represents a lower alkanesulfonyl group such as a methanesulfonyl group or an arylsulfonyl group such as a p-toluenesulfonyl group. X ₃ and X ₄ represent a halogen atom. B ₀ represents a lower alkylene group. ]

  The reaction between the compound (16) and the compound (17) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.

  The reaction for converting compound (16) to compound (19) is carried out by reacting compound (16) with a halogenating agent in a suitable solvent or without solvent.

  Examples of halogenating agents include mineral acids such as hydrochloric acid and hydrobromic acid, N, N-diethyl-1,2,2-trichlorovinyl azide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, mesyl Examples include sulfonyl halide compounds such as chloride and tosyl chloride, a mixture of carbon tetrabromide and triphenylphosphine, and the like. The sulfonyl halide compound is used in combination with a basic compound.

  As the basic compound, any of the basic compounds used in the reaction of the compound (2) of the reaction formula-1 and the compound (3) can be used.

  Examples of the solvent used include ethers such as dioxane, tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, dimethylformamide and the like, or a mixed solvent thereof.

  With respect to the use amount of the halogenating agent, when a sulfonyl halide compound and a basic compound are used as the halogenating agent, the sulfonyl halide compound is usually at least equimolar, preferably equimolar to 2 with respect to the compound (16). It is better to use a double molar amount. The basic compound is usually used in a catalytic amount, preferably a catalytic amount to an equimolar amount with respect to the compound (16). When another halogenating agent is used, it is preferable to use the halogenating agent in an amount of at least equimolar, usually a large excess, relative to compound (16).

  The reaction normally proceeds suitably at room temperature to 200 ° C, preferably room temperature to 150 ° C, and is generally completed in about 1 to 80 hours.

The reaction between the compound (18) and the compound (20) and the reaction between the compound (19) and the compound (20) are both the same as the reaction between the compound (2) and the compound (3) in the reaction formula-1. Performed under reaction conditions.
[Reaction Formula-11]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , Y, T and A ₁ are the same as above. X ₅ represents a halogen atom. R ²⁰ represents a hydrogen atom or a lower alkyl group. ]

  The reaction of compound (21) and compound (22) is carried out in a suitable solvent in the presence of a basic compound and a catalyst.

  As the solvent, a solvent inert to the reaction can be widely used, for example, water, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme and diglyme. , Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, fatty acids such as acetic acid, ethyl acetate, methyl acetate, etc. Esters, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, N-methylpyrrolidone, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide or a mixed solvent thereof It can be mentioned.

  Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and potassium phosphate. Metal phosphates such as sodium phosphate, sodium hydride, potassium hydride, potassium, sodium, sodium amide, sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium bis Alkylsilylamide alkali metal salts such as (trimethylsilyl) amide, pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, -Methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2. 2.2] Organic bases such as octane (DABCO) or mixtures thereof.

  Examples of the catalyst include palladium acetate, bis (tributyltin) / bis (dibenzylideneacetone) palladium, copper iodide / 2,2′-bipyridyl, bis (dibenzylideneacetone) palladium, copper iodide / bis (triphenyl). Phosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium, R-tris (dibenzylideneacetone) dipalladium, S-tris (dibenzylideneacetone) dipalladium, palladium (II) acetate, [1,1′-bis ( Diphenylphosphino) ferrocene] dichloropalladium (II), palladium compounds such as tetrakis (triphenylphosphine) palladium, R-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (R-BINAP) , S-2,2'-bis Diphenylphosphino) -1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (RAC-BINAP), 2,2-bis (diphenyl) Compounds such as imidazolidinylidene), xanthene compounds such as 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, borates such as tritert-butylphosphine tetrafluoroborate, etc., or mixtures thereof Etc.

  The basic compound is used in an amount of at least 0.5 times mol, preferably 0.5 times mol to 40 times mol of the compound (21). As a usage-amount of a catalyst, it is good to set it as a normal catalyst amount with respect to a compound (21).

  The amount of compound (22) to be used is at least 0.5 mol, preferably 0.5 to 3 mol, relative to compound (21).

The reaction is usually completed at room temperature to 200 ° C., preferably from room temperature to 150 ° C., in about 0.5 to 20 hours.
[Reaction formula-12]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , Y, T and A ₁ are the same as above. In the compound (24), B represents a boron atom. ]

  The reaction of compound (23) and compound (24) is carried out in a suitable solvent in the presence of a basic compound and a catalyst.

  Examples of the solvent used include aromatic hydrocarbons such as water, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme and diglyme, dichloromethane, dichloroethane, chloroform, and four. Halogenated hydrocarbons such as carbon chloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, acetone, methyl ethyl ketone, etc. Examples include ketones, acetonitrile, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, and mixed solvents thereof.

  Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, and the like. Metal alkoxides such as potassium hydride, potassium, sodium, sodium amide, sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, pyridine, imidazole, N-ethyldiisopropylamine, Dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3,0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] Undecene -7 (DBU), and 1,4-diazabicyclo [2.2.2] organic base or a mixture thereof, such as octane (DABCO).

  Examples of the catalyst include palladium compounds such as tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) palladium (II), and copper compounds such as copper acetate (II).

  The amount of the basic compound used is usually at least equimolar, preferably equimolar to 5-fold molar relative to compound (23).

  The amount of the catalyst to be used is generally 0.001 to equimolar amount, preferably 0.01 to 0.5 times molar amount relative to the compound (23).

  The amount of compound (24) to be used is generally at least equimolar, preferably equimolar to 5-fold molar amount relative to compound (23).

The reaction is usually performed at -30 to 200 ° C, preferably around 0 to 150 ° C, and is generally completed in about 0.5 to 30 hours. In the reaction system, molecular sieves such as molecular sieve 3A (MS-3A), molecular sieve 4A (MS-4A), etc. may be added.
[Reaction Formula-13]

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , Y, T, A ₁ , X ₅ , B ₃ and n are the same as above. ]

  The reaction between the compound (21) and the compound (25) is performed under the same reaction conditions as the reaction between the compound (21) and the compound (22) in the above Reaction Scheme-11.

Production method of raw material compound In each of the above reaction formulas, each compound used as a starting material is a known compound, or a method shown in Reference Examples below, a method shown in each of the above reaction formulas, or these methods Easy to manufacture. Among them, typical production methods are shown in the following reaction formula-14 to reaction formula-37.
[Reaction formula-14]

[Wherein R ² , Y, A ₁ , T ₁ , R ³ and R ⁴ are the same as above. R ²¹ represents R ¹ , an alkoxycarbonyl group, a halogen atom or an amino group which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group and a lower alkanoyl group as a substituent. Here, R ¹ is the same as described above. ]

The reaction between the compound (26) and the compound (5) is performed under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the above Reaction Scheme-2.
[Reaction formula-15]

[Wherein, R ² , Y, A ₁ , T, R ^3a , R ^4a , R ^3b , R ^4b , R ¹⁷ and R ¹⁸ are the same as above. However, the carbon number of the alkyl moiety of the group R ¹⁷ (R ¹⁸ ) CH— in the compound (29) shall not exceed 6. ]

The reaction between the compound (28) and the compound (6) is performed under the same reaction conditions as the reaction between the compound (1a) and the compound (6) in the above Reaction Scheme-3.
[Reaction formula-16]

[Wherein, R ² , Y, A ₁ , T, R ^3c , R ^4c , R ^3d and R ^4d are the same as above. ]

The reaction leading from compound (30) to compound (31) is carried out under the same reaction conditions as the reaction leading from compound (1c) to compound (1d) in the above Reaction Scheme-4.
[Reaction Formula-17]

[Wherein R ² , Y, A ₁ and T ₁ are the same as above. R ²² represents a hydrogen atom, a lower alkyl group or a lower alkoxy group. R ²³ represents a lower alkyl group. R ²⁴ represents R ⁵ , a lower alkyl group or a lower alkoxy group. R ⁵ is the same as above. ]

The reaction between the compound (32) and the compound (33) is performed under the same reaction conditions as the reaction between the compound (1a) and the compound (6) in the above Reaction Scheme-3.
[Reaction formula-18]

[Wherein, R ² , Y, A ₁ , T ₁ , R ²³ , R ²⁴ , B ₇ and X ₂ are the same as above. ]

The reaction between the compound (35) and the compound (36) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.
[Reaction Formula-19]

Wherein R ² , Y, X ₁ and R ⁵ are the same as above. ]

The reaction between the compound (38) and the compound (39) is performed under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the above Reaction Scheme-2.
[Reaction formula-20]

[Wherein, R ² , Y, A ₁ , T ₁ , R ³ , R ⁴ , R ⁵ and R ²³ are the same as above. ]

  The reaction for converting the compound (41) to the compound (43) can be carried out under the same reaction conditions as the hydrolysis B described in the above reaction scheme-4.

  Any ordinary esterification reaction conditions can be applied to the reaction between the compound (43) and the compound (42). For example, the reaction is performed in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride or the like. The compound (42) is used in a large excess amount relative to the compound (43). The reaction normally proceeds suitably at about 0 to 150 ° C., preferably about 50 to 100 ° C., and is generally completed in about 1 to 10 hours.

  The esterification reaction may be performed using a condensing agent such as carbodiimide in the presence of a basic compound such as dimethylaminopyridine, or a reaction between compound (4) and compound (5) in Reaction Formula-2. The usual amide bond formation reaction conditions used may be applied.

  The reaction between the compound (43) and the compound (42) is also performed in the same basic compound and solvent as those used in the reaction between the compound (2) and the compound (3) in Reaction Scheme-1. Is called. The reaction temperature of this reaction is usually 0 to 100 ° C., preferably around 0 to 70 ° C., and the reaction is generally completed in about 1 to 30 hours.

  A compound (41) is produced in the same manner as in the reaction of the compound (2) and the compound (3) in the above reaction scheme-1, using a halogenated lower alkyl such as methyl iodide in place of the compound (42). You can also.

  The reaction leading compound (41) to compound (45) can be carried out, for example, by (1) reducing compound (41) using a catalytic hydrogen reducing agent in a suitable solvent, or (2) in a suitable inert solvent. The compound (41) is reduced by using a mixture of a metal or metal salt and acid or a metal or metal salt and alkali metal hydroxide, sulfide, ammonium salt or the like as a reducing agent.

  When employing the method of (1) above, examples of the solvent include alcohols such as water, acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as n-hexane and cyclohexane, dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol. Ethers such as dimethyl ether, esters such as ethyl acetate and methyl acetate, aprotic polar solvents such as N, N-dimethylformamide, or a mixed solvent thereof can be used. As the contact hydrogen reducing agent, for example, palladium, palladium-black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used. These reducing agents are used singly or in combination of two or more. In general, the reducing agent is preferably used in an amount of about 0.02 to 1 times the weight of the compound (41). The reaction temperature is usually around −20 to 150 ° C., preferably around 0 to 100 ° C., the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 100 hours. An acid such as hydrochloric acid may be added to the reaction system of the reaction.

  When the method (2) is adopted, iron, zinc, tin or stannous chloride and mineral acid such as hydrochloric acid or sulfuric acid, or alkali metal hydroxide such as iron, ferrous sulfate, zinc or tin and sodium hydroxide, etc. And a mixture with a sulfide such as ammonium sulfide, ammonium salt such as aqueous ammonia and ammonium chloride are used as the reducing agent. Examples of the inert solvent include water, alcohols such as acetic acid, methanol, and ethanol, ethers such as dioxane, and mixed solvents thereof. The conditions for the reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as the reducing agent, it is preferably around 0 ° C. to 150 ° C. for about 0.5 to 10 hours. It is better to carry out the reaction. The reducing agent is used in an amount of at least equimolar amount, usually equimolar to 5-fold molar amount with respect to the compound (41).

  The reaction between the compound (45) and the compound (8) is performed under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the above Reaction Scheme-2.

  The reaction for converting the compound (46) to the compound (47) can be carried out under the same reaction conditions as the hydrolysis B described in the above reaction scheme-3.

The reaction between the compound (43) and the compound (5) is carried out under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the above Reaction Scheme-2.
[Reaction Formula-21]

[Wherein R ² , Y, and X ₂ are the same as above. R ^14a is the same as R ¹⁴ except for a hydrogen atom. R ^30a represents the group —T—NR ³ R ⁴ or the group —T ₁ —COOR ²³ . T, T ₁ , R ³ ,
R ⁴ and R ²³ are the same as described above. A ₂ represents a heterocyclic ring described in A ₁ having at least one secondary amine on the heterocyclic group, and A ₃ represents a heterocyclic ring described in A ₁ having at least one tertiary amine substituted by R ^14a on the heterocyclic ring. Indicates a ring. ]

The reaction between the compound (48) and the compound (49) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.
[Reaction formula -22]

[Wherein R ² , Y, A ₁ , B ₄ , R ³ and R ⁴ are the same as above. R ²⁵ and R ²⁶ each represent a hydrogen atom or a lower alkyl group. ]

The reaction between the compound (48) and the compound (51) is performed under the same reaction conditions as the reaction between the compound (1a) and the compound (6) in the above Reaction Scheme-3.
[Reaction Formula-23]

[Wherein, R ² , Y, A ₁ , T ₁ , R ³ , R ⁴ , R ^6a and X ₂ are the same as above. R ²⁷ represents a lower alkoxycarbonyl group. ]

  The reaction between the compound (53) and the compound (54) is performed under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the above Reaction Scheme-2.

  The reaction between the compound (55) and the compound (36) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction for converting the compound (56) to the compound (57) can be carried out under the same reaction conditions as the hydrolysis B described in the above reaction scheme-3.
[Reaction Formula-24]

[Wherein, R ¹ , R ² , Y, A ₁ and T ₁ are the same as above. R ²⁸ represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group. ]

  Compound (59) is produced by reducing compound (58).

For the reduction reaction, a reduction method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, borane, diborane, lithium borohydride-trimethoxyborane, and the like. These reducing agents are used singly or in combination of two or more. The amount of the hydrogenation reducing agent to be used is generally at least equimolar, preferably equimolar to 15-fold molar relative to compound (1f). This reduction reaction is usually carried out in a suitable solvent, for example, lower alcohols such as water, methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether and diglyme, and halogenation such as dichloromethane, chloroform and carbon tetrachloride. Using hydrocarbons or a mixture thereof, the reaction is carried out at about -60 to 150 ° C, preferably -30 to 100 ° C, generally for about 10 minutes to 40 hours. When lithium aluminum hydride or borane is used as the reducing agent, the solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc. is preferably an anhydrous solvent.
[Reaction formula-25]

[Wherein, R ² , Y and X ₁ are the same as above. R ²⁹ represents a nitro group or a halogen atom. R ³⁰ represents a group -A ₁ -T-NR ³ R ⁴ or a group -A ₁ -T ₁ -COOR ²³ . A ₁ , T, T ₁ , R ³ , R ⁴ and R ²³ are the same as described above. ]

The reaction between the compound (60) and the compound (61) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.
[Reaction formula-26]

[Wherein, R ² , Y and R ³⁰ are the same as above. ]

The reaction leading compound (63) to compound (64) is carried out under the same reaction conditions as the reaction leading from compound (41) to compound (45) in the above Reaction Scheme-20.
[Reaction formula-27]

Wherein R ² , Y, X ₁ and R ³⁰ are the same as above. R ³¹ represents R ¹ (R ¹ is as defined above), a nitro group or a lower alkoxycarbonyl group. ]

The reaction between compound (65) and compound (61) is carried out under the same reaction conditions as in the reaction between compound (60) and compound (61) in the aforementioned Reaction Scheme-25.
[Reaction formula-28]

[Wherein R ² , A ₂ , Y, X ₁ and B ₄ are the same as above. R ³² represents R ¹ , a lower alkoxycarbonyl group or a nitro group. R ³³ represents —CONR ³ R ⁴ or —COOR ²³ . R ¹ , R ³ , R ⁴ and R ²³ are the same as described above. A ₄ represents the heterocyclic ring described in A ₁ having at least one tertiary amine substituted with a group —B ₄ R ^{33 on} the heterocyclic ring. ]

The reaction between the compound (67) and the compound (68) is performed under the same reaction conditions as in the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.
[Reaction formula-29]

[Wherein R ² , Y, A ₁ , T ₁ and R ²¹ are the same as above. R ³⁴ represents a lower alkyl group or a phenyl lower alkyl group. ]

  The reaction for converting the compound (70) to the compound (26) can be carried out under the same reaction conditions as the hydrolysis B described in the above reaction scheme-4.

  The reaction between compound (26) and compound (71) is carried out under the same reaction conditions as in the reaction between compound (43) and compound (42) in the aforementioned Reaction Scheme-20.

In the same manner as described above, a lower alkyl halide such as methyl iodide is used in place of the compound (71), and the reaction is performed under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above reaction scheme-1. Also, the compound (70) can be produced.
[Reaction formula-30]

[Wherein, R ² , Y, A ₁ , T ₁ , X ₂ and R ⁵ are the same as above. R ³⁵ represents a hydrogen atom or a lower alkyl group. B ₈ represents a lower alkylene group or a direct bond. ]

  The reaction between compound (72) and compound (73) is carried out in a suitable inert solvent in the presence of a condensing agent.

  Examples of the inert solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Halogenated hydrocarbons such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol and other lower alcohols, α-dimethylaminoacetic acid, acetic acid and other fatty acids, ethyl acetate, methyl acetate and other esters, acetone And ketones such as methyl ethyl ketone, acetonitrile, 1-methyl-2-pyrrolidone, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, or a mixed solvent thereof. Kill.

  Examples of the condensing agent include palladium complexes such as bis (benzonitrile) dichloropalladium (II).

  The amount of the condensing agent to be used is generally 0.01 to equimolar amount, preferably 0.01 mol to 0.5 molar amount, relative to compound (72).

  The reaction usually proceeds suitably at 0 to 200 ° C., preferably at room temperature to 150 ° C., and is generally completed in about 10 minutes to 20 hours.

When a fatty acid alkali metal salt such as sodium acetate is added to the reaction system, the reaction proceeds advantageously.
[Reaction formula-31]

[Wherein, R ² , R ³² , Y and A ₁ are the same as above. R ³⁶ represents a lower alkanoyl group. R ³⁷ represents a lower alkoxycarbonyl group. R ³⁸ and R ³⁹ each represent a lower alkoxy group. R ⁴⁰ represents a hydrogen atom or a lower alkyl group. R ⁴¹ represents an amino group, a lower alkoxycarbonyl group, or R ¹ (R ¹ is the same as described above). Here, the carbon number of the C (R ⁴⁰ ) ═CH moiety and the carbon number of the CH (R ⁴⁰ ) CH ₂ moiety shall not exceed 6. ]

  The reaction between compound (75) and compound (76) is carried out in a suitable solvent in the presence of a basic compound.

  Any known solvent can be used as long as it does not affect the reaction. Examples of such solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic carbonization such as n-hexane, heptane and cyclohexane. Hydrogen, amines such as pyridine, N, N-dimethylaniline, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, alcohols such as methanol, ethanol, isopropanol or the like And the like.

  Examples of basic compounds include metal hydroxides such as metal sodium, metal potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. Carbonate, sodium methylate, sodium ethylate, metal alcoholates such as potassium tert-butoxide, alkyl and aryl lithium or lithium amides such as methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide, pyridine, piperidine, Examples thereof include organic bases such as quinoline, triethylamine, diisopropylethylamine, and N, N-dimethylaniline. These basic compounds are used individually by 1 type or in mixture of 2 or more types. The basic compound is generally used in an amount of 0.1 to 10-fold mol amount, preferably 0.5 to 5-fold mol amount based on Compound (75).

  The amount of compound (76) to be used is generally at least equimolar amount, preferably equimolar to 5-fold molar to compound (75).

  The reaction is usually −80 to 150 ° C., preferably around −80 to 120 ° C., and the reaction is generally completed in about 0.5 to 40 hours.

  When an organic base is used as the basic compound, the reaction proceeds advantageously when a lithium salt such as lithium chloride is added to the reaction system.

The reaction for converting compound (77) to compound (78) is performed under the same reaction conditions as the reaction for converting compound (41) to the compound (45) in the aforementioned Reaction Scheme-20.
[Reaction formula-32]

[Wherein R ² , R ³⁰ and Y are the same as above. ^R42 represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group. ]

The reaction for converting compound (79) to compound (80) is performed under the same reaction conditions as the reaction for converting compound (58) to the compound (59) in the aforementioned Reaction Scheme-24.
[Reaction formula-33]

[Wherein, R ² , B ₀ , R ³⁰ , Y and X ₄ are the same as above. R ⁴³ represents a lower alkanesulfonyl group such as a methanesulfonyl group or an arylsulfonyl group such as a tosyl group. ]

The reaction between the compound (81) and the compound (82) is performed under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.
[Reaction formula-34]

[Wherein R ² , R ⁵ , R ³⁰ and Y are the same as above. Z ₂ represents a lower alkenylene group. Z ₃ represents a lower alkylene group. ]

  The reaction for converting compound (84) to compound (85) is carried out in a suitable solvent in the presence of a catalytic hydrogen reducing agent.

  Examples of the solvent include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, diethyl ether, dimethoxyethane, Ethers such as tetrahydrofuran, monoglyme, diglyme and 1,4-dioxane, esters such as methyl acetate, ethyl acetate and butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like Examples thereof include a protic polar solvent or a mixed solvent thereof.

  Examples of the contact hydrogen reducing agent include palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, Raney nickel, palladium acetate and the like.

  The catalytic hydrogen reducing agent is generally used in an amount of about 0.01 to about the same weight as the compound (84).

The above reaction usually proceeds suitably at about -20 to 150 ° C, preferably about 0 to 100 ° C, and is generally completed in about 0.5 to 20 hours. The hydrogen pressure is usually about 1 to 10 atm.
[Reaction formula-35]

[Wherein, R ¹ , R ² , Y and A ₁ are the same as above. ]

  The reaction for converting compound (86) to compound (87) is carried out in a suitable solvent in the presence of an oxidizing agent.

  Examples of the solvent include water, fatty acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, esters such as ethyl acetate and methyl acetate, alcohols such as methanol, ethanol and isopropanol, dioxane, tetrahydrofuran and diethyl ether. Ethers, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, hexamethylphosphoric triamide, N, N-dimethylformamide, dimethyl Examples thereof include sulfoxide, pyridine and the like, and mixed solvents thereof.

Examples of the oxidizing agent include peracids such as formic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperiodate, Dichromates such as dichromic acid, sodium dichromate and potassium dichromate, permanganates such as manganese dioxide, permanganate, sodium permanganate and potassium permanganate, and lead salts such as lead tetraacetate Silver oxide, Dess-Martin periodinane, o-iodoxybenzoic acid, 1-hydroxy-1,2-benziodoxolone-3 (1H) -one 1-oxide, and the like. The oxidizing agent is generally used in an amount of at least equimolar amount, preferably equimolar to 3-fold molar amount with respect to compound (86).
[Reaction formula-36]

[Wherein R ² , R ³¹ and Y are the same as above. ]

The reaction for reducing compound (88) to lead to compound (89) is performed under the same reaction conditions as the reaction for leading compound (58) to compound (59) in the aforementioned Reaction Scheme-24. As the hydrogenation reducing agent, in addition to the hydrogenation reducing agent exemplified in the reaction leading to the compound (59) from the compound (58), complexes such as borane-pyridine and borane-trimethylamine can be used. As the solvent, dioxane can be used in addition to the solvent exemplified in the reaction leading to the compound (59) from the compound (58).
[Reaction formula-37]

[Wherein R ² , R ³⁰ and Y are the same as above. R ⁴⁴ represents a lower alkyl group. ]

The reaction for converting the compound (90) to the compound (91) can be carried out under the same reaction conditions as the hydrolysis B described in the above reaction scheme-4.
[Reaction formula-38]

[Wherein, R ¹ , R ² , Y, A ₁ and T are the same as above.

R ^3e and R ^4e each have at least one other nitrogen atom in addition to the nitrogen atom to which T is bonded, except that the 5- to 10-membered saturated heterocycle defined by R ³ and R ⁴ is used. Same as the cyclic group.

R ^3f and R ^4f are defined as R ³ and R ⁴ except that they have at least one nitrogen atom substituted with an N-oxide group in addition to the nitrogen atom to which T is bonded. The same as the saturated heterocyclic group of the member ring. ]

  The reaction for converting compound (92) to compound (93) is carried out in a suitable solvent in the presence of an oxidizing agent.

  Examples of the oxidizing agent include peracids such as formic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperiodate, Examples include dichromates such as dichromic acid, sodium dichromate and potassium dichromate, permanganates such as permanganate, sodium permanganate and potassium permanganate, and lead salts such as lead tetraacetate. It is done. These oxidizing agents are used singly or in combination of two or more.

  Examples of the solvent include water, methanol, ethanol, isopropanol, butanol, tert-butanol, lower alcohols such as ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, Examples thereof include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene, or a mixed solvent thereof.

  The amount of the oxidizing agent to be used is usually at least equimolar, preferably equimolar to 3-fold molar relative to compound (92).

  The reaction is usually performed at −30 to 200 ° C., preferably around −10 to 100 ° C., and is generally completed in about 0.5 to 30 hours.

  Each target compound obtained by each reaction formula shown above is prepared by cooling the reaction mixture, for example, and then separating the crude reaction product by an isolation operation such as filtration, concentration, extraction, etc., column chromatography, recrystallization The reaction mixture can be isolated and purified by a usual purification operation such as.

  Each raw material compound in the above reaction formula-1 to reaction formula-38 may be an appropriate salt or an appropriate reactive derivative. Moreover, those target compounds may also form suitable salts. Examples of such salts include the same salts as the heterocyclic compound (1).

  Each raw material compound in the above reaction formula-14 to reaction formula-38 is a known compound or is easily produced according to a known method.

  The compound represented by the general formula (1) of the present invention includes stereoisomers, optical isomers, and solvates (hydrates, ethanolates, etc.).

  The compound represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by acting a pharmaceutically acceptable acid, and the present invention includes this acid addition salt. . In the above, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, and tartaric acid. , Citric acid, malonic acid, methanesulfonic acid, benzoic acid, trifluoroacetic acid, benzenesulfonic acid, formic acid, toluenesulfonic acid, organic acids such as lactic acid, or amino acids (for example, arginine, aspartic acid, glutamic acid, etc.) be able to.

  Moreover, the compound which has an acidic group among the compounds represented by General formula (1) of this invention can form a salt easily by making a pharmacologically acceptable basic compound act. Examples of such salts include metal salts such as alkali metal salts (for example, sodium salts and potassium salts) and alkaline earth metal salts (for example, calcium salts and magnesium salts); ammonium salts; organic base salts (for example, , Trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.). Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

  Next, a medical preparation containing the compound of the present invention as an active ingredient will be described.

  The above-mentioned medical preparation is prepared by formulating the compound of the present invention in the form of a normal medical preparation, and is usually used as a filler, a bulking agent, a binder, a moistening agent, a disintegrant, a surfactant, and a lubricant. It is prepared using a diluent or excipient.

  Such a medical preparation can be selected from various forms depending on the purpose of treatment, and representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories. Agents, injections (solutions, suspensions, etc.), ointments and the like.

  Known carriers can be widely used as a carrier for molding into tablets. For example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like can be used. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, white sugar, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors, Class Anne Absorption accelerators such as nium base, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol And the like.

  Furthermore, the tablet can be made into a tablet with an ordinary tablet skin, if necessary, such as a sugar coating, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet.

  As the carrier used for forming into a pill form, known ones can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.

  As the carrier used for forming into a suppository form, known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

  When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. As diluents used for forming these liquids, emulsions and suspensions, known ones that are widely used can be used, for example, water, aqueous lactic acid, ethanol, propylene Examples include glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbetane fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizer, buffer, soothing agent, etc. Further, if necessary, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained.

  In formulating in the form of paste, cream and gel, conventionally known ones in this field can be widely used as diluents, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite, etc. .

  The amount of the compound of the present invention contained in the medical preparation is not particularly limited and can be appropriately selected from a wide range. Usually, it is preferable to contain 1 to 70% by weight of the compound of the present invention in the medical preparation. .

  There is no restriction | limiting in particular as the administration method of the medical formulation which concerns on this invention, It administers by the method according to various formulation forms, a patient's age, sex, a disease state, and other conditions. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of injections, they are administered alone or mixed with normal fluids such as glucose and amino acids and administered intravenously, and further, if necessary, alone intramuscularly, intradermally, subcutaneously or intraperitoneally. Can be administered. In the case of a suppository, it is administered intrarectally.

  The dosage of the above-mentioned medical preparation may be appropriately selected according to usage, patient age, sex, disease severity, and other conditions. Usually, the amount of the compound of the general formula (1) which is an active ingredient is 1 0.001 to 100 mg, preferably 0.001 to 50 mg, per 1 kg body weight per day is administered in 1 to several divided doses.

  Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage exceeding the above range may be necessary.

  Patents, patent applications and references cited in this application are inserted for reference.

  The compound of the present invention is remarkably excellent in suppressing the production of collagen.

  Therefore, the heterocyclic compound (1) or a salt thereof of the present invention is useful as a collagen production inhibitor and a fibrosis inhibitor. More specifically, it is effective for the prevention or treatment of diseases accompanied by fibrosis caused by excessive production of collagen. For example (i) idiopathic and interstitial pulmonary fibrosis, pneumoconiosis, ARDS, liver fibrosis, neonatal liver fibrosis, cirrhosis, pancreatic pustular fibrosis, myelofibrosis, (ii) scleroderma, Elephant skin disease, morphea, traumatic and postoperative thickening scar, skin diseases such as keloid after burn, (iii) vascular diseases such as atherosclerosis, arteriosclerosis, (iv) diabetic retinopathy, posterior lens fibrosis Proliferative diseases, angiogenesis associated with corneal transplantation, glaucoma, proliferative vitreoretinopathy, postoperative corneal scars and other ophthalmic diseases, (v) atrophic nephropathy, nephrosclerosis, renal fibrosis, interstitial nephropathy, IgA nephropathy, glomerulosclerosis, membrane proliferative nephritis, diabetic nephropathy, chronic interstitial nephritis, chronic glomerulonephritis, etc., (vi) cartilage such as rheumatoid arthritis, chronic arthritis, osteoarthritis Or it is effective as a preventive or therapeutic agent for diseases in bone. Among these, it is excellent in the effect of suppressing fibrosis associated with organ diseases exemplified in the above (i), and is particularly useful for the prevention and treatment of pulmonary fibrosis, liver fibrosis, and glomerulosclerosis.

The compounds of the present invention are also significantly superior in antitumor effects.
Examples of tumors that exhibit an antitumor effect include malignant tumors.

  Examples of malignant tumors include solid tumors (eg, cancer types, sarcomas, etc.), lymphomas, leukemias, and the like.

  More specifically, malignant tumors include, for example, pediatric brain tumors such as astrocytoma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, ependymoma; glioma, glioma, meningioma, lower Adult brain tumors such as pituitary adenoma, schwannoma; maxillary sinus cancer, pharyngeal cancer (nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), laryngeal cancer, oral cancer, lip cancer, tongue cancer, parotid gland cancer, etc. Head and neck cancer; breast cancer and tumors such as small cell lung cancer, non-small cell lung cancer, thymoma, mesothelioma; esophageal cancer, liver cancer, primary liver cancer, gallbladder cancer, bile duct cancer, stomach cancer, colon cancer, colon cancer, Gastrointestinal cancers and tumors such as rectal cancer, anal cancer, pancreatic cancer, pancreatic endocrine tumors; penile cancer, renal pelvic / ureteral cancer, renal cell carcinoma, testicular tumor, prostate cancer, bladder cancer, Wilms tumor, urothelium Urological cancers and tumors such as cancer; vulva cancer, cervical cancer, uterine body cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, breast cancer, ovarian cancer, egg Gynecological cancers and tumors such as germ cell tumors; Soft tissue sarcomas in adults and children; Bone tumors such as osteosarcomas and Ewing tumors; Cancers and tumors of endocrine tissues such as adrenal cortex cancer and thyroid cancer; Malignant lymphoma, non-Hodgkin lymphoma Malignant lymphoma and leukemia such as Hodgkin's disease, multiple myeloma, plasma cell tumor, acute myeloid leukemia, acute lymphocytic leukemia, adult T cell leukemia lymphoma, chronic myelogenous leukemia, chronic lymphocytic leukemia; chronic myeloproliferative Skin cancers and tumors such as diseases, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, mycosis fungoides, etc .; metastases of the above tumors and cancers and the like.

  When the compound of the present invention is used as the above-mentioned disease therapeutic agent, it is simultaneously or continuously with other drugs that have collagen production inhibitory action, drugs that have fibrosis inhibitory action, antiviral agents, anti-inflammatory agents, antitumor agents, etc Can be used. The compound of the present invention has few side effects and is excellent in safety.

  Production examples of the compounds used in the present invention are shown below together with the pharmacological test results of those compounds.

Reference example 1
Preparation of 6-hydroxy-1-methyl-1H-indole-2-carboxylic acid methyl ester N, N-dimethylformamide of 6-methoxy-1H-indole-2-carboxylic acid methyl ester (11.57 g, 56.38 mmol) (DMF) (100 ml) solution was added with 60% sodium hydride (40% mineral oil added, the same applies hereinafter) (2.93 g, 73.29 mmol) under ice-cooling, stirred for 15 minutes, and then methyl iodide ( 3.86 ml, 62.02 mmol) was added. The reaction solution was further stirred at the same temperature for 1 hour. Water and diethyl ether were added to the reaction solution, and the precipitate was collected by filtration. The obtained white solid was dissolved in dichloromethane (200 ml), boron tribromide (100 ml) was added under an ice stream under ice cooling, and the mixture was stirred for 1 hour. After adding methanol to the reaction solution, the solvent was distilled off. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated to give 10.19 g of the title compound.
Properties: Brown powder
¹ H-NMR (CDCl ₃ ) δ ppm:
3.88 (3H, s), 3.99 (3H, s), 5.01 (1H, s), 6.72 (1H, dd, J = 8.5 Hz, 2.2 Hz), 6.77 ( 1H, d, J = 2.1 Hz), 7.23 (1H, d, J = 1.0 Hz), 7.52 (1H, dd, J = 8.6 Hz, 0.5 Hz).

Reference example 2
Preparation of 4- (6-hydroxy-1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 6-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (10 g, 33 .86 mmol), a mixed solution of methyl iodide (2.32 ml, 37.10 mmol) in THF (100 ml) and DMF (50 ml) was ice-cooled, and 60% sodium hydride (1.63 g, 40.75 mmol) was added. Stir for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in ethanol (100 ml), 5M aqueous sodium hydroxide solution (20.3 ml, 101.5 mmol) was added, and the mixture was heated to reflux for 2 hours. The reaction solution was ice-cooled and acidified with 6M hydrochloric acid. After stirring, the precipitate was collected by filtration, washed with water and dried. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. Piperazine-1-carboxylic acid t-butyl ester (7.57 g, 40.63 mmol) was added to a DMF (120 ml) solution of the filtered product and the extract from the filtrate, and the mixture was ice-cooled and 1-ethyl-3 -(3-Dimethylaminopropyl) carbodiimide hydrochloride (9.7 g, 50.60 mmol) and 1-hydroxybenzotriazole monohydrate (6.1 g, 39.83 mmol) were added and stirred overnight at room temperature. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was stirred for 1 hour. The precipitate was collected by filtration and dried. This was dissolved in dichloromethane, washed with 1M aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. A suspension of 10% Pd / C (1.2 g) in ethanol (60 ml) was added to a solution of the residue in 1,4-dioxane (60 ml) under ice cooling, and the mixture was stirred at 40 ° C. for 3 hours in a hydrogen atmosphere (1 atm). . The reaction solution was filtered through Celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 3, volume ratio, the same applies hereinafter), crystallized from diethyl ether and collected by filtration. After drying under reduced pressure, 7.23 g of the title compound was obtained.
Properties: White powder
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 3.50 (4H, t, J = 5.3 Hz), 3.71 (3H, s), 3.76 (4H, t, J = 5.1 Hz), 5. 53 (1H, s), 6.53 (1H, s), 6.69-6.72 (2H, m), 7.43 (1H, d, J = 8.2 Hz).

Reference example 3
Preparation of 6-hydroxy-2,3-dihydroindole-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester 6-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (3.0 g, 10 mmol) ) In ethyl acetate (30 ml) was added triethylamine (2.1 ml, 15 mmol) and N, N-dimethylaminopyridine (0.12 g, 1.0 mmol). Under ice-cooling, di-t-butyl dicarbonate (2.7 g, 12 mmol) was added and stirred for 30 minutes. Water (30 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. To a solution of the obtained brown oily substance in ethanol (40 ml) was added 10% palladium-activated carbon (0.4 g), and the mixture was stirred at 50 ° C. for 6 hours in a hydrogen atmosphere (1 atm). 10% palladium-activated carbon was filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain 2.3 g of the title compound.
Properties: colorless oil
¹ H-NMR (CDCl ₃ ) δ ppm:
1.28 (3H, t, J = 5.3 Hz), 1.50 (9H, d, J = 1.3 Hz), 3.01 (1H, dd, J = 16.0 Hz, 4.5 Hz), 3 .43 (1H, dd, J = 15.7 Hz, 11.4 Hz), 4.18-4.23 (2H, m), 4.82-4.87 (1H, m), 5.04 (1H, s), 6.44 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 7.9 Hz), 7.46 (1H, s).

Reference example 4
Preparation of 6-benzyloxy-1-methoxymethyl-1H-indole-2-carboxylic acid ethyl ester 6-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (3.0 g, 10 mmol) in DMF (30 ml) Under ice cooling, 60% sodium hydride (0.49 g, 12 mmol) was added to the solution, and after stirring for 15 minutes, chloromethyl methyl ether (1.0 ml, 13 mmol) was added and stirred for 30 minutes. Water (60 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give 3.45 g of the title compound.
Properties: light brown oil
¹ H-NMR (CDCl ₃ ) δ ppm:
1.40 (3H, t, J = 7.3 Hz), 3.27 (3H, s), 4.36 (2H, q, J = 7.1 Hz), 5.14 (2H, s), 5. 93 (2H, s), 6.94 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.04 (1H, d, J = 2.3 Hz), 7.31-7.43 (5H , M), 7.46-7.49 (2H, m), 7.55 (1H, d, J = 8.9 Hz).

Reference Example 5
Preparation of 6-hydroxy-1-methoxymethyl-1H-indole-2-carboxylic acid ethyl ester 6-benzyloxy-1-methoxymethyl-1H-indole-2-carboxylic acid ethyl ester (3.45 g, 10 mmol) in ethanol (35 ml) To the solution was added 10% palladium-activated carbon (0.35 g), and the mixture was stirred at 50 ° C. for 2 hours under a hydrogen atmosphere (1 atm). After allowing to cool, 10% palladium-activated carbon was filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 2.0 g of the title compound.
Properties: colorless crystals
¹ H-NMR (CDCl ₃ ) δ ppm:
1.40 (3H, t, J = 7.1 Hz), 3.30 (3H, s), 4.36 (2H, q, J = 7.1 Hz), 4.85 (1H, s), 5. 91 (2H, s), 6.77 (1H, dd, J = 8.6 Hz, 2.3 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.30 (1H, d, J = 0.7 Hz), 7.53 (1H, d, J = 8.6 Hz).

Reference Example 6
Preparation of 6-hydroxy-1,3-dimethyl-1H-indole-2-carboxylic acid ethyl ester 6-benzyloxy-1,3-dimethyl-1H-indole-2-carboxylic acid ethyl ester (547 mg, 1.69 mmol) Sodium hydride (81 mg, 2.03 mmol) was added to a DMF (10 ml) solution under ice cooling. After stirring at the same temperature for 10 minutes, methyl iodide (116 μl, 1.86 mmol) was added while cooling with ice. The mixture was further stirred for 1 hour at the same temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 20 → 1: 4) to give white crystals (392 mg). The obtained white crystals were dissolved in a mixed solvent of ethanol (8 ml) and dioxane (4 ml), and 10% palladium carbon (40 mg) was added. The mixture was stirred for 7 hours at 40 ° C. under a hydrogen atmosphere. After filtration through celite, the filtrate was concentrated under reduced pressure to obtain 277 mg of the title compound.
Properties: White powder
¹ H-NMR (CDCl ₃ ) δ ppm:
1.42 (3H, t, J = 7.1 Hz), 2.55 (3H, s), 3.92 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 4. 82 (1H, s), 6.68-6.73 (2H, m), 7.51 (1H, dd, J = 8.4 Hz, 0.7 Hz).

Reference Example 7
Preparation of 5- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid methyl ester 5-hydroxy-1H-indole-2-carboxylic acid methyl ester (0.845 g, 4.42 mmol) and 2 -Chloro-5-nitropyridine (0.771 g, 4.86 mmol) was dissolved in DMF (5 ml), anhydrous potassium carbonate (0.611 g, 4.42 mmol) was added, and the mixture was stirred at 80 ° C. for 18 hours. Water (80 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) and recrystallized from a mixed solvent of ethyl acetate-n-hexane to obtain 0.753 g of the title compound.
Properties: Yellow powder
¹ H-NMR (CDCl ₃ ) δ ppm:
3.96 (3H, s), 7.04 (1H, d, J = 9.1 Hz), 7.13 (1H, dd, J = 9.0 Hz, 2.2 Hz), 7.23 (1H, d , J = 2.0 Hz), 7.47-7.50 (2H, m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.96 (1H, brs), 9 .05 (1H, d, J = 2.8 Hz).

  The following compounds were produced in the same manner as in Reference Example 7 using appropriate starting materials.

Reference Example 8
4- (5-Nitropyridin-2-yloxy) -1H-indole
¹ H-NMR (CDCl ₃ ) δ ppm:
6.27-6.30 (1H, m), 6.93-6.96 (1H, m), 7.02 (1H, d, J = 9.1 Hz), 7.17-7.27 (2H) , M), 7.34-7.38 (1H, m), 8.32 (1H, brs), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H , D, J = 2.8 Hz).

Reference Example 9
5- (5-Nitropyridin-2-yloxy) -1H-indole
¹ H-NMR (CDCl ₃ ) δ ppm:
6.56-6.59 (1H, m), 6.96-7.00 (2H, m), 7.28-7.30 (1H, m), 7.41-7.46 (2H, m) ), 8.28 (1H, brs), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

Reference Example 10
6- (1H-Indol-4-yloxy) -N- (4-trifluoromethylphenyl) nicotinamide
¹ H-NMR (CDCl ₃ ) δ ppm:
6.26-6.28 (1H, m), 6.90-6.94 (1H, m), 6.99 (1H, d, J = 8.6 Hz), 7.13-7.15 (1H M), 7.18-7.24 (1H, m), 7.29-7.32 (1H, m), 7.60 (2H, d, J = 8.7 Hz), 7.73 (2H) , D, J = 8.4 Hz), 8.08 (1H, brs), 8.19 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.39 (1H, brs), 8.67 (1H, d, J = 2.5 Hz).

Reference Example 11
4- [5- (5-Nitropyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.50 (9H, s), 3.57 (4H, t, J = 5.2 Hz), 3.92 (4H, brs), 6.78 (1H, s), 7.03 (1H, d, J = 9.1 Hz), 7.08 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.43 (1H, d, J = 2.3 Hz), 7.49 (1H, d, J = 8.9 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.6 Hz), 9.04 (1H, d, J = 2.6 Hz), 9.41 (1H, brs).

Reference Example 12
[5- (5-Bromopyridin-2-yloxy) indol-1-yl] acetic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.28 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 4.84 (2H, s), 6.54 (1H, dd, J = 3) .2 Hz, 0.7 Hz), 6.78 (1 H, dd, J = 8.7 Hz, 0.5 Hz), 6.99 (1 H, dd, J = 8.7 Hz, 2.3 Hz), 7.14 ( 1H, d, J = 3.2 Hz), 7.21-7.31 (1H, m), 7.37 (1H, d, J = 2.3 Hz), 7.71 (1H, dd, J = 8) .7 Hz, 2.6 Hz), 8.21 (1 H, dd, J = 2.6 Hz, 0.5 Hz).

Reference Example 13
6- (1H-Indol-4-yloxy) nicotinic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.38 (3H, t, J = 7.1 Hz), 4.37 (2H, q, J = 7.1 Hz), 6.28-6.30 (1H, m), 6.90-6.95 (2H, m), 7.14-7.16 (1H, m), 7.19-7.25 (1H, m), 7.30-7.33 (1H, m), 8.25 (1H , Dd, J = 8.7 Hz, 2.5 Hz), 8.34 (1H, brs), 8.85 (1H, d, J = 2.5 Hz).

Reference Example 14
4- [1-Methyl-5- (4-methyl-5-nitropyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 2.66 (3H, s), 3.50 (4H, brs), 3.76 (4H, brs), 3.86 (3H, s), 6.59 (1H) , S), 6.81 (1H, s), 7.07 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.37 (1H, d, J = 2.4 Hz), 7.41 (1H, d, J = 8.9 Hz), 8.88 (1H, s).

Reference Example 15
4- [1-Methyl-5- (6-methyl-5-nitropyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 2.76 (3H, s), 3.49-3.53 (4H, m), 3.75-3.80 (4H, m), 3.88 (3H, s), 6.59 (1H, s), 6.72 (1H, d, J = 9.2 Hz), 7.09 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.38 ( 1H, s), 7.40 (1H, d, J = 6.2 Hz), 8.33 (1H, d, J = 8.9 Hz).

Reference Example 16
4- [1-Methyl-5- (5-nitropyrimidin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 3.50 (4H, brs), 3.74-3.77 (4H, m), 3.87 (3H, s), 6.61 (1H, s), 7 .13 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.42-7.45 (2H, m), 9.31 (2H, s).

Reference Example 17
1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid methyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
3.93 (3H, s), 4.11 (3H, s), 7.03 (1H, d, J = 8.9 Hz), 7.15 (1H, dd, J = 2.2 Hz, 9.2 Hz) ), 7.27 (1H, d, J = 8.1 Hz), 7.44-7.47 (2H, m), 8.46 (1H, dd, J = 2.7 Hz, 8.9 Hz), 9 .03 (1H, d, J = 2.7 Hz).

Reference Example 18
(S) -3-Methyl-4- [1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.31 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 2.88 (1H, brs), 3.05 (1H, brs), 3.28 (1H, t, J = 11.3 Hz), 3.84 (3H, s), 3.92 (1H, s), 4.21 (2H, brs), 4.70 (1H, brs), 6.57 (1H, s) ), 7.02 (1H, dd, J = 0.5 Hz, 8.9 Hz), 7.08 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.39-7.43 (2H, m), 8.46 (1H, dd, J = 2.7 Hz, 8.9 Hz), 9.03 (1H, dd, J = 0.5 Hz, 2.7 Hz).

Reference Example 19
1-methyl-6- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.42 (3H, t, J = 7.0 Hz), 4.04 (3H, s), 4.38 (2H, q, J = 7.0 Hz), 6.94 (1H, dd, J = 2) .2 Hz, 8.6 Hz), 7.05 (1 H, d, J = 8.9 Hz), 7.19 (1 H, d, J = 1.6 Hz), 7.32 (1 H, d, J = 1. 6 Hz), 7.71 (1 H, d, J = 8.6 Hz), 8.48 (1 H, dd, J = 2.7 Hz, 8.9 Hz), 9.05 (1 H, d, J = 3.0 Hz) ).

Reference Example 20
1-methyl-7- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.40 (3H, t, J = 7.0 Hz), 4.09 (3H, s), 4.35 (2H, q, J = 7.0 Hz), 3.94 (3H, s), 7. 01 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.08 (1H, d, J = 8.9 Hz), 7.14 (1H, t, J = 7.8 Hz), 7.35 (1H, s), 7.60 (1H, dd, J = 0.8 Hz, 7.8 Hz), 8.51 (1H, dd, J = 3.0 Hz, 8.9 Hz), 9.05 (1H, dd, J = 0.8 Hz, 3.0 Hz).

Reference Example 21
1-methyl-4- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.36 (3H, t, J = 7.0 Hz), 4.11 (3H, s), 4.34 (2H, q, J = 7.0 Hz), 6.96 (1H, dd, J = 1) .4 Hz, 7.3 Hz), 7.03 (1 H, d, J = 0.8 Hz), 7.07 (1 H, dd, J = 0.5 Hz, 8.9 Hz), 7.32-7.43 ( 2H, m), 8.48 (1H, dd, J = 2.7 Hz, 8.9 Hz), 9.03 (1H, dd, J = 0.8 Hz, 3.0 Hz).

Reference Example 22
1,4-Dimethyl-5- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (3H, t, J = 7.0 Hz), 2.35 (3H, s), 4.09 (3H, s), 4.39 (2H, q, J = 7.0 Hz), 7. 01 (1H, dd, J = 0.5 Hz, 9.2 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 0.8 Hz), 8.46 (1H, dd, J = 2.7 Hz, 8.9 Hz), 9.02 (1H, dd, J = 0.3 Hz, 2.7 Hz).

Reference Example 23
1-methyl-6- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid methyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
3.92 (3H, s), 4.05 (3H, s), 6.94 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.06 (1H, d, J = 9.1 Hz) ), 7.19 (1H, d, J = 2.0 Hz), 7.32 (1H, s), 7.72 (1H, d, J = 8.6 Hz), 8.49 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

Reference Example 24
1-methyl-6- (5-nitropyrimidin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.42 (3H, t, J = 7.2 Hz), 4.06 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 6.98 (1H, dd, J = 8) .7 Hz, 2.1 Hz), 7.23 (1 H, d, J = 2.1 Hz), 7.34 (1 H, d, J = 0.8 Hz), 7.74 (1 H, d, J = 8. 7 Hz), 9.34 (2H, s).

Reference Example 25
6- (5-Nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.42 (3H, t, J = 7.1 Hz), 4.42 (2H, q, J = 7.1 Hz), 6.96 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7 .06 (1H, d, J = 9.2 Hz), 7.24-7.26 (2H, m), 7.73 (1H, d, J = 8.6 Hz), 8.49 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.96 (1H, s), 9.05 (1H, d, J = 2.6 Hz).

Reference Example 26
1-methoxymethyl-6- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.42 (3H, t, J = 7.3 Hz), 3.31 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 5.95 (2H, s), 7. 00 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.39 (1H, s), 7.73 (1H, d, J = 8.6 Hz), 8.49 (1H, dd, J = 8.9 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz).

Reference Example 27
6- (5-Nitropyridin-2-yloxy) -2,3-dihydroindole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.30 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 3.13 (1H, dd, J = 17.0 Hz, 4.8 Hz), 3.53 (1H, dd) , J = 16.2 Hz, 11.5 Hz), 4.23 (2 H, m), 4.90 (1 H, d, J = 10.9 Hz), 6.74 (1 H, d, J = 6.3 Hz) , 7.01 (1H, d, J = 8.9 Hz), 7.15 (1H, d, J = 7.9 Hz), 7.72 (1H, s), 8.46 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.06 (1H, d, J = 3.0 Hz).

Reference Example 28
1-methyl-6- {5- [methyl (4-trifluoromethoxybenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carboxylic acid
¹ H-NMR (CDCl ₃ ) δ ppm:
3.48 (3H, s), 4.05 (3H, s), 6.87-6.91 (2H, m), 7.09-7.11 (3H, m), 7.36-7. 38 (3H, m), 7.46 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.90 (1H, d, J = 3.0 Hz).

Reference Example 29
1,3-Dimethyl-6- (5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.45 (3H, t, J = 7.2 Hz), 2.60 (3H, s), 3.97 (3H, s), 4.42 (2H, q, J = 7.1 Hz), 6. 92 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.05 (1H, d, J = 9.1 Hz), 7.14 (1H, d, J = 1.8 Hz), 7.71 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.5 Hz).

Reference Example 30
4- [1-Methyl-6- (5-nitropyrimidin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 3.51 (4H, t, J = 4.7 Hz), 3.76 (4H, t, J = 5.1 Hz), 3.82 (3H, s), 6. 64 (1H, d, J = 0.7 Hz), 6.98 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.21 (1H, d, J = 2.1 Hz), 7.69 (1H, d, J = 8.6 Hz), 9.33 (2H, s).

Reference Example 31
1-methyl-6- (4-methyl-5-nitropyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.34 (3H, t, J = 7.1 Hz), 2.61 (3H, s), 3.99 (3H, s), 4.33 (2H, q, J = 7.1 Hz), 6. 97 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.19 (1H, s), 7.31 (1H, d, J = 0.7 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.74 (1 H, d, J = 8.9 Hz), 8.84 (1 H, s).

Reference Example 32
Preparation of 4- [1-methyl-6- (5-nitropyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester 6-Hydroxy-1-methyl-1H- A solution of indole-2-carboxylic acid (12.27 g, 64.2 mmol), piperazine-1-carboxylic acid t-butyl ester (14.34 g, 77.0 mmol) in DMF (80 ml) was cooled to 1-ethyl-3 under ice-cooling. -(3-Dimethylaminopropyl) carbodiimide hydrochloride (18.4 g, 96.0 mmol) and 1-hydroxybenzotriazole monohydrate (11.6 g, 75.7 mmol) were added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue for liquid separation. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in DMF (80 ml), 2-chloro-5-nitropyridine (10.05 g, 63.4 mmol) and potassium carbonate (11.92 g, 86.2 mmol) were added and stirred overnight. The solvent was distilled off, water and diethyl ether were added to the residue, and the mixture was stirred for 1 hour. The precipitate was collected by filtration and dried to obtain 23.2 g of the title compound.
Properties: Yellow powder
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 3.51 (4H, brs), 3.76 (4H, t, J = 5.1 Hz), 3.82 (3H, s), 6.63 (1H, s) 6.94 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.05 (1H, d, J = 9.2 Hz), 7.17 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 3.0 Hz).

Reference Example 33
Preparation of [4- (5-aminopyridin-2-yloxy) indol-1-yl] acetic acid ethyl ester [4- (5-nitropyridin-2-yloxy) indol-1-yl] acetic acid ethyl ester (1.49 g , 4.35 mmol) was dissolved in THF (tetrahydrofuran) (15 ml), 5% palladium-carbon (0.15 g) was added, and catalytic reduction was carried out at normal temperature and pressure for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 1.43 g of the title compound.
Properties: pale yellow oil
¹ H-NMR (CDCl ₃ ) δ ppm:
1.26 (3H, t, J = 7.1 Hz), 3.49 (2H, brs), 4.22 (2H, q, J = 7.1 Hz), 4.82 (2H, s), 6. 38 (1H, d, J = 3.3 Hz), 6.75-6.80 (2H, m), 7.00-7.08 (3H, m), 7.14-7.20 (1H, m ), 7.73 (1H, d, J = 3.0 Hz).

  The following compounds were produced in the same manner as in Reference Example 33 using appropriate starting materials.

Reference Example 34
2- [4- (5-Aminopyridin-2-yloxy) indol-1-yl] -1- (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) ethanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.27-2.42 (4H, m), 3.39-3.66 (8H, m), 4.88 (2H, s), 5.94 (2H, s), 6.38 (1H, d, J = 3.3 Hz), 6.71-6.82 (5H, m), 6.99 (1H, d, J = 3.3 Hz), 7.04 (1H, d, J = 3.0 Hz) ), 7.06-7.07 (1H, m), 7.13-7.19 (1H, m), 7.72-7.74 (1H, m).

Reference Example 35
2- [5- (5-Aminopyridin-2-yloxy) -2,3-dihydroindol-1-yl] -1- (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl ) Ethanon
¹ H-NMR (CDCl ₃ ) δ ppm:
2.43 (4H, brs), 2.97 (2H, t, J = 8.2 Hz), 3.39-3.52 (6H, m), 3.55 (2H, t, J = 4.9 Hz) ), 3.65 (2H, t, J = 4.9 Hz), 3.82 (2H, s), 5.95 (2H, s), 6.41 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.7 Hz), 6.73-6.80 (3H, m), 6.85-6.86 (2H, m), 7.04 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.69 (1H, d, J = 3.1 Hz).

Reference Example 36
2- [4- (5-Aminopyridin-2-yloxy) -2,3-dihydroindol-1-yl] -1- (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl ) Ethanon
¹ H-NMR (CDCl ₃ ) δ ppm:
2.42 (4H, brs), 2.85 (2H, t, J = 8.2 Hz), 3.42 (2H, s), 3.43 (2H, t, J = 8.3 Hz), 3. 51-3.55 (4H, m), 3.64 (2H, t, J = 4.9 Hz), 3.86 (2H, s), 5.95 (2H, s), 6.24 (1H, d, J = 7.8 Hz), 6.37 (1H, d, J = 7.8 Hz), 6.70-6.77 (3H, m), 6.85 (1H, s), 7.00- 7.08 (2H, m), 7.71 (1H, d, J = 3.0 Hz).

Reference Example 37
4- [5- (5-Aminopyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 3.48 (2H, s), 3.55 (4H, t, J = 5.8 Hz), 3.90 (4H, brs), 6.72 (1H, d, J = 3.0 Hz), 6.76 (1H, s), 7.03-7.12 (2H, m), 7.33 (1H, d, J = 2.3 Hz), 7.40 (1H, d, J = 8.9 Hz), 7.70 (1H, d, J = 2.9 Hz), 9.19 (1H, brs).

Reference Example 38
[5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) methanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.47 (4H, brs), 3.45 (4H, s), 3.76 (4H, brs), 3.82 (3H, s), 5.95 (2H, s), 6.51 (1H , D, J = 0.6 Hz), 6.72 (1H, dd, J = 8.6 Hz, 0.6 Hz), 6.75 (2H, s), 6.86 (1H, s), 7.05 (1H, d, J = 9.0 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 2.3 Hz), 7.32 (1H, d, J = 9.0 Hz), 7.68 (1H, dd, J = 2.3 Hz, 0.6 Hz).

Reference Example 39
[5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] (4-benzylpiperazin-1-yl) methanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.50 (4H, brs), 3.44 (2H, brs), 3.55 (2H, s), 3.77 (4H, brs), 3.82 (3H, s), 6.51 (1H , D, J = 0.7 Hz), 6.72 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.8 Hz), 7.06 (1H, dd, J = 8.8 Hz, 0.7 Hz), 7.22-7.39 (7 H, m), 7.68 (1 H, d, J = 3.0 Hz).

Reference Example 40
4- [5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 3.49 (6H, brs), 3.75 (4H, t, J = 5.0 Hz), 3.83 (3H, s), 6.53 (1H, s) 6.73 (1H, d, J = 8.7 Hz), 7.06 (1H, d, J = 8.7 Hz), 7.07 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.33 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 2.9 Hz).

Reference Example 41
[5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] [4- (4-methoxybenzyl) piperazin-1-yl] methanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.47 (4H, brs), 3.45 (2H, brs), 3.49 (4H, s), 3.76-3.79 (4H, m), 3.80 (3H, s), 3 .82 (3H, s), 6.52 (1H, s), 6.72 (1H, d, J = 8.4 Hz), 6.88 (2H, d, J = 8.4 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.06 (1H, dd, J = 1.1 Hz, 8.6 Hz), 7.21-7.34 (4H, m), 7.69 (1H, d, J = 3.0 Hz).

Reference Example 42
[5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] [4- (4-difluoromethoxybenzyl) piperazin-1-yl] methanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.48 (4H, brs), 3.46 (2H, brs), 3.52 (2H, s), 3.77 (4H, brs), 3.82 (3H, s), 6.50 (1H) , T, J = 74 Hz), 6.52 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.0 Hz), 7.02 −7.15 (2H, m), 7.27−7.34 (2H, m), 7.32 (2H, d, J = 8.0 Hz), 7.69 (1H, d, J = 2. 5Hz).

Reference Example 43
[6- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-yl } Methanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.47 (4H, brs), 3.50 (4H, s), 3.76 (7H, s), 4.35 (2H, q, J = 8.1 Hz), 6.55 (1H, s) , 6.76 (1H, d, J = 8.6 Hz), 6.88 (1H, dd, J = 8.3 Hz, 2.0 Hz), 6.91 (2H, d, J = 8.3 Hz), 7.05 (1H, d, J = 2.0 Hz), 7.07 (1H, dd, J = 8.6 Hz, 2.9 Hz), 7.27 (2H, d, J = 8.3 Hz), 7 .54 (1H, d, J = 8.5 Hz), 7.71 (1H, d, J = 2.9 Hz).

Reference Example 44
[5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-yl } Methanone
¹ H-NMR (CDCl ₃ ) δ ppm:
2.47 (4H, brs), 3.45 (2H, s), 3.50 (2H, s), 3.76 (4H, brs), 3.82 (3H, s), 4.34 (2H , Q, J = 8.2 Hz), 6.52 (1H, s), 6.72 (1H, d, J = 8.6 Hz), 6.91 (2H, d, J = 8.6 Hz), 7 .05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.02-7.10 (1H, m), 7.27 (2H, d, J = 8.6 Hz), 7.24- 7.37 (2H, m), 7.68 (1H, d, J = 3.0 Hz).

Reference Example 45
4- [6- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 3.50 (4H, t, J = 5.6 Hz), 3.75 (4H, t, J = 5.6 Hz), 3.77 (3H, s), 3. 67-3.88 (2H, m), 6.57 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 6.90 (1H, dd, J = 8.6 Hz, 2 0.0 Hz), 7.05 (1H, d, J = 2.0 Hz), 7.08 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.56 (1H, d, J = 8. 6 Hz), 7.71 (1H, d, J = 3.0 Hz).

Reference Example 46
6- (5-Aminopyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.33 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 6.76-6.79 (2H, m ), 6.90 (1H, s), 7.07-7.12 (2H, m), 7.56-7.61 (2H, m), 11.68 (1H, s).

Reference Example 47
6- (5-Aminopyridin-2-yloxy) -1-methoxymethyl-1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.41 (3H, t, J = 7.2 Hz), 3.28 (3H, s), 3.52 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 5. 90 (2H, s), 6.81 (1H, d, J = 8.6 Hz), 6.95 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.25 (1 H, dd, J = 10.8 Hz, 1.9 Hz), 7.33 (1 H, d, J = 1.0 Hz), 7.62 (1 H, d, J = 8.9 Hz), 7.73 (1H, d, J = 3.0 Hz).

Reference Example 48
6- (5-Aminopyrimidin-2-yloxy) -1-methyl-1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 3.50 (2H, s), 4.03 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 6. 96 (1H, dd, J = 8.7 Hz, 2.0 Hz), 7.19 (1H, d, J = 1.6 Hz), 7.29 (1H, s), 7.66 (1H, d, J = 8.6 Hz), 8.08 (2H, s).

Reference Example 49
6- (5-Aminopyridin-2-yloxy) indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.39 (3H, t, J = 7.3 Hz), 1.59 (9H, s), 3.53 (2H, brs), 4.36 (2H, q, J = 7.1 Hz), 6. 81 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.08-7.12 (2H, m), 7.54 (1H , D, J = 8.2 Hz), 7.75 (2H, dd, J = 10.7 Hz, 2.5 Hz).

Reference Example 50
6- (5-Amino-4-methylpyridin-2-yloxy) -1-methyl-1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.39-1.42 (3H, m), 2.20 (3H, s), 3.45 (2H, brs), 3.99 (3H, s), 4.34-4.38 (2H, m), 6.70 (1H, s), 6.89 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.04 (1H, d, J = 2.0 Hz), 7.27- 7.27 (1H, m), 7.61 (1H, d, J = 8.6 Hz), 7.67 (1H, s).

Reference Example 51
Preparation of 5- [5- (3,4-dichlorobenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid methyl ester 5- (5-nitropyridin-2-yloxy) -1H-indole- 2-Carboxylic acid methyl ester (0.750 g, 2.39 mmol) was dissolved in THF (20 ml), 5% palladium-carbon (0.10 g) was added, and catalytic reduction was performed at room temperature and normal pressure for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 0.677 g of a pale yellow oil. This was dissolved in THF (30 ml), triethylamine (0.333 ml, 2.39 mmol) and then 3,4-dichlorobenzoyl chloride (0.501 g, 2.39 mmol) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated brine (30 ml), and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was crystallized from ethyl acetate to give 1.00 g of the title compound.
Properties: White powder
¹ H-NMR (DMSO-d ₆ ) δ ppm:
3.89 (3H, s), 7.02 (1H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.15 (1H, d , J = 1.2 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.48 (1H, d, J = 8.7 Hz), 7.84 (1H, d, J = 8. 4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.16 (1 H, dd, J = 8.8 Hz, 2.7 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.45 (1 H, d, J = 2.5 Hz), 10.52 (1 H, s), 12.00 (1 H, brs).

  The following compounds were produced in the same manner as in Reference Example 51 using appropriate starting materials.

Reference Example 52
4- {1-Methyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 3.49 (4H, brs), 3.76-3.73 (4H, m), 3.84 (3H, s), 6.56 (1H, s), 6 .93 (1H, d, J = 8.9 Hz), 7.11 (1H, dd, J = 8.9 Hz, 2.2 Hz), 7.39-7.36 (1 H, m), 7.75 ( 2H, d, J = 8.1 Hz), 7.99 (3H, d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.25 (1H , D, J = 2.2 Hz).

Reference Example 53
4- {5- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 3.49 (4H, brs), 3.74 (4H, brs), 3.82 (3H, d, J = 1.4 Hz), 6.88 (1H, dd, J = 1.6 Hz, 8.9 Hz), 7.09 (1 H, dd, J = 1.6 Hz, 8.6 Hz), 7.34-7.37 (2 H, m), 7.53 (1 H, dd) , J = 2.2 Hz, 8.6 Hz), 7.70 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.98 (1H, d, J = 2.2 Hz), 8.10 ( 2H, dd, J = 1.9 Hz, 8.9 Hz), 8.23 (1H, d, J = 2.7 Hz).

Reference Example 54
4- {1-Methyl-5- [4-methyl-5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.49 (9H, s), 2.78 (3H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.83 (3H, s), 6.55 (1H , S), 6.77 (1H, s), 7.10 (1H, dd, J = 1.1 Hz, 8.9 Hz), 7.35-7.38 (2H, m), 7.71 (1H) , S), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.25 (1H, s).

Reference Example 55
4- {1-Methyl-5- [6-methyl-5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 2.44 (3H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.83 (3H, s), 6.54 (1H) , S), 6.57 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 9.2 Hz), 7.36 (1H, s), 7.77 (3H, d) , J = 8.1 Hz), 7.90-7.96 (1H, m), 8.02 (2H, d, J = 8.1 Hz).

Reference Example 56
4- {5- [5- (3,4-Dichlorobenzoylamino) -4-methylpyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 2.26 (3H, s), 3.49-3.52 (4H, m), 3.73-3.77 (4H, m), 3.83 (3H, s), 6.55 (1H, s), 6.76 (1H, s), 7.10 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.35 (1H, d, J = 3.5 Hz), 7.37 (1 H, d, J = 3.5 Hz), 7.58 (1 H, d, J = 8.1 Hz), 7.59 (1 H, s), 7.73 (1 H, dd, J = 1.9 Hz, 8.4 Hz), 8.01 (1H, d, J = 1.6 Hz), 8.12 (1H, s).

Reference Example 57
4- {5- [5- (3,4-Dichlorobenzoylamino) -6-methylpyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 2.84 (3H, s), 3.49-3.52 (4H, m), 3.74-3.76 (4H, m), 3.79 (3H, s), 6.49-6.52 (2H, m), 7.10 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.30-7.34 (2H, m), 7. 57 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.75 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.98 (1H, s), 8.04 (1H, d, J = 2.2 Hz).

Reference Example 58
4- {1-Methyl-5- [5- (4-trifluoromethylbenzoylamino) pyrimidin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 3.49 (4H, brs), 3.72-3.76 (4H, m), 3.83 (3H, s), 6.58 (1H, s), 7 .15 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.39 (1H, d, J = 9.2 Hz), 7.43 (1H, d, J = 2.2 Hz), 7. 75 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.11 (1H, s), 8.85 (2H, s).

Reference Example 59
4- {5- [5- (3,4-Dichlorobenzoylamino) pyrimidin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.48 (9H, s), 3.44-3.49 (4H, m), 3.74 (4H, brs), 3.82 (3H, s), 6.57 (1H, s), 7 .13 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.37 (1H, d, J = 8.6 Hz), 7.41 (1H, d, J = 2.2 Hz), 7. 53 (1H, d, J = 8.6 Hz), 7.72 (1H, dd, J = 2.2 Hz, 8.4 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.37 (1H, s), 8.82 (2H, s).

Reference Example 60
1-methyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid methyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
3.92 (3H, s), 4.09 (3H, s), 6.95 (1H, d, J = 4.1 Hz), 7.16 (1H, dd, J = 2.4 Hz, 8.9 Hz) ), 7.39-7.43 (3H, m), 7.75 (2H, d, J = 8.4 Hz), 7.92 (1H, s), 7.98 (2H, d, J = 8) .1 Hz), 8.19 (1 H, dd, J = 2.7 Hz, 8.9 Hz), 8.24 (1 H, d, J = 1.9 Hz).

Reference Example 61
(S) -3-Methyl-4- {1-methyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.29 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 2.86 (1H, brs), 3.04 (1H, brs), 3.21-3.30 ( 1H, m), 3.80 (3H, s), 3.92 (1H, d, J = 12.2 Hz), 4.20 (2H, brs), 4.69 (1H, brs), 6.52 (1H, s), 6.90 (1H, d, J = 8.9 Hz), 7.09 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.34-7.37 (2H, m), 7.73 (2H, d, J = 8.4 Hz), 7.98 (2H, d, J = 7.8 Hz), 8.12-8.16 (2H, m), 8.25 ( 1H, d, J = 2.4 Hz).

Reference Example 62
1-methyl-6- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.41 (3H, t, J = 7.0 Hz), 4.03 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 6.94 (1H, dd, J = 2) .2 Hz, 8.4 Hz), 7.00 (1 H, d, J = 8.9 Hz), 7.15 (1 H, d, J = 1.9 Hz), 7.30 (1 H, d, J = 0. 8 Hz), 7.66 (1 H, d, J = 8.6 Hz), 7.77 (2 H, d, J = 8.4 Hz), 7.83 (1 H, s), 7.99 (2 H, d, J = 8.1 Hz), 8.22 (1H, dd, J = 2.7 Hz, 8.4 Hz), 8.27 (2H, d, J = 2.7 Hz).

Reference Example 63
1-methyl-7- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.40 (3H, t, J = 7.0 Hz), 4.16 (3H, s), 4.35 (2H, q, J = 7.0 Hz), 6.97-7.01 (2H, m ), 7.11 (1H, t, J = 7.8 Hz), 7.33 (1H, s), 7.53 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.77 (3H , D, J = 8.4 Hz), 7.99 (2H, d, J = 8.4 Hz), 8.25-8.28 (2H, m).

Reference Example 64
1-methyl-4- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.36 (3H, t, J = 7.0 Hz), 4.09 (3H, s), 4.33 (2H, q, J = 7.0 Hz), 6.89 (1H, dd, J = 1) .1 Hz, 7.6 Hz), 7.00 (2H, d, J = 9.7 Hz), 7.12 (1H, d, J = 0.8 Hz), 7.23-7.37 (2H, m) 7.74 (1H, d, J = 8.1 Hz,), 7.92 (1H, s), 7.97 (2H, d, J = 8.1 Hz), 8.20-8.25 (2H , M).

Reference Example 65
1,4-Dimethyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (3H, t, J = 7.0 Hz), 2.38 (3H, s), 4.08 (3H, s), 4.39 (2H, q, J = 7.0 Hz), 6. 91 (1H, dd, J = 1.6 Hz, 7.8 Hz), 7.11 (1H, d, J = 8.9 Hz), 7.26 (1H, d, J = 8.9 Hz), 7.34 (1H, s), 7.76 (3H, d, J = 8.4 Hz), 7.99 (2H, d, J = 8.1 Hz), 8.17-8.21 (2H, m).

Reference Example 66
1-methyl-6- [5- (4-trifluoromethoxybenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 4.02 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 6.94 (1H, dd, J = 8) .6 Hz, 2.0 Hz), 6.99 (1 H, d, J = 8.9 Hz), 7.15 (1 H, d, J = 2.0 Hz), 7.26-7.35 (3 H, m) 7.66 (1H, d, J = 8.9 Hz), 7.80 (1H, s), 7.93 (2H, dd, J = 6.6 Hz, 2.0 Hz), 8.20-8. 26 (2H, m).

Reference Example 67
6- [5- (2-Chloro-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 4.03 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 6.94 (1H, dd, J = 8) .6 Hz, 2.0 Hz), 7.00 (1 H, d, J = 9.2 Hz), 7.16 (1 H, d, J = 2.0 Hz), 7.26-7.31 (1 H, m) 7.67 (2H, dd, J = 8.2 Hz, 2.3 Hz), 7.75 (1H, s), 7.85 (1H, s), 7.89 (1H, d, J = 8. 2Hz), 8.22-8.27 (2H, m).

Reference Example 68
6- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid methyl ester 1H-NMR (CDCl 3) δ ppm:
3.91 (3H, s), 4.03 (3H, s), 6.94 (1H, dd, J = 8.7 Hz, 2.1 Hz), 6.99 (1H, d, J = 8.7 Hz) ), 7.16 (1H, d, J = 1.9 Hz), 7.29 (1H, d, J = 0.5 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.67. (1H, d, J = 9.1 Hz), 7.71 (1H, dd, J = 8.4 Hz, 1.9 Hz), 7.82 (1H, brs), 7.98 (1H, d, J = 2.1 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26 (1H, d, J = 2.6 Hz).

Reference Example 69
1-methyl-6- [5- (4-trifluoromethylbenzoylamino) pyrimidin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.42 (3H, t, J = 7.1 Hz), 4.05 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 7.00 (1H, dd, J = 8) .6 Hz, 2.1 Hz), 7.24 (1 H, dd, J = 1.4 Hz, 0.7 Hz), 7.32 (1 H, d, J = 0.8 Hz), 7.71 (1 H, d, J = 8.7 Hz), 7.78 (1H, s), 7.79 (2H, d, J = 8.4 Hz), 8.01 (2H, d, J = 8.1 Hz), 8.88 ( 2H, s).

Reference Example 70
6- (5-acetylaminopyridin-2-yloxy) -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.34 (3H, t, J = 7.1 Hz), 2.05 (3H, s), 3.79 (3H, s), 4.32 (2H, q, J = 7.0 Hz), 6. 88 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.00 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 0.7 Hz), 7.34 (1H, d, J = 2.3 Hz), 7.68 (1H, d, J = 8.6 Hz), 8.05 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.29 ( 1H, d, J = 2.3 Hz), 10.07 (1H, s).

Reference Example 71
6- [5- (4-Nitrobenzoylamino) pyridin-2-yloxy] -2,3-dihydroindole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.22-1.32 (3H, m), 1.56 (9H, s), 3.10 (1H, dd, J = 16.3 Hz, 4.8 Hz), 3.50 (1H, dd, J = 16.5 Hz, 10.9 Hz), 4.23 (2H, d, J = 7.3 Hz), 4.88 (1 H, s), 6.73 (1 H, d, J = 6.9 Hz), 6 .95 (1H, d, J = 8.2 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.68 (1H, s), 7.97 (1H, s), 8.05 (2H, d, J = 8.9 Hz), 8.18 (1 H, s), 8.28 (1 H, s), 8.34 (1 H, d, J = 8.9 Hz).

Reference Example 72
6- [5- (2-Methoxy-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid methyl ester 1H-NMR (CDCl 3) δ ppm:
3.91 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 6.95 (1H, d, J = 8.1 Hz), 6.99 (1H, dd, J = 8.6 Hz, 1.9 Hz), 7.16 (1 H, d, J = 2.0 Hz), 7.27 (1 H, s), 7.29 (1 H, d, J = 0.8 Hz), 7.41 (1H, dd, J = 8.1 Hz, 0.8 Hz), 7.67 (1H, d, J = 8.6 Hz), 8.26-8.32 (2H, m), 8.40 (1H, dd, J = 8.2 Hz, 0.7 Hz), 9.65 (1H, brs).

Reference Example 73
6- [5- (2,4-Bistrifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid methyl ester 1H-NMR (CDCl 3) δ ppm:
3.91 (3H, s), 4.04 (3H, s), 6.95 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.01 (1H, d, J = 9.7 Hz) ), 7.17 (1H, d, J = 2.0 Hz), 7.30 (1H, d, J = 0.8 Hz), 7.44 (1H, brs), 7.68 (1H, d, J = 8.6 Hz), 7.83 (1 H, d, J = 7.9 Hz), 7.95 (1 H, d, J = 7.4 Hz), 8.02 (1 H, s), 8.16-8. .22 (2H, m).

Reference Example 74
4- {1-methyl-6- [5- (2-methyl-4-trifluoromethylbenzoylamino) pyrimidin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.48 (9H, s), 2.52 (3H, s), 3.48 (4H, t, J = 4.2 Hz), 3.72 (4H, t, J = 4.8 Hz), 3. 77 (3H, s), 6.58 (1H, d, J = 0.8 Hz), 6.98 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.19 (1H, d, J = 1.0 Hz), 7.50 (1 H, d, J = 10.2 Hz), 7.52 (1 H, s), 7.58 (1 H, d, J = 7.7 Hz), 7.64 (1 H , D, J = 8.6 Hz), 8.08 (1H, brs), 8.87 (2H, s).

Reference Example 75
Preparation of {4- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] indol-1-yl} acetic acid ethyl ester [4- (5-aminopyridin-2-yloxy) indol-1-yl Acetic acid ethyl ester (0.715 g, 2.30 mmol) was dissolved in THF (10 ml) and triethylamine (0.320 ml, 2.30 mmol) was added followed by 3,4-dichlorobenzoyl chloride (0.481 g, 2.30 mmol). In addition, the mixture was stirred at room temperature for 30 minutes. Saturated brine (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from a mixed solvent of ethyl acetate-n-hexane to obtain 0.972 g of the title compound.
Properties: White powder 1 H-NMR (CDCl 3) δ ppm:
1.27 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 4.84 (2H, s), 6.33-6.35 (1H, m ), 6.88-6.96 (2H, m), 7.02 (1H, d, J = 3.1 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.21 (1H) , D, J = 7.8 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.69 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.83 (1H, brs), 7.97 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.24 (1H, d, J = 2.6 Hz). ).

  The following compounds were produced in the same manner as in Reference Example 75 using appropriate starting materials.

Reference Example 76
{4- [5- (4-Trifluoromethylbenzoylamino) pyridin-2-yloxy] indol-1-yl} acetic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.27 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 4.84 (2H, s), 6.35 (1H, dd, J = 3) .3 Hz, 0.7 Hz), 6.91 (1 H, dd, J = 7.6 Hz, 0.7 Hz), 6.96 (1 H, d, J = 8.9 Hz), 7.04 (1 H, d, J = 3.1 Hz), 7.13 (1H, d, J = 8.2 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.75-7.81 (3H, m), 7.9 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.26 (1H, d, J = 2.3 Hz).

Reference Example 77
4- {5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (DMSO-d6) δppm:
1.43 (9H, s), 3.44 (4H, brs), 3.75 (4H, brs), 6.82 (1H, d, J = 1.5 Hz), 6.98 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J = 8.9 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.45 (1H, d, J = 8.9 Hz) ), 7.93 (2H, d, J = 8.1 Hz), 8.16 (2H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 8.7 Hz, 2.5 Hz) 8.47 (1H, d, J = 2.5 Hz), 10.58 (1H, s), 11.66 (1H, s).

Reference Example 78
4- {5- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.42 (9H, s), 3.36-3.55 (4H, m), 3.75-3.89 (4H, m), 6.82 (1H, d, J = 2.0 Hz), 6.98 (1H, d, J = 8.9 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 2.5 Hz), 7.45 (1H , D, J = 8.6 Hz), 7.84 (1H, d, J = 8.3 Hz), 7.94 (1H, dd, J = 8.3 Hz, 2.1 Hz), 8.15 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1 H, d, J = 2.1 Hz), 8.45 (1 H, d, J = 2.8 Hz), 10.52 (1 H, s) ), 11.68 (1H, s).

Reference Example 79
4- {1-methyl-6- [5- (2-methyl-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 2.56 (3H, s), 3.50 (4H, t, J = 4.9 Hz), 3.75 (4H, t, J = 5.2 Hz), 3. 79 (3H, s), 6.59 (1H, s), 6.94 (1H, dd, J = 8.6 Hz, 1.9 Hz), 6.98 (1H, d, J = 9.7 Hz), 7.14 (1H, d, J = 1.6 Hz), 7.52-7.63 (5H, m), 8.23-8.25 (2H, m).

Reference Example 80
4- {6- [5- (2-Fluoro-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.48 (9H, d, J = 2.0 Hz), 3.50 (4H, s), 3.76 (4H, s), 3.80 (3H, d, J = 2.0 Hz), 6. 60 (1H, s), 6.96 (2H, t, J = 8.4 Hz), 7.15 (1H, s), 7.49 (1H, d, J = 11.9 Hz), 7.60− 7.64 (2H, m), 8.18 (1H, d, J = 9.2 Hz), 8.28-8.36 (3H, m).

Reference Example 81
1-methoxymethyl-6- [5- (4-nitrobenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.42 (3H, t, J = 7.1 Hz), 3.29 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 5.92 (2H, s), 7. 00 (1H, dd, J = 8.6 Hz, 1.9 Hz), 7.01 (1H, d, J = 8.9 Hz), 7.33 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.91 (1H, s), 8.03-8.07 (2H, m), 8 .21 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28 (1H, d, J = 2.3 Hz), 8.35 (2H, dt, J = 9.1 Hz, 2.1 Hz) ).

Reference Example 82
1-methyl-6- {5- [methyl (4-methylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.26 (3H, s), 3.32 (3H, s), 3.95 (3H, s), 6.82 (1H, dd, J = 8.6 Hz, 2.0 Hz), 6.97 ( 1H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.2 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.23 (1H, d, J = 0.7 Hz), 7.32 (1 H, s), 7.66 (1 H, d, J = 8.6 Hz), 7.76 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7 .90 (1H, d, J = 2.6 Hz), 12.89 (1H, s).

Reference Example 83
4- (1-Methyl-6- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyrimidin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.50 (3H, s), 3.51 (4H, s), 3.75 (4H, t, J = 4.9 Hz), 3.79 (3H, s) , 6.60 (1H, s), 6.92 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.15 (1H, d, J = 1.6 Hz), 7.44 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 7.7 Hz), 7.63 (1H, d, J = 8.6 Hz), 8.31 (2H, brs).

Reference Example 84
4- (1-Methyl-6- {5- [methyl (toluene-4-sulfonyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H- NMR (CDCl3) δ ppm:
1.49 (9H, s), 2.42 (3H, s), 3.16 (3H, s), 3.49-3.52 (4H, m), 3.74-3.78 (4H, m), 3.81 (3H, s), 6.60 (1H, s), 6.87 (1H, d, J = 8.9 Hz), 6.93 (1H, dd, J = 8.6 Hz) 2.0 Hz), 7.15 (1H, d, J = 1.6 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.49 (2H, d, J = 8.2 Hz), 7.54 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.62 (1H, d, J = 8.6 Hz), 7.77 (1H, d, J = 2.6 Hz).

Reference Example 85
6- {5-[(4-Difluoromethoxybenzoyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (CDCl 3) δ ppm:
3.48 (3H, s), 4.01 (3H, s), 6.50 (1H, t, J = 73.2 Hz), 6.90 (2H, dd, J = 8.6 Hz, 2.0 Hz) ), 6.98 (2H, d, J = 8.9 Hz), 7.13 (1H, d, J = 2.0 Hz), 7.33-7.37 (3H, m), 7.45 (1H) , Dd, J = 8.6 Hz, 2.6 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.89 (1H, d, J = 2.6 Hz).

Reference Example 86
1,3-dimethyl-6- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.50 (3H, s), 3.37 (3H, s), 3.87 (3H, s), 6.77 (1H, dd, J = 8.7 Hz, 1.3 Hz), 6.98 ( 1H, d, J = 8.7 Hz), 7.24 (1H, d, J = 1.3 Hz), 7.51 (2H, d, J = 6.9 Hz), 7.65 (1H, d, J = 8.9 Hz), 7.68 (2H, d, J = 8.1 Hz), 7.83 (1H, dd, J = 8.6 Hz, 2.5 Hz), 7.96 (1H, brs), 13 .01 (1H, brs).

Reference Example 87
Preparation of 4- {5- [5- (3,4-dichlorobenzenesulfonylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 4 -[5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester (4.69 g, 10.4 mmol) in THF (250 ml) ) 3,4-Dichlorobenzenesulfonyl chloride (3.7 g, 15.1 mmol) and pyridine (1.51 ml, 18.7 mmol) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 5.26 g of the title compound.
Properties: Pale yellow powder 1H-NMR (CDCl3) δ ppm:
1.48 (9H, s), 3.50 (4H, brs), 3.74 (4H, brs), 3.82 (3H, s), 6.53 (1H, s), 6.81 (1H , D, J = 8.7 Hz), 7.04 (1H, dd, J = 9.1 Hz, 2.3 Hz), 7.21 (1H, brs), 7.31 (1H, d, J = 2. 3 Hz), 7.35 (1 H, d, J = 9.1 Hz), 7.49 (2 H, d, J = 1.0 Hz), 7.51 (1 H, dd, J = 8.7 Hz, 2.8 Hz) ), 7.70 (1H, d, J = 2.8 Hz), 7.81 (1H, t, J = 1.2 Hz).

  The following compounds were produced in the same manner as in Reference Example 87 using appropriate starting materials.

Reference Example 88
4- {1-methyl-5- [5- (4-trifluoromethylbenzenesulfonylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.48 (9H, s), 3.50 (4H, brs), 3.74 (4H, brs), 3.82 (3H, s), 6.53 (1H, s), 6.80 (1H , D, J = 8.8 Hz), 7.03 (1H, dd, J = 8.9 Hz, 2.1 Hz), 7.27-7.33 (1H, m), 7.31 (1H, d, J = 2.1 Hz), 7.34 (1H, d, J = 8.9 Hz), 7.51 (1H, dd, J = 8.8 Hz, 2.7 Hz), 7.68 (1H, d, J = 2.7 Hz), 7.69 (2H, d, J = 8.1 Hz), 7.82 (2H, d, J = 8.1 Hz).

Reference Example 89
4- {6- [5- (3,4-Dichlorobenzenesulfonylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.50 (4H, brs), 3.74-3.77 (7H, m), 6.59 (1H, d, J = 0.7 Hz), 6.86- 6.91 (2H, m), 6.99 (1H, s), 7.10 (1 H, d, J = 2.0 Hz), 7.52-7.62 (4H, m), 7.75 ( 1H, d, J = 2.3 Hz), 7.83 (1H, t, J = 1.2 Hz).

Reference Example 90
4- {1-Methyl-6- [5- (4-trifluoromethylbenzenesulfonylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.48-3.52 (4H, m), 3.73-3.77 (7H, m), 6.58 (1H, s), 6.85-6. 90 (2H, m), 7.10 (1 H, d, J = 2.0 Hz), 7.55-7.61 (2H, m), 7.70-7.74 (3H, m), 7. 85 (2H, d, J = 8.2 Hz).

Reference Example 91
4- {1-methyl-5- [5- (toluene-4-sulfonylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl 3 ) Δ ppm:
1.48 (9H, s), 2.39 (3H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.83 (3H, s), 6.55 (1H , S), 6.80-6.84 (2H, m), 7.04 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.22 (2H, d, J = 7.9 Hz) , 7.33-7.36 (2H, m), 7.53-7.60 (3H, m), 7.68 (1H, d, J = 2.6 Hz).

Reference Example 92
6- (5-Methanesulfonylaminopyridin-2-yloxy) indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.40 (3H, t, J = 7.1 Hz), 1.61 (9H, s), 3.01 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 6. 33 (1H, brs), 6.98 (1H, d, J = 8.6 Hz), 7.07 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.11 (1H, s), 7.61 (1H, d, J = 8.6 Hz), 7.75 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.90 (1H, d, J = 2.0 Hz), 8 .04 (1H, d, J = 3.0 Hz).

Reference Example 93
6- [5- (3,4-Dichlorobenzenesulfonylamino) -4-methylpyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 2.26 (3H, s), 4.02 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 6. 33 (1H, s), 6.78 (1H, s), 6.88 (1H, dd, J = 8.9 Hz, 2.0 Hz), 7.12 (1H, d, J = 1.6 Hz), 7.29 (1H, s), 7.56 (2H, d, J = 0.7 Hz), 7.66 (2H, t, J = 4.3 Hz), 7.86 (1H, d, J = 0) .7 Hz).

Reference Example 94
Preparation of 6- (5-acetylaminopyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester 6- (5-aminopyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester ( Acetic anhydride (2.2 g, 21 mmol) was added to a pyridine (13 ml) solution of 2.6 g, 8.6 mmol) under ice cooling, and the mixture was stirred for 2 hours. Water (30 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was crystallized from 2-propyl alcohol, and the crystals were collected by filtration and dried under reduced pressure to obtain 0.85 g of the title compound. Further, the residue of the mother liquor was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 3) to obtain 1.26 g of the title compound, giving a total of 2.11 g of the title compound.
Property: Pale yellow crystal 1H-NMR (DMSO-d6) δ ppm:
1.34 (3H, t, J = 7.1 Hz), 2.05 (3H, s), 4.34 (2H, q, J = 7.0 Hz), 6.85 (1H, dd, J = 8 .7 Hz, 2.1 Hz), 7.00 (1 H, d, J = 8.9 Hz), 7.08 (1 H, d, J = 2.0 Hz), 7.16 (1 H, d, J = 1. 3 Hz), 7.66 (1 H, d, J = 8.9 Hz), 8.05 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 8.30 (1 H, d, J = 2.3 Hz) ), 10.08 (1H, s), 11.81 (1H, s).

Reference Example 95
Preparation of 5- [5- (3,4-dichlorobenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 5- [5- (3,4-dichlorobenzoylamino) pyridin-2-yloxy ] -1H-indole-2-carboxylic acid methyl ester (1.00 g, 2.19 mmol) was dissolved in THF (30 ml), and 1N aqueous sodium hydroxide solution (3.50 ml, 3.50 mmol) and water (15 ml) were added. And heated to reflux for 3 hours. The reaction mixture was ice-cooled, 1N hydrochloric acid (3.50 ml, 3.50 mmol) and saturated brine (50 ml) were added, and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was crystallized with n-hexane to give 0.875 g of the title compound.
Property: Pale yellow powder 1H-NMR (DMSO-d6) δ ppm:
6.9-7.08 (3H, m), 7.38 (1H, d, J = 2.1 Hz), 7.47 (1H, d, J = 8.9 Hz), 7.83 (1H, d , J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.22 ( 1H, d, J = 2.0 Hz), 8.45 (1H, d, J = 2.5 Hz), 10.52 (1H, s), 11.83 (1H, s), 13.00 (1H, brs).

  The following compounds were produced in the same manner as in Reference Example 95 using appropriate starting materials.

Reference Example 96
[4- (5-Nitropyridin-2-yloxy) indol-1-yl] acetic acid 1H-NMR (CDCl 3 + DMSO-d 6) δ ppm:
4.85 (2H, s), 6.29 (1H, d, J = 3.3 Hz), 6.92-6.95 (1H, m), 7.01 (1H, d, J = 9.1 Hz) ), 7.10 (1H, d, J = 3.3 Hz), 7.25-7.27 (2H, m), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9 .06 (1H, d, J = 2.8 Hz).

Reference Example 97
{4- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] indol-1-yl} acetic acid 1H-NMR (DMSO-d6) δ ppm:
5.03 (2H, s), 6.11 (1H, d, J = 2.6 Hz), 6.78 (1H, d, J = 6.9 Hz), 7.06 (1H, d, J = 8) .9Hz), 7.11-7.17 (1H, m), 7.25-7.29 (2H, m), 7.83 (1H, d, J = 8.4 Hz), 7.95 (1H) , Dd, J = 8.4 Hz, 2.0 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1H, d, J = 2.0 Hz), 8. 45 (1H, d, J = 2.5 Hz), 10.55 (1H, s).

Reference Example 98
{4- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] indol-1-yl} acetic acid 1H-NMR (DMSO-d6) δ ppm:
5.03 (2H, s), 6.11 (1H, d, J = 3.3 Hz), 6.78 (1H, d, J = 7.4 Hz), 7.06 (1H, d, J = 8) 0.9 Hz), 7.11-7.17 (1H, m), 7.25-7.29 (2H, m), 7.93 (2H, d, J = 8.4 Hz), 8.16 (2H) , D, J = 8.1 Hz), 8.21 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.47 (1H, d, J = 2.6 Hz), 10.63 (1H, s).

Reference Example 99
[5- (5-Nitropyridin-2-yloxy) -2,3-dihydroindol-1-yl] acetic acid 1H-NMR (CDCl 3) δ ppm:
3.10 (2H, t, J = 8.3 Hz), 3.62 (2H, t, J = 8.3 Hz), 3.92 (2H, s), 6.47 (1H, d, J = 8) .4 Hz), 6.87 (1H, dd, J = 8.4 Hz, 2.3 Hz), 6.93 (1H, t, J = 2.1 Hz), 6.98 (1H, d, J = 9. 1 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

Reference Example 100
[4- (5-Nitropyridin-2-yloxy) -2,3-dihydroindol-1-yl] acetic acid 1H-NMR (DMSO-d6) δ ppm:
2.71 (2H, t, J = 8.5 Hz), 3.49 (2H, t, J = 8.5 Hz), 3.96 (2H, s), 6.35-6.40 (2H, m ), 7.02-7.08 (1H, m), 7.20 (1H, d, J = 9.1 Hz), 8.61 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9 .05 (1H, d, J = 3.0 Hz), 12.63 (1H, brs).

Reference Example 101
1-methyl-5- (5-methylaminopyridin-2-yloxy) -1H-indole-2-carboxylic acid 1H-NMR (CDCl 3) δ ppm:
2.67 (3H, s), 3.43 (2H, brs), 4.02 (3H, s), 6.78 (1H, d, J = 8.7 Hz), 7.03 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.06 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.15 (1H, s), 7.22 (1H, d, J = 2) .3 Hz), 7.48 (1H, d, J = 2.8 Hz), 7.55 (1H, d, J = 8.9 Hz).

Reference Example 102
[5- (5-Bromopyridin-2-yloxy) indol-1-yl] acetic acid 1H-NMR (DMSO-d6) δ ppm:
5.03 (2H, s), 6.43 (1H, d, J = 3.1 Hz), 6.91 (1H, dd, J = 8.8 Hz, 2.3 Hz), 6.95 (1H, d , J = 8.8 Hz), 7.30 (1H, d, J = 2.3 Hz), 7.34-7.47 (2H, m), 7.99 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.23 (1 H, d, J = 2.6 Hz), 12.60-13.30 (1 H, m).

Reference Example 103
6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indol-4-yloxy} nicotine Acid 1H-NMR (DMSO-d6) δ ppm:
2.34-2.41 (4H, m), 2.66 (2H, t, J = 8.2 Hz), 3.40-3.46 (8H, m), 4.05 (2H, s), 5.99 (2H, s), 6.31-6.34 (2H, m), 6.75-6.78 (1H, m), 6.84-6.88 (2H, m), 6. 97-7.06 (2H, m), 8.26 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.68 (1H, d, J = 2.0 Hz).

Reference Example 104
1-methyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
4.05 (3H, s), 7.02 (1H, d, J = 8.1 Hz), 7.13 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.20 (1H, s) ), 7.40 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.93 (2H, d, J = 8.1 Hz), 8.16 (2H, d, J = 8.9 Hz), 8.21 (1H, d, J = 2.7 Hz), 8.47 (1H, d, J = 2.7 Hz), 10.59 (1H, s) , 12.96 (1H, s).

Reference Example 105
1-methyl-6- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.98 (3H, s), 6.90 (1 H, dd, J = 2.2 Hz, 8.6 Hz), 7.08 (1 H, d, J = 8.9 Hz), 7.24 (1 H, s ), 7.36 (1H, d, J = 1.9 Hz), 7.69 (1H, d, J = 8.6 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.17 (2H, d, J = 8.4 Hz), 8.23 (1H, dd, J = 2.7 Hz, 8.9 Hz), 8.51 (1H, d, J = 2.7 Hz), 10.65 ( 1H, s).

Reference Example 106
1-methyl-7- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
4.04 (3H, s), 6.80 (1H, d, J = 7.6 Hz), 6.83 (1H, s), 6.98 (1H, t, J = 8.1 Hz), 7. 07 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.92 (2H, d, J = 8.1 Hz), 8.16 (1H, d , J = 8.1 Hz), 8.24 (1H, dd, J = 2.7 Hz, 8.9 Hz), 8.46 (1H, d, J = 2.4 Hz), 10.66 (1H, s) .

Reference Example 107
1-methyl-4- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
4.05 (3H, s), 6.79 (1H, s), 6.87 (1H, d, J = 7.6 Hz), 7.13 (1H, d, J = 8.6 Hz), 7. 35 (1H, t, J = 7.6 Hz), 7.45 (1H, d, J = 8.4 Hz), 8.16 (2H, d, J = 8.4 Hz), 8.24 (1H, dd) , J = 2.7 Hz, 8.9 Hz), 8.47 (1H, d, J = 2.4 Hz), 10.63 (1H, s).

Reference Example 108
1,4-Dimethyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.27 (3H, s), 4.04 (3H, s), 6.98 (1H, d, J = 8.9 Hz), 7.07 (1H, d, J = 8.9 Hz), 7. 29 (1H, s), 7.45 (1H, d, J = 8.9 Hz), 7.93 (2H, d, J = 8.1 Hz), 8.14-8.20 (3H, m), 8.41 (1H, d, J = 2.7 Hz), 10.59 (1H, s), 12.96 (1H, brs).

Reference Example 109
1-methyl-6- [5- (4-trifluoromethoxybenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.98 (3H, s), 6.90 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.25 (1H, s ), 7.36 (1H, s), 7.54 (2H, d, J = 8.2 Hz), 7.69 (1H, d, J = 8.6 Hz), 8.10 (2H, d, J = 8.9 Hz), 8.21 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.49 (1 H, d, J = 2.6 Hz), 10.51 (1 H, s).

Reference Example 110
6- [5- (2-Chloro-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.98 (3H, s), 6.90 (1H, dd, J = 8.6 Hz, 1.3 Hz), 7.08 (1H, d, J = 8.9 Hz), 7.24 (1H, s ), 7.36 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 7.87 (2H, s), 8.05 (1H, s), 8.18 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.43 (1H, d, J = 2.6 Hz), 10.80 (1H, s), 12.86 (1H, s).

Reference Example 111
6- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.98 (3H, s), 6.90 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.25 (1H, d , J = 0.7 Hz), 7.36 (1H, d, J = 2.1 Hz), 7.69 (1H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8. 4 Hz), 7.95 (1 H, dd, J = 8.4 Hz, 2.1 Hz), 8.20 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.23 (1 H, d, J = 2.1 Hz), 8.48 (1H, d, J = 2.6 Hz), 10.55 (1H, s), 12.85 (1H, brs).

Reference Example 112
1-methyl-6- [5- (4-trifluoromethylbenzoylamino) pyrimidin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.99 (3H, s), 6.97 (1 H, dd, J = 8.6 Hz, 2.0 Hz), 7.24 (1 H, s), 7.47 (1 H, d, J = 2.0 Hz) ), 7.70 (1H, d, J = 8.6 Hz), 7.96 (2H, d, J = 8.2 Hz), 8.19 (2H, d, J = 8.1 Hz), 8.96 (2H, s), 10.80 (1H, s), 13.04 (1H, brs).

Reference Example 113
1-methyl-6- (5-methylaminopyridin-2-yloxy) -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.68 (3H, s), 3.93 (3H, s), 5.67 (1H, s), 6.78 (1H, dd, J = 8.7 Hz, 1.5 Hz), 6.84 ( 1H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.9 Hz, 3.0 Hz), 7.13 (1H, s), 7.19 (1H, s), 7. 51 (1H, d, J = 3.0 Hz), 7.61 (1H, d, J = 8.9 Hz), 12.78 (1H, s).

Reference Example 114
6- (5-Aminopyridin-2-yloxy) -1H-indole-2-carboxylic acid 1H-NMR (CDCl 3) δ ppm:
5.20 (1H, s), 6.77 (2H, d, J = 8.6 Hz), 6.89 (1H, d, J = 1.0 Hz), 7.07 (1H, s), 7. 09 (1H, dd, J = 8.6 Hz, 1.4 Hz), 7.55-7.56 (2H, m), 11.56 (1H, s).

Reference Example 115
6- (5-Methylaminopyridin-2-yloxy) -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.69 (3H, s), 5.70 (1H, s), 6.77 (1H, dd, J = 8.6 Hz, 2.3 Hz), 6.84 (1H, d, J = 8.9 Hz) ), 6.90 (1H, d, J = 2.3 Hz), 7.06 (1H, d, J = 2.6 Hz), 7.08 (1H, dd, J = 8.9 Hz, 3.0 Hz) 7.53 (1H, d, J = 3.0 Hz), 7.59 (1H, d, J = 8.6 Hz), 11.56 (1H, s).

Reference Example 116
1-methyl-6- (5-methylaminopyrimidin-2-yloxy) -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.70 (3H, s), 3.96 (3H, s), 5.81 (1H, s), 6.85 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.22 ( 1H, s), 7.30 (1H, d, J = 2.0 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.97 (2H, s), 12.86 (1H, brs).

Reference Example 117
1-methoxymethyl-6- (5-methylaminopyridin-2-yloxy) -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.69 (3H, s), 3.14 (3H, s), 5.87 (2H, s), 6.83 (1H, dd, J = 8.4 Hz, 2.2 Hz), 6.86 ( 1H, d, J = 8.6 Hz), 7.08 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.23 (1H, d, J = 1.6 Hz), 7.29 (1H , S), 7.51 (1H, d, J = 3.0 Hz), 7.64 (1H, d, J = 8.6 Hz).

Reference Example 118
6- [5- (Methanesulfonylmethylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.00 (3H, s), 3.25 (3H, s), 6.87 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.06 (1H, d, J = 8.9 Hz) ), 7.12-7.13 (2H, m), 7.67 (1H, d, J = 8.6 Hz), 7.91 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8 .17 (1H, d, J = 3.0 Hz), 11.77 (1H, s), 12.94 (1H, s).

Reference Example 119
6- [5- (2-Methoxy-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.96 (3H, s), 3.98 (3H, s), 6.89 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.06 (1H, d, J = 8.7 Hz) ), 7.25 (1H, s), 7.35 (1H, d, J = 2.0 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.46 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 7.77 (1H, d, J = 7.6 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8 .45 (1H, d, J = 2.6 Hz), 10.42 (1H, s), 12.85 (1H, brs).

Reference Example 120
6- [5- (2,4-Bistrifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
3.99 (3H, s), 6.89 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.08 (1H, d, J = 8.9 Hz), 7.21 (1H, s ), 7.36 (1H, d, J = 1.5 Hz), 7.68 (1H, d, J = 8.7 Hz), 8.02 (1H, d, J = 7.9 Hz), 8.15 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23-8.26 (2H, m), 8.39 (1H, d, J = 2.6 Hz), 10.87 (1H, s), 12.87 (1H, brs).

Reference Example 121
1-methyl-6- (5-methylaminopyridin-2-yloxy) -2,3-dihydro-1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
2.66-2.67 (6H, m), 2.84 (1H, dd, J = 15.7 Hz, 9.4 Hz), 2.99 (1H, dd, J = 15.8 Hz, 9.6 Hz) 3.66 (1H, t, J = 9.6 Hz), 5.61 (1H, q, J = 4.9 Hz), 5.90 (1H, d, J = 2.0 Hz), 5.97 ( 1H, dd, J = 7.6 Hz, 2.0 Hz), 6.71 (1H, d, J = 8.6 Hz), 6.79 (1H, d, J = 7.9 Hz), 7.02 (1H , Dd, J = 8.7 Hz, 3.1 Hz), 7.50 (1H, d, J = 3.0 Hz).

Reference Example 122
6- [5- (3,4-Dichlorobenzenesulfonylamino) -4-methylpyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (CDCl 3) δ ppm:
2.08 (3H, s), 3.96 (3H, s), 6.85 (1H, dd, J = 8.9 Hz, 2.0 Hz), 6.90 (1H, s), 7.23 ( 1H, s), 7.35 (1H, s), 7.54 (1H, s), 7.62 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.67 (1H, d, J = 8.6 Hz), 7.85 (1H, d, J = 2.0 Hz), 7.88 (1H, d, J = 8.2 Hz), 10.01 (1H, s).

Reference Example 123
6- (5-t-Butoxycarbonylamino-4-methylpyridin-2-yloxy) -1-methyl-1H-indole-2-carboxylic acid 1H-NMR (DMSO-d6) δ ppm:
1.45 (9H, s), 2.21 (3H, s), 3.97 (3H, s), 6.84-6.88 (2H, m), 7.23 (1H, d, J = 0.7 Hz), 7.33 (1 H, d, J = 2.0 Hz), 7.67 (1 H, d, J = 8.6 Hz), 7.94 (1 H, s), 8.67 (1 H, s), 12.86 (1H, brs).

Reference Example 124
Preparation of 1- (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [4- (5-nitropyridin-2-yloxy) indol-1-yl] ethanone [4 -(5-Nitropyridin-2-yloxy) indol-1-yl] acetic acid (0.210 g, 0.670 mmol) was dissolved in a mixture of THF (10 ml) -DMF (2 ml) and 1-benzo [1,3 Add dioxol-5-ylmethylpiperazine (0.148 g, 0.670 mmol) followed by 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.129 g, 0.670 mmol) at room temperature. Stir for 3 hours. To the reaction solution was added saturated brine (50 ml), and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.258 g of the title compound.
Properties: Light brown powder 1H-NMR (CDCl3) δ ppm:
2.37 (2H, t, J = 4.9 Hz), 2.43 (2H, t, J = 4.9 Hz), 3.42 (2H, s), 3.48 (2H, t, J = 4) .9 Hz), 3.66 (2H, t, J = 4.9 Hz), 4.93 (2H, s), 5.95 (2H, s), 6.29-6.30 (1H, m), 6.70-6.77 (2H, m), 6.83 (1H, d, J = 1.2 Hz), 6.93 (1H, dd, J = 7.0 Hz, 1.3 Hz), 7.00 (1H, d, J = 9.1 Hz), 7.06 (1H, d, J = 3.3 Hz), 7.19-7.29 (2H, m), 8.44 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.06 (1H, d, J = 2.8 Hz).

  The following compounds were produced in the same manner as in Reference Example 124 using appropriate starting materials.

Reference Example 125
1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [5- (5-nitropyridin-2-yloxy) -2,3-dihydroindol-1-yl ] Ethanone 1H-NMR (CDCl3) δ ppm:
2.44 (4H, t, J = 4.8 Hz), 3.03 (2H, t, J = 8.2 Hz), 3.44 (2H, s), 3.49-3.55 (4H, m ), 3.65 (2H, t, J = 4.8 Hz), 3.88 (2H, s), 5.95 (2H, s), 6.44 (1H, d, J = 8.2 Hz), 6.74-6.75 (2H, m), 6.80-6.89 (3H, m), 6.96 (1H, d, J = 9.1 Hz), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

Reference Example 126
1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [4- (5-nitropyridin-2-yloxy) -2,3-dihydroindol-1-yl ] Ethanone 1H-NMR (CDCl3) δ ppm:
2.44 (4H, t, J = 4.9 Hz), 2.83 (2H, t, J = 8.2 Hz), 3.44 (2H, s), 3.51 (2H, t, J = 8) .2 Hz), 3.52 (2H, t, J = 4.8 Hz), 3.65 (2H, t, J = 4.8 Hz), 3.92 (2H, s), 5.95 (2H, s) ), 6.35 (1H, d, J = 7.6 Hz), 6.45 (1H, d, J = 8.1 Hz), 6.74-6.75 (2H, m), 6.85 (1H) , S), 6.99 (1H, d, J = 9.1 Hz), 7.10-7.16 (1H, m), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz) 9.07 (1H, d, J = 2.8 Hz).

Reference Example 127
(4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) [1-methyl-5- (5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] methanone 1H -NMR (CDCl3) δ ppm:
2.20 (1H, brs), 2.47 (4H, brs), 2.81 (3H, s), 3.45 (2H, s), 3.76 (4H, brs), 3.81 (3H , S), 5.95 (2H, s), 6.51 (1H, s), 6.75 (2H, s), 6.75 (1H, d, J = 8.8 Hz), 6.86 ( 1H, s), 6.98 (1H, dd, J = 8.8 Hz, 3.0 Hz), 7.05 (1H, dd, J = 8.8 Hz, 2.3 Hz), 7.28 (1H, d , J = 2.3 Hz), 7.32 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 3.0 Hz).

Reference Example 128
1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [5- (5-bromopyridin-2-yloxy) indol-1-yl] ethanone 1H-NMR ( CDCl3) δ ppm:
2.25-2.50 (4H, m), 3.41 (2H, s), 3.40-3.54 (2H, m), 3.57-3.72 (2H, m), 4. 90 (2H, s), 5.95 (2H, s), 6.50-6.55 (1H, m), 6.68-6.79 (3H, m), 6.40-6.46 ( 1H, m), 6.98 (1H, dd, J = 8.8 Hz, 2.3 Hz), 7.12 (1H, d, J = 3.2 Hz), 7.22-7.30 (1H, m ), 7.36 (1H, d, J = 2.3 Hz), 7.70 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.18-8.23 (1H, m).

Reference Example 129
6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indol-4-yloxy} nicotine Acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.38 (3H, t, J = 7.1 Hz), 2.41-2.45 (4H, m), 2.82 (2H, t, J = 8.2 Hz), 3.41-3.50 (2H, m), 3.43 (2H, s), 3.51-3.55 (2H, m), 3.63-3.66 (2H, m), 3.90 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 5.95 (2H, s), 6.33 (1H, d, J = 7.8 Hz), 6.47 (1H, d, J = 7) .9 Hz), 6.73-6.74 (2H, m), 6.85-6.91 (2H, m), 7.08-7.14 (1H, m), 8.25 (1H, dd) , J = 8.6 Hz, 2.5 Hz), 8.84 (1H, d, J = 2.5 Hz).

Reference Example 130
(R) -3-Methyl-4- {1-methyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-Butyl ester 1H-NMR (CDCl 3) δ ppm:
1.30 (3H, d, J = 6.5 Hz), 1.48 (9H, s), 2.88 (1H, brs), 3.05 (1H, brs), 3.27 (1H, brs) , 3.82 (3H, s), 3.91 (1H, brs), 4.22 (2H, brs), 4.69 (1H, brs), 6.54 (1H, s), 6.94 ( 1H, d, J = 8.9 Hz), 7.10 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.36-7.39 (2H, m), 7.76 (2H, d) , J = 8.4 Hz), 7.85 (1 H, s), 7.99 (2 H, d, J = 8.4 Hz), 8.17 (1 H, dd, J = 2.7 Hz, 8.6 Hz) , 8.24 (1H, d, J = 2.4 Hz).

Reference Example 131
4- {1-methyl-6- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR ( CDCl3) δ ppm:
1.48 (9H, s), 3.50 (4H, brs), 3.76 (4H, t, J = 4.9 Hz), 3.80 (3H, s), 6.60 (1H, s) 6.95 (1H, dd, J = 2.2 Hz, 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.15 (1H, d, J = 1.9 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.83 (1H, s), 8.00 (2H, d, J = 8) .1 Hz), 8.21 (1H, dd, J = 2.7 Hz, 8.9 Hz), 8.27 (1H, d, J = 2.4 Hz).

Reference Example 132
4- {1,4-dimethyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H- NMR (CDCl3) δ ppm:
1.49 (9H, s), 2.35 (3H, s), 3.51-3.52 (4H, m), 3.75-3.78 (4H, m), 3.83 (3H, s), 6.62 (1H, s), 6.91 (1H, d, J = 8.9 Hz), 7.06 (1H, d, J = 8.9 Hz), 7.24 (1H, d, J = 10.8 Hz), 7.76 (2H, d, J = 8.1 Hz), 7.83 (1H, s), 7.99 (1H, d, J = 8.4 Hz), 8.18 ( 1H, dd, J = 2.7 Hz, 8.6 Hz), 8.22 (1H, d, J = 2.2 Hz).

Reference Example 133
4- {1-methyl-6- [5- (4-trifluoromethoxybenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR ( CDCl3) δ ppm:
1.49 (9H, s), 3.51 (4H, d, J = 5.3 Hz), 3.75 (4H, t, J = 5.1 Hz), 3.79 (3H, s), 6. 60 (1H, d, J = 0.7 Hz), 6.93-6.99 (2H, m), 7.14 (1H, d, J = 2.0 Hz), 7.33 (2H, d, J = 7.9 Hz), 7.62 (1 H, d, J = 8.6 Hz), 7.82 (1 H, s), 7.94 (2 H, dt, J = 9.2 Hz, 2.5 Hz), 8 .18-8.26 (2H, m).

Reference Example 134
4- {6- [5- (2-Chloro-4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.34-3.50 (4H, m), 3.76 (4H, t, J = 5.1 Hz), 3.80 (3H, s), 6.60 ( 1H, s), 6.93-7.01 (2H, m), 7.15 (1H, s), 7.61-7.67 (2H, m), 7.75 (1H, s), 7 .89 (1H, d, J = 7.9 Hz), 7.92 (1H, s), 8.23 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.27 (1H, d, J = 2.6 Hz).

Reference Example 135
4- {6- [5- (3,4-Dichlorobenzoylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR ( CDCl3) δ ppm:
1.49 (9H, s), 3.50 (4H, t, J = 4.9 Hz), 3.74 (4H, t, J = 5.6 Hz), 3.78 (3H, s), 6. 59 (1H, s), 6.68 (1H, dd, J = 8.6 Hz, 1.9 Hz), 6.95 (1H, d, J = 8.9 Hz), 7.13 (1H, d, J = 2.0 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.71 (1H, dd, J = 8.4 Hz) 2.1 Hz), 7.92 (1 H, brs), 7.98 (1 H, d, J = 2.0 Hz), 8.15 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 8. 26 (1H, d, J = 2.6 Hz).

Reference Example 136
4- [1-Methyl-6- (5-methylaminopyrimidin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.49 (9H, s), 2.87 (3H, d, J = 4.9 Hz), 3.50 (4H, t, J = 5.1 Hz), 3.56-3.58 (1H, m ), 3.75 (4H, t, J = 4.9 Hz), 3.80 (3H, s), 6.59 (1H, d, J = 0.7 Hz), 6.97 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.17 (1 H, d, J = 2.0 Hz), 7.61 (1 H, d, J = 8.6 Hz), 7.98 (2 H, s).

Reference Example 137
4- [1-Methyl-6- (5-methylaminopyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.49 (9H, s), 2.83 (3H, s), 3.45-3.60 (4H, m), 3.76 (7H, s), 6.57 (1H, s), 6 .80 (1H, d, J = 8.9 Hz), 6.90 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.00 (1H, dd, J = 8.6 Hz, 3.2 Hz) ), 7.04 (1H, d, J = 1.9 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 3.0 Hz).

Reference Example 138
[1-Methyl-6- (5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] [4- (4-propoxybenzyl) piperazin-1-yl] methanone 1H-NMR (CDCl 3) δ ppm :
1.04 (3H, t, J = 7.6 Hz), 1.74-1.87 (2H, m), 2.47 (4H, s), 2.87 (3H, s), 3.49 ( 2H, s), 3.53 (1H, s), 3.75 (7H, s), 3.92 (2H, t, J = 6.5 Hz), 6.55 (1H, d, J = 0. 7 Hz), 6.80 (1H, d, J = 8.2 Hz), 6.85-6.91 (3H, m), 6.99-7.04 (2H, m), 7.22 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 3.0 Hz).

Reference Example 139
[1-Methoxymethyl-6- (5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1 -Il} methanone 1H-NMR (CDCl 3) δ ppm:
2.45 (4H, s), 2.79 (3H, s), 3.20 (3H, s), 3.48 (2H, s), 3.76 (5H, s), 4.34 (2H) , Q, J = 8.2 Hz), 5.56 (2H, s), 6.60 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 6.88-6.99. (4H, m), 7.19 (1H, d, J = 1.6 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.56 (1H, t, J = 7.1 Hz) , 7.61 (1H, d, J = 3.0 Hz).

Reference Example 140
[6- (5-Methylaminopyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-yl} methanone 1H -NMR (CDCl3) δ ppm:
2.51 (4H, t, J = 5.1 Hz), 2.85 (3H, s), 3.51 (2H, s), 3.57 (1H, s), 3.91 (4H, s) 4.35 (2H, q, J = 8.1 Hz), 6.72 (1H, dd, J = 2.0 Hz, 1.0 Hz), 6.81 (1H, dd, J = 8.6 Hz, 0) .7 Hz), 6.88-6.95 (3 H, m), 7.01 (1 H, dd, J = 8.9 Hz, 3.0 Hz), 7.07 (1 H, d, J = 1.9 Hz) 7.29 (2H, d, J = 8.4 Hz), 7.57 (1 H, d, J = 8.9 Hz), 7.65 (1H, d, J = 3.0 Hz), 9.00 ( 1H, s).

Reference Example 141
[6- (5-Aminopyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-yl} methanone 1H— NMR (CDCl3) δ ppm:
2.51 (4H, t, J = 4.9 Hz), 3.51 (4H, s), 3.91 (4H, s), 4.35 (2H, q, J = 8.1 Hz), 6. 72 (1H, d, J = 2.0 Hz), 6.77 (1H, d, J = 8.6 Hz), 6.88-6.93 (3H, m), 7.06-7.10 (2H M), 7.29 (2H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 3.0 Hz), 9 .03 (1H, s).

Reference Example 142
[1-Methyl-6- (5-methylaminopyridin-2-yloxy) -2,3-dihydro-1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) [Benzyl] piperazin-1-yl} methanone 1H-NMR (CDCl 3) δ ppm:
2.40 (2H, s), 2.47 (2H, s), 2.70 (3H, s), 2.77 (3H, s), 2.93 (1H, dd, J = 15.8 Hz, 9.9 Hz), 3.24 (1 H, dd, J = 15.5 Hz, 9.9 Hz), 3.48 (2 H, s), 4.29 (1 H, t, J = 9.7 Hz), 4. 34 (2H, q, J = 7.8 Hz), 4.53 (1H, s), 6.14 (1H, d, J = 2.0 Hz), 6.28 (1H, dd, J = 7.9 Hz) 2.0 Hz), 6.71 (1 H, d, J = 8.9 Hz), 6.87-6.96 (4 H, m), 7.26 (2 H, d, J = 8.6 Hz), 7 .60 (1H, d, J = 3.0 Hz).

Reference Example 143
[4- (4-Isopropoxybenzyl) piperazin-1-yl] [1-methyl-6- (5-methylaminopyrimidin-2-yloxy) -1H-indol-2-yl] methanone 1H-NMR (CDCl 3) δppm:
1.34 (6H, d, J = 6.3 Hz), 2.48 (4H, brs), 2.86 (3H, d, J = 5.3 Hz), 3.48 (2H, s), 3. 55-3.57 (1H, m), 3.78 (7H, s), 4.49-4.58 (1H, m), 6.57 (1H, s), 6.85 (2H, d, J = 8.6 Hz), 6.95 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.17-7.21 (3H, m), 7.59 (1H, d, J = 8) .6 Hz), 7.98 (2H, s).

Reference Example 144
[4-Methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] carbamic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.50 (9H, s), 2.26 (3H, s), 2.48 (4H, brs), 3.51 (2H, s), 3.77 (7H, s), 4.35 (2H) , Q, J = 8.1 Hz), 6.05 (1H, brs), 6.57 (1H, s), 6.72 (1H, s), 6.88-6.95 (3H, m), 7.10 (1H, d, J = 1.6 Hz), 7.28-7.32 (2H, m), 7.57 (1H, d, J = 8.6 Hz), 8.25 (1H, brs) ).

Reference Example 145
Preparation of 5- (5-nitropyridin-2-yloxy) -2,3-dihydro-1H-indole 5- (5-Nitropyridin-2-yloxy) -1H-indole (3.00 g, 11.8 mmol) was prepared. It was dissolved in 1,4-dioxane (30 ml), borane-trimethylamine complex (3.43 g, 47.0 mmol) and hydrochloric acid (1.96 ml, 23.5 mmol) were added, and the mixture was heated to reflux for 1 hour. After cooling for 30 minutes, 6N hydrochloric acid (9.40 ml, 56.4 mmol) was added, and the mixture was heated to reflux again. After 30 minutes, the reaction solution was ice-cooled, and concentrated aqueous sodium hydroxide solution was added dropwise to adjust the pH to 8. Water (150 ml) was added to the mixture, and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2.82 g of the title compound.
Properties: Red-orange oil 1H-NMR (CDCl3) δ ppm:
3.07 (2H, t, J = 8.4 Hz), 3.62 (2H, t, J = 8.4 Hz), 3.78 (1H, brs), 6.65 (1H, d, J = 8) .4 Hz), 6.78 (1 H, dd, J = 8.4 Hz, 2.3 Hz), 6.90 (1 H, d, J = 2.0 Hz), 6.97 (1 H, d, J = 9. 1 Hz), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz).

  The following compounds were produced in the same manner as in Reference Example 145 using appropriate starting materials.

Reference Example 146
4- (5-Nitropyridin-2-yloxy) -2,3-dihydro-1H-indole 1H-NMR (CDCl3) δ ppm:
2.85 (2H, t, J = 8.4 Hz), 3.59 (2H, t, J = 8.4 Hz), 6.47 (1H, d, J = 7.9 Hz), 6.57 (1H , D, J = 7.8 Hz), 7.00 (1H, d, J = 9.1 Hz), 7.06-7.12 (1H, m), 8.46 (1H, dd, J = 9. 1 Hz, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz).

Reference Example 147
6- (2,3-Dihydro-1H-indol-4-yloxy) nicotinic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.38 (3H, t, J = 7.1 Hz), 2.84 (2H, t, J = 8.4 Hz), 3.56 (2H, t, J = 8.4 Hz), 3.88 (1H , Brs), 4.38 (2H, q, J = 7.1 Hz), 6.48 (1H, d, J = 8.1 Hz), 6.54 (1H, d, J = 7.8 Hz), 6 .89 (1H, d, J = 8.6 Hz), 7.04-7.10 (1H, m), 8.26 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.85 ( 1H, d, J = 2.3 Hz).

Reference Example 148
Preparation of [4- (5-nitropyridin-2-yloxy) indol-1-yl] acetic acid ethyl ester 4- (5-nitropyridin-2-yloxy) -1H-indole (3.34 g, 13.1 mmol) was prepared. Dissolve in DMF (20 ml), add 60% sodium hydride (0.523 g, 13.1 mmol) and then ethyl bromoacetate (1.45 ml, 13.1 mmol) under ice-cooling. Stir for hours. Ice water (150 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) and recrystallized from a mixed solvent of ethyl acetate-n-hexane to obtain 1.84 g of the title compound.
Properties: Yellow powder 1H-NMR (CDCl3) δ ppm:
1.28 (3H, t, J = 7.1 Hz), 4.24 (2H, q, J = 7.1 Hz), 4.86 (2H, s), 6.30 (1H, d, J = 3) .3 Hz), 6.95 (1H, dd, J = 7.3 Hz, 1.2 Hz), 7.02 (1H, d, J = 9.1 Hz), 7.08 (1H, d, J = 3. 3 Hz), 7.21 (1 H, d, J = 8.2 Hz), 7.25-7.31 (1 H, m), 8.47 (1 H, dd, J = 9.1 Hz, 3.0 Hz), 9.06 (1H, d, J = 2.8 Hz).

  The following compounds were produced in the same manner as in Reference Example 148 using appropriate starting materials.

Reference Example 149
[5- (5-Nitropyridin-2-yloxy) -2,3-dihydroindol-1-yl] acetic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.29 (3H, t, J = 7.1 Hz), 3.06 (2H, t, J = 8.4 Hz), 3.62 (2H, t, J = 8.4 Hz), 3.90 (2H , S), 4.22 (2H, q, J = 7.1 Hz), 6.39 (1H, d, J = 8.4 Hz), 6.82 (1H, dd, J = 8.4 Hz, 2. 5 Hz), 6.88 (1 H, d, J = 2.1 Hz), 6.95 (1 H, d, J = 9.1 Hz), 8.43 (1 H, dd, J = 9.1 Hz, 2.8 Hz) ), 9.07 (1H, d, J = 2.8 Hz).

Reference Example 150
[4- (5-Nitropyridin-2-yloxy) -2,3-dihydroindol-1-yl] acetic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.29 (3H, t, J = 7.1 Hz), 2.86 (2H, t, J = 8.4 Hz), 3.59 (2H, t, J = 8.4 Hz), 3.90 (2H , S), 4.22 (2H, q, J = 7.1 Hz), 6.32 (1H, d, J = 7.8 Hz), 6.45 (1H, d, J = 8.1 Hz), 6 .98 (1H, d, J = 9.1 Hz), 7.09-7.15 (1H, m), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.07 ( 1H, d, J = 2.8 Hz).

Reference Example 151
5- {5-[(3,4-Dichlorobenzoyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carboxylic acid methyl ester 1H-NMR (CDCl 3) δ ppm:
3.45 (3H, s), 3.92 (3H, s), 4.08 (3H, s), 6.85 (1H, d, J = 8.7 Hz), 7.03-7.14 ( 2H, m), 7.23-7.27 (1H, m), 7.29 (1H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.84 ( 1H, d, J = 2.6 Hz).

Reference Example 152
4- (1-Methyl-5- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.47 (3H, s), 3.48 (4H, brs), 3.74 (4H, brs), 3.84 (3H, s), 6.55 (1H) , S), 6.83 (1H, d, J = 8.7 Hz), 7.03 (1H, dd, J = 8.9 Hz, 2.1 Hz), 7.31 (1H, d, J = 2. 1 Hz), 7.35 (1 H, d, J = 8.9 Hz), 7.35-7.46 (1 H, m), 7.40 (2 H, d, J = 8.0 Hz), 7.50 ( 2H, d, J = 8.0 Hz), 7.82 (1H, brs).

Reference Example 153
4- (5- {5-[(3,4-Dichlorobenzoyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.45 (3H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.84 (3H, s), 6.56 (1H) , S), 6.86 (1H, d, J = 8.7 Hz), 7.05 (1H, dd, J = 9.0 Hz, 2.3 Hz), 7.08 (1H, dd, J = 8. 2Hz, 1.8Hz), 7.29 (1H, d, J = 8.2Hz), 7.33 (1H, d, J = 2.3Hz), 7.37 (1H, d, J = 9.0Hz) ), 7.42 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.42 (1H, d, J = 1.8 Hz), 7.83 (1H, d, J = 2.5 Hz) .

Reference Example 154
4- [1-Methyl-5- (5-nitropyridin-2-yloxy) -1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.49 (9H, s), 3.51 (4H, brs), 3.76 (4H, brs), 3.87 (3H, s), 6.59 (1H, s), 7.02 (1H , D, J = 9.1 Hz), 7.09 (1H, dd, J = 8.9 Hz, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.42 (1H, d, J = 8.9 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

Reference Example 155
4- (5- {5-[(3,4-Dichlorophenyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H- NMR (CDCl3) δ ppm:
1.48 (9H, s), 3.24 (3H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.85 (3H, s), 6.58 (1H) , Dd, J = 8.7 Hz, 2.8 Hz), 6.58 (1H, s), 6.83 (1H, d, J = 2.8 Hz), 6.90 (1H, d, J = 8. 7 Hz), 7.13 (1H, dd, J = 8.9 Hz, 2.1 Hz), 7.21 (1H, d, J = 8.9 Hz), 7.38 (1H, s), 7.40 ( 1H, d, J = 2.1 Hz), 7.46 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.01 (1H, d, J = 2.8 Hz).

Reference Example 156
{6- [2- (4-Benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} ethylcarbamic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.14 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 2.65-3.40 (4H, m), 3.62 (2H, q, J = 7.1 Hz) ), 3.82 (3H, s), 3.95-4.50 (6H, m), 6.58 (1H, s), 6.87 (1H, d, J = 8.9 Hz), 7. 12 (1H, dd, J = 8.9 Hz, 2.0 Hz), 7.33-7.69 (8H, m), 7.98 (1H, d, J = 2.6 Hz).

Reference Example 157
4- (1-Methyl-5- {5- [methyl (4-trifluoromethylphenyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.48 (9H, s), 3.31 (3H, s), 3.50 (4H, brs), 3.75 (4H, t, J = 5.0 Hz), 3.85 (3H, s) , 6.57 (1H, s), 6.76 (2H, d, J = 8.6 Hz), 6.93 (1H, dd, J = 8.7 Hz, 0.6 Hz), 7.14 (1H, dd, J = 8.8 Hz, 2.2 Hz), 7.38 (1H, d, J = 8.8 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.42 (2H, d , J = 8.6 Hz), 7.50 (1H, dd, J = 8.7 Hz, 3.0 Hz), 8.05 (1H, d, J = 3.0 Hz).

Reference Example 158
{6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} ethylcarbamic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.13 (3H, t, J = 7.1 Hz), 1.42 (9H, s), 2.59 (4H, brs), 3.57 (2H, s), 3.62 (2H, q, J = 7.1 Hz), 3.83 (3H, s), 3.87 (4H, brs), 5.96 (2H, s), 6.55 (1H, s), 6.74-6.80. (2H, m), 6.85 (1H, d, J = 8.8 Hz), 6.91 (1H, s), 7.09 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7 .36 (1H, d, J = 2.3 Hz), 7.36 (1H, d, J = 2.3 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.99 (1H, d, J = 2.5 Hz).

Reference Example 159
4- (1-Ethyl-5- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.40 (3H, t, J = 7.0 Hz), 1.48 (9H, s), 3.47 (7H, s), 3.74 (4H, brs), 4.31 (2H, q, J = 7.0 Hz), 6.52 (1 H, s), 6.83 (1 H, d, J = 8.9 Hz), 7.01 (1 H, dd, J = 8.6 Hz, 2.2 Hz), 7.52-7.30 (7H, m), 7.83 (1H, s).

Reference Example 160
4- (1-methyl-5- {4-methyl-5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 2.24 (3H, s), 3.38 (3H, s), 3.49 (4H, brs), 3.74 (4H, brs), 3.83 (3H , S), 6.54 (1H, s), 6.68 (1H, s), 7.00 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.26-7.37 (5H) M), 7.47 (2H, d, J = 8.4 Hz), 7.98 (1H, s).

Reference Example 161
4- (1-methyl-5- {6-methyl-5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.48 (9H, s), 2.32 (3H, s), 3.38 (3H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.85 (3H , S), 6.46 (1H, d, J = 8.4 Hz), 6.55 (1H, s), 7.02 (1H, dd, J = 2.2 Hz, 8.6 Hz), 7.25 -7.39 (5H, m), 7.48 (2H, d, J = 8.1 Hz).

Reference Example 162
4- (5- {5-[(3,4-dichlorobenzoyl) methylamino] -4-methylpyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.48 (9H, s), 2.23 (3H, s), 3.35 (3H, s), 3.49 (4H, brs), 3.74 (4H, brs), 3.84 (3H , S), 6.56 (1H, s), 6.70 (1H, s), 7.03 (2H, d, J = 8.6 Hz), 7.24-7.38 (4H, m), 7.80 (1H, s).

Reference Example 163
4- (5- {5-[(3,4-dichlorobenzoyl) methylamino] -6-methylpyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.48 (9H, s), 2.30 (3H, s), 3.35 (3H, s), 3.50 (4H, brs), 3.76 (4H, brs), 3.85 (3H , S), 6.51 (1H, d, J = 8.4 Hz), 6.56 (1H, s), 7.05 (2H, d, J = 8.6 Hz), 7.26-7.41. (5H, m).

Reference Example 164
[4- (4-Methoxybenzyl) piperazin-1-yl] [1-methyl-5- (5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] methanone 1H-NMR (CDCl 3) δ ppm :
2.47 (4H, brs), 2.83 (3H, s), 3.49 (2H, s), 3.76 (4H, brs), 3.80 (3H, s), 3.81 (3H , S), 6.51 (1H, s), 6.75 (1H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.9 Hz), 6.98 (1H, dd) , J = 3.2 Hz, 8.9 Hz), 7.06 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.21-7.33 (4H, m), 7.61 (1H, d, J = 3.0 Hz).

Reference Example 165
(R) -3-Methyl-4- (1-methyl-5- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1 -Carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.29 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 2.88 (1H, brs), 3.05 (1H, brs), 3.25 (1H, t, J = 12.2 Hz), 3.47 (3H, s), 3.81 (3H, s), 3.91 (1H, brs), 4.20 (2H, brs), 4.68 (1H, brs) ), 6.52 (1H, d, J = 0.5 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 2.2 Hz, 8.6 Hz) 7.30-7.41 (5H, m), 7.50 (2H, d, J = 8.4 Hz), 8.01 (1H, s).

Reference Example 166
(S) -3-Methyl-4- (1-methyl-5- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1 -Carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.29 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 2.88 (1H, brs), 3.05 (1H, brs), 3.25 (1H, t, J = 12.2 Hz), 3.47 (3H, s), 3.81 (3H, s), 3.91 (1H, brs), 4.20 (2H, brs), 4.68 (1H, brs) ), 6.52 (1H, d, J = 0.5 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 2.2 Hz, 8.6 Hz) 7.30-7.41 (5H, m), 7.50 (2H, d, J = 8.4 Hz), 8.01 (1H, s).

Reference Example 167
4- (1-Methyl-6- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.48 (3H, s), 3.52 (4H, brs), 3.73-3.75 (4H, m), 3.77 (3H, s), 6 .59 (1H, s), 6.86 (1H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.4 Hz), 7.08 (1H, d, J = 1. 6 Hz), 7.40-7.42 (3 H, m), 7.51 (2 H, d, J = 8.1 Hz), 7.60 (1 H, d, J = 8.4 Hz), 7.85 ( 1H, s).

Reference Example 168
4- (1,4-Dimethyl-5- {5- [methyl (4-trifluoromethylbenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylate t-butyl Ester 1H-NMR (CDCl 3) δ ppm:
1.49 (9H, s), 2.19 (3H, s), 3.48 (3H, s), 3.50 (4H, brs), 3.73-3.77 (4H, m), 3 .81 (3H, s), 6.58 (1H, s), 6.83 (1H, d, J = 8.6 Hz), 6.98 (1H, d, J = 8.9 Hz), 7.21 (1H, d, J = 8.9 Hz), 7.37 (3H, d, J = 8.1 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.75 (1H, s) .

Reference Example 169
4- (6- {5-[(2-chloro-4-trifluoromethylbenzoyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.49 (7H, s), 3.74-3.79 (7H, m), 6.58 (1H, s), 6.79-6.84 (2H, m), 7.00-7.05 (1H, m), 7.32 (1H, d, J = 8.2 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.49- 7.75 (3H, m), 7.92 (1H, d, J = 2.6 Hz).

Reference Example 170
4- (1-Methyl-6- {5- [methyl (4-trifluoromethoxybenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.47-3.52 (7H, m), 3.74-3.77 (7H, m), 6.59 (1H, s), 6.84-6. 89 (2H, m), 7.06 (1H, s), 7.10 (2H, s), 7.35 (2H, d, J = 8.9 Hz), 7.42 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.86 (1H, d, J = 2.6 Hz).

Reference Example 171
Methyl- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] carbamic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.45 (9H, s), 2.48 (4H, brs), 3.24 (3H, s), 3.51 (2H, s), 3.78 (7H, s), 4.35 (2H) , Q, J = 8.0 Hz), 6.58 (1H, s), 6.87 (1H, d, J = 8.9 Hz), 6.87-7.00 (1H, m), 6.91 (1H, d, J = 8.6 Hz), 6.92 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.13 (1H, d, J = 2.0 Hz), 7.28 ( 2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz), 8.06 (1H, d, J = 2.9 Hz).

Reference Example 172
4- (6- {5-[(3,4-Dichlorobenzoyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H -NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.46 (3H, s), 3.50 (4H, t, J = 4.9 Hz), 3.75 (4H, t, J = 5.1 Hz), 3. 79 (3H, s), 6.59 (1H, s), 6.89 (2H, dd, J = 8.7 Hz, 1.6 Hz), 7.09 (1H, dd, J = 8.1 Hz, 4 .1 Hz), 7.10 (1 H, s), 7.30 (1 H, d, J = 8.2 Hz), 7.41 (1 H, d, J = 1.9 Hz), 7.44 (1 H, dd) , J = 8.9 Hz, 2.7 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.85 (1H, d, J = 2.6 Hz).

Reference Example 173
6- [5- (Acetylmethylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.42 (3H, t, J = 7.1 Hz), 1.90 (3H, s), 3.25 (3H, s), 4.04 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 6.96 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.00 (1H, d, J = 8.6 Hz), 7.19 (1H, s), 7.31 (1H, s), 7.54 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.69 (1H, d, J = 8.6 Hz), 8.05 (1H, d , J = 2.3 Hz).

Reference Example 174
6- [5- (Acetylmethylamino) pyridin-2-yloxy] indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.40 (3H, t, J = 7.3 Hz), 1.59 (9H, s), 1.90 (3H, s), 3.25 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 7.02 (1H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.9 Hz, 2.1 Hz), 7.12 (1H, s), 7.56 (1H, dd, J = 8.6 Hz, 2.6 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.94 (1H, d, J = 1.6 Hz), 8 .05 (1H, d, J = 2.6 Hz).

Reference Example 175
4- (6- {5-[(2-Fluoro-4-trifluoromethylbenzoyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t -Butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.48-3.52 (7H, m), 3.72-3.76 (7H, m), 6.58 (1H, s), 6.83 (2H, dd, J = 8.7 Hz, 2.5 Hz), 7.06 (1H, s), 7.14 (1H, d, J = 8.9 Hz), 7.35 (1H, d, J = 7.9 Hz) ), 7.47 (2H, t, J = 7.4 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.84 (1H, d, J = 2.6 Hz).

Reference Example 176
4- (6- {5-[(3,4-dichlorobenzenesulfonyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.21 (3H, s), 3.51-3.52 (4H, m), 3.74-3.78 (4H, m), 3.81 (3H, s), 6.60 (1H, s), 6.92 (1H, d, J = 8.1 Hz), 6.93 (1H, dd, J = 8.4 Hz, 1.9 Hz), 7.15 ( 1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.55 (1H, dd, J = 8.9 Hz, 3.0 Hz), 7 .57 (1H, d, J = 8.6 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 2.0 Hz), 7.82 (1H, d, J = 2.3 Hz).

Reference Example 177
4- (1-Methyl-5- {5- [methyl (4-trifluoromethylbenzenesulfonyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.20 (3H, s), 3.50 (4H, brs), 3.75 (4H, t, J = 4.9 Hz), 3.85 (3H, s) 6.57 (1H, s), 6.87-6.89 (1H, m), 7.09 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.38-7.40 ( 2H, m), 7.51 (1H, dd, J = 8.9 Hz, 2.6 Hz), 7.76-7.77 (5H, m).

Reference Example 178
4- (5- {5-[(3,4-Dichlorobenzenesulfonyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H-NMR (CDCl3) δ ppm:
1.49 (9H, s), 3.20 (3H, s), 3.50 (4H, brs), 3.75 (4H, t, J = 4.9 Hz), 3.85 (3H, s) , 6.57 (1H, s), 6.89 (1H, d, J = 8.9 Hz), 7.09 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.37-7. 38 (2H, m), 7.41 (1H, d, J = 2.3 Hz), 7.51 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.71 (1 H, d, J = 2.3 Hz), 7.80 (1 H, d, J = 3.0 Hz).

Reference Example 179
4- (1-Methyl-5- {5- [methyl (toluene-4-sulfonyl) amino] pyridin-2-yloxy} -1H-indole-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester 1H- NMR (CDCl3) δ ppm:
1.49 (9H, s), 2.42 (3H, s), 3.15 (3H, s), 3.50 (4H, brs), 3.75 (4H, t, J = 4.9 Hz) , 3.85 (3H, s), 6.57 (1H, s), 6.84 (1H, d, J = 8.9 Hz), 7.09 (1H, dd, J = 9.1 Hz, 2. 1 Hz), 7.26-7.28 (2H, m), 7.38-7.39 (2H, m), 7.48-7.52 (3H, m), 7.75 (1H, d, J = 2.6 Hz).

Reference Example 180
6- [5- (t-Butoxycarbonylmethylamino) pyrimidin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 3.27 (3H, s), 4.04 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 6.99 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.31 (1H, d, J = 0.8 Hz), 7.69 (1H, d, J = 8.7 Hz), 8.48 (2H, s).

Reference Example 181
1-methoxymethyl-6- {5- [methyl (4-nitrobenzoyl) amino] pyridin-2-yloxy} -1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.3 Hz), 3.28 (3H, s), 3.50 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 5. 91 (2H, s), 6.89 (1H, d, J = 9.7 Hz), 6.93 (1H, dd, J = 8.9 Hz, 1.9 Hz), 7.27 (1H, s), 7.34 (1H, d, J = 0.7 Hz), 7.46 (3H, d, J = 8.2 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.84 (1H , S), 8.11 (2H, d, J = 8.6 Hz).

Reference Example 182
6- [5- (Methanesulfonylmethylamino) pyridin-2-yloxy] indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.40 (3H, t, J = 7.1 Hz), 1.59 (9H, s), 2.88 (3H, s), 3.32 (3H, s), 4.38 (2H, q, J = 7.1 Hz), 6.97 (1H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.11 (1H, d, J = 0.7 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 8.9 Hz, 3.0 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 2.6 Hz).

Reference Example 183
1-methyl-6- {5- [methyl (4-nitrobenzoyl) amino] pyridin-2-yloxy} -2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.30 (3H, t, J = 7.3 Hz), 2.79 (3H, s), 3.09 (1H, dd, J = 16.8 Hz, 9.2 Hz), 3.32 (1H, dd) , J = 16.2 Hz, 10.2 Hz), 3.48 (3H, s), 4.13 (1H, dd, J = 9.5 Hz, 8.1 Hz), 4.21-4.29 (2H, m), 6.15 (1H, d, J = 2.0 Hz), 6.33 (1H, dd, J = 7.9 Hz, 2.0 Hz), 6.79 (1H, d, J = 8.9 Hz) ), 6.98 (1H, d, J = 7.9 Hz), 7.40 (1H, s), 7.45 (2H, d, J = 8.6 Hz), 7.85 (1H, s), 8.08 (2H, d, J = 8.6 Hz).

Reference Example 184
Methyl [4-methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine -3-yl] carbamic acid t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.35 (5H, s), 1.61 (4H, s), 2.21 (3H, s), 2.48 (4H, brs), 3.15 (3H, s), 3.51 (2H , S), 3.78 (7H, s), 4.35 (2H, q, J = 8.1 Hz), 6.58 (1H, s), 6.75 (1H, s), 6.91- 6.92 (3H, m), 7.13 (1H, s), 7.27-7.29 (2H, m), 7.60 (1 H, d, J = 8.6 Hz), 7.91 ( 1H, s).

Reference Example 185
Preparation of 6- {5-[(3,4-dichlorobenzenesulfonyl) methylamino] -4-methylpyridin-2-yloxy} -1-methyl-1H-indole-2-carboxylic acid 6- [5- (3 , 4-Dichlorobenzenesulfonylamino) -4-methylpyridin-2-yloxy] -1-methyl-1H-indole-2-carboxylic acid ethyl ester (3.1 g, 5.80 mmol) was dissolved in DMF (30 ml). 60% sodium hydride (0.302 g, 7.54 mmol) was added, and the mixture was stirred at 0 ° C. for a while, methyl iodide (0.399 ml, 6.38 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with 1M hydrochloric acid and saturated brine, and the solvent was distilled off. The residue was suspended in ethanol (30 ml), 5M aqueous sodium hydroxide solution (3.48 ml, 17.40 mmol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated, water and 6M hydrochloric acid were added to the residue, and the precipitate was collected by filtration and dried to give 3.03 g of the title compound.
Properties: White powder 1H-NMR (DMSO-d6) δ ppm:
2.29 (3H, s), 3.17 (3H, s), 4.01 (3H, s), 6.73-6.77 (2H, m), 6.91 (1H, s), 7 .18 (1H, d, J = 1.3 Hz), 7.51 (2H, d, J = 8.9 Hz), 7.64 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7. 90-7.92 (2H, m).

Reference Example 186
Preparation of N- {6- [1-methyl-2- (piperazine-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 4- {1-methyl- 5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester (2.75 g, 4.41 mmol) in ice Under cooling, trifluoroacetic acid (16 ml) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 5M aqueous sodium hydroxide solution was added to the residue to make it alkaline, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 2.03 g of the title compound.
Properties: Yellow amorphous powder 1H-NMR (CDCl 3) δ ppm:
2.92 (4H, brs), 3.75 (4H, brs), 3.81 (3H, s), 6.54 (1H, s), 6.89 (1H, d, J = 8.9 Hz) 7.08 (1H, dd, J = 8.9 Hz, 2.2 Hz), 7.37-7.34 (2H, m), 7.73 (2H, d, J = 8.1 Hz), 7. 99 (2H, d, J = 8.1 Hz), 8.14 (1H, dd, J = 8.6 Hz, 2.7 Hz), 8.23 (1 H, s), 8.26 (1 H, d, J = 2.7 Hz).

  The following compounds were produced in the same manner as in Reference Example 186 using appropriate starting materials.

Reference Example 187
N- {6- [1-ethyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -N-methyl-4-trifluoromethylbenzamide 1H-NMR (CDCl 3 ) Δ ppm:
1.38 (3H, t, J = 7.0 Hz), 2.96 (4H, brs), 3.45 (3H, s), 3.80 (4H, brs), 4.29 (2H, q, J = 7.0 Hz), 6.50 (1 H, s), 6.81 (1 H, d, J = 8.9 Hz), 6.99 (1 H, dd, J = 8.9 Hz, 2.4 Hz), 7.50-7.28 (7H, m), 7.82 (1H, s).

Reference Example 188
3,4-Dichloro-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide 1H-NMR (CDCl 3) δ ppm:
2.76 (4H, brs), 3.57 (4H, brs), 3.77 (3H, s), 6.61 (1H, s), 6.99 (1H, d, J = 9.7 Hz) 7.03 (1H, dd, J = 8.9 Hz, 2.2 Hz), 7.33 (1H, d, J = 2.4 Hz), 7.55 (1H, d, J = 8.9 Hz), 7.83 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 1.9 Hz), 8.15 (1H, dd, J = 8.9 Hz, 2. 4 Hz), 8.22 (1 H, d, J = 1.9 Hz), 8.44 (1 H, d, J = 2.4 Hz).

Reference Example 189
N- {4-Methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3 ) Δ ppm:
2.26 (3H, s), 2.92 (4H, brs), 3.74 (4H, brs), 3.82 (3H, s), 6.54 (1H, s), 6.74 (1H , S), 7.09 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.35 (1H, d, J = 5.1 Hz), 7.36 (1H, s), 7.75 (1H, s), 7.76 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz), 8.25 (1H, s).

Reference Example 190
N-methyl-N- {4-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.23 (3H, s), 2.91 (4H, brs), 3.37 (3H, s), 3.73 (4H, brs), 3.83 (3H, s), 6.53 (1H , S), 6.67 (1H, s), 6.99 (1H, dd, J = 1.9 Hz, 8.9 Hz), 7.24-7.28 (1H, m), 7.32-7 .37 (3H, m), 7.46 (2H, d, J = 8.6 Hz), 7.80 (1H, s).

Reference Example 191
3,4-Dichloro-N- {4-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide 1H-NMR (CDCl 3 ) Δ ppm:
2.16 (3H, s), 2.94 (4H, brs), 3.77 (7H, brs), 6.49 (1H, s), 6.65 (1H, s), 7.07 (1H , Dd, J = 2.4 Hz, 8.9 Hz), 7.29 (1H, s), 7.32 (1H, d, J = 2.2 Hz), 7.55 (1H, d, J = 8. 4 Hz), 7.76 (1 H, dd, J = 1.6 Hz, 8.1 Hz), 8.05-8.10 (3 H, m).

Reference Example 192
N- {2-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (DMSO -D6) δ ppm:
2.59 (3H, s), 2.74 (4H, brs), 3.57 (4H, brs), 3.77 (3H, s), 6.61 (1H, s), 6.75 (1H , D, J = 8.4 Hz), 7.05 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.56 (1H, d, J = 8.9 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8) .1 Hz), 10.21 (1 H, s).

Reference Example 193
N-methyl-N- {2-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.32 (3H, s), 2.92 (4H, brs), 3.38 (3H, s), 3.75 (4H, brs), 3.84 (3H, s), 6.45 (1H , D, J = 8.6 Hz), 6.54 (1H, s), 7.01 (1H, dd, J = 2.2 Hz, 8.6 Hz), 7.24-7.39 (5H, m) 7.46 (2H, d, J = 8.4 Hz).

Reference Example 194
3,4-Dichloro-N-methyl-N- {4-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide 1H -NMR (CDCl3) δ ppm:
2.22 (3H, s), 2.92 (4H, brs), 3.35 (3H, s), 3.74 (4H, brs), 3.83 (3H, s), 6.55 (1H) , S), 6.69 (1H, s), 7.01 (1H, t, J = 1.9 Hz), 7.04 (1H, t, J = 1.9 Hz), 7.24-7.39. (4H, m), 7.81 (1H, s).

Reference Example 195
3,4-Dichloro-N- {2-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide 1H-NMR (CDCl3 ) Δ ppm:
2.38 (3H, s), 2.93 (4H, brs), 3.77 (7H, s), 6.47-6.49 (2H, m), 7.08 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.25-7.33 (2 H, m), 7.57 (1 H, d, J = 8.4 Hz), 7.70 (1 H, d, J = 7.6 Hz) ), 7.76 (1H, dd, J = 1.6 Hz, 8.4 Hz), 8.02 (1H, s), 8.06 (1H, d, J = 1.9 Hz).

Reference Example 196
3,4-Dichloro-N-methyl-N- {2-methyl-6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide 1H -NMR (CDCl3) δ ppm:
2.30 (3H, s), 2.88-2.95 (4H, m), 3.35 (3H, s), 3.75 (4H, brs), 3.85 (3H, s), 6 .50 (1H, d, J = 8.4 Hz), 6.55 (1H, s), 7.04 (2H, d, J = 8.4 Hz), 7.25-7.42 (5H, m) .

Reference Example 197
N- {2- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyrimidin-5-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3 + CD 3 OD) δ ppm:
3.00 (4H, brs), 3.84 (7H, s), 6.61 (1H, s), 7.15 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.40- 7.43 (2H, m), 7.75 (2H, d, J = 8.4 Hz), 8.07 (2H, d, J = 8.1 Hz), 8.92 (2H, s).

Reference Example 198
3,4-Dichloro-N- {2- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyrimidin-5-yl} benzamide 1H-NMR (CDCl 3) δ ppm:
2.91 (4H, brs), 3.73 (4H, brs), 3.80 (2H, s), 6.55 (1H, s), 7.12 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.36 (1 H, d, J = 8.9 Hz), 7.40 (1 H, d, J = 2.2 Hz), 7.53 (1 H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 2.2 Hz, 8.4 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.39 (1H, brs), 8.82 (2H, s ).

Reference Example 199
N- {6- [1-methyl-2-((R) -2-methylpiperazine-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H- NMR (CDCl3) δ ppm:
1.38 (3H, d, J = 7.0 Hz), 2.75 (1H, dt, J = 3.2 Hz, 12.2 Hz), 2.85 (1H, d, J = 11.6 Hz), 2 .96 (1H, dd, J = 3.8 Hz, 12.4 Hz), 3.04 (1H, d, J = 11.6 Hz), 3.23 (1H, t, J = 12.2 Hz), 3. 79 (3H, s), 4.18 (1H, d, J = 12.7 Hz), 4.60 (1H, brs), 6.51 (1H, d, J = 0.5 Hz), 6.89 ( 1H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.33-7.36 (2H, m), 7.73 (2H, d) , J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.11-8.15 (2H, m), 8.25 (1H, d, J = 2.4 Hz) .

Reference Example 200
N-methyl-N- {6- [1-methyl-2-((R) -2-methylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoro Methylbenzamide 1H-NMR (CDCl3) δ ppm:
1.38 (3H, d, J = 6.8 Hz), 2.70-3.06 (4H, m), 3.23 (1H, t, J = 12.1 Hz), 3.47 (3H, s ), 3.80 (3H, s), 4.18 (1H, d, J = 12.1 Hz), 4.59 (1H, brs), 6.51 (1H, s), 6.82 (1H, d, J = 8.6 Hz), 7.00 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.29-7.41 (5H, m), 7.50 (2H, d, J = 8.1 Hz), 7.82 (1H, s).

Reference Example 201
N- {6- [1-methyl-2-((S) -2-methylpiperazine-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H- NMR (CDCl3) δ ppm:
1.37 (3H, d, J = 6.8 Hz), 2.68-3.05 (4H, m), 3.18-3.26 (1H, m), 3.76 (3H, s), 4.13 (1H, brs), 4.56 (1H, brs), 6.49 (1H, s), 6.84 (1H, d, J = 8.9 Hz), 7.05 (1H, dd, J = 1.6 Hz, 8.6 Hz), 7.30-7.33 (2H, m), 7.68 (2H, d, J = 7.8 Hz), 7.97 (2H, d, J = 8) .1 Hz), 8.07 (1H, d, J = 8.9 Hz), 8.26 (1H, d, J = 2.7 Hz), 8.43 (1H, brs).

Reference Example 202
N-methyl-N- {6- [1-methyl-2-((S) -2-methylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoro Methylbenzamide 1H-NMR (CDCl3) δ ppm:
1.38 (3H, d, J = 7.0 Hz), 2.70-3.06 (5H, m), 3.23 (1H, t, J = 12.4 Hz), 3.47 (3H, s ), 3.80 (3H, s), 4.18 (1H, d, J = 11.3 Hz), 4.58 (1H, brs), 6.51 (1H, s), 6.82 (1H, d, J = 8.6 Hz), 7.00 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.29-7.41 (5H, m), 7.50 (2H, d, J = 8.1 Hz), 7.82 (1H, s).

Reference Example 203
N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3 ) Δ ppm:
2.92 (4H, brs), 3.48 (3H, s), 3.74 (4H, brs), 3.77 (3H, s), 6.57 (1H, d, J = 0.8 Hz) 6.85 (1H, d, J = 8.4 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.07 (1H, d, J = 1.9 Hz), 7.40− 7.42 (3H, m), 7.50 (2H, d, J = 8.4 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.85 (1H, s).

Reference Example 204
N- {6- [1,4-dimethyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -N-methyl-4-trifluoromethylbenzamide 1H-NMR (CDCl3) δ ppm:
2.19 (3H, s), 2.92 (4H, brs), 3.48 (3H, s), 3.74 (4H, brs), 3.81 (3H, s), 6.56 (1H , S), 6.81 (1H, d, J = 8.6 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.9 Hz), 7 .36-7.49 (5H, m), 7.75 (1H, s).

Reference Example 205
N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethoxybenzamide 1H-NMR (CDCl3 ) Δ ppm:
2.92 (4H, s), 3.47 (3H, s), 3.73-3.77 (7H, m), 6.58 (1H, s), 6.86 (2H, dd, J = 8.9 Hz, 2.6 Hz), 7.06-7.09 (3 H, m), 7.35 (2 H, d, J = 8.6 Hz), 7.41 (1 H, dd, J = 8.6 Hz) , 2.6 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.86 (1H, d, J = 2.6 Hz).

Reference Example 206
N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
1.26 (1H, brs), 2.90 (4H, brs), 3.71 (7H, s), 6.54 (1H, s), 6.88 (1H, d, J = 8.6 Hz) 6.90 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.08 (1H, d, J = 1.5 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.96 (2H, d, J = 8.2 Hz), 8.12 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8 .30 (1H, d, J = 2.6 Hz), 8.69 (1H, s).

Reference Example 207
N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3 ) Δ ppm:
1.59 (1H, brs), 2.92 (4H, brs), 3.47 (3H, s), 3.74 (4H, brs), 3.83 (3H, s), 6.54 (1H , S), 6.82 (1H, d, J = 8.7 Hz), 7.01 (1H, dd, J = 8.7 Hz, 2.2 Hz), 7.30 (1H, d, J = 2. 2 Hz), 7.35 (1 H, d, J = 8.9 Hz), 7.36-7.46 (1 H, m), 7.40 (2 H, d, J = 8.1 Hz), 7.50 ( 2H, d, J = 8.1 Hz), 7.83 (1H, brs).

Reference Example 208
3,4-Dichloro-N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide 1H-NMR (CDCl 3 ) Δ ppm:
1.66 (1H, s), 2.92 (4H, brs), 3.45 (3H, s), 3.74 (4H, brs), 3.84 (3H, s), 6.56 (1H , S), 6.85 (1H, d, J = 8.8 Hz), 7.03 (1H, dd, J = 8.9 Hz, 2.2 Hz), 7.07 (1H, dd, J = 8. 3 Hz, 2.0 Hz), 7.29 (1 H, d, J = 8.3 Hz), 7.33 (1 H, d, J = 2.2 Hz), 7.37 (1 H, d, J = 8.9 Hz) ), 7.41 (1H, dd, J = 8.8 Hz, 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.83 (1H, d, J = 2.5 Hz) .

Reference Example 209
[1-Methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] piperazin-1-ylmethanone 1H-NMR (CDCl 3) δ ppm:
1.64 (1H, brs), 2.93 (4H, brs), 3.75 (4H, brs), 3.86 (3H, s), 6.58 (1H, s), 7.02 (1H , D, J = 9.0 Hz), 7.07 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.39 (1H, d, J = 2.3 Hz), 7.42 (1H, d, J = 8.9 Hz), 8.45 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

Reference Example 210
3,4-dichloro-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzenesulfonamide trifluoroacetate 1H-NMR (DMSO-d6) δ ppm:
3.21 (4H, brs), 3.79 (3H, s), 3.85 (4H, brs), 6.74 (1H, s), 6.91 (1H, d, J = 8.8 Hz) 7.01 (1H, dd, J = 8.8 Hz, 2.2 Hz), 7.31 (1H, d, J = 2.2 Hz), 7.51 (1H, dd, J = 8.8 Hz, 2 .8 Hz), 7.52 (1 H, d, J = 8.8 Hz), 7.63 (1 H, dd, J = 8.6 Hz, 2.2 Hz), 7.76 (1 H, d, J = 2. 8 Hz), 7.87 (1 H, d, J = 8.6 Hz), 7.89 (1 H, d, J = 2.2 Hz), 8.93 (1 H, brs), 10.41 (1 H, s) .

Reference Example 211
N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzenesulfonamide trifluoroacetate 1H-NMR (DMSO-d6) δ ppm:
3.21 (4H, brs), 3.79 (3H, s), 3.85 (4H, brs), 6.73 (1H, s), 6.90 (1H, d, J = 8.7 Hz) , 7.00 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.30 (1H, d, J = 2.3 Hz), 7.51 (1H, dd, J = 8.7 Hz, 2 .8 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.76 (1H, d, J = 2.8 Hz), 7.92 (2H, d, J = 8.4 Hz), 7 .98 (2H, d, J = 8.4 Hz), 8.90 (1H, brs), 10.49 (1H, s).

Reference Example 212
(5- {5-[(3,4-Dichlorophenyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indol-2-yl) piperazin-1-ylmethanone 1H-NMR (CDCl 3) δ ppm:
1.73 (1H, brs), 2.92 (4H, brs), 3.24 (3H, s), 3.75 (4H, brs), 3.85 (3H, s), 6.57 (1H , S), 6.58 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.83 (1H, d, J = 2.8 Hz), 6.90 (1H, d, J = 8. 7 Hz), 7.12 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.21 (1H, d, J = 8.9 Hz), 7.38 (1H, d, J = 8.7 Hz) ), 7.40 (1H, s), 7.45 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.00 (1H, d, J = 2.5 Hz).

Reference Example 213
(4-Benzylpiperazin-1-yl) [5- (5-ethylaminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] methanone 1H-NMR (CDCl 3) δ ppm:
1.30 (3H, t, J = 7.1 Hz), 3.21 (5H, brs), 3.22 (2H, q, J = 7.1 Hz), 3.81 (3H, s), 4. 23 (4H, brs), 4.24 (2H, s), 6.55 (1H, s), 6.84 (1H, d, J = 8.9 Hz), 7.06 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.35 (1H, d, J = 8.9 Hz), 7.35-7.50 (6H, m ), 7.95 (1H, d, J = 3.0 Hz).

Reference Example 214
(1-Methyl-5- {5- [methyl (4-trifluoromethylphenyl) amino] pyridin-2-yloxy} -1H-indol-2-yl) piperazin-1-ylmethanone 1H-NMR (CDCl 3) δ ppm:
1.80 (1H, brs), 2.93 (4H, brs), 3.31 (3H, s), 3.76 (4H, brs), 3.85 (3H, s), 6.57 (1H , S), 6.75 (2H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 7.12 (1H, dd, J = 8.7 Hz, 2. 1 Hz), 7.39 (1 H, d, J = 8.7 Hz), 7.40 (1 H, d, J = 2.1 Hz), 7.42 (2 H, d, J = 8.7 Hz), 7. 50 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.05 (1H, d, J = 2.8 Hz).

Reference Example 215
(4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) [5- (5-ethylaminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] methanone 1H -NMR (CDCl3) δ ppm:
1.25 (3H, t, J = 7.1 Hz), 2.47 (4H, brs), 3.12 (2H, q, J = 7.1 Hz), 3.35 (1H, brs), 3. 45 (2H, s), 3.76 (4H, brs), 3.82 (3H, s), 5.95 (2H, s), 6.51 (1H, s), 6.74 (1H, d , J = 8.8 Hz), 6.74 (2H, s), 6.86 (1H, s), 6.97 (1H, dd, J = 8.8 Hz, 2.8 Hz), 7.05 (1H) , Dd, J = 8.9 Hz, 2.3 Hz), 7.28 (1H, d, J = 2.3 Hz), 7.31 (1H, d, J = 8.9 Hz), 7.61 (1H, d, J = 2.8 Hz).

Reference Example 216
2-Chloro-N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.92 (4H, s), 3.49 (3H, s), 3.75-3.80 (7H, m), 6.58 (1H, d, J = 7.9 Hz), 6.78- 6.83 (2H, m), 7.04 (1H, s), 7.31 (1H, d, J = 7.9 Hz), 7.41 (1H, d, J = 8.2 Hz), 7. 48-7.83 (3H, m), 7.92 (1H, d, J = 2.6 Hz).

Reference Example 217
2-Chloro-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3 ) Δ ppm:
2.91 (4H, brs), 3.73 (4H, brs), 3.76 (3H, s), 6.56 (1H, s), 6.92 (1H, dd, J = 8.6 Hz, 2.0 Hz), 6.93 (1 H, d, J = 8.8 Hz), 7.12 (1 H, d, J = 2.0 Hz), 7.61 (1 H, d, J = 8.6 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.71 (1H, s), 7.82 (1H, d, J = 8.2 Hz), 8.18 (1H, dd, J = 8) .8 Hz, 2.7 Hz), 8.20 (1 H, s), 8.28 (1 H, d, J = 2.7 Hz).

Reference Example 218
[1-Methyl-6- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] piperazin-1-ylmethanone 1H-NMR (CDCl 3) δ ppm:
2.95 (4H, t, J = 4.8 Hz), 3.79 (4H, t, J = 4.8 Hz), 3.81 (3H, s), 6.62 (1H, s), 6. 93 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.04 (1H, d, J = 8.9 Hz), 7.16 (1H, d, J = 2.0 Hz), 7.66 (1H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.05 (1H, d, J = 2.6 Hz).

Reference Example 219
[1-Methyl-6- (5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1- IL} methanone 1H-NMR (CDCl 3) δ ppm:
2.47 (4H, brs), 2.84 (3H, s), 3.50 (2H, s), 3.57 (1H, brs), 3.75 (7H, s), 4.35 (2H) , Q, J = 8.1 Hz), 6.55 (1H, s), 6.80 (1H, d, J = 8.5 Hz), 6.88 (1H, dd, J = 8.5 Hz, 1. 9 Hz), 6.91 (2H, d, J = 8.3 Hz), 7.00 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.04 (1H, d, J = 1.9 Hz) ), 7.28 (2H, d, J = 8.3 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 3.0 Hz).

Reference Example 220
3,4-Dichloro-N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} benzamide 1H-NMR (CDCl 3 ) Δ ppm:
1.27 (1H, s), 2.92 (4H, t, J = 5.1 Hz), 3.46 (3H, s), 3.74 (4H, t, J = 4.9 Hz), 3. 78 (3H, s), 6.58 (1H, d, J = 0.8 Hz), 6.876 (1H, dd, J = 8.4 Hz, 1.4 Hz), 6.879 (1H, dd, J = 8.9 Hz, 1.6 Hz), 7.086 (1H, dd, J = 8.1 Hz, 2.2 Hz), 7.090 (1H, d, J = 2.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.42 (1H, d, J = 1.9 Hz), 7.43 (1H, dd, J = 8.6 Hz, 2.7 Hz), 7.60 (1H, dd) , J = 8.6 Hz, 0.5 Hz), 7.85 (1H, d, J = 2.8 Hz).

Reference Example 221
2-Methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl3 ) Δ ppm:
1.59 (1H, s), 2.56 (3H, s), 2.92 (4H, t, J = 4.5 Hz), 3.75 (4H, t, J = 4.9 Hz), 3. 79 (3H, s), 6.58 (1H, d, J = 0.7 Hz), 6.94 (1H, dd, J = 8.6 Hz, 1.9 Hz), 6.95 (1H, d, J = 9.7 Hz), 7.14 (1H, d, J = 2.0 Hz), 7.48-7.63 (5H, m), 8.21-8.25 (2H, m).

Reference Example 222
3,4-Dichloro-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} benzamide 1H-NMR (DMSO-d6) δ ppm :
2.77 (4H, t, J = 4.5 Hz), 3.38 (1H, brs), 3.59 (4H, t, J = 4.5 Hz), 3.71 (3H, s), 6. 66 (1H, d, J = 0.5 Hz), 6.88 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.03 (1H, d, J = 8.9 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.83 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.5 Hz, 2.1 Hz), 8.18 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.47 (1H , D, J = 2.5 Hz), 10.53 (1H, brs).

Reference Example 223
3,4-Dichloro-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} benzenesulfonamide hydrochloride 1H-NMR (DMSO -D6) δ ppm:
3.21 (4H, s), 3.72 (3H, s), 3.88 (4H, s), 6.80 (1H, s), 6.84 (1H, dd, J = 8.6 Hz, 2.0 Hz), 6.95 (1 H, d, J = 8.6 Hz), 7.31 (1 H, d, J = 2.0 Hz), 7.53-7.67 (3 H, m), 7. 80 (1H, d, J = 2.3 Hz), 7.87 (1H, d, J = 8.6 Hz), 7.91 (1H, d, J = 2.3 Hz), 9.15 (2H, brs) ), 10.48 (1H, s).

Reference Example 224
3,4-Dichloro-N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} benzenesulfonamide hydrochloride 1H -NMR (DMSO-d6) δ ppm:
3.18 (3H, s), 3.18-3.25 (4H, m), 3.75 (3H, s), 3.85-3.89 (4H, m), 6.82 (1H, s), 6.90 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.01 (1H, d, J = 8.9 Hz), 7.39 (1H, d, J = 1.6 Hz) ), 7.48 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.64 (2H, dd, J = 8.9 Hz, 2.6 Hz), 7.77 (1H, d, J = 2.0 Hz), 7.90 (1H, d, J = 8.2 Hz), 7.95 (1H, d, J = 2.6 Hz), 9.20 (2H, s).

Reference Example 225
2-Fluoro-N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide hydrochloride Salt 1H-NMR (CDCl3) δ ppm:
3.32 (4H, brs), 3.48 (3H, s), 3.78 (3H, s), 4.19 (4H, brs), 6.63 (1H, s), 6.86 (2H) , D, J = 8.9 Hz), 7.08 (1H, s), 7.14 (1H, d, J = 8.9 Hz), 7.35 (1H, d, J = 7.3 Hz), 7 .45-7.52 (2H, m), 7.61 (1H, d, J = 8.6 Hz), 7.82 (1H, s), 10.28 (2H, brs).

Reference Example 226
N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzenesulfonamide hydrochloride 1H-NMR (DMSO -D6) δ ppm:
3.19 (4H, s), 3.72 (3H, s), 3.90 (4H, s), 6.80-6.85 (2H, m), 6.94 (1H, d, J = 8.9 Hz), 7.30 (1 H, d, J = 2.0 Hz), 7.53-7.62 (2 H, m), 7.81 (1 H, d, J = 3.0 Hz), 7. 97 (4H, dd, J = 12.5 Hz, 8.9 Hz), 9.48 (2H, brs), 10.63 (1H, s).

Reference Example 227
N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzenesulfonamide hydrochloride 1H -NMR (DMSO-d6) δ ppm:
3.17-3.19 (7H, m), 3.32 (1H, s), 3.80 (3H, s), 3.88 (4H, brs), 6.76 (1H, s), 6 .96 (1H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.38 (1H, d, J = 2.3 Hz), 7. 58 (2H, dt, J = 8.9 Hz, 1.2 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.91 (1H, d, J = 2.6 Hz), 8.01 (2H, d, J = 8.2 Hz), 9.30 (2H, brs).

Reference Example 228
3,4-Dichloro-N-methyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzenesulfonamide hydrochloride 1H -NMR (DMSO-d6) δ ppm:
3.17-3.19 (7H, m), 3.32 (1H, s), 3.80 (3H, s), 3.88 (4H, brs), 6.76 (1H, s), 6 .96 (1H, d, J = 8.9 Hz), 7.06 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.37 (1H, d, J = 2.0 Hz), 7. 48 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.56-7.64 (2H, m), 7.76 (1H, d, J = 2.3 Hz), 7.90 (1H , D, J = 8.6 Hz), 7.93 (1H, d, J = 2.3 Hz), 9.29 (2H, brs).

Reference Example 229
4, N-dimethyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzenesulfonamide hydrochloride 1H-NMR (CDCl 3 ) Δ ppm:
2.42 (3H, s), 3.15 (3H, s), 3.31 (4H, brs), 3.86 (3H, s), 4.19 (4H, brs), 6.61 (1H) , S), 6.87 (1H, d, J = 8.9 Hz), 7.13 (1H, dd, J = 8.9 Hz, 2.0 Hz), 7.26-7.29 (2H, m) , 7.41 (2H, d, J = 8.9 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.53 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.75 (1H, d, J = 2.6 Hz), 10.29 (2H, brs).

Reference Example 230
1-methyl-6- (5-methylaminopyrimidin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 2.87 (3H, d, J = 5.4 Hz), 3.54-3.56 (1H, m), 4.01 (3H, s) ), 4.37 (2H, q, J = 7.1 Hz), 6.96 (1H, dd, J = 8.8 Hz, 1.9 Hz), 7.18 (1H, d, J = 1.6 Hz) 7.29 (1H, d, J = 0.8 Hz), 7.65 (1 H, d, J = 8.7 Hz), 7.99 (2H, s).

Reference Example 231
N-methyl-N- {2- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyrimidin-5-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl 3 ) Δ ppm:
1.60 (1H, s), 2.92 (4H, brs), 3.50 (3H, s), 3.75 (4H, brs), 3.78 (3H, s), 6.59 (1H , S), 6.91 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.14 (1H, d, J = 1.8 Hz), 7.44 (2H, d, J = 7. 3 Hz), 7.57 (2H, d, J = 7.7 Hz), 7.62 (1H, d, J = 8.6 Hz), 8.31 (2H, brs).

Reference Example 232
6- [5- (4-Nitrobenzoylamino) pyridin-2-yloxy] -2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.29 (3H, t, J = 7.3 Hz), 3.20-3.40 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 4.40 (1H, dd) , J = 10.3 Hz, 5.9 Hz), 4.53 (1 H, s), 6.37-6.42 (2 H, m), 6.87 (1 H, d, J = 8.9 Hz), 7 0.00 (1H, d, J = 7.6 Hz), 8.02 (2H, d, J = 8.9 Hz), 8.13 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8. 23-8.27 (3H, m), 8.69 (1H, s).

Reference Example 233
4, N-dimethyl-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} benzenesulfonamide hydrochloride 1H-NMR (DMSO -D6) δ ppm:
2.40 (3H, s), 3.11 (3H, s), 3.20 (4H, s), 3.75 (3H, s), 3.89 (4H, s), 6.82 (1H , S), 6.89 (1H, dd, J = 8.6 Hz, 2.0 Hz), 6.97 (1H, d, J = 8.9 Hz), 7.38 (1H, d, J = 1. 9 Hz), 7.40-7.47 (4 H, m), 7.53 (1 H, dd, J = 8.7 Hz, 2.8 Hz), 7.64 (1 H, d. J = 8.6 Hz), 7.86 (1H, d, J = 2.6 Hz), 9.23 (2H, s).

Reference Example 234
2-Methyl-N- {2- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyrimidin-5-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl3 ) Δ ppm:
1.65 (1H, brs), 2.52 (3H, s), 2.90 (4H, brs), 3.72 (4H, t, J = 4.9 Hz), 3.76 (3H, s) 6.56 (1 H, d, J = 0.8 Hz), 6.97 (1 H, dd, J = 8.6 Hz, 2.0 Hz), 7.18 (1 H, d, J = 2.0 Hz), 7.50 (1H, d, J = 8.9 Hz), 7.52 (1H, s), 7.58 (1H, d, J = 7.9 Hz), 7.63 (1H, d, J = 8) .6 Hz), 8.00 (1H, brs), 8.85 (2H, s).

Reference Example 235
2-Fluoro-N- {6- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.20 (4H, brs), 3.74 (3H, s), 3.89 (4H, brs), 6.82 (1H, s), 6.89 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.06 (1 H, d, J = 8.9 Hz), 7.34 (1 H, d, J = 1.6 Hz), 7.63 (1 H, d, J = 8.6 Hz), 7.75 (1H, d, J = 8.2 Hz), 7.91-7.93 (2H, m), 8.17 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44 (1H, d, J = 2.6 Hz), 9.31 (2H, brs), 10.78 (1H, s).

Reference Example 236
[6- (5-Amino-4-methylpyridin-2-yloxy) -1-methyl-1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine -1-yl} methanone 1H-NMR (CDCl 3) δ ppm:
2.18 (3H, s), 2.48 (4H, brs), 3.42 (2H, brs), 3.51 (2H, s), 3.75-3.77 (7H, m), 4 .35 (2H, q, J = 8.1 Hz), 6.55 (1H, s), 6.66 (1H, s), 6.87-6.92 (3H, m), 7.04 (1H) , D, J = 1.6 Hz), 7.27-7.29 (2H, m), 7.54 (1H, d, J = 8.6 Hz), 7.65 (1H, s).

Reference Example 237
[1-Methyl-6- (4-methyl-5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] Piperazin-1-yl} methanone 1H-NMR (CDCl 3) δ ppm:
2.14 (3H, s), 2.47 (4H, brs), 2.89 (3H, s), 3.30 (1H, brs), 3.50 (2H, s), 3.76-3 .78 (7H, m), 4.35 (2H, q, J = 8.1 Hz), 6.55 (1H, s), 6.68 (1H, s), 6.89-6.92 (3H M), 7.04 (1H, d, J = 2.3 Hz), 7.27-7.29 (2H, m), 7.53-7.55 (2H, m).

Reference Example 238
Preparation of (4-Benzylpiperazin-1-yl) [1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] methanone [1-Methyl-5- (5-nitro Pyridin-2-yloxy) -1H-indol-2-yl] (piperazin-1-yl) methanone (2.09 g, 5.5 mmol) was dissolved in 1,2-dichloroethane (45 ml) and ice-cooled. To this solution were added benzaldehyde (1.16 g, 10 mmol), sodium triacetyloxyborohydride (2.33 g, 11 mmol) and acetic acid (0.7 ml, 11 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere. After 14 hours, the solvent was distilled off under reduced pressure, water was added to the obtained residue, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane: methanol = 60: 1) to obtain 2.66 g of the title compound.
Properties: pale brown oily 1H-NMR (CDCl3) δ ppm:
2.51 (4H, brs), 3.56 (2H, s), 3.78 (4H, brs), 3.85 (3H, s), 6.58 (1H, s), 7.01 (1H , D, J = 9.1 Hz), 7.06 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.23-7.39 (6H, m), 7.41 (1H, d, J = 8.9 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

  The following compounds were produced in the same manner as in Reference Example 238 using appropriate starting materials.

Reference Example 239
[4- (4-Methoxybenzyl) piperazin-1-yl] [1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] methanone 1H-NMR (CDCl 3) δ ppm:
2.48 (4H, brs), 3.50 (2H, s), 3.77 (4H, brs), 3.80 (3H, s), 3.85 (3H, s), 6.57 (1H , S), 6.86 (2H, d, J = 8.1 Hz), 7.00 (1H, d, J = 9.2 Hz), 7.06 (1H, ddd, J = 0.8 Hz, 2. 2 Hz, 8.9 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.37 (1 H, d, J = 2.4 Hz), 7.40 (1 H, d, J = 8.9 Hz) ), 8.45 (1H, ddd, J = 0.5 Hz, 2.7 Hz, 8.9 Hz), 9.03 (1H, d, J = 3.0 Hz).

Reference Example 240
[4- (4-Difluoromethoxybenzyl) piperazin-1-yl] [1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] methanone 1H-NMR (CDCl 3) δ ppm :
2.49 (4H, brs), 3.53 (2H, s), 3.78 (4H, brs), 3.86 (3H, s), 6.50 (1H, t, J = 73.5 Hz) , 6.58 (1H, s), 7.02 (1H, d, J = 8.9 Hz), 7.03-7.18 (1H, m), 7.09 (2H, d, J = 8. 5 Hz), 7.33 (2H, d, J = 8.5 Hz), 7.30-7.50 (2H, m), 8.45 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

Reference Example 241
(4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) [1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] methanone 1H- NMR (CDCl3) δ ppm:
2.48 (4H, brs), 3.46 (2H, s), 3.77 (4H, brs), 3.85 (3H, s), 5.95 (2H, s), 6.57 (1H , S), 6.75 (2H, s), 6.86 (1H, s), 7.01 (1H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.9 Hz) 2.2 Hz), 7.38 (1 H, d, J = 2.2 Hz), 7.40 (1 H, d, J = 8.9 Hz), 8.44 (1 H, dd, J = 9.0 Hz), 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

Reference Example 242
[1-Methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-yl } Methanone 1H-NMR (CDCl 3) δ ppm:
2.48 (4H, brs), 3.51 (2H, s), 3.77 (4H, brs), 3.85 (3H, s), 4.35 (2H, q, J = 8.2 Hz) , 6.58 (1H, s), 6.91 (2H, d, J = 8.6 Hz), 7.01 (1H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 2.3 Hz), 7.41 (1H, d, J = 8) .9 Hz), 8.45 (1H, dd, J = 8.9 Hz, 2.9 Hz), 9.03 (1H, d, J = 2.9 Hz).

Reference Example 243
[1-Methyl-6- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-yl } Methanone 1H-NMR (CDCl 3) δ ppm:
2.49 (4H, brs), 3.51 (2H, s), 3.80 (7H, s), 4.35 (2H, q, J = 8.1 Hz), 6.61 (1H, s) , 6.91 (2H, d, J = 8.6 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.03 (1H, d, J = 8.9 Hz), 7.16 ( 1H, s), 7.28 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.5 Hz), 8.47 (1H, dd, J = 8.9 Hz, 3 .0Hz), 9.05 (1H, d, J = 3.0 Hz).

Reference Example 244
1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [4- (5-hydroxymethylpyridin-2-yloxy) -2,3-dihydroindole-1- Yl] ethanone 6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indole- 4-yloxy} nicotinic acid (0.789 g, 1.53 mmol) was suspended in THF (15 ml), triethylamine (0.234 ml, 1.68 mmol) and then ethyl chloroformate (0.161 ml, 0.16 ml) under ice-salt cooling. 1.68 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered, and 80% aqueous methanol solution (20 ml) of sodium borohydride (0.289 g, 7.64 mmol) was added to the filtrate under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was concentrated and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 0.671 g of the title compound.
Properties: Light brown amorphous powder 1H-NMR (CDCl3) δ ppm:
2.43 (4H, t, J = 5.0 Hz), 2.83 (2H, t, J = 8.4 Hz), 3.40-3.48 (5H, m), 3.53 (2H, t , J = 4.6 Hz), 3.64 (2H, t, J = 4.6 Hz), 3.88 (2H, s), 4.65 (2H, s), 5.95 (2H, s), 6.30 (1H, d, J = 7.8 Hz), 6.45 (1H, d, J = 8.1 Hz), 6.71-6.78 (2H, m), 6.85-6.89 (2H, m), 7.05-7.11 (1H, m), 7.71 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.16 (1H, d, J = 2. 5Hz).

Reference Example 245
Preparation of 4- {5- [5- (3,4-dichlorophenylamino) pyridin-2-yloxy] -1-methyl-1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 4- [ 5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indole-2-carbonyl] piperazine-1-carboxylic acid t-butyl ester (1.67 g, 3.70 mmol) in dichloromethane (30 ml) 3,4-dichlorophenylboronic acid (1.41 g, 7.39 mmol), copper (II) acetate (0.68 g, 3.74 mmol), molecular sieve 4A (4.4 g) and triethylamine (1.03 ml, 7.39 mmol). 33 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The insoluble material was filtered off through Celite, the filtrate was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 60: 1) to give 1.41 g of the title compound.
Properties: Dark brown powder 1 H-NMR (CDCl 3) δ ppm:
1.48 (9H, s), 3.50 (4H, brs), 3.75 (4H, brs), 3.84 (3H, s), 5.57 (1H, s), 6.57 (1H , S), 6.69 (1H, dd, J = 8.8 Hz, 2.7 Hz), 6.88 (1H, d, J = 8.8 Hz), 6.94 (1H, d, J = 2. 7 Hz), 7.11 (1H, dd, J = 8.8 Hz, 2.2 Hz), 7.23 (1H, d, J = 8.9 Hz), 7.38 (1H, d, J = 2.5 Hz) ), 7.38 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8 Hz, 2.7 Hz), 7.99 (1H, d, J = 2.7 Hz) .

  The following compounds were produced in the same manner as in Reference Example 245 using appropriate starting materials.

Reference Example 246
4- {1-methyl-5- [5- (4-trifluoromethylphenylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 1H-NMR ( CDCl3) δ ppm:
1.48 (9H, s), 3.50 (4H, brs), 3.77 (4H, brs), 3.85 (3H, s), 5.76 (1H, s), 6.56 (1H , S), 6.87 (2H, d, J = 8.4 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.12 (1H, dd, J = 8.9 Hz, 2. 1 Hz), 7.39 (1 H, d, J = 2.1 Hz), 7.39 (1 H, d, J = 8.9 Hz), 7.44 (2 H, d, J = 8.4 Hz), 7. 53 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.04 (1H, d, J = 2.6 Hz).

Reference Example 247
Preparation of 4- {1-ethyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester 4- {5- (5-Nitropyridin-2-yloxy) -1H-indole-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester (2.73 g, 5.84 mmol) and ethyl iodide (0.6 ml, To a solution of 7.50 mmol) in anhydrous DMF (25 ml), 60% sodium hydride (300 mg, 7.50 mmol) was added under ice-cooling and stirred for 1.5 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 → 40: 1 → 30: 1) to obtain 1.82 g of a pale yellow amorphous. This was dissolved in ethanol (20 ml), a suspension of 10% palladium-carbon (200 mg) in ethanol (20 ml) was added, and the mixture was stirred at 40 ° C. for 3 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 ml), ice-cooled, triethylamine (0.70 ml, 5.02 mmol) was added, and 4- (trifluoromethyl) benzoyl chloride (0.60 ml, 4.04 mmol) was added dropwise. The reaction solution was stirred for 2 hours, and then water was added for liquid separation. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 → 30: 1) to obtain 800 mg of the title compound.
Properties: Light brown amorphous powder 1H-NMR (CDCl3) δ ppm:
1.41 (3H, t, J = 7.0 Hz), 1.48 (9H, s), 3.49 (4H, brs), 3.75 (4H, brs), 4.32 (2H, q, J = 7.0 Hz), 6.94 (1H, d, J = 8.9 Hz), 7.09 (1H, dd, J = 8.6 Hz, 1.9 Hz), 7.38-7.41 (2H) M), 7.75 (2H, d, J = 8.1 Hz), 7.97-8.00 (3H, m), 8.17 (1H, dd, J = 8.9 Hz, 2.7 Hz) , 8.26 (1H, d, J = 2.7 Hz).

Reference Example 248
Preparation of {6- [2- (4-benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} carbamic acid t-butyl ester [5- (5-amino To a solution of pyridin-2-yloxy) -1-methyl-1H-indol-2-yl] (4-benzylpiperazin-1-yl) methanone (1.23 g, 2.79 mmol) in dichloromethane (15 ml) was added di-dicarbonate. t-Butyl (0.91 g, 4.17 mmol) and triethylamine (0.78 ml, 5.6 mmol) were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 60: 1) to obtain 870 mg of the title compound.
Properties: White powder 1 H-NMR (CDCl 3) δ ppm:
1.51 (9H, s), 2.50 (4H, brs), 3.56 (2H, s), 3.78 (4H, brs), 3.83 (3H, s), 6.38 (1H , Brs), 6.54 (1H, s), 6.83 (1H, d, J = 8.9 Hz), 7.05 (1H, dd, J = 8.9 Hz, 2.5 Hz), 7.24 -7.38 (8H, m), 7.97 (1H, d, J = 2.5 Hz).

  The following compounds were produced in the same manner as in Reference Example 248 using appropriate starting materials.

Reference Example 249
{6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} carbamic acid t- Butyl ester 1H-NMR (CDCl 3) δ ppm:
1.50 (9H, s), 2.47 (4H, brs), 3.45 (2H, s), 3.76 (4H, brs), 3.82 (3H, s), 5.95 (2H) , S), 6.42 (1H, brs), 6.53 (1H, s), 6.75 (2H, s), 6.83 (1H, d, J = 8.9 Hz), 6.86 ( 1H, s), 7.05 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.32 (1H, s), 7.34 (1H, d, J = 8.6 Hz), 7. 88-7.98 (1 H, m), 7.97 (1 H, d, J = 2.7 Hz).

Reference Example 250
[6- (1-Methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] Carbamate t-butyl ester 1H-NMR (CDCl 3) δ ppm:
1.51 (9H, s), 2.48 (4H, brs), 3.51 (2H, s), 3.77 (7H, s), 4.35 (2H, q, J = 8.1 Hz) , 6.43 (1H, brs), 6.57 (1H, s), 6.86-6.98 (1H, m), 6.90 (1H, dd, J = 8.9 Hz, 2.0 Hz) 6.91 (2H, d, J = 8.9 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.27 (2H, d, J = 8.9 Hz), 7.57 ( 1H, d, J = 8.6 Hz), 7.95 (1H, d, J = 8.2 Hz), 8.01 (1H, d, J = 2.7 Hz).

Reference Example 251
6- (5-acetylaminopyridin-2-yloxy) indole-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.39 (3H, t, J = 7.1 Hz), 1.57 (9H, s), 2.12 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 6. 89 (1H, d, J = 8.9 Hz), 7.02 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.09 (1H, d, J = 0.7 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.83 (1H, d, J = 2.0 Hz), 8.05 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.15 ( 1H, d, J = 2.2 Hz), 8.18 (1H, s).

Reference Example 252
6- (5-t-Butoxycarbonylaminopyrimidin-2-yloxy) -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 1.52 (9H, s), 4.03 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 6. 50 (1H, s), 6.97 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.30 (1H, d, J = 0.7 Hz), 7.67 (1 H, d, J = 8.6 Hz), 8.62 (2 H, s).

Reference Example 253
6- (5-Nitropyridin-2-yloxy) indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.40 (3H, t, J = 7.3 Hz), 1.61 (9H, s), 4.39 (2H, q, J = 7.1 Hz), 7.07-7.11 (3H, m ), 7.65 (1H, d, J = 8.6 Hz), 7.95 (1H, d, J = 2.0 Hz), 8.49 (1H, dd, J = 9.1 Hz, 2.8 Hz) 9.04 (1H, d, J = 2.6 Hz).

Reference Example 254
6- (5-t-Butoxycarbonylamino-4-methylpyridin-2-yloxy) -1-methyl-1H-indole-2-carboxylic acid ethyl ester 1H-NMR (CDCl 3) δ ppm:
1.41 (3H, t, J = 7.1 Hz), 1.52 (9H, s), 2.27 (3H, s), 4.01 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 6.04 (1H, brs), 6.75 (1H, s), 6.91 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.12 (1H, t, J = 1.0 Hz), 7.29 (1H, d, J = 1.0 Hz), 7.64 (1H, d, J = 8.2 Hz), 8.27 (1H, s).

Reference Example 255
Preparation of 6- (1-carboxymethyl-2,3-dihydro-1H-indol-4-yloxy) nicotinic acid ethyl ester 6- (2,3-dihydro-1H-indol-4-yloxy) nicotinic acid ethyl ester ( 1.13 g, 3.97 mmol) was dissolved in DMF (5 ml), triethylamine (0.665 ml, 4.77 mmol) and bromoacetic acid t-butyl ester (0.704 ml, 4.77 mmol) were added, and the mixture was stirred at room temperature for 16 hours. , And stirred at 50 ° C. for 4 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 1.58 g of a light brown oil. This was dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, adjusted to pH 5 with saturated aqueous sodium hydrogen carbonate solution, and extracted with a mixed solvent of ethyl acetate-THF (50 ml-25 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from a mixed solvent of ethyl acetate-n-hexane to obtain 0.220 g of the title compound.
Property: Light brown powder 1H-NMR (DMSO-d6) δ ppm:
1.31 (3H, t, J = 7.1 Hz), 2.67 (2H, t, J = 8.6 Hz), 3.48 (2H, t, J = 8.6 Hz), 3.94 (2H , S), 4.32 (2H, q, J = 7.1 Hz), 6.33-6.36 (2H, m), 7.00-7.09 (2H, m), 8.29 (1H , Dd, J = 8.7 Hz, 2.5 Hz), 8.71 (1H, d, J = 2.5 Hz).

  The following compounds were produced in the same manner as in Reference Example 255 using appropriate starting materials.

Reference Example 256
N-methyl-N- {2- [1-methyl-2- (piperazin-1-carbonyl) -1H-indol-5-yloxy] pyrimidin-5-yl} -4-trifluoromethylbenzamide 1H-NMR (CDCl3 ) Δ ppm:
2.91 (4H, brs), 3.48 (3H, s), 3.74 (4H, brs), 3.83 (3H, s), 6.56 (1H, s), 7.06 (1H , Dd, J = 2.2 Hz, 8.9 Hz), 7.36-7.44 (4H, m), 7.56 (2H, d, J = 8.1 Hz), 8.29 (2H, s) .

Reference Example 257
[6- (5-Ethylaminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1- IL} methanone 1H-NMR (CDCl 3) δ ppm:
1.27 (3H, t, J = 7.1 Hz), 2.47 (4H, s), 3.14 (2H, q, J = 7.1 Hz), 3.40 (1H, s), 3. 50 (2H, s), 3.75 (7H, s), 4.35 (2H, q, J = 8.1 Hz), 6.55 (1H, s), 6.79 (1H, d, J = 8.6 Hz), 6.87-6.93 (3 H, m), 7.00 (1 H, dd, J = 8.7 Hz, 3.1 Hz), 7.04 (1 H, d, J = 1.6 Hz) ), 7.26-7.30 (2H, m), 7.54 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 3.0 Hz).

Reference Example 258
[6- (5-Isopropylaminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1- IL} methanone 1H-NMR (CDCl 3) δ ppm:
1.21 (6H, d, J = 6.3 Hz), 2.48 (4H, s), 3.28 (1H, s), 3.51-3.61 (3H, m), 3.76 ( 7H, s), 4.35 (2H, q, J = 8.1 Hz), 6.55 (1H, s), 6.79 (1H, d, J = 8.9 Hz), 6.87-6. 93 (3H, m), 6.99 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.04 (1H, d, J = 1.6 Hz), 7.26-7.30 (2H M), 7.54 (1H, d, J = 8.6 Hz), 7.62 (1H, d, J = 3.0 Hz).

Reference Example 259
(6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) carbamic acid t-butyl ester [4- ( 4-methoxybenzyl) piperazin-1-yl] [1-methyl-5- (5-nitropyridin-2-yloxy) -1H-indol-2-yl] methanone (6.3 g, 12.56 mmol) and dicarbonate To a suspension of di-t-butyl (4.11 g, 18.8 mmol) in ethyl acetate (50 ml) was added a suspension of 5% platinum-carbon (630 mg) in ethyl acetate (50 ml), and a hydrogen atmosphere at 40 ° C. Stir for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Hexane, diethyl ether and acetone were added to the residue and solidified. The precipitate was collected by filtration and dried to give 6.33 g of the title compound.
Properties: Pale yellow powder 1H-NMR (CDCl3) δ ppm:
1.50 (9H, s), 2.47 (4H, brs), 3.49 (2H, s), 3.76 (4H, brs), 3.80 (3H, s), 3.82 (3H , S), 6.45 (1H, s), 6.53 (1H, s), 6.81-6.89 (3H, m), 7.05 (1H, dd, J = 2.7 Hz, 8 .9 Hz), 7.21-7.35 (4 H, m), 7.92 (1 H, d, J = 7.6 Hz), 7.97 (1 H, d, J = 2.2 Hz).

Reference Example 260
Preparation of 1,3-dimethyl-6- (5-methylaminopyridin-2-yloxy) -1H-indole-2-carboxylic acid 1,3-dimethyl-6- (5-nitropyridin-2-yloxy) -1H 2-Carboxylic acid ethyl ester (383 mg, 1.08 mmol) was dissolved in a mixed solvent of ethanol (8 ml) and dioxane (4 ml), and 10% palladium carbon (40 mg) was added. The mixture was stirred for 3 hours at 40 ° C. under a hydrogen atmosphere. After filtration through celite, the filtrate was concentrated under reduced pressure to give a colorless oil (358 mg). The resulting oil was dissolved in ethyl acetate (6 ml). Triethylamine (196 μl, 1.41 mmol) and acetyl chloride (98 μl, 1.38 mmol) were added under ice cooling. The mixture was stirred for 30 minutes at the same temperature. After adding water to the reaction solution, liquid separation was performed. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 → 10: 1) to obtain white crystals (309 mg). The obtained crystals were dissolved in DMF (6 ml). Sodium hydride (34 mg, 0.85 mmol) was added under ice cooling. After stirring at the same temperature for 10 minutes, methyl iodide (58 μl, 0.91 mmol) was added while cooling with ice. The mixture was further stirred for 1 hour at the same temperature. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a white powder (319 mg). To a solution of the obtained powder in ethanol (6 ml), 5M aqueous sodium hydroxide solution (0.84 ml, 4.2 mmol) was added. The mixture was stirred overnight with heating under reflux. The solvent was distilled off after standing_to_cool. After diluting with water, 5M aqueous hydrogen chloride solution was added to make it acidic. Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 292 mg of the title compound.
Properties: Brown powder 1H-NMR (DMSO-d6) δ ppm:
2.50 (3H, s), 2.68 (3H, s), 3.86 (3H, s), 5.67 (1H, s), 6.76 (1H, dd, J = 8.7 Hz, 2.1 Hz), 6.83 (1 H, d, J = 8.6 Hz), 7.05-7.09 (2 H, m), 7.51 (1 H, d, J = 3.1 Hz), 7. 62 (1H, d, J = 8.7 Hz), 12.84 (1H, s).

Example 1
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indole-5 Ileoxy} pyridin-3-yl) -3,4-dichlorobenzamide 2- [5- (5-aminopyridin-2-yloxy) -2,3-dihydroindol-1-yl] -1- (4- Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) ethanone (0.240 g, 0.492 mmol) is dissolved in THF (10 ml), triethylamine (0.0686 ml, 0.492 mmol), then 3, 4-Dichlorobenzoyl chloride (0.103 g, 0.492 mmol) was added and stirred at room temperature for 30 minutes. Saturated brine (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to give 0.143 g of the title compound.
Property: Grayish white powder 1H-NMR (CDCl 3) δ ppm:
2.42-2.43 (4H, m), 2.92 (2H, t, J = 8.2 Hz), 3.40 (2H, t, J = 8.2 Hz), 3.44 (2H, s ), 3.54-3.63 (4H, m), 3.82 (2H, s), 5.30 (2H, s), 6.35 (1H, d, J = 8.4 Hz), 6. 74-6.85 (6H, m), 7.52 (1H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.99 (1H , D, J = 2.0 Hz), 8.08 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz), 8.51 (1H, s).

  The following compounds were prepared in the same manner as in Example 1 using appropriate starting materials.

Example 2
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -1H-indol-4-yloxy} pyridine-3- Yl) -3,4-dichlorobenzamide 1H-NMR (DMSO-d6) δ ppm:
2.34 (2H, brs), 2.45 (2H, brs), 3.44 (4H, s), 3.58 (2H, brs), 5.18 (2H, s), 6.00 (2H) , S), 6.08 (1H, d, J = 3.1 Hz), 6.74-6.79 (2H, m), 6.85-6.89 (2H, m), 7.03-7 .13 (2H, m), 7.19-7.22 (2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.93-7.97 (1H, m), 8 .16-8.22 (2H, m), 8.45 (1 H, d, J = 2.6 Hz), 10.55 (1 H, s).

Example 3
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -1H-indol-4-yloxy} pyridine-3- Yl) -4-trifluoromethylbenzamide 1H-NMR (DMSO-d6) δ ppm:
2.34-2.50 (4H, m), 3.44-3.63 (6H, m), 5.18 (2H, s), 6.00 (2H, s), 6.09 (1H, d, J = 3.1 Hz), 6.74-6.79 (2H, m), 6.85-6.90 (2H, m), 7.04-7.14 (2H, m), 7. 20-7.22 (2H, m), 7.93 (2H, d, J = 8.4 Hz), 8.15-8.23 (3H, m), 8.47 (1H, d, J = 2) .5 Hz), 10.63 (1 H, s).

Example 4
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indole-4- Yloxy} pyridin-3-yl) -3,4-dichlorobenzamide 1H-NMR (DMSO-d6) δ ppm:
2.31-2.38 (4H, m), 2.68 (2H, t, J = 8.5 Hz), 3.41-3.46 (8H, m), 4.03 (2H, s), 5.99 (2H, s), 6.26-6.30 (2H, m), 6.75 (1H, dd, J = 7.8 Hz, 1.4 Hz), 6.84-6.88 (2H) M), 6.95-7.02 (2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.0 Hz) , 8.17 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.47 (1H, d, J = 2.3 Hz), 10.54 (1H, brs).

Example 5
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indole-4- Yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H-NMR (DMSO-d6) δ ppm:
2.31-2.38 (4H, m), 2.68 (2H, t, J = 8.4 Hz), 3.41-3.46 (8H, m), 4.03 (2H, s), 5.99 (2H, s), 6.26-6.30 (2H, m), 6.76 (1H, dd, J = 7.9 Hz, 1.5 Hz), 6.84-6.88 (2H) M), 6.95-7.03 (2H, m), 7.93 (2H, d, J = 8.2 Hz), 8.16 (2H, d, J = 7.9 Hz), 8.20. (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.50 (1H, d, J = 2.5 Hz), 10.61 (1H, brs).

Example 6
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 , 4-Dichloro-N-methylbenzamide hydrobromide melting point: 222-226 ° C.

Example 7
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 , 4-Dichlorobenzamide hydrobromide Melting point: 264-269 ° C.

Example 8
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4 -Trifluoromethylbenzamide hydrobromide melting point: 240-244 [deg.] C.

Example 9
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -2 , 4-Bistrifluoromethylbenzamide hydrobromide Melting point: 258-261 ° C (decomposition).

Example 10
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -2 -Methoxy-4-trifluoromethylbenzamide hydrobromide melting point: 228-231 [deg.] C (decomposition).

Example 11
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4 -Pyrrol-1-ylbenzamide hydrobromide melting point: 227-232 ° C (decomposition).

Example 12
(E) -N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridine-3- IL} -3- (3,5-difluorophenyl) -N-methylacrylamide hydrobromide melting point: 176-178 ° C.

Example 13
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N -Methyl-4-trifluoromethoxybenzamide hydrobromide melting point: 220-222 [deg.] C.

Example 14
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -2-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 249-251 ° C.

Example 15
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -2, N-dimethyl-4 -Trifluoromethylbenzamide hydrobromide 1H-NMR (CDCl3) δ ppm:
2.36 (3H, s), 2.47 (4H, brs), 3.49 (3H, s), 3.76 (4H, brs), 3.81 (6H, s), 6.52 (1H , S), 6.75 (1H, d, J = 8.9 Hz), 6.87 (2H, d, J = 8.4 Hz), 6.95 (1H, d, J = 8.4 Hz), 7 .10 (1H, d, J = 7.3 Hz), 7.22-7.32 (8H, m), 7.80 (1H, s).

Example 16
2-Chloro-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide oxalate melting point: 163-165 ° C.

Example 17
N- (6- {2- [4- (4-methoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethoxybenzamide odor Hydrochloride melting point: 226-227 ° C.

Example 18
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethoxybenzamide maleate melting point: 147-148 ° C.

Example 19
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -3-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 188-191 ° C.

Example 20
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -3, N-dimethyl-4 -Trifluoromethylbenzamide hydrobromide melting point: 199-202 ° C.

Example 21
5-trifluoromethylpyridine-2-carboxylic acid (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl ) Methylamide dioxalate melting point: 152-154 ° C.

Example 22
2-Fluoro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride melting point: 234.5-235.8 [deg.] C.

Example 23
4, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzamide hydrobromide melting point: 226.1-227.3 [deg.] C.

Example 24
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -6-trifluoromethylnicotinamide hydrochloride melting point: 195.4 [deg.] C.

Example 25
3-Fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride melting point: 259.0-263.2 ° C.

Example 26
N-ethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 189.8-192.8 ° C.

Example 27
N-isopropyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
1.20 (6H, d, J = 6.9 Hz), 2.48 (4H, s), 3.51 (2H, s), 3.76 (7H, s), 4.35 (2H, q, J = 8.1 Hz), 5.12 (1H, brs), 6.57 (1H, d, J = 0.7 Hz), 6.82-6.84 (2H, m), 6.91-6. 92 (2H, m), 7.06 (1H, s), 7.24-7.33 (5H, m), 7.47 (2H, d, J = 7.3 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.81 (1H, s).

Example 28
3,4-dichloro-N-isopropyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 232.8-235.6 ° C.

Example 29
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] methanesulfonamide hydrochloride melting point: 252.7-253.6 ° C.

Example 30
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide hydrobromide melting point: 234.6-235.2 ° C.

Example 31
Methyl butane-1-sulfonate- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] amide hydrochloride melting point: 253.6-254.4 [deg.] C.

Example 32
4, N-dimethyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) benzenesulfone Amide melting point: 135.9-136.8 ° C.

Example 33
3,4-Dichloro-N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridine-3- I) Benzenesulfonamide melting point: 231.7-235 ° C (decomposition).

Example 34
Methyl 2,2,2-trifluoroethanesulfonate- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H -Indol-6-yloxy) pyridin-3-yl] amide hydrochloride melting point: 243.4-244.4 [deg.] C.

Example 35
N- [6- (1-methoxymethyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3 -Yl] -N-methyl-4-trifluoromethylbenzamide 1H-NMR (CDCl3) δ ppm:
2.47 (4H, s), 3.22 (3H, s), 3.48 (3H, s), 3.15 (2H, s), 3.77 (4H, s), 4.35 (2H) , Q, J = 8.1 Hz), 5.56 (2H, s), 6.60 (1H, s), 6.83-6.92 (4H, m), 7.25-7.30 (2H) M), 7.39-7.52 (5H, m), 7.59 (1H, d, J = 8.6 Hz), 7.80-7.83 (1.5 H, m), 8.27. (0.5H, d, J = 7.9 Hz).

Example 36
N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazin-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] -4 -Trifluoromethylbenzamide melting point: 281.3-282.3 [deg.] C.

Example 37
2,4,6-trimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
2.24 (6H, s), 2.27 (3H, s), 3.16 (2H, brs), 3.39-3.65 (4H, m), 3.74 (3H, s), 4 .33 (2H, s), 4.43-4.47 (2H, m), 4.81 (2H, q, J = 9.1 Hz), 6.80 (1H, s), 6.88 (1H) , Dd, J = 8.7 Hz, 1.7 Hz), 6.93 (2H, s), 7.02 (1H, d, J = 8.7 Hz), 7.16 (2H, d, J = 8. 2 Hz), 7.33 (1 H, s), 7.58 (2 H, d, J = 8.4 Hz), 7.63 (1 H, d, J = 8.4 Hz), 8.18 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.44 (1H, d, J = 2.6 Hz), 10.44 (1 H, s), 11.10 (1 H, brs).

Example 38
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -2,3-dihydro-1H- Indol-6-yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
2.40 (2H, s), 2.46 (2H, s), 2.73 (3H, s), 2.97 (1H, dd, J = 15.8 Hz, 9.9 Hz), 3.28 ( 1H, dd, J = 15.7 Hz, 10.1 Hz), 3.46 (3H, s), 3.48 (2H, s), 3.55-3.62 (2H, m), 3.72- 3.76 (2H, m), 4.30-4.39 (3H, m), 6.13 (1H, d, J = 2.0 Hz), 6.31 (1H, dd, J = 7.9 Hz) 2.0 Hz), 6.78 (1 H, d, J = 8.9 Hz), 6.90 (2 H, d, J = 11.1 Hz), 6.95 (1 H, d, J = 7.9 Hz) 7.27 (2H, d, J = 8.6 Hz), 7.44 (5H, dd, J = 24.1 Hz, 8.2 Hz), 7.86 (1 H, s).

Example 39
N-methyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzenesulfonamide Melting point: 200.1-200.2 ° C.

Example 40
3,4-Dichloro-N-methyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 225.2-229.3 <0> C.

Example 41
4, N-dimethyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] benzenesulfonamide melting point: 184.0-184.2 ° C.

Example 42
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -N-methyl-4- Trifluoromethylbenzenesulfonamide melting point: 186.6-187.3 ° C.

Example 43
3,4-dichloro-N- (2- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl)- N-methylbenzenesulfonamide melting point: 191.2-193.0 ° C.

Example 44
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -4, N-dimethylbenzene Sulfonamide melting point: 154.3-155.1 ° C.

Example 45
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -N-methylmethanesulfonamide Melting point: 134.3-135.6 ° C.

Example 46
N- [4-Methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 222.4-224.6 ° C.

Example 47
N-methyl-N- [4-methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 220.0-222.5 ° C.

Example 48
2- {Methyl [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine acetate Preparation of -3-yl] carbamoyl} -5-trifluoromethylphenyl ester To a solution of 2-acetoxy-4-trifluoromethylbenzoic acid (180 mg, 0.73 mmol) in dichloromethane (6 ml) was added oxalyl chloride (0.08 ml, 0.91 mmol) and DMF (1 drop) were added, and the mixture was stirred at room temperature for 1 hour. By distilling off the reaction solution, 190 mg of acetic acid (2-chlorocarbonyl-5-trifluoromethylphenyl) ester was obtained.
[1-Methyl-6- (5-methylaminopyridin-2-yloxy) -1H-indol-2-yl] {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1- Yl} methanone (340 mg, 0.6 mmol) in ethyl acetate (4 ml) under cooling with ice, triethylamine (0.13 ml, 0.91 mmol) and acetic acid (2-chlorocarbonyl-5-trifluoromethylphenyl) ester ( A solution of 190 mg, 0.73 mmol) in ethyl acetate (3 ml) was added, and the mixture was stirred for 10 minutes under ice cooling. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain 0.46 g of the title compound.
Properties: White powder 1 H-NMR (CDCl 3) δ ppm:
2.32 (3H, s), 2.48 (4H, brs), 3.47 (2H, s), 3.51 (3H, s), 3.76 (7H, s), 4.35 (2H) , Q, J = 7.3 Hz), 6.57 (1H, s), 6.72-6.89 (2H, m), 6.92 (2H, d, J = 8.2 Hz), 7.07 (1H, brs), 7.28 (2H, d, J = 8.2 Hz), 7.18-7.53 (4H, m), 7.58 (1H, d, J = 8.6 Hz), 7 .99 (1H, brs).

  The following compounds were prepared in the same manner as in Example 48 using appropriate starting materials.

Example 49
4-chloro-3-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzamide hydrochloride melting point: 182.9 [deg.] C.

Example 50
4-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -3-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.17 (2H, brs), 3.35-3.48 (4H, brs), 3.64 (2H, brs), 3.75 (3H, brs), 4.34-4.46 (2H, m), 4.72-4.80 (2H, m), 6.67-6.81 (1H, m), 6.88-6.92 (1H, m), 7.01 (1H, s) 7.05 (1H, d, J = 8.9 Hz), 7.16-7.19 (1H, m), 7.28-7.32 (1H, m), 7.35 (1H, brs) 7.54-7.64 (2H, m), 7.95 (1H, d, J = 8.4 Hz), 8.18 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8. 28 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.40 (1H, d, J = 2.2 Hz), 8.47 (1H, d, J = 2.7 Hz), 10.49 (1H, brs , 10.68 (1H, s).

Example 51
3-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
2.54 (3H, d, J = 1.9 Hz), 3.15 (2H, brs), 3.35-3.48 (4H, m), 3.65 (2H, brs), 3.75 ( 3H, brs), 4.33-4.49 (2H, m), 4.72-4.85 (2H, m), 6.66-6.81 (1H, m), 6.90 (1H, d, J = 8.1 Hz), 7.01 (1H, brs), 7.05 (1H, d, J = 8.9 Hz), 7.17 (1H, d, J = 7.6 Hz), 7. 27-7.34 (2H, m), 7.54-7.65 (2H, m), 7.85 (1H, d, J = 8.4 Hz), 7.95 (1H, d, J = 8) .1 Hz), 8.01 (1H, s), 8.21 (1 H, dd, J = 8.6 Hz, 2.7 Hz), 8.49 (1 H, d, J = 2.4 Hz), 10.58. (1H, s), 10. 1 (1H, s).

Example 52
4-chloro-3-fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzamide hydrochloride
¹ H-NMR (DMSO-d6) δ ppm:
3.16 (2H, brs), 3.35-3.48 (4H, s), 3.65 (2H, brs), 3.72 (3H, brs), 4.34-4.46 (2H, m), 4.72-4.83 (2H, m), 6.66-6.81 (1H, m), 6.89 (1H, d, J = 7.8 Hz), 7.00 (1H, s), 7.04 (1H, d, J = 8.9 Hz), 7.18 (1H, d, J = 8.9 Hz), 7.27-7.33 (2H, m), 7.52- 7.64 (2H, m), 7.77-7.88 (2H, m), 8.00 (1H, dd, J = 10.0 Hz, 1.6 Hz), 8.18 (1 H, dd, J = 8.6 Hz, 2.7 Hz), 8.47 (1 H, d, J = 2.4 Hz), 10.47 (1 H, brs), 10.52 (1 H, s).

Example 53
3, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
2.38 (3H, s), 3.19 (2H, brs), 3.32-3.48 (4H, m), 3.48 (3H, s), 3.72 (3H, s), 4 .36 (2H, brs), 4.42-4.47 (2H, m), 4.82 (2H, q, J = 8.8 Hz), 6.78 (1H, brs), 6.80 (1H) , S), 6.99 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.20 (2H, brs), 7.29 (1H, s) ), 7.43-7.62 (5H, m), 7.84 (1H, dd, J = 8.6 Hz, 2.1 Hz), 7.92 (1H, s), 9.86 (1H, brs) ).

Example 54
4-chloro-3, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
2.26 (3H, s), 3.15 (2H, brs), 3.36 (3H, s), 3.36-3.50 (4H, m), 3.72 (3H, s), 4 .34 (2H, s), 4.42-4.46 (2H, m), 4.82 (2H, q, J = 8.7 Hz), 6.79 (1H, s), 6.81 (1H) , Dd, J = 8.6 Hz, 1.6 Hz), 6.98 (1H, d, J = 8.7 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.30-7.35 (3H, m), 7.54 (2H, d, J = 8.1 Hz), 7.61 (1H, d, J = 8.6 Hz) ), 7.80 (1H, dd, J = 8.6 Hz, 2.8 Hz), 7.90 (1H, d, J = 1.6 Hz), 10.66 (1H, brs).

Example 55
4-Chloro-3-fluoro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] benzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.11-3.19 (2H, m), 3.35 (3H, s), 3.38-3.47 (4H, m), 3.63 (2H, brs), 3.72 (3H, s), 4.34 (2H, s), 4.42-4.46 (2H, m), 4.82 (2H, q, J = 8.8 Hz), 6.79 (1H, s), 6 .80 (1H, d, J = 8.6 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.01-7.15 (2H, m), 7.17 (1H, d, J = 8.4 Hz), 7.29 (1H, s), 7.39 (1H, d, J = 9.7 Hz), 7.51-7.63 (4H, m), 7.83 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.96 (1H, s), 10.80 (1H, brs).

Example 56
4-chloro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] -3-trifluoromethylbenzamide oxalate 1H-NMR (DMSO-d6) δ ppm:
2.65 (4H, brs), 3.37 (3H, s), 3.69 (3H, s), 3.72 (6H, brs), 4.76 (2H, q, J = 8.9 Hz) , 6.69 (1H, s), 6.76 (1H, d, J = 8.9 Hz), 7.00 (1H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.7 Hz), 7.24 (1H, s), 7.34 (2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.74 (1H, brs), 7.86 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.96 (1H, brs).

Example 57
2-Fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.13-3.20 (2H, m), 3.39-3.49 (4H, m), 3.75 (3H, s), 4.34 (2H, brs), 4.43-4. 77 (2H, m), 4.82 (2H, q, J = 8.9 Hz), 6.81 (1H, s), 6.90 (1H, dd, J = 8.7 Hz, 1.9 Hz), 7.06 (1H, d, J = 8.9 Hz), 7.17 (2H, d, J = 8.2 Hz), 7.35 (1H, d, J = 1.5 Hz), 7.57 (2H , D, J = 8.2 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.75 (1H, d, J = 8.1 Hz), 7.90-7.96 (2H, m), 8.17 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44 (1H, d, J = 2.6 Hz), 10.78 (1H, s), 10.96 ( 1H, brs).

Example 58
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.11 (2H, brs), 3.56-3.65 (6H, m), 3.73 (3H, s), 4.33 (2H, brs), 4.78 (2H, q, J = 8.3 Hz), 6.73 (1 H, s), 6.89 (1 H, dd, J = 8.7 Hz, 1.9 Hz), 7.06 (1 H, d, J = 8.6 Hz), 7. 10 (2H, brs), 7.34 (1H, d, J = 1.9 Hz), 7.42 (2H, brs), 7.63 (1H, d, J = 8.6 Hz), 7.87 ( 2H, s), 8.05 (1H, s), 8.16 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.43 (1H, d, J = 2.8 Hz), 10. 83 (1H, s), 10.97 (1H, brs).

Example 59
2-methoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
2.48 (4H, brs), 3.51 (2H, s), 3.78 (4H, brs), 3.79 (3H, s), 4.12 (3H, s), 4.35 (2H) , Q, J = 8.2 Hz), 6.58 (1H, d, J = 0.7 Hz), 6.89-6.97 (4H, m), 7.14 (1H, d, J = 2. 0 Hz), 7.26-7.30 (3 H, m), 7.41 (1 H, d, J = 8.1 Hz), 7.60 (1 H, d, J = 8.6 Hz), 8.24- 8.28 (2H, m), 8.40 (1H, d, J = 8.1 Hz), 9.64 (1H, brs).

Example 60
2, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
2.31 (3H, s), 3.10-3.22 (4H, m), 3.40 (3H, s), 3.70 (3H, s), 3.76 (2H, brs), 4 .36 (2H, s), 4.42-4.48 (2H, m), 4.82 (2H, q, J = 8.9 Hz), 6.73 (1H, dd, J = 8.4 Hz, 1.6 Hz), 6.80 (1 H, s), 6.92 (1 H, d, J = 8.7 Hz), 7.18 (2 H, d, J = 8.6 Hz), 7.25 (1 H, s), 7.37 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 7.6 Hz), 7.50 (1H, d, J = 8.2 Hz), 7. 52 (2H, s), 7.58 (1H, d, J = 8.6 Hz), 7.82 (1H, dd, J = 9.0 Hz, 2.6 Hz), 7.92 (1H, d, J = 2.3 Hz), 9.88 (1H brs).

Example 61
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -2,4-bistrifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
2.89 (4H, brs), 3.42-4.16 (6H, m), 3.73 (3H, s), 4.78 (2H, q, J = 8.8 Hz), 6.73 ( 1H, brs), 6.89 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.06 (1H, d, J = 8.9 Hz), 7.10 (2H, s), 7. 34 (1H, d, J = 1.6 Hz), 7.41 (2H, brs), 7.63 (1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 7.9 Hz) ), 8.13 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23-8.27 (2H, m), 8.38 (1H, d, J = 2.6 Hz), 10 .88 (1H, s), 11.00 (1H, brs).

Example 62
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 , 4-Dichlorobenzenesulfonamide hydrochloride [5- (5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] (4-benzo [1,3] dioxol-5- To a solution of ylmethylpiperazin-1-yl) methanone (0.26 g, 0.54 mmol) in THF (7 ml) under ice cooling, 3,4-dichlorobenzenesulfonyl chloride (0.14 g, 0.54 mmol) and pyridine ( 0.07 ml, 0.81 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain 190 mg of a pale yellow powder. This was dissolved in ethyl acetate, 6M hydrochloric acid (46 μl, 0.276 mmol) was added, and the precipitate was collected by filtration. After drying under reduced pressure, 0.18 g of the title compound was obtained.
Property: White powder Melting point: 167-177 ° C.

  The following compounds were prepared in the same manner as in Example 62 using appropriate starting materials.

Example 63
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indole-5 Yloxy} pyridin-3-yl) -4-trifluoromethylbenzenesulfonamide Melting point: 182.0-183.0 ° C.

Example 64
N- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indole-5 Yloxy} pyridin-3-yl) -3,4-dichlorobenzenesulfonamide Melting point: 152.0-153.0 ° C.

Example 65
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4 -Trifluoromethylbenzenesulfonamide hydrobromide melting point: 210-212 [deg.] C.

Example 66
N- {6- [2- (4-Benzylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3,4-dichlorobenzenesulfonamide 1H-NMR ( CDCl3) δ ppm:
1.59 (1H, brs), 2.50 (4H, brs), 3.55 (2H, s), 3.77 (4H, brs), 3.81 (3H, s), 6.51 (1H , S), 6.80 (1H, d, J = 8.9 Hz), 7.02 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.25-7.37 (7H, m) 7.45-7.52 (2H, m), 7.50 (1H, dd, J = 6.0 Hz, 2.6 Hz), 7.69 (1H, d, J = 2.6 Hz), 7. 81 (1H, t, J = 1.0 Hz).

Example 67
N- {6- [2- (4-Benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzenesulfonamide 1H-NMR ( CDCl3) δ ppm:
1.59 (1H, brs), 2.49 (4H, brs), 3.55 (2H, s), 3.77 (4H, brs), 3.81 (3H, s), 6.50 (1H) , S), 6.79 (1H, d, J = 8.8 Hz), 7.01 (1H, dd, J = 8.8 Hz, 2.3 Hz), 7.20-7.37 (7H, m) 7.49 (1H, dd, J = 8.8 Hz, 2.6 Hz), 7.66 (1H, d, J = 2.6 Hz), 7.70 (2H, d, J = 8.2 Hz), 7.83 (2H, d, J = 8.2 Hz).

Example 68
3,4-Dichloro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide melting point: 165.9-167.2 [deg.] C.

Example 69
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzenesulfonamide hydrochloride melting point: 256.9-257.7 ° C.

Example 70
4, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 246.4-247.2 [deg.] C.

Example 71
4-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide melting point: 198.3-200.3 ° C.

Example 72
3,4-Dichloro-N-ethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 226.9-227.2 [deg.] C.

Example 73
4-methoxy-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 213.4-214.1 ° C.

Example 74
Propane-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide 1H-NMR (CDCl 3) δ ppm:
1.41 (6H, d, J = 6.9 Hz), 2.48 (4H, brs), 3.18-3.29 (1H, m), 3.51 (2H, s), 3.78 ( 7H, s), 4.35 (2H, q, J = 8.2 Hz), 6.38 (1H, s), 6.58 (1H, s), 6.89 (2H, d, J = 2. 6 Hz), 6.92 (2H, d, J = 2.3 Hz), 7.12 (1 H, d, J = 1.6 Hz), 7.30 (1 H, s), 7.60 (1 H, d, J = 8.6 Hz), 7.72 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.02 (1H, d, J = 3.0 Hz).

Example 75
2,4,6-trimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 191.3-192.5 [deg.] C.

Example 76
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] methanesulfonamide hydrobromide melting point: 237.8-240.1 ° C.

Example 77
N- [4-Methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] methanesulfonamide hydrobromide melting point: 229.3-231.2 ° C.

Example 78
N-methyl-N- [4-methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] methanesulfonamide hydrobromide melting point: 235.8-237.8 ° C.

Example 79
4-methoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 710 [M + H] +.

Example 80
4-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 714 [M + H] +.

Example 81
Naphthalene-1-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 730 [M + H] +.

Example 82
Naphthalene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 730 [M + H] +.

Example 83
2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 694 [M + H] +.

Example 84
4-fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 698 [M + H] +.

Example 85
5-chloro-2-methoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 744 [M + H] +.

Example 86
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -2-trifluoromethylbenzenesulfonamide MS: 748 [M + H] +.

Example 87
Thiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 686 [M + H] +.

Example 88
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 714 [M + H] +.

Example 89
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -2-trifluoromethoxybenzenesulfonamide MS: 764 [M + H] +.

Example 90
2- [6- (1-Methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Irsulfamoyl] benzoic acid methyl ester MS: 738 [M + H] +.

Example 91
2-cyano-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 705 [M + H] +.

Example 92
3-methoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 710 [M + H] +.

Example 93
3-Fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 698 [M + H] +.

Example 94
2-Fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 698 [M + H] +.

Example 95
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -3-trifluoromethylbenzenesulfonamide MS: 748 [M + H] +.

Example 96
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethoxybenzenesulfonamide MS: 764 [M + H] +.

Example 97
Biphenyl-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 756 [M + H] +.

Example 98
3,4-Dimethoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 740 [M + H] +.

Example 99
2,5-dimethoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 740 [M + H] +.

Example 100
3-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 694 [M + H] +.

Example 101
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -2-nitrobenzenesulfonamide MS: 725 [M + H] +.

Example 102
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -3-nitrobenzenesulfonamide MS: 725 [M + H] +.

Example 103
3-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 714 [M + H] +.

Example 104
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] benzenesulfonamide MS: 680 [M + H] +.

Example 105
2-Methoxy-5-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 724 [M + H] +.

Example 106
2,6-dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 748 [M + H] +.

Example 107
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -3-trifluoromethoxybenzenesulfonamide MS: 764 [M + H] +.

Example 108
Quinoline-8-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 731 [M + H] +.

Example 109
5-Dimethylaminonaphthalene-1-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] amide MS: 773 [M + H] +.

Example 110
1-methyl-1H-imidazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 684 [M + H] +.

Example 111
2,3-Dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 748 [M + H] +.

Example 112
2,5-dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 748 [M + H] +.

Example 113
2,4-Dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 748 [M + H] +.

Example 114
2,3,4-trichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 782 [M + H] +.

Example 115
4-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -3-nitrobenzenesulfonamide MS: 739 [M + H] +.

Example 116
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzenesulfonamide MS: 782 [M + H] +.

Example 117
4-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -3-nitrobenzenesulfonamide MS: 759 [M + H] +.

Example 118
2,4,6-trichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 782 [M + H] +.

Example 119
2-Chloro-4-fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 732 [M + H] +.

Example 120
2,4-dichloro-5-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 762 [M + H] +.

Example 121
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -5-trifluoromethylbenzenesulfonamide MS: 782 [M + H] +.

Example 122
2,4,5-trichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 782 [M + H] +.

Example 123
2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -5-nitrobenzenesulfonamide MS: 739 [M + H] +.

Example 124
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -3-nitrobenzenesulfonamide MS: 759 [M + H] +.

Example 125
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -5-nitrobenzenesulfonamide MS: 759 [M + H] +.

Example 126
2-Chloro-4-cyano-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 739 [M + H] +.

Example 127
2-Chloro-4,5-difluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 750 [M + H] +.

Example 128
N- {4- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine -3-ylsulfamoyl] phenyl} acetamide MS: 737 [M + H] +.

Example 129
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-nitrobenzenesulfonamide MS: 725 [M + H] +.

Example 130
3,5-dichloro-2-hydroxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 764 [M + H] +.

Example 131
4-methoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -2-nitrobenzenesulfonamide MS: 755 [M + H] +.

Example 132
4-t-butyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 736 [M + H] +.

Example 133
4-iodo-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 806 [M + H] +.

Example 134
3- [6- (1-Methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Irsulfamoyl] benzoic acid MS: 724 [M + H] +.

Example 135
2-Bromo-5-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 792 [M + H] +.

Example 136
2,5-Dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 708 [M + H] +.

Example 137
2,5-difluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 716 [M + H] +.

Example 138
3-cyano-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 705 [M + H] +.

Example 139
4-Methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2, -trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy ) Pyridin-3-yl] naphthalene-1-sulfonamide MS: 744 [M + H] +.

Example 140
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -2,3-dihydrobenzo [1,4] dioxy-6-sulfonamide MS: 738 [M + H] +.

Example 141
2,4-dichloro-6-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 762 [M + H] +.

Example 142
3-chloro-5-fluoro-2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 746 [M + H] +.

Example 143
4-Bromo-2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 772 [M + H] +.

Example 144
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-phenoxybenzenesulfonamide MS: 772 [M + H] +.

Example 145
3-bromo-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 758 [M + H] +.

Example 146
4-cyano-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 705 [M + H] +.

Example 147
N- {2-chloro-4- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-ylsulfamoyl] phenyl} acetamide MS: 771 [M + H] +.

Example 148
2,4-Difluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 716 [M + H] +.

Example 149
2-Methoxy-4-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 724 [M + H] +.

Example 150
3-chloro-2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 728 [M + H] +.

Example 151
2,6-difluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 716 [M + H] +.

Example 152
5-Fluoro-2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 712 [M + H] +.

Example 153
4-Chloro-2,5-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 742 [M + H] +.

Example 154
2-chloro-6-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 728 [M + H] +.

Example 155
4-Isopropyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 722 [M + H] +.

Example 156
3-chloro-4-fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 732 [M + H] +.

Example 157
4-Bromo-2-fluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 776 [M + H] +.

Example 158
3-chloro-4-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 728 [M + H] +.

Example 159
3,4-Difluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 716 [M + H] +.

Example 160
5-chloronaphthalene-1-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 764 [M + H] +.

Example 161
5-chloronaphthalene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 764 [M + H] +.

Example 162
2-Bromo-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzenesulfonamide MS: 758 [M + H] +.

Example 163
5-Chlorothiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 720 [M + H] +.

Example 164
3,5-dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide MS: 748 [M + H] +.

Example 165
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-oxazol-5-ylbenzenesulfonamide MS: 747 [M + H] +.

Example 166
3- {4- [6- (1-Methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine -3-ylsulfamoyl] phenyl} propionic acid methyl ester MS: 766 [M + H] +.

Example 167
4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) )] Benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 751 [M + H] +.

Example 168
3-Methylquinoline-8-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 745 [M + H] +.

Example 169
N- {5- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine -3-ylsulfamoyl] naphthalen-1-yl} acetamide MS: 787 [M + H] +.

Example 170
Isoquinoline-5-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 731 [M + H] +.

Example 171
2,2,2-trifluoroethanesulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] amide MS: 686 [M + H] +.

Example 172
4-Methoxy-2,3,6-trimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 752 [M + H] +.

Example 173
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] trifluoromethanesulfonamide MS: 672 [M + H] +.

Example 174
5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1 -Carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 732 [M + H] +.

Example 175
3,5-dimethylisoxazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 699 [M + H] +.

Example 176
2-hydroxy-5- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-ylsulfamoyl] benzoic acid MS: 740 [M + H] +.

Example 177
4,5-dichlorothiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] amide MS: 754 [M + H] +.

Example 178
2,5-dichlorothiophene-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] amide MS: 754 [M + H] +.

Example 179
5-Bromothiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 764 [M + H] +.

Example 180
4- [6- (1-Methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Irsulfamoyl] benzoic acid MS: 724 [M + H] +.

Example 181
N- {4-Methyl-5- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-ylsulfamoyl] thiazol-2-yl} acetamide MS: 758 [M + H] +.

Example 182
3- [6- (1-Methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Irsulfamoyl] thiophene-2-carboxylic acid methyl ester MS: 744 [M + H] +.

Example 183
5-Bromo-2-methoxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 788 [M + H] +.

Example 184
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] benzylsulfonamide MS: 694 [M + H] +.

Example 185
(E) -2-Phenylethenesulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] amide MS: 706 [M + H] +.

Example 186
2,3,4-trifluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 734 [M + H] +.

Example 187
2,4,5-trifluoro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 734 [M + H] +.

Example 188
Benzo [b] thiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] amide MS: 736 [M + H] +.

Example 189
3- (4-Methoxyphenoxy) propane-1-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] amide MS: 768 [M + H] +.

Example 190
2-Naphthalen-1-ylethanesulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] amide MS: 758 [M + H] +.

Example 191
Cyclopropanesulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] amide MS: 644 [M + H] +.

Example 192
4- (1-Methyl-1H-pyrazol-3-yl) -N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1 -Carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 760 [M + H] +.

Example 193
1-methyl-1H-indole-7-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 733 [M + H] +.

Example 194
3- [1,3] Dioxolan-2-ylthiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1 -Carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 758 [M + H] +.

Example 195
2,5-Dimethylthiophene-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] amide MS: 714 [M + H] +.

Example 196
2-cyano-5-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide MS: 719 [M + H] +.

Example 197
5-methylthiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 700 [M + H] +.

Example 198
2-methyl-5- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-ylsulfamoyl] furan-3-carboxylic acid methyl ester MS: 742 [M + H] +.

Example 199
1-methyl-5- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-ylsulfamoyl] -1H-pyrrole-2-carboxylic acid methyl ester MS: 741 [M + H] +.

Example 200
5-Pyridin-2-ylthiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H -Indol-6-yloxy) pyridin-3-yl] amide MS: 763 [M + H] +.

Example 201
5-Chloro-3-methylbenzo [b] thiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl) } -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 784 [M + H] +.

Example 202
Benzofuran-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] amide MS: 720 [M + H] +.

Example 203
5-Methyl-1-phenyl-1H-pyrazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl) } -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 760 [M + H] +.

Example 204
2,5-Dimethylfuran-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] amide MS: 698 [M + H] +.

Example 205
5-Phenylthiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 762 [M + H] +.

Example 206
4-methoxy-5- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-ylsulfamoyl] thiophene-3-carboxylic acid methyl ester MS: 774 [M + H] +.

Example 207
4-phenyl-5-trifluoromethylthiophene-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 830 [M + H] +.

Example 208
5-methylbenzo [b] thiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 750 [M + H] +.

Example 209
5-Methyl-3-phenylisoxazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] amide MS: 761 [M + H] +.

Example 210
1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl) } -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 712 [M + H] +.

Example 211
2-chloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] benzylsulfonamide MS: 728 [M + H] +.

Example 212
Benzo [b] thiophene-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] amide MS: 736 [M + H] +.

Example 213
6-Chloroimidazo [2,1-b] thiazole-5-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1- Carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 760 [M + H] +.

Example 214
3,5-Dimethyl-1-phenyl-1H-pyrazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1 -Carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 774 [M + H] +.

Example 215
3-Bromothiophene-2-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 -Yloxy) pyridin-3-yl] amide MS: 764 [M + H] +.

Example 216
5-methyl-2-trifluoromethylfuran-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 752 [M + H] +.

Example 217
1-methyl-1H-pyrazole-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 684 [M + H] +.

Example 218
1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1 -Carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] amide MS: 752 [M + H] +.

Example 219
2-Methyl-2H-pyrazole-3-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 684 [M + H] +.

Example 220
1-methyl-1H-indole-4-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] amide MS: 733 [M + H] +.

Example 221
2,4-Dimethylthiazole-5-sulfonic acid [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] amide MS: 715 [M + H] +.

Example 222
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -3,4-dichloro Preparation of benzamide 5- [5- (3,4-dichlorobenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid (0.250 g, 0.565 mmol) was dissolved in THF (20 ml) and 1 -Benzo [1,3] dioxol-5-ylmethylpiperazine (0.125 g, 0.565 mmol) followed by 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.119 g, 0.622 mmol) And stirred at room temperature for 15 hours. Water (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to give 0.360 g of the title compound.
Properties: Pale yellow powder 1H-NMR (DMSO-d6) δ ppm:
2.43 (4H, brs), 3.44 (2H, s), 3.75 (4H, brs), 5.99 (2H, s), 6.76-6.79 (2H, m), 6 .84-6.90 (2H, m), 6.95-6.99 (2H, m), 7.32 (1H, d, J = 2.1 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.83 (1 H, d, J = 8.4 Hz), 7.94 (1 H, dd, J = 8.4 Hz, 2.0 Hz), 8.15 (1 H, dd, J = 8) .9 Hz, 2.6 Hz), 8.22 (1 H, d, J = 2.0 Hz), 8.44 (1 H, d, J = 2.3 Hz), 10.50 (1 H, s), 11.64 (1H, s).

  The following compounds were prepared in the same manner as in Example 222 using appropriate starting materials.

Example 223
N- (6- {1- [2- (4-Benzylpiperazin-1-yl) -2-oxoethyl] -1H-indol-4-yloxy} pyridin-3-yl) -3,4-dichlorobenzamide 1H- NMR (DMSO-d6) δ ppm:
2.36 (2H, brs), 2.47 (2H, brs), 3.47 (2H, brs), 3.53 (2H, s), 3.59 (2H, brs), 5.19 (2H) , S), 6.08 (1H, d, J = 3.1 Hz), 6.75 (1H, d, J = 7.6 Hz), 7.05 (1H, d, J = 8.9 Hz), 7 .07-7.13 (2H, m), 7.20-7.36 (5H, m), 7.84 (2H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.19 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.22-8.23 (1 H, m), 8.45 (1 H, d, J = 2.8 Hz), 10.56 (1 H, s).

Example 224
N- (6- {1- [2- (4-Benzylpiperazin-1-yl) -2-oxoethyl] -1H-indol-4-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H- NMR (DMSO-d6) δ ppm:
2.36 (2H, brs), 2.49 (2H, brs), 3.47 (2H, brs), 3.54 (2H, s), 3.59 (2H, brs), 5.19 (2H) , S), 6.09 (1H, d, J = 3.1 Hz), 6.76 (1H, d, J = 7.1 Hz), 7.06 (1H, d, J = 8.9 Hz), 7 .08-7.14 (1H, m), 7.20-7.23 (2H, m), 7.27-7.36 (5H, m), 7.93 (2H, d, J = 8. 4 Hz), 8.17 (2 H, d, J = 8.1 Hz), 8.21 (1 H, dd, J = 8.9 Hz, 2.6 Hz), 8.47 (1 H, d, J = 2.6 Hz) ), 10.64 (1H, s).

Example 225
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -6 -Pyrrol-1-ylnicotinamide melting point: 155-158 [deg.] C.

Example 226
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -6-pyrrol-1-yl Nicotinamide melting point: 194-195 ° C.

Example 227
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-6-pyrrole -1-ylnicotinamide dioxalate melting point: 185-187 ° C.

Example 228
5-Bromo-1H-indole-2-carboxylic acid (6- {2- [4- (4-methoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) Amidohydrobromide melting point: 263-265 ° C.

Example 229
5-Bromo-1H-indole-2-carboxylic acid (6- {2- [4- (4-methoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) Methylamide maleate melting point: 205-207 ° C.

Example 230
5-trifluoromethylpyridine-2-carboxylic acid (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl ) Amide dihydrobromide melting point: 241-243 ° C.

Example 231
2-Chloro-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide hydrobromide melting point: 239-241 ° C.

Example 232
N- [6- (2- {4-[(4-methoxybenzyl) methylamino] piperidin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -4-tri Fluoromethylbenzamide oxalate 1H-NMR (DMSO-d6) δ ppm:
1.72-1.79 (2H, m), 2.07 (2H, brs), 2.49-2.51 (3H, brs), 3.01 (2H, brs), 3.37 (1H, brs), 3.777 (3H, s), 3.783 (3H, s), 4.10 (4H, brs), 6.69 (1H, s), 6.97-7.07 (4H, m ), 7.35 (1H, d, J = 2.4 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.9 Hz), 7.93. (2H, d, J = 8.1 Hz), 8.15-8.20 (3H, m), 8.47 (1H, d, J = 2.4 Hz), 10.61 (1H, s).

Example 233
N- [6- (2- {4-[(4-methoxyphenyl) methylamino] piperidin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -4-tri Fluoromethylbenzamide melting point: 139-142 ° C.

Example 234
N- {6- [1,4-dimethyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethyl Benzamide dimethanesulfonate melting point: 149-150 ° C.

Example 235
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethyl Benzamide melting point: 219-221 ° C.

Example 236
N- {6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide Oxalate melting point: 176-178 ° C.

Example 237
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.50 (4H, s), 3.60 (2H, s), 3.70-3.79 (7H, m), 6.57 (1H, s), 6.94 (2H, t, J = 7.3 Hz), 7.12 (1H, s), 7.47 (2H, d, J = 8.1 Hz), 7.58-7.68 (3H, m), 7.74 (2H, d, J = 7.3 Hz), 7.99 (2H, d, J = 8.2 Hz), 8.11 (1H, brs), 8.18 (1H, d, J = 8.9 Hz), 8.28 ( 1H, d, J = 2.6 Hz).

Example 238
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.48 (4H, s), 3.50 (2H, s), 3.77 (7H, s), 3.81 (3H, s), 6.57 (1H, s), 6.84-6 .97 (4H, m), 7.12 (1H, d, J = 1.5 Hz), 7.19-7.23 (2H, m), 7.59 (1H, d, J = 8.6 Hz) , 7.75 (2H, d, J = 7.9 Hz), 7.99 (3H, d, J = 8.2 Hz), 8.18 (1H, d, J = 8.7 Hz), 8.27 ( 1H, d, J = 2.5 Hz).

Example 239
N- (6- {1-methyl-2- [4- (pyridin-2-carbonyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Melting point: 162-164 ° C.

Example 240
N- (6- {2- [4- (4-methoxybenzoyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide melting point 195-196 ° C.

Example 241
N- (6- {2- [4- (4-methoxybenzoyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide melting point: 126-128 ° C.

Example 242
N- (6- {2- [4- (4-cyanobenzoyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide melting point: 135-137 ° C.

Example 243
N- {6- [1-Methyl-2- (4-pyridin-2-ylmethylpiperazine-1-carbonyl) -1H-indol-7-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide Oxalate melting point: 121-123 ° C.

Example 244
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-7-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.45 (4H, brs), 3.47 (2H, s), 3.71 (4H, brs), 3.79 (3H, s), 3.80 (3H, s), 6.52 (1H , S), 6.85 (3H, d, J = 8.7 Hz), 6.90 (1H, dd, J = 7.7 Hz, 0.7 Hz), 7.07 (1H, t, J = 7. 7 Hz), 7.19-7.24 (2 H, m), 7.43 (1 H, dd, J = 8.0 Hz, 0.7 Hz), 7.69 (2 H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.28 (1H, d, J = 2.6 Hz), 8 .46 (1H, s).

Example 245
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-7-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide melting point : 228-229 degreeC.

Example 246
N- {6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-4-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide odor Hydrohalide melting point: 186-189 ° C.

Example 247
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-4-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.43 (4H, brs), 3.46 (2H, s), 3.71 (4H, brs), 3.79 (6H, s), 6.33 (1H, s), 6.82-6 .89 (4H, m), 7.16-7.31 (4H, m), 7.73 (2H, d, J = 8.1 Hz), 8.00 (2H, d, J = 8.2 Hz) , 8.05 (1H, d, J = 9.1 Hz), 8.23 (1H, d, J = 2.6 Hz), 8.28 (1H, s).

Example 248
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-4-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide 1H -NMR (CDCl3) δ ppm:
2.45 (4H, brs), 3.57 (2H, s), 3.73 (4H, brs), 3.80 (3H, s), 6.36 (1H, s), 6.82-6 .89 (2H, m), 7.19 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8. 2 Hz), 7.60 (2H, d, J = 8.4 Hz), 7.74 (2H, d, J = 8.2 Hz), 8.00 (2H, d, J = 8.1 Hz), 8. 06 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.24 (2H, d, J = 2.6 Hz).

Example 249
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -2-methoxymethoxy-4 -Trifluoromethylbenzamide 1H-NMR (CDCl3) δ ppm:
2.49 (4H, brs), 3.53 (2H, s), 3.58 (3H, s), 3.78 (4H, brs), 3.84 (3H, s), 5.44 (2H) , S), 6.50 (1H, t, J = 74 Hz), 6.55 (1H, s), 6.92 (1H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.3 Hz), 7.03-7.18 (1 H, m), 7.32 (2 H, d, J = 8.3 Hz), 7.30-7.55 (4 H, m), 8.22 (1H, d, J = 2.5 Hz), 8.27 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.36 (1H, d, J = 7.9 Hz), 9.61 ( 1H, s).

Example 250
N- [6- (1-methyl-2- {4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 279-282 ° C. (decomposition).

Example 251
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethoxybenzamide Hydrobromide melting point: 265-267 ° C. (decomposition).

Example 252
N- (6- {2- [4- (4-t-butylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethyl Benzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
1.30 (9H, s), 3.10-3.60 (6H, m), 3.76 (3H, s), 4.37 (2H, s), 4.35-4.60 (2H, m), 6.82 (1H, s), 6.90 (1H, d, J = 8.7 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.35 (1H, s) 7.48 (2H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.2 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.93 ( 2H, d, J = 8.2 Hz), 8.17 (2H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 8.5 Hz, 2.6 Hz), 8.50 (1H , D, J = 2.6 Hz), 10.61 (1H, s).

Example 253
2-chloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide hydrobromide melting point: 237.2-238.2 ° C.

Example 254
3,4-dichloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzamide Hydrobromide melting point: 249.0-253.7 ° C.

Example 255
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzamide Hydrobromide melting point: 239.7-243.5 ° C.

Example 256
3,4-Dichloro-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 239.2-240.4 ° C.

Example 257
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-6-yloxy] pyridin-3-yl} -3 , 4-dichlorobenzamide hydrobromide melting point: 241.3-243.9 ° C.

Example 258
3,4-Dichloro-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 234.6-237.2 ° C.

Example 259
3,4-dichloro-N- (6- {2- [4- (4-methoxymethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzamide Hydrobromide melting point: 243.6-247.7 ° C.

Example 260
3,4-Dichloro-N- (6- {2- [4- (4-isobutylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 255.8-257.4 ° C.

Example 261
3,4-Dichloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) -3-methoxybenzyl] piperazine-1-carbonyl} -1-methyl-1H-indole-6 -Yloxy) pyridin-3-yl] benzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.19-3.48 (8H, m), 3.76 (3H, s), 3.84 (3H, s), 4.34-4.42 (4H, m), 6.40 (1H, tt, J = 54.5 Hz, 3.7 Hz), 6.82 (1H, s), 6.91 (1H, dd, J = 8.5 Hz, 1.9 Hz), 7.05 (2H, d, J = 8.9 Hz), 7.15-7.18 (2 H, m), 7.36 (1 H, d, J = 1.5 Hz), 7.65 (1 H, d, J = 8.6 Hz), 7 .84 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.3 Hz, 1.6 Hz), 8.18 (1H, dd, J = 8.8 Hz, 2.7 Hz) ), 8.22 (1H, d, J = 2.0 Hz), 8.47 (1H, d, J = 2.8 Hz), 9.86 (1H, brs), 10.53 (1H, s).

Example 262
3,4-dichloro-N- (6- {1-methyl-2- [4- (4-trifluoromethylbenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) Benzamide hydrobromide melting point: 259.4-260.7 ° C.

Example 263
3,4-Dichloro-N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 263.9-267.4 ° C.

Example 264
3,4-dichloro-N- (6- {1-methyl-2- [4- (4-trifluoromethoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) Benzamide hydrobromide melting point: 261.6-264.7 ° C.

Example 265
3,4-dichloro-N- (6- {2- [4- (2-fluoro-4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine-3 -Yl) benzamide hydrobromide melting point: 242.5-246.7 [deg.] C.

Example 266
3,4-Dichloro-N- (6- {2- [4- (3-fluoro-4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine-3 -Yl) benzamide hydrobromide melting point: 244.3-247.0 [deg.] C.

Example 267
2-hydroxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 214-219 ° C. (decomposition).

Example 268
3,4-Dichloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine -3-yl] benzamide hydrobromide melting point: 221.5-222.3 ° C.

Example 269
3,4-dichloro-N- {6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-6-yloxy] pyridin-3-yl} benzamide Hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.40 (4H, brs), 3.98 (3H, s), 4.25 (4H, brs), 4.57 (2H, brs), 6.82 (1H, s), 6.91 (1H , Dd, J = 8.1 Hz, 2.7 Hz), 7.05 (1H, d, J = 8.1 Hz), 7.36 (1H, d, J = 2.7 Hz), 7.49-7. 61 (2H, m), 7.64 (1H, d, J = 8.1 Hz), 7.85 (1H, d, J = 8.1 Hz), 7.91-8.02 (2H, m), 8.18 (1H, dd, J = 8.1 Hz, 2.7 Hz), 8.23 (1H, d, J = 2.7 Hz), 8.48 (1H, d, J = 2.7 Hz), 8 .73 (1H, d, J = 5.4 Hz), 10.53 (1H, brs).

Example 270
2-hydroxy-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.21 (2H, brs), 3.39 (4H, brs), 3.75 (3H, s), 4.37 (2H, s), 4.46 (2H, brs), 4.82 (2H) , Q, J = 8.6 Hz), 6.81 (1H, s), 6.90 (1H, dd, J = 8.6 Hz, 1.7 Hz), 7.05 (1H, d, J = 8. 6 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.29 (1 H, s), 7.30 (1 H, d, J = 8.6 Hz), 7.35 (1 H, d, J = 1.7 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8.6 Hz) ), 8.17 (1H, dd, J = 8.6 Hz, 2.7 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.91 (1H, s), 10.53 (1H) , S).

Example 271
N- [2- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyrimidine-5 Yl] -4-trifluoromethylbenzamide hydrochloride melting point: 250.8-254.2 ° C.

Example 272
N- [2- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyrimidin-5-yl]- 4-trifluoromethylbenzamide hydrochloride melting point: 251.4-253.5 ° C.

Example 273
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide Hydrochloride melting point: 249.8-251.0 ° C.

Example 274
N- (2- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide Hydrochloride melting point: 247.7-249.8 ° C.

Example 275
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 4, N-dimethylbenzamide hydrochloride melting point: 207.8-209.3 ° C.

Example 276
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzamide Melting point: 140.1-141.3 ° C.

Example 277
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzamide Hydrochloride melting point: 230.1-232.0 ° C.

Example 278
4, N-dimethyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) benzamide hydrochloride Salt melting point: 231.2-231.8 ° C.

Example 279
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -N-methyl-4-trifluoromethoxybenzamide hydrobromide melting point: 227.5-230.3 [deg.] C.

Example 280
4-Difluoromethoxy-N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl ) Benzamide hydrochloride melting point: 226.9-229.0 ° C.

Example 281
4-Difluoromethoxy-N- (6- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N -Methylbenzamide hydrochloride melting point: 229.7-230.4 ° C.

Example 282
4-Difluoromethoxy-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N -Methylbenzamide hydrobromide melting point: 198.7-200.5C.

Example 283
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 4-difluoromethoxy-N-methylbenzamide hydrobromide melting point: 196.9-198.6 [deg.] C.

Example 284
4-Difluoromethoxy-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole -6-yloxy) pyridin-3-yl] benzamide hydrobromide melting point: 203.8-205.6 ° C.

Example 285
N-methyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] methanesulfonamide melting point: 167.0-168.1C.

Example 286
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -2-methoxy-4-trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
2.49 (4H, brs), 3.50 (2H, s), 3.78 (4H, brs), 3.79 (3H, s), 4.12 (3H, s), 4.58-4 .77 (5H, m), 6.58 (1H, d, J = 0.7 Hz), 6.92-6.96 (4H, m), 7.14 (1H, d, J = 2.0 Hz) 7.25-7.28 (3H, m), 7.41 (1H, dd, J = 8.2 Hz, 0.8 Hz), 7.60 (1H, d, J = 8.7 Hz), 8. 26 (2H, m), 8.40 (1H, dd, J = 8.2 Hz, 0.7 Hz), 9.63 (1H, s).

Example 287
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 2-Methoxy-4-trifluoromethylbenzamide 1H-NMR (CDCl3) δ ppm:
2.51 (4H, brs), 3.53 (2H, s), 3.78 (3H, s), 3.80 (4H, s), 4.12 (3H, s), 4.18 (2H) , Td, J = 13.3 Hz, 4.3 Hz), 6.09 (1H, tt, J = 55.1 Hz, 4.2 Hz), 6.58 (1H, s), 6.89 (2H, d, J = 8.6 Hz), 6.92-6.97 (3 H, m), 7.14 (1 H, d, J = 1.6 Hz), 7.26-7.29 (3 H, m), 7. 41 (1H, d, J = 7.9 Hz), 7.60 (1H, d, J = 8.6 Hz), 8.24-8.29 (2H, m), 8.40 (1H, d, J = 7.9 Hz), 9.63 (1 H, s).

Example 288
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2-methoxy-4- Trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
1.33 (3H, s), 1.36 (3H, s), 2.49 (4H, brs), 3.49 (2H, s), 3.77 (4H, brs), 3.78 (3H , S), 4.12 (3H, s), 4.49-4.58 (1H, m), 6.58 (1H, d, J = 0.7 Hz), 6.85 (2H, dt, J = 9.2 Hz, 2.4 Hz), 6.91-6.97 (2H, m), 7.13 (1H, d, J = 2.0 Hz), 7.22 (2H, d, J = 8. 6 Hz), 7.26-7.27 (1 H, m), 7.41 (1 H, d, J = 8.1 Hz), 7.60 (1 H, d, J = 8.6 Hz), 8.23- 8.28 (2H, m), 8.40 (1 H, d, J = 8.1 Hz), 9.64 (1 H, s).

Example 289
2-methoxy-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
1.04 (3H, t, J = 7.4 Hz), 1.81 (2H, td, J = 14.1 Hz, 7.3 Hz), 2.49 (4H, brs), 3.50 (2H, brs) ), 3.78 (7H, brs), 3.92 (2H, t, J = 6.6 Hz), 4.12 (3H, s), 6.58 (1H, d, J = 0.5 Hz), 6.87 (2H, dt, J = 9.0 Hz, 2.2 Hz), 6.92-6.97 (2H, m), 7.14 (1H, d, J = 2.0 Hz), 7.24 −7.27 (3H, m), 7.41 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.6 Hz), 8.24-8.27 (2H, m), 8.40 (1H, d, J = 8.1 Hz), 9.64 (1H, s).

Example 290
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2-methoxy-4- Trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
2.49 (4H, brs), 3.54 (2H, s), 3.79 (7H, brs), 4.12 (3H, s), 6.51 (1H, t, J = 74.0 Hz) 6.59 (1H, d, J = 0.7 Hz), 6.93-6.96 (2H, m), 7.07-7.14 (3H, m), 7.27 (1H, s) , 7.34 (2H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz), 8.24- 8.28 (2H, m), 8.39 (1H, d, J = 8.1 Hz), 9.64 (1H, s).

Example 291
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethoxybenzamide Hydrochloride melting point: 256.2-256.5 ° C.

Example 292
N- (6- {2-[(S) -4- (4-difluoromethoxybenzyl) -3-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl ) -4-Trifluoromethoxybenzamide hydrobromide melting point: 199.4-202.1 <0> C.

Example 293
N- [6- (1-methyl-2-{(S) -3-methyl-4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] -4-trifluoromethoxybenzamide hydrobromide melting point: 199.4-203.1 [deg.] C.

Example 294
N- (6- {2-[(S) -4- (4-difluoromethoxybenzyl) -3-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl ) -N-methyl-4-trifluoromethoxybenzamide 1H-NMR (CDCl3) δ ppm:
1.21 (3H, brs), 2.17 (1H, brs), 2.55 (1H, brs), 2.71 (1H, brs), 3.22 (2H, d, J = 13.5 Hz) 3.38-3.50 (4H, m), 3.76 (3H, s), 3.99-4.12 (3H, m), 6.50 (1 H, t, J = 72.9 Hz). 6.56 (1H, s), 6.83-6.87 (2H, m), 7.07-7.10 (5H, m), 7.32-7.36 (4H, m), 7 .42 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.85 (1H, d, J = 2.6 Hz).

Example 295
N-methyl-N- [6- (1-methyl-2-{(S) -3-methyl-4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] -4-trifluoromethoxybenzamide 1H-NMR (CDCl 3) δ ppm:
1.17 (3H, brs), 2.17 (1H, brs), 2.52 (1H, brs), 2.71 (1H, brs), 3.19 (2H, d, J = 13.5 Hz) 3.31 (1H, brs), 3.49 (3H, s), 3.76 (3H, s), 3.98 (3H, d, J = 12.9 Hz), 4.35 (2H, q , J = 8.2 Hz), 6.56 (1H, s), 6.85 (2H, d, J = 8.6 Hz), 6.91 (2H, d, J = 8.6 Hz), 7.06 −7.08 (3H, m), 7.28 (2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8.9 Hz), 7.42 (1H, d, J = 6.3 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.85 (1H, d, J = 2.6 Hz).

Example 296
2-Methoxy-N- [6- (1-methyl-2-{(S) -3-methyl-4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
1.09-1.59 (3H, m), 2.11-2.19 (1H, m), 2.64-2.68 (1H, m), 3.10-3.26 (2H, m ), 3.44 (1H, s), 3.70-3.74 (3H, m), 3.86-3.91 (1H, m), 3.96 (3H, s), 4.02- 4.10 (1H, m), 4.30-4.39 (2H, m), 4.68-4.86 (2H, m), 6.65-6.80 (1H, m), 6. 85-6.90 (1H, m), 7.00-7.05 (2H, m), 7.17 (1H, d, J = 8.1 Hz), 7.28-7.31 (2H, m ), 7.42 (1H, d, J = 8.1 Hz), 7.46 (1H, s), 7.57-7.64 (2H, m), 7.76 (1H, d, J = 7) .6 Hz), 8.17 (1H, dd, J = 8.8 Hz, .7Hz), 8.44 (1H, d, J = 2.5Hz), 10.40 (1H, s), 10.86 (1H, brs).

Example 297
N- [6- (1,3-dimethyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] -N-methyl-4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
2.23-2.28 (3H, m), 3.17-3.27 (4H, m), 3.37 (3H, s), 3.41-3.50 (2H, m), 3. 58-3.65 (3H, m), 4.36-4.64 (4H, m), 4.82 (2H, q, J = 8.8 Hz), 6.77 (1H, d, J = 7) .4Hz), 6.96 (1H, d, J = 8.6 Hz), 7.16-7.23 (3H, m), 7.48-7.57 (5H, m), 7.68 (2H) , D, J = 8.1 Hz), 7.83 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.93 (1H, brs), 9.89 (1H, brs).

Example 298
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1,3-dimethyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl- 4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
2.21-2.31 (3H, m), 3.05-3.24 (4H, m), 3.37 (3H, s), 3.43-3.46 (2H, m), 3. 56-3.65 (3H, m), 3.94 (2H, brs), 4.40-4.45 (2H, m), 6.76 (1H, d, J = 7.4 Hz), 6. 96 (1H, d, J = 8.7 Hz), 7.23 (1H, s), 7.29-7.31 (2H, m), 7.32 (1H, t, J = 73.7 Hz), 7.50-7.70 (7H, m), 7.83 (1H, dd, J = 8.7 Hz, 2.2 Hz), 7.93 (1H, brs), 9.94 (1H, brs).

Example 299
N- (6- {2-[(S) -4- (4-difluoromethoxybenzyl) -3-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl ) -2-Methoxy-4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
1.36-1.52 (3H, m), 3.17-3.52 (3H, m), 3.75 (3H, s), 3.96 (3H, s), 4.11 (3H, brs), 4.37-4.51 (2H, m), 4.79-4.84 (1H, m), 6.82 (1H, t, J = 71.8 Hz), 6.89 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.30-7.34 (4H, m), 7.43 (1H, d, J = 8.1 Hz), 7.47 (1 H, s), 7.60-7.69 (3 H, m), 7.76 (1 H, d, J = 7.7 Hz), 8.17 (1 H, dd) , J = 8.9 Hz, 2.6 Hz), 8.45 (1H, d, J = 2.6 Hz), 9.96 (1H, brs), 10.41 (1H, s).

Example 300
N- [6- (1-methyl-2-{(S) -3-methyl-4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] -2,4-bistrifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
1.35-1.53 (3H, m), 3.16-3.51 (3H, m), 3.75 (3H, s), 4.04 (4H, brs), 4.34-4. 50 (2H, m), 4.82 (2H, q, J = 8.9 Hz), 6.82 (1H, s), 6.90 (1H, dd, J = 8.5 Hz, 1.9 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.36 (1H, s), 7.54 (1H, d, J = 8) .6 Hz), 7.60 (1 H, d, J = 8.4 Hz), 7.65 (1 H, d, J = 8.7 Hz), 8.02 (1 H, d, J = 7.9 Hz), 8 .13 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.22 (1H, s), 8.25 (1H, d, J = 8.9 Hz), 8.39 (1H, d, J = 2.6 Hz), 9.96 ( H, brs), 10.86 (1H, s).

Example 301
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -2,4-bistrifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.18-3.25 (2H, m), 3.40-3.45 (4H, m), 3.76 (3H, s), 4.36 (2H, brs), 4.36 (2H, brs), 4.44-4.50 (2H, m), 4.56-5.10 (5H, m), 6.82 (1H, s), 6.91 (1H, dd, J = 8. 6 Hz, 2.1 Hz), 7.07 (1 H, d, J = 8.9 Hz), 7.16 (2 H, d, J = 8.7 Hz), 7.36 (1 H, d, J = 1.8 Hz) ), 7.50 (2H, d, J = 8.7 Hz), 7.65 (1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.22 (1H, s), 8.25 (1H, d, J = 8.9 Hz), 8.39 (1H, d, J = 2.6 Hz), 9.98 (1 , Brs), 10.86 (1H, s).

Example 302
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 2,4-bistrifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.18-3.25 (2H, m), 3.40-3.46 (4H, m), 3.76 (3H, s), 4.37 (2H, td, J = 14.7 Hz, 3 .5 Hz), 4.45-4.50 (4 H, m), 6.41 (1 H, tt, J = 54.4 Hz, 3.5 Hz), 6.82 (1 H, s), 6.91 (1 H) , Dd, J = 8.6 Hz, 2.1 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.36 (1H, d, J = 2.0 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.65 (1H, d, J = 8.7 Hz), 8.02 (1H, d, J = 8) .1 Hz), 8.13 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1 H, s), 8.25 (1 H, d, J = 8.4 Hz), 8.39. (1H, d, J = 2 6Hz), 10.03 (1H, brs), 10.86 (1H, s).

Example 303
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2,4-bistrifluoro Methylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
1.27 (3H, s), 1.29 (3H, s), 3.18-3.25 (2H, m), 3.40-3.48 (4H, m), 3.76 (3H, s), 4.33-4.35 (2H, m), 4.45-4.50 (2H, m), 4.56-4.73 (1H, m), 6.82 (1H, s) 6.90 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.01 (2H, d, J = 8.7 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.36 (1H, d, J = 2.0 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.6 Hz), 8.02 (1H , D, J = 7.9 Hz), 8.13 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.22 (1H, s), 8.25 (1H, d, J = 8. 4Hz), 8.40 (1H, d, J = 2) 6Hz), 10.00 (1H, brs), 10.87 (1H, s).

Example 304
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -2,4-bistrifluoromethyl Benzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
0.98 (3H, t, J = 7.4 Hz), 1.74 (2H, td, J = 13.9 Hz, 7.1 Hz), 3.18-3.25 (2H, m), 3.44 (4H, m), 3.76 (3H, s), 3.96 (2H, t, J = 6.4 Hz), 4.35 (2H, d, J = 3.5 Hz), 4.45-4 .50 (2H, m), 6.82 (1H, s), 6.91 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.02-7.08 (3H, m), 7 .36 (1H, d, J = 1.8 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 8.7 Hz), 8.02 (1H, d, J = 7.7 Hz), 8.14 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.22 (1H, s), 8.25 (1H, d, J = 8.7 Hz) ), 8.40 (1H, d, = 2.5Hz), 10.02 (1H, brs), 10.87 (1H, s).

Example 305
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2,4-bistrifluoro Methylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.27 (2H, brs), 3.40-3.46 (4H, m), 3.76 (3H, s), 4.45 (2H, brs), 4.50 (2H, brs), 6 .82 (1H, s), 6.91 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.34 (1H, t, J = 73.7 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.63-7.68 (3H, m), 8.02 (1H, d, J = 7.9 Hz), 8.14 (1 H, dd, J = 8.9 Hz, 2.8 Hz), 8.22 (1 H, s), 8.25 (1 H, d , J = 8.2 Hz), 8.40 (1H, d, J = 2.6 Hz), 10.25 (1H, brs), 10.88 (1H, s).

Example 306
3,4-Dichloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} -4-methylpyridine-3 -Yl) benzenesulfonamide 1H-NMR (CDCl3) δ ppm:
2.22 (3H, s), 2.49 (4H, brs), 3.53 (2H, s), 3.76 (7H, s), 6.42 (1H, s), 6.51 (1H , T, J = 72.9 Hz), 6.56 (1H, s), 6.74 (1H, s), 6.87 (1H, dd, J = 8.6 Hz, 1.6 Hz), 7.09 (3H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.56-7.58 (4H, m), 7.85 (1H, s).

Example 307
3,4-dichloro-N- [4-methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzenesulfonamide 1H-NMR (CDCl 3) δ ppm:
2.22 (3H, s), 2.48 (4H, brs), 3.51 (2H, s), 3.75 (7H, brs), 4.35 (2H, q, J = 8.1 Hz) 6.43 (1H, brs), 6.56 (1H, s), 6.73 (1H, s), 6.87 (1H, dd, J = 8.6 Hz, 2.0 Hz), 6.91. (2H, d, J = 8.6 Hz), 7.07 (1H, s), 7.26-7.30 (4H, m), 7.55-7.58 (4H, m), 7.85 (1H, s).

Example 308
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} -4-methylpyridine-3 -Yl) benzenesulfonamide 1H-NMR (CDCl3) δ ppm:
1.34 (6H, d, J = 6.3 Hz), 2.20 (3H, s), 2.48 (4H, brs), 3.49 (2H, s), 3.71 (7H, s) , 4.49-4.58 (1H, m), 6.55 (2H, s), 6.72 (1H, s), 6.84-6.87 (3H, m), 7.07 (1H , D, J = 1.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.50-7.59 (4H, m), 7.85 (1H, t, J = 1. 2 Hz).

Example 309
3,4-Dichloro-N- (6- {2-[(R) -4- (4-difluoromethoxybenzyl) -3-methylpiperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy } -4-methylpyridin-3-yl) benzenesulfonamide 1H-NMR (CDCl3) δ ppm:
1.21 (3H, brs), 2.22 (4H, s), 2.55 (1H, brs), 2.71 (1H, brs), 3.22 (2H, d, J = 13.2 Hz) , 3.39 (1H, brs), 3.75 (3H, s), 4.00 (4H, d, J = 13.5 Hz), 6.45 (1H, brs), 6.51 (1H, t , J = 75.6 Hz), 6.55 (1H, s), 6.74 (1H, s), 6.87 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.09 (3H , D, J = 7.3 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.52-7.58 (4H, m), 7.85 (1H, s).

Example 310
3,4-Dichloro-N- [4-methyl-6- (1-methyl-2-{(R) -3-methyl-4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine -1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] benzenesulfonamide 1H-NMR (CDCl 3) δ ppm:
1.22 (3H, brs), 2.17-2.22 (4H, m), 2.53 (1H, brs), 2.72 (1H, brs), 3.19 (2H, d, J = 13.2 Hz), 3.38 (1H, brs), 3.75 (3H, s), 3.98 (4H, d, J = 13.2 Hz), 4.35 (2H, q, J = 8. 1 Hz), 6.44 (1H, brs), 6.55 (1H, s), 6.73 (1H, s), 6.87-6.91 (3H, m), 7.08 (1H, d) , J = 2.0 Hz), 7.26-7.30 (2H, m), 7.55-7.58 (4H, m), 7.85 (1H, s).

Example 311
3,4-Dichloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} -4-methylpyridine-3 -Yl) -N-methylbenzenesulfonamide hydrobromide melting point: 213.5-215.3 [deg.] C.

Example 312
3,4-Dichloro-N-methyl-N- [4-methyl-6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl } -1H-indol-6-yloxy) pyridin-3-yl] benzenesulfonamide 1H-NMR (CDCl 3) δ ppm:
2.41 (3H, s), 2.48 (4H, brs), 3.19 (3H, s), 3.51 (2H, s), 3.79 (7H, s), 4.35 (2H) , Q, J = 8.2 Hz), 6.58 (1H, s), 6.82 (1H, s), 6.89-6.92 (3H, m), 7.12 (1H, d, J = 1.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.41 (1H, s), 7.53 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7 .59 (2H, dd, J = 8.6 Hz, 2.6 Hz), 7.84 (1H, d, J = 2.0 Hz).

Example 313
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} -4-methylpyridine-3 -Yl) -N-methylbenzenesulfonamide melting point: 151.0-151.6 [deg.] C.

Example 314
3,4-Dichloro-N- (6- {2-[(R) -4- (4-difluoromethoxybenzyl) -3-methylpiperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy } -4-methylpyridin-3-yl) -N-methylbenzenesulfonamide 1H-NMR (CDCl3) δ ppm:
1.21 (3H, brs), 2.18 (1H, brs), 2.42 (3H, s), 2.55 (1H, brs), 2.72 (1H, brs), 3.19-3 .24 (5H, m), 3.40 (1H, brs), 3.79 (3H, s), 4.01 to 4.08 (3H, m), 6.50 (1H, t, J = 72) .9 Hz), 6.57 (1 H, s), 6.83 (1 H, s), 6.90 (1 H, d, J = 8.6 Hz), 7.08-7.11 (3 H, m), 7.29-7.38 (3H, m), 7.51-7.62 (3H, m), 7.84 (1H, d, J = 2.0 Hz).

Example 315
3,4-Dichloro-N-methyl-N- [4-methyl-6- (1-methyl-2-{(R) -3-methyl-4- [4- (2,2,2-trifluoroethoxy) ) Benzyl] piperazin-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] benzenesulfonamide 1H-NMR (CDCl 3) δ ppm:
1.16 (3H, brs), 2.16 (1H, brs), 2.41 (3H, s), 2.52 (1H, brs), 2.71 (1H, brs), 3.17-3 .19 (5H, m), 3.38 (1H, brs), 3.78 (3H, s), 3.99-4.10 (3H, m), 4.35 (2H, q, J = 8) .2 Hz), 6.57 (1 H, s), 6.82 (1 H, s), 6.88-6.92 (3 H, m), 7.11 (1 H, d, J = 1.6 Hz), 7.26-7.30 (2H, m), 7.41 (1H, s), 7.52-7.57 (2H, m), 7.61 (1H, d, J = 3.6 Hz), 7.84 (1H, d, J = 2.0 Hz).

Example 316
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -2 -Fluoro-4-trifluoromethylbenzamide hydrobromide Melting point: 254-257 ° C (decomposition).

Example 317
6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -2,3-dihydro-1H-indol-4-yloxy}- Preparation of N- (4-trifluoromethylphenyl) nicotinamide 6- (2,3-dihydro-1H-indol-4-yloxy) -N- (4-trifluoromethylphenyl) nicotinamide (0.268 g, 0 .671 mmol) was dissolved in DMF (3 ml), triethylamine (0.187 ml, 1.34 mmol) and bromoacetic acid t-butyl ester (0.198 ml, 1.34 mmol) were added, and the mixture was stirred at 50 ° C for 3 hours. Water (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 0.345 g of a brown powder. This brown powder was dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, adjusted to pH 5 with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 0.307 g of a brown oil. This brown oil was dissolved in DMF (3 ml) and 1-benzo [1,3] dioxol-5-ylmethylpiperazine (0.163 g, 0.738 mmol) followed by 1-ethyl-3- (3-dimethylaminopropyl). ) Carbodiimide hydrochloride (0.141 g, 0.738 mmol) was added and stirred at room temperature for 16 hours. To the reaction solution was added saturated brine (100 ml), and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 0.106 g of the title compound.
Properties: pale brown oily 1H-NMR (CDCl3) δ ppm:
2.44 (4H, brs), 2.83 (2H, t, J = 8.6 Hz), 3.44-3.52 (6H, m), 3.65 (2H, brs), 3.92 ( 2H, s), 5.95 (2H, s), 6.32 (1H, d, J = 7.8 Hz), 6.46 (1H, d, J = 8.1 Hz), 6.75 (2H, s), 6.85 (1H, s), 6.99 (1H, d, J = 8.7 Hz), 7.08-7.14 (1H, m), 7.63 (2H, d, J = 8.7 Hz), 7.77 (2 H, d, J = 8.6 Hz), 8.02 (1 H, brs), 8.21 (1 H, dd, J = 8.7 Hz, 2.5 Hz), 8. 69 (1H, d, J = 2.5 Hz).

Example 318
2,4,6, N-tetramethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H Preparation of -indol-6-yloxy) pyridin-3-yl] benzenesulfonamide 2,4,6-trimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2) -Trifluoroethoxy) benzyl] piperazin-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] benzenesulfonamide (0.38 g, 0.53 mmol) in N, N-dimethylformamide (4 ml) Under ice cooling, 60% sodium hydride (0.025 g, 0.63 mmol) was added to the solution, and after stirring for 10 minutes, methyl iodide (36 μl, 0.58 mmol) was added and stirred for 2 hours. It was. 8 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate → methanol: ethyl acetate = 5: 95) to obtain 0.28 g of the title compound.
Properties: colorless amorphous 1H-NMR (CDCl3) δ ppm:
2.28 (3H, s), 2.51 (10H, s), 3.22 (3H, s), 3.51 (2H, s), 3.78 (7H, s), 4.35 (2H , Q, J = 8.2 Hz), 6.57 (1H, s), 6.85-6.93 (6H, m), 7.10 (1H, d, J = 2.0 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.64 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.85 ( 1H, d, J = 2.6 Hz).

  The following compounds were produced in the same manner as in Reference Example 318 using appropriate starting materials.

Example 319
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -2 -Fluoro-N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 187-190 [deg.] C.

Example 320
N- [6- (2- {4-[(4-methoxyphenyl) methylamino] piperidin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -N-methyl -4-trifluoromethylbenzamide methanesulfonate 1H-NMR (CDCl3) δ ppm:
1.76-1.90 (3H, m), 2.36 (1H, d, J = 11.9 Hz), 2.87 (3H, s), 3.02 (2H, brs), 3.26 ( 3H, s), 3.47 (3H, s), 3.65-3.73 (1H, m), 3.80 (3H, s), 3.85 (3H, s), 4.64 (2H) , Brs), 6.55 (1H, s), 6.81 (1H, d, J = 8.6 Hz), 7.30-7.54 (9H, m), 7.95 (1H, s), 12.74 (1H, brs).

Example 321
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 267-270 ° C.

Example 322
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 233-235 ° C.

Example 323
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-7-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide oxalate melting point: 134-135 ° C.

Example 324
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-7-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 200-201 ° C.

Example 325
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-4-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide oxalate melting point: 139-141 ° C.

Example 326
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-4-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 273-276 ° C.

Example 327
Propane-2-sulfonic acid methyl- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] amide hydrochloride melting point: 256.5-259.8 [deg.] C.

Example 328
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N -Preparation of methyl-4-trifluoromethylbenzamide hydrobromide N-methyl-N- {6- [1-methyl-2- (piperazine-1-carbonyl) -1H-indol-5-yloxy] pyridine- To a solution of 3-yl} -4-trifluoromethylbenzamide (0.22 g, 0.41 mmol) in 1,2-dichloroethane (8 ml) under ice cooling, piperonal (0.13 g, 0.82 mmol) and triacetoxyhydro Sodium borate (0.18 g, 0.82 mmol) and acetic acid (0.05 ml, 0.82 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 60: 1), ethanol and an equimolar amount of hydrobromic acid were added, and the precipitate was collected by filtration. After drying under reduced pressure, 0.18 g of the title compound was obtained.
Property: White powder Melting point: 228-231 ° C.

  The following compounds were produced in the same manner as in Reference Example 328 using appropriate starting materials.

Example 329
N- {6- [2- (4-Benzylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N-methyl-4-trifluoromethylbenzamido bromide Hydronate melting point: 189-201 ° C.

Example 330
N- {6- [2- (4-Benzylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3,4-dichloro-N-methylbenzamido bromide Hydronate melting point: 210-213 ° C.

Example 331
3,4-dichloro-N- (6- {1-methyl-2- [4- (tetrahydropyran-4-yl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) Benzenesulfonamide melting point: 208-210 ° C.

Example 332
N- (6- {1-methyl-2- [4- (tetrahydropyran-4-yl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethyl Benzenesulfonamide melting point: 174-178 ° C.

Example 333
(4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) (5- {5-[(3,4-dichlorophenyl) methylamino] pyridin-2-yloxy} -1-methyl-1H -Indol-2-yl) methanone hydrobromide melting point: 205-214 ° C.

Example 334
(4-Benzylpiperazin-1-yl) (5- {5-[(3,4-dichlorophenyl) methylamino] pyridin-2-yloxy} -1-methyl-1H-indol-2-yl) methanone hydrogen bromide Acid salt melting point: 209-217 ° C.

Example 335
(4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) (1-methyl-5- {5- [methyl (4-trifluoromethylphenyl) amino] pyridin-2-yloxy}- 1H-indol-2-yl) methanone hydrobromide melting point: 211-215 ° C.

Example 336
(4-Benzylpiperazin-1-yl) (1-methyl-5- {5- [methyl (4-trifluoromethylphenyl) amino] pyridin-2-yloxy} -1H-indol-2-yl) methanone bromide Hydronate melting point: 212-218 ° C.

Example 337
(1-Methyl-5- {5- [methyl (4-trifluoromethylphenyl) amino] pyridin-2-yloxy} -1H-indol-2-yl) (4-pyridin-4-ylmethylpiperazine-1- I) Methanone hydrobromide melting point: 167-174 [deg.] C.

Example 338
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate 1H-NMR (DMSO-d6) δ ppm:
3.07 (4H, brs), 3.22-3.55 (2H, m), 3.40 (3H, s), 3.78 (8H, s), 4.12 (2H, brs), 6 .12 (2H, s), 6.68 (1H, s), 6.92 (1H, d, J = 8.5 Hz), 6.92-7.05 (1H, m), 7.01 (2H) , D, J = 8.5 Hz), 7.28 (1H, d, J = 2.1 Hz), 7.37 (2H, d, J = 8.5 Hz), 7.43-7.57 (1H, m), 7.52 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 7.81 (1H, d, J = 8.5 Hz), 7. 92 (1H, brs).

Example 339
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 251-255 ° C. (decomposition).

Example 340
N- (6- {2- [4- (3,4-diethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoro Methylbenzamide hydrobromide melting point: 196-198 ° C.

Example 341
N- (6- {2- [4- (3,4-diethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl- 4-trifluoromethylbenzamide hydrobromide melting point: 215-218 ° C.

Example 342
N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate melting point: 131-135 ° C.

Example 343
N-methyl-N- (6- {1-methyl-2- [4- (4-trifluoromethoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4 -Trifluoromethylbenzamide hydrobromide melting point: 213-216 [deg.] C.

Example 344
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-ethyl-1H-indol-5-yloxy] pyridin-3-yl} -N -Methyl-4-trifluoromethylbenzamide hydrobromide melting point: 179-183 [deg.] C.

Example 345
N- (6- {2- [4- (3,4-dimethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide hydrobromide melting point: 175-177 [deg.] C.

Example 346
N- (6- {2- [4- (6-methoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide maleate melting point: 128-130 ° C.

Example 347
3,4-dichloro-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N -Methylbenzamide maleate melting point: 171-172 [deg.] C.

Example 348
N- (6- {2- [4- (6-methoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide maleate melting point: 135-138 ° C.

Example 349
3,4-Dichloro-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 244-247 ° C (decomposition).

Example 350
N- (6- {2- [4- (3,4-dimethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethyl Benzamide hydrobromide melting point: 233-235 ° C.

Example 351
N- (6- {2- [4- (3-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 217-219 ° C.

Example 352
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Acid salt melting point: 181-183 ° C.

Example 353
N- (6- {2- [4- (3-methoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrohalide melting point: 231-233 ° C.

Example 354
N- (6- {2- [4- (2-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Acid salt melting point: 142-144 ° C.

Example 355
N- (6- {2- [4- (2-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide oxalate melting point: 140-142 ° C.

Example 356
N- [6- (2- {4-[(E) -3- (4-methoxyphenyl) allyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl ] -N-methyl-4-trifluoromethylbenzamide methanesulfonate melting point: 195-197 [deg.] C.

Example 357
N- [6- (2- {4-[(E) -3- (4-methoxyphenyl) allyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl ] -4-Trifluoromethylbenzamide methanesulfonate Melting point: 246-249 ° C (decomposition).

Example 358
N- [6- (2- {4-[(E) -3- (2-methoxyphenyl) allyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl ] -4-Trifluoromethylbenzamide methanesulfonate Melting point: 268-271 ° C (decomposition).

Example 359
N- [6- (2- {4-[(E) -3- (2-methoxyphenyl) allyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl ] -N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 187-190 [deg.] C.

Example 360
3,4-Dichloro-N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) benzamide odor Hydrohalide melting point: 235-238 ° C (decomposition).

Example 361
3,4-dichloro-N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N -Methylbenzamide methanesulfonate melting point: 168-170 ° C.

Example 362
N- {4-Methyl-6- [1-methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dihydrobromide melting point: 228-232 ° C. (decomposition).

Example 363
N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrohalide melting point: 231-234 ° C.

Example 364
3,4-Dichloro-N- (6- {2- [4- (4-ethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -4-methylpyridine-3- Yl) benzamide hydrobromide melting point: 197-199 ° C.

Example 365
N- (6- {2- [4- (4-ethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -4-methylpyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide hydrobromide melting point: 163-166 ° C.

Example 366
3,4-Dichloro-N- (6- {2- [4- (4-ethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -4-methylpyridine-3- Yl) -N-methylbenzamide hydrobromide melting point: 201-204 ° C.

Example 367
N- (6- {2- [4- (4-methoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -2-methylpyridin-3-yl) -4-tri Fluoromethylbenzamide hydrobromide melting point: 206-208 ° C.

Example 368
N- (6- {2- [4- (4-Ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -2-methylpyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide hydrobromide melting point: 188-191 [deg.] C.

Example 369
3,4-Dichloro-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 249-252 ° C (decomposition).

Example 370
3,4-Dichloro-N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazine-1-carbonyl] -1H-indol-5-yloxy} pyridine-3- Yl) benzamide maleate melting point: 163-164 ° C.

Example 371
3,4-Dichloro-N- (6- {2- [4- (4-ethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -2-methylpyridine-3- Yl) benzamide oxalate 1H-NMR (DMSO-d6) δ ppm:
1.31 (3H, t, J = 7.0 Hz), 2.25 (3H, s), 2.66 (4H, brs), 3.69 (2H, s), 3.74 (4H, brs) 3.77 (3H, s), 4.02 (2H, q, J = 7.0 Hz), 6.64 (1H, s), 6.74 (1H, d, J = 8.4 Hz), 6 .90 (2H, d, J = 8.4 Hz), 7.05 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.26 (2H, d, J = 8.4 Hz), 7. 34 (1H, d, J = 2.2 Hz), 7.53 (1H, d, J = 8.9 Hz), 7.70 (1H, d, J = 8.6 Hz), 7.79 (1H, d , J = 8.4 Hz), 7.93 (1H, dd, J = 1.9 Hz, 8.4 Hz), 8.19 (1H, d, J = 1.6 Hz), 10.03 (1H, s) .

Example 372
3,4-Dichloro-N- (6- {2- [4- (4-ethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -2-methylpyridine-3- Yl) -N-methylbenzamide maleate melting point: 131-132 ° C.

Example 373
3,4-Dichloro-N- (6- {2- [4- (3-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) benzamide odor Hydrohalide melting point: 225-227 ° C.

Example 374
3,4-dichloro-N- (6- {2- [4- (3-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N -Methylbenzamide maleate melting point: 99-100 ° C.

Example 375
3,4-dichloro-N- (6- {2- [4- (4-methoxymethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) benzamide Hydrobromide melting point: 244-249 ° C. (decomposition).

Example 376
3,4-dichloro-N- (6- {2- [4- (4-methoxymethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl)- N-methylbenzamide maleate melting point: 100-101 ° C.

Example 377
N- {2-methyl-6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dioxalate 1H-NMR (CDCl3) δ ppm:
2.26 (3H, s), 2.77 (4H, brs), 3.77 (4H, brs), 3.79 (3H, s), 3.93 (2H, s), 6.68 (1H) , S), 6.76 (1H, d, J = 8.6 Hz), 7.07 (1H, dd, J = 2.4 Hz, 8.9 Hz), 7.32-7.36 (2H, m) , 7.50 (1H, d, J = 7.6 Hz), 7.57 (1H, d, J = 9.2 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.83 ( 1H, dt, J = 1.9 Hz, 7.6 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.17 (2H, d, J = 8.1 Hz), 8.56 (1H , Dd, J = 0.8 Hz, 4.9 Hz), 10.22 (1H, s).

Example 378
3,4-Dichloro-N- (6- {2- [4- (5-ethoxypyridin-2-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) benzamide dihydrobromide melting point: 218-220 ° C.

Example 379
3,4-Dichloro-N- (6- {2- [4- (5-ethoxypyridin-2-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) -N-methylbenzamide maleate melting point: 98-99 ° C.

Example 380
N- (2- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide melting point : 179-180 ° C.

Example 381
N- (2- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyrimidin-5-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate melting point: 160-161 ° C.

Example 382
N- {2- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyrimidin-5-yl} -4-trifluoromethylbenzamide melting point 181-182 ° C.

Example 383
N- (2- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyrimidin-5-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate melting point: 154-156 ° C.

Example 384
3,4-Dichloro-N- (2- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyrimidin-5-yl) benzamide melting point 156-157 ° C.

Example 385
3,4-Dichloro-N- {2- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyrimidin-5-yl} benzamide melting point : 161-163 ° C.

Example 386
3,4-Dichloro-N- (6- {2- [4- (5-cyanopyridin-2-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) benzamide dihydrobromide melting point: 216-219 ° C.

Example 387
N- (6- {2- [4- (5-methoxypyridin-2-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide maleate melting point: 143-144 ° C.

Example 388
3,4-Dichloro-N- (6- {2- [4- (5-methoxypyridin-2-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) benzamide dihydrobromide melting point: 223-225 ° C.

Example 389
3,4-Dichloro-N- (6- {2- [4- (5-methoxypyridin-2-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3- Yl) -N-methylbenzamide maleate melting point: 155-156 ° C.

Example 390
N- (6- {2- [4- (4-ethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrohalide melting point: 239-241 ° C.

Example 391
N- (6- {2- [4- (4-Ethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide oxalate melting point: 167-169 ° C.

Example 392
N- {6- [1-methyl-2-((R) -2-methyl-4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide dioxalate melting point: 128-130 ° C.

Example 393
N- (6- {2-[(R) -4- (4-methoxybenzyl) -2-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide oxalate melting point: 161-163 ° C.

Example 394
N- (6- {2-[(R) -4- (4-methoxybenzyl) -2-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-trifluoromethylbenzamide oxalate melting point: 126-130 ° C.

Example 395
N-methyl-N- {6- [1-methyl-2-((R) -2-methyl-4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridine- 3-yl} -4-trifluoromethylbenzamide dioxalate 1H-NMR (DMSO-d6) δ ppm:
1.35 (3H, d, J = 6.8 Hz), 2.26-2.44 (2H, m), 2.79 (1H, d, J = 11.1 Hz), 2.96 (1H, d , J = 11.1 Hz), 3.36 (4H, s), 3.68-3.84 (5H, m), 4.09 (1H, brs), 4.50 (1H, brs), 6. 57 (1H, s), 6.91 (1H, d, J = 8.4 Hz), 6.93 (1H, d, J = 2.2 Hz, 8.9 Hz), 7.24 (1H, d, J = 1.9 Hz), 7.31 (1H, dd, J = 4.9 Hz, 6.2 Hz), 7.49 (2H, d, J = 3.8 Hz), 7.52 (2H, d, J = 2.4 Hz), 7.67 (2H, d, J = 7.6 Hz), 7.77-7.85 (2H, m), 7.91 (1H, s), 8.52 (1H, dd, J = 1.1 Hz, 4. Hz).

Example 396
N- (6- {2-[(S) -4- (4-methoxybenzyl) -2-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide oxalate melting point: 159-160 ° C.

Example 397
N- {6- [1-methyl-2-((S) -2-methyl-4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide dioxalate melting point: 126-127 ° C.

Example 398
N- (6- {2-[(S) -4- (4-methoxybenzyl) -2-methylpiperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-trifluoromethylbenzamide oxalate melting point: 134-136 ° C.

Example 399
N-methyl-N- {6- [1-methyl-2-((S) -2-methyl-4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridine- 3-yl} -4-trifluoromethylbenzamide dioxalate 1H-NMR (DMSO-d6) δ ppm:
1.35 (3H, d, J = 6.8 Hz), 2.22-2.30 (1 H, m), 2.38 (1 H, d, J = 8.9 Hz), 2.77 (1 H, d , J = 11.3 Hz), 2.94 (1H, d, J = 11.3 Hz), 3.36 (4H, s), 3.66-3.81 (5H, m), 4.07 (1H , Brs), 4.49 (1H, brs), 6.57 (1H, s), 6.92 (1H, d, J = 8.9 Hz), 6.93 (1H, dd, J = 2.2 Hz) , 8.6 Hz), 7.24 (1H, d, J = 2.2 Hz), 7.30 (1H, ddd, J = 1.1 Hz, 5.1 Hz, 7.6 Hz), 7.49-7. 52 (3H, m), 7.67 (2H, d, J = 7.8 Hz), 7.77-7.85 (3H, m), 7.91 (1H, s), 8.52 (1H, dd, J = 0.8 z, 4.9Hz).

Example 400
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide melting point: 229-231 ° C.

Example 401
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide maleate melting point: 146-147 ° C.

Example 402
N- [6- (1-methyl-2- {4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine- 3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 255-257 ° C.

Example 403
N-methyl-N- [6- (1-methyl-2- {4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-5 Iroxy) pyridin-3-yl] -4-trifluoromethylbenzamide maleate melting point: 137-139 ° C.

Example 404
N- {4-methyl-6- [1-methyl-2- (4-pyridin-3-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dihydrobromide melting point: 215-217 ° C.

Example 405
N- {4-methyl-6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dioxalate 1H-NMR (DMSO-d6) δ ppm:
2.24 (3H, s), 2.74 (4H, brs), 3.75 (4H, brs), 3.78 (3H, s), 3.90 (2H, s), 6.66 (1H) , S), 6.91 (1H, s), 7.05 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.31-7.35 (1H, m), 7.49 (1H) , D, J = 8.6 Hz), 7.56 (1H, d, J = 8.9 Hz), 7.82 (1H, dt, J = 1.9 Hz, 7.6 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.01 (1H, s), 8.17 (2H, d, J = 8.1 Hz), 8.55 (1H, d, J = 4.1 Hz), 10. 20 (1H, s).

Example 406
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl]- N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 196-200 ° C.

Example 407
3,4-Dichloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridine -3-yl] benzamide hydrobromide melting point: 241-245 ° C.

Example 408
N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -N- Methyl-4-trifluoromethylbenzamide maleate melting point: 152-154 ° C.

Example 409
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridine-3 -Yl] benzamide hydrobromide melting point: 240-243 [deg.] C.

Example 410
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide maleate melting point: 140-142 ° C.

Example 411
N-methyl-N- (6- {1-methyl-2- [4- (4-propylbenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide maleate melting point: 132-134 ° C.

Example 412
N- (6- {2- [4- (4-Isopropylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate melting point: 129-131 ° C.

Example 413
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide maleate melting point: 144-147 ° C.

Example 414
N-methyl-N- (6- {1-methyl-2- [4- (4-octyloxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide maleate melting point: 125-126 ° C.

Example 415
N- (6- {2- [4- (4-methoxymethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide maleate melting point: 137-139 ° C.

Example 416
N- (6- {2- [4- (4-isobutylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate melting point: 147-149 ° C.

Example 417
N- (6- {2- [4- (5-ethoxypyridin-2-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide maleate melting point: 129-130 ° C.

Example 418
N- (6- {2- [4- (3-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 234-236 ° C.

Example 419
N- (6- {2- [4- (4-Ethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 241-243 ° C.

Example 420
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide hydrobromide melting point: 246-248 ° C.

Example 421
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide hydrobromide melting point: 251-253 ° C.

Example 422
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide hydrobromide melting point: 229-230 ° C.

Example 423
N- (6- {2- [4- (6-Ethoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide maleate melting point: 149-151 ° C.

Example 424
N- (6- {2- [4- (6-Isopropoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide maleate melting point: 157-159 ° C.

Example 425
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide hydrobromide melting point: 249-252 [deg.] C.

Example 426
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide melting point: 184-186 [deg.] C.

Example 427
N- (6- {2- [4- (4-Ethoxybenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide hydrobromide melting point: 224-226 [deg.] C.

Example 428
N- (6- {2- [4- (4-Isopropylbenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide hydrobromide melting point: 225-229 [deg.] C.

Example 429
N- (6- {2- [4- (4-Isopropylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 255-258 ° C.

Example 430
N- (6- {2- [4- (4-isobutylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 262-265 ° C.

Example 431
N-methyl-N- (6- {1-methyl-2- [4- (4-propylbenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide hydrobromide melting point: 255-257 ° C.

Example 432
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide dihydrobromide melting point: 211-212 ° C.

Example 433
N- (6- {2- [4- (4-methoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -4-methylpyridin-3-yl) -4-tri Fluoromethylbenzamide oxalate melting point: 144-147 ° C.

Example 434
N- (6- {1,4-dimethyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide hydrobromide melting point: 204-208 ° C.

Example 435
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl- 4-trifluoromethylbenzamide hydrobromide melting point: 224-226 ° C.

Example 436
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 225.0-226.4 ° C.

Example 437
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 218.4-219.9 ° C.

Example 438
N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl] -N- Methyl-4-trifluoromethylbenzamide hydrobromide melting point: 215.3-216.6 ° C.

Example 439
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine- 3-yl) -N-methyl-4-trifluoromethylbenzamide oxalate melting point: 155.7-156.9 ° C.

Example 440
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine- 3-yl) -N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 243.3-245.1 ° C.

Example 441
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} Pyridin-3-yl) -N-methyl-4-trifluoromethylbenzamide melting point: 97.9-99.5 ° C.

Example 442
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl- 4-trifluoromethylbenzamide melting point: 150.5-151.4 ° C.

Example 443
N-methyl-N- [6- (1-methyl-2- {4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 245.4-247.6 [deg.] C.

Example 444
N- (6- {2- [4- (6-Isopropoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide maleate melting point: 156.8-157.4 ° C.

Example 445
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 230.8-231.4 ° C.

Example 446
N-methyl-N- (6- {1-methyl-2- [4- (4-trifluoromethoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4 -Trifluoromethylbenzamide hydrobromide melting point: 237-239 [deg.] C.

Example 447
2-Chloro-N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl ] -N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 223.6-225.4 [deg.] C.

Example 448
2-Chloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3 -Yl] -N-methyl-4-trifluoromethylbenzamide hydrobromide melting point: 232.4-232.8 <0> C.

Example 449
2-Chloro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 239.5-240.6 <0> C.

Example 450
2-Chloro-N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide hydrobromide melting point: 238.6-240.1 ° C.

Example 451
2-chloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide hydrobromide melting point: 248.3-252.3 ° C.

Example 452
2-Chloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide hydrobromide melting point: 238.6-243.9 ° C.

Example 453
N- (6- {2- [4- (6-Isopropoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide hydrobromide melting point: 251.3-254.8 ° C.

Example 454
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-6-yloxy] pyridin-3-yl} -4 -Trifluoromethylbenzamide hydrobromide melting point: 264.0-265.6 [deg.] C.

Example 455
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine- 3-yl) -4-trifluoromethylbenzamide hydrobromide melting point: 273.6-275.9 ° C.

Example 456
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethoxybenzamide hydrobromide melting point: 227.4-229.2 ° C.

Example 457
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- N-methyl-4-trifluoromethoxybenzamide hydrobromide melting point: 222.8-226.8 [deg.] C.

Example 458
N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl] -N- Methyl-4-trifluoromethoxybenzamide hydrobromide melting point: 220.8-221.6 ° C.

Example 459
N- (6- {2- [4- (4-hydroxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrochloride melting point: 241.4-242.7 ° C.

Example 460
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide melting point: 236.8-243.8 ° C.

Example 461
N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -4- Trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.18-3.45 (4H, m), 3.82 (3H, s), 3.91 (4H, brs), 4.23 (1H, d, J = 4.0 Hz), 4.33 ( 1H, t, J = 4.0 Hz), 4.46 (2H, brs), 4.67 (1H, t, J = 3.8 Hz), 4.84 (1H, t, J = 3.8 Hz), 6.76 (1H, s), 7.04 (2H, d, J = 8.9 Hz), 7.08 (1H, dd, J = 8.6 Hz, 2.2 Hz), 7.10 (1H, s) ), 7.37 (1H, d, J = 2.1 Hz), 7.47 (2H, d, J = 8.7 Hz), 7.59 (1H, d, J = 8.9 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.16 (2H, d, J = 8.4 Hz), 8.18 (1H, dd, J = 8.6 Hz, 2.7 Hz), 8.47 ( 1H, d, J = 2.6H ), 9.85 (1H, brs), 10.59 (1H, s).

Example 462
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl]- 4-Trifluoromethylbenzamide hydrobromide melting point: 229.1-230.8 [deg.] C.

Example 463
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide hydrobromide Melting point: 236.8-237.5 ° C.

Example 464
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3 -Yl] benzamide hydrobromide melting point: 232.4-234.2 <0> C.

Example 465
3,4-Dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzamide hydrobromide melting point: 251.8-253.5 [deg.] C.

Example 466
3,4-dichloro-N- (6- {2- [4- (6-isopropoxypyridin-3-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine-3 -Yl) benzamide hydrobromide melting point: 236.9-240.4 [deg.] C.

Example 467
3,4-dichloro-N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indole- 6-yloxy} pyridin-3-yl) benzamide hydrobromide melting point: 253.0-254.8 ° C.

Example 468
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide hydrobromide Melting point: 262.9-264.7 ° C.

Example 469
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.19 (4H, brs), 3.82 (3H, s), 4.35-4.47 (4H, s), 4.56-4.69 (2H, m), 4.73-4. 86 (2H, m), 4.94-5.09 (1H, m), 6.76 (1H, s), 7.02 (1H, d, J = 8.1 Hz), 7.08 (1H, dd, J = 8.1 Hz, 2.7 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.37 (1H, d, J = 2.7 Hz), 7.46 (2H, d , J = 8.1 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.93 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8. 1 Hz), 8.18 (1 H, dd, J = 8.1 Hz, 2.7 Hz), 8.47 (1 H, d, J = 2.7 Hz), 9.81 (1 H, s), 10.58 ( 1H, s).

Example 470
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indole-6 Yloxy) pyridin-3-yl] benzamide hydrobromide melting point: 242.8-243.9 [deg.] C.

Example 471
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethoxybenzamide hydrobromide melting point: 240-242 ° C.

Example 472
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethoxybenzamide hydrobromide melting point: 237.2-238.5 ° C.

Example 473
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethoxybenzamide hydrobromide melting point: 226-229 ° C.

Example 474
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide hydrobromide Melting point: 269.0-270.3 ° C.

Example 475
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrochloride melting point: 254.0-255.7 ° C.

Example 476
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide melting point: 258.7-259.6 ° C.

Example 477
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide melting point: 265.6-268.3 ° C.

Example 478
N- (6- {1-methyl-2- [4- (4-propylbenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrochloride melting point: 267.0-268.2 ° C.

Example 479
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 4-trifluoromethylbenzamide hydrobromide melting point: 260.7-261.2 ° C.

Example 480
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine- 3-yl) -4-trifluoromethylbenzamide hydrobromide melting point: 246.6-248.1 [deg.] C.

Example 481
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrochloride melting point: 234.7-235.1 ° C.

Example 482
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3 -Yl] -N-methylbenzamide hydrobromide melting point: 186.9-188.8 [deg.] C.

Example 483
3,4-Dichloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine -3-yl] -N-methylbenzamide hydrobromide melting point: 182.4-184.6 ° C.

Example 484
3,4-Dichloro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-6-yloxy) pyridin-3-yl] benzamide hydrobromide melting point: 197.1-201.5 <0> C.

Example 485
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indole-6 Yloxy) pyridin-3-yl] -N-methylbenzamide hydrobromide melting point: 188.2-191.8 [deg.] C.

Example 486
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl)- N-methylbenzamide hydrobromide melting point: 220.2-223.5 ° C.

Example 487
3,4-Dichloro-N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridine-3- Yl) benzamide hydrobromide melting point: 204.9-208.5 [deg.] C.

Example 488
3,4-dichloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl)- N-methylbenzamide hydrobromide melting point: 185.6-189.3 [deg.] C.

Example 489
3,4-dichloro-N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indole- 6-yloxy} pyridin-3-yl) -N-methylbenzamide hydrobromide melting point: 225.4-227.1 [deg.] C.

Example 490
N- {6- [2- (4-Isobutylpiperazine-1-carbonyl) -1-methyl-1H-indol-6-yloxy] pyridin-3-yl} -N-methyl-4-trifluoromethylbenzamide hydrochloride Melting point: 253.1-254.5 ° C.

Example 491
N- {6- [2- (4-Isobutylpiperazine-1-carbonyl) -1-methyl-1H-indol-6-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide hydrochloride melting point: 270. 2-272.2 ° C.

Example 492
2-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride melting point: 217.4-218.3 ° C.

Example 493
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -2-methyl-4-trifluoromethylbenzamide hydrochloride Melting point: 192.5-195.4 ° C.

Example 494
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2-methyl-4- Trifluoromethylbenzamide hydrochloride melting point: 197.7-199.3 ° C.

Example 495
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine- 3-yl) -2-methyl-4-trifluoromethylbenzamide hydrochloride melting point: 207.9-211.5 [deg.] C.

Example 496
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2-methyl-4- Trifluoromethylbenzamide hydrochloride melting point: 204.9-205.7 ° C.

Example 497
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 2-methyl-4-trifluoromethylbenzamide hydrochloride melting point: 203.9-206.3 [deg.] C.

Example 498
N- (6- {2- [4- (4-hydroxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrochloride melting point: 227.1-229.4 ° C.

Example 499
3,4-Dichloro-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-6 Yloxy) pyridin-3-yl] benzenesulfonamide 1H-NMR (CDCl 3) δ ppm:
2.48 (4H, brs), 3.51 (2H, s), 3.76 (7H, s), 4.35 (2H, q, J = 8.1 Hz), 6.56 (1H, d, J = 0.7 Hz), 6.84-6.90 (4 H, m), 6.92-6.93 (1 H, m), 7.08 (1 H, d, J = 2.0 Hz), 7. 26-7.30 (2H, m), 7.50-7.60 (4H, m), 7.73 (1H, d, J = 2.6 Hz), 7.82 (1H, t, J = 1) .2 Hz).

Example 500
3,4-Dichloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine -3-yl] benzenesulfonamide 1H-NMR (CDCl3) δ ppm:
2.41 (4H, brs), 3.43 (2H, s), 3.68 (7H, s), 4.11 (2H, td, J = 13.0 Hz, 4.2 Hz), 6.01 ( 1H, tt, J = 55.2 Hz, 4.1 Hz), 6.49 (1H, s), 6.76-6.83 (4H, m), 7.01 (1H, d, J = 1.6 Hz) ), 7.18-7.21 (3H, m), 7.43-7.52 (4H, m), 7.66 (1H, d, J = 2.6 Hz), 7.75 (1H, s) ).

Example 501
3,4-Dichloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) benzene Sulfonamide 1H-NMR (CDCl3) δ ppm:
2.49 (4H, brs), 3.53 (2H, s), 3.74-3.79 (7H, m), 6.51 (1H, t, J = 74.0 Hz), 6.56 ( 1H, d, J = 1.0 Hz), 6.78-6.89 (3H, m), 7.09 (3H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8) .6 Hz), 7.47-7.60 (4 H, m), 7.73-7.74 (1 H, m), 7.82 (1 H, d, J = 1.3 Hz).

Example 502
3,4-Dichloro-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) benzenesulfone Amide 1H-NMR (CDCl 3) δ ppm:
1.04 (3H, t, J = 7.4 Hz), 1.81 (2H, td, J = 14.1 Hz, 7.1 Hz), 2.48 (4H, brs), 3.49 (2H, s) ), 3.75 (7H, s), 3.92 (2H, t, J = 6.6 Hz), 6.56 (1H, s), 6.85-6.89 (4H, m), 7. 08 (1H, d, J = 1.6 Hz), 7.21-7.26 (3H, m), 7.50-7.60 (4H, m), 7.73 (1H, d, J = 2) .6 Hz), 7.82 (1 H, s).

Example 503
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 2-Fluoro-N-methyl-4-trifluoromethylbenzamide hydrochloride melting point: 226.4-228.6 [deg.] C.

Example 504
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2-fluoro-N- Methyl-4-trifluoromethylbenzamide hydrochloride melting point: 228.7-230.4 [deg.] C.

Example 505
2-Fluoro-N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide hydrochloride melting point: 247.1-249.2 <0> C.

Example 506
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indole-6 Yloxy) pyridin-3-yl] -N-methylbenzenesulfonamide melting point: 157.7-160.2 [deg.] C.

Example 507
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl)- N-methylbenzenesulfonamide melting point: 186.8-187 ° C.

Example 508
3,4-dichloro-N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indole- 6-yloxy} pyridin-3-yl) -N-methylbenzenesulfonamide melting point: 149.9-151.3 ° C.

Example 509
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzenesulfonamide 1H-NMR (CDCl 3) δ ppm:
2.48 (4H, brs), 3.51 (2H, s), 3.76-3.79 (7H, m), 4.35 (2H, q, J = 8.1 Hz), 6.56 ( 1H, s), 6.85-6.96 (5H, m), 7.09 (1H, d, J = 1.6 Hz), 7.27-7.30 (2H, m), 7.54- 7.60 (2H, m), 7.70-7.73 (3H, m), 7.85 (2H, d, J = 8.2 Hz).

Example 510
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzene Sulfonamide 1H-NMR (CDCl3) δ ppm:
2.51 (4H, brs), 3.55 (2H, s), 3.74-3.79 (7H, m), 6.51 (1H, t, J = 73.7 Hz), 6.56 ( 1H, s), 6.82-6.88 (2H, m), 7.09 (4H, d, J = 8.6 Hz), 7.34 (2H, d, J = 5.9 Hz), 7. 52-7.59 (2H, m), 7.67-7.74 (3H, m), 7.84 (2H, d, J = 8.2 Hz).

Example 511
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzenesulfone Amide hydrobromide melting point: 223.7-224.8 ° C.

Example 512
3,4-Dichloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine -3-yl] -N-methylbenzenesulfonamide melting point: 168.4-168.6 ° C.

Example 513
3,4-Dichloro-N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3 -Yl] -N-methylbenzenesulfonamide melting point: 195.2-196.8 [deg.] C.

Example 514
3,4-dichloro-N- (6- {2- [4- (4-cyclopropylmethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methylbenzenesulfonamide melting point: 194.1-195.8C.

Example 515
3,4-dichloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl)- N-methylbenzenesulfonamide melting point: 143.4-147.2 [deg.] C.

Example 516
3,4-Dichloro-N-methyl-N- [6- (1-methyl-2- {4- [4- (3-methylbutoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy ) Pyridin-3-yl] benzenesulfonamide melting point: 145.9-147.1 [deg.] C.

Example 517
3,4-dichloro-N- (6- {2- [4- (6-isopropoxypyridin-3-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine-3 -Yl) -N-methylbenzenesulfonamide melting point: 179.1-179.7 [deg.] C.

Example 518
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-6-yloxy] pyridin-3-yl} -4 , N-dimethylbenzenesulfonamide hydrochloride Melting point: 242-249 ° C.

Example 519
N-methyl-N- [2- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyrimidin-5-yl] -4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.16 (2H, brs), 3.39 (3H, s), 3.35-3.45 (4H, m), 3.64 (2H, brs), 3.73 (3H, s), 4 .34-4.44 (2H, m), 4.82 (2H, q, J = 8.9 Hz), 6.80 (1H, s), 6.84 (1H, d, J = 8.6 Hz) 7.17 (2H, d, J = 8.6 Hz), 7.38 (1H, s), 7.52-7.63 (5H, m), 7.72-7.74 (2H, m) , 8.58 (2H, brs), 10.56 (1H, brs).

Example 520
N- [2- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyrimidine-5 Yl] -N-methyl-4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.16 (2H, brs), 3.39 (3H, s), 3.35-3.46 (4H, m), 3.64 (2H, brs), 3.73 (3H, s), 4 .32-4.44 (2H, s), 4.56-4.69 (2H, m), 4.73-4.85 (2H, m), 4.95-5.09 (1H, m) 6.80 (1H, s), 6.86 (1 H, d, J = 7.0 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.38 (1H, s), 7 .50-7.60 (5H, m), 7.72 (2H, brs), 8.58 (2H, brs), 10.55 (1H, brs).

Example 521
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -N-methyl-4- Trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
1.26 (3H, s), 1.28 (3H, s), 3.14 (2H, brs), 3.39 (3H, s), 3.35-3.49 (4H, m), 3 .60-3.64 (2H, m), 3.72 (3H, s), 4.29-4.43 (2H, m), 4.62-4.70 (1H, m), 6.79 (1H, s), 6.85 (1H, d, J = 7.6 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.20 (1H, brs), 7.37 (1H , S), 7.48 (2H, d, J = 7.6 Hz), 7.57-7.63 (3H, m), 7.72-7.81 (2H, m), 8.58 (2H) , Brs), 10.80 (1H, brs).

Example 522
N- [2- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyrimidin-5-yl]- N-methyl-4-trifluoromethylbenzamide hydrochloride 1H-NMR (DMSO-d6) δ ppm:
3.17 (2H, brs), 3.39 (3H, s), 3.36-3.47 (4H, m), 3.60-3.69 (2H, m), 3.73 (3H, s), 4.18-4.67 (4H, m), 6.40 (1H, t, J = 57.0 Hz), 6.80 (1H, s), 6.82-6.98 (1H, m), 6.97 (1H, d, J = 7.3 Hz), 7.12 (1H, d, J = 7.8 Hz), 7.26 (1H, d, J = 6.8 Hz), 7. 35-7.38 (1H, m), 7.51 (1H, d, J = 8.6 Hz), 7.57-7.63 (3H, m), 7.72-7.74 (2H, m ), 8.58 (2H, s), 10.40 (1H, s).

Example 523
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -4, N-dimethylbenzenesulfonamide Melting point: 116.5-116.6 ° C.

Example 524
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 4, N-dimethylbenzenesulfonamide melting point: 121.9-122.5 ° C.

Example 525
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzene Sulfonamide melting point: 140.9-145.8 ° C.

Example 526
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine- 3-yl) -4, N-dimethylbenzenesulfonamide hydrochloride melting point: 240-243 [deg.] C.

Example 527
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzenesulfonamide Melting point: 191.8-194.4 ° C.

Example 528
3,4-Dichloro-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H- Indol-5-yloxy) pyridin-3-yl] benzenesulfonamide melting point: 174.8-175.8 [deg.] C.

Example 529
4, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-5 Yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride melting point: 239.1-239.8 [deg.] C.

Example 530
N- (6- {2- [4- (4-cyclopropylmethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethyl Benzenesulfonamide melting point: 135.6-138.6 ° C.

Example 531
N- [6- (2- {4- [4- (2-fluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl] -4, N-dimethylbenzenesulfonamide melting point: 138.7-139.8 ° C.

Example 532
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzene Sulfonamide hydrobromide melting point: 214.5-218.5 ° C. (decomposition).

Example 533
4, N-dimethyl-N- [6- (1-methyl-2- {4- [4- (3-methylbutoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3 -Yl] benzenesulfonamide hydrobromide melting point: 236.5-238.3 [deg.] C (decomposition).

Example 534
N- (6- {2- [4- (6-Isopropoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzenesulfonamide melting point: 131.1-132.8 ° C.

Example 535
2-chloro-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
1.03 (3H, t, J = 8.6 Hz), 1.73-1.86 (2H, m), 2.44 (4H, s), 3.47 (2H, s), 3.68 ( 7H, s), 3.91 (2H, t, J = 6.5 Hz), 6.49 (1H, s), 6.83-6.90 (4H, m), 7.06 (1H, d, J = 1.6 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.58 (3H, dd, J = 14.0 Hz) , 8.4 Hz), 8.09 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.6 Hz), 9.09 (1H, s).

Example 536
2-Chloro-N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide hydrochloride melting point: 235.5-236.1 ° C.

Example 537
2-chloro-N- [6- (2- {4- [4- (2-fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide melting point: 239.8-240.8 ° C.

Example 538
2-Chloro-N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3 -Yl] -4-trifluoromethylbenzamide hydrochloride melting point: 232.5-233.5 [deg.] C.

Example 539
2-Fluoro-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide hydrochloride melting point: 264.0-266.3 ° C.

Example 540
2-Fluoro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide hydrochloride melting point: 267.6-268.2 ° C.

Example 541
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2-fluoro-4- Trifluoromethylbenzamide hydrochloride melting point: 265.3-265.8 ° C.

Example 542
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 2-Fluoro-4-trifluoromethylbenzamide hydrochloride melting point: 272.3-275.0 ° C.

Example 543
2-Fluoro-N- [6- (2- {4- [4- (2-fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrochloride melting point: 267.3-267.7 ° C.

Example 544
2-methyl-N- [2- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyrimidin-5-yl] -4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
2.48 (3H, s), 3.12-3.44 (6H, m), 3.76 (3H, s), 4.37 (2H, s), 4.46-4.51 (2H, m), 4.82 (2H, q, J = 8.8 Hz), 6.82 (1H, s), 6.96 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.18 ( 2H, d, J = 8.6 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.72-7.74 (3H, m), 8.91 (2H, s), 9.95 (1H, brs), 10.77 (1H, s).

Example 545
N- [2- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyrimidine-5 Yl] -2-methyl-4-trifluoromethylbenzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
2.47 (3H, s), 3.18-3.45 (6H, m), 3.76 (3H, s), 4.35 (2H, s), 4.45-4.50 (2H, m), 4.56-5.11 (5H, m), 6.82 (1H, s), 6.96 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.48 (2H, d, J = 8.7 Hz), 7.66 (1H, d, J = 8) .6 Hz), 7.72-7.75 (3H, m), 8.91 (2H, s), 9.89 (1H, brs), 10.77 (1H, s).

Example 546
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -2-methyl-4- Trifluoromethylbenzamide 1H-NMR (CDCl 3) δ ppm:
1.32 (3H, s), 1.35 (3H, s), 2.47 (4H, brs), 2.53 (3H, s), 3.48 (2H, brs), 3.75 (4H) , Brs), 3.76 (3H, s), 4.47-4.60 (1H, m), 6.56 (1H, s), 6.85 (2H, dt, J = 9.3 Hz, 2 .5 Hz), 6.97 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.18 (1H, d, J = 2.0 Hz), 7.21 (2H, d, J = 8. 6 Hz), 7.51-7.64 (4H, m), 7.77 (1H, s), 8.86 (2H, s).

Example 547
Preparation of N- {6- [2- (4-Isobutylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide N- {6 A solution of [1-methyl-2- (piperazine-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide (250 mg, 0.478 mmol) in acetonitrile (2 ml) To the mixture, 1-bromo-2-methylpropane (0.123 ml, 1.13 mmol), diisopropylethylamine (0.25 ml, 1.44 mmol) and sodium iodide (180 mg, 1.2 mmol) were added, and the mixture was heated to reflux for 14 hours. The reaction solution was distilled off, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane: methanol = 40: 1). Ethanol (2 ml) was added to the obtained purified product, and the precipitate was collected by filtration to obtain 100 mg of the title compound.
Property: White powder.
Melting point: 200-202 ° C.

  The following compounds were prepared in the same manner as in Example 547 using appropriate starting materials.

Example 548
N-methyl-N- {6- [1-methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dihydrobromide melting point: 196-198 ° C.

Example 549
N- (6- {2- [4- (4-fluorobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide melting point: 218-220 ° C.

Example 550
N- {6- [1-Methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide Hydrobromide melting point: 211-215 ° C. (decomposition).

Example 551
N- (6- {2- [4- (4-fluorobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrochloride melting point: 254-257 ° C.

Example 552
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide malein Acid salt melting point: 149-152 ° C.

Example 553
N-methyl-N- (6- {1-methyl-2- [4- (4-trifluoromethylbenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4 -Trifluoromethylbenzamide hydrobromide melting point: 254-260 ° C (decomposition).

Example 554
3,4-Dichloro-N-methyl-N- {6- [1-methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridine-3- Il} benzamide dihydrobromide melting point: 204-208 ° C. (decomposition).

Example 555
3,4-Dichloro-N- {6- [1-methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide Hydrobromide melting point: 214-219 ° C. (decomposition).

Example 556
3,4-Dichloro-N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) benzamide odor Hydrochloride melting point: 267-272 ° C (decomposition).

Example 557
3,4-dichloro-N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N -Methylbenzamide hydrobromide melting point: 238-240 ° C.

Example 558
N- {6- [1-methyl-2- (4-pyridin-3-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide Hydrobromide melting point: 201-204 ° C.

Example 559
N-methyl-N- {6- [1-methyl-2- (4-pyridin-3-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dihydrobromide melting point: 191-193 ° C.

Example 560
N- {6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide Methanesulfonate melting point: 137-139 ° C.

Example 561
N-methyl-N- {6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dioxalate melting point: 114-117 ° C.

Example 562
N- {6- [2- (4-Isobutylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N-methyl-4-trifluoromethylbenzamide melting point: 163-164 ° C.

Example 563
3,4-dichloro-N- {6- [1-methyl-2- (4-pyridin-3-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide Hydrobromide melting point: 249-252 ° C. (decomposition).

Example 564
3,4-Dichloro-N- {6- [1-methyl-2- (4-pyridin-2-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} benzamide Hydrobromide melting point: 231-233 ° C. (decomposition).

Example 565
N- {2-methyl-6- [1-methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-tri Fluoromethylbenzamide dihydrobromide melting point: 223-225 ° C (decomposition).

Example 566
N-methyl-N- {2-methyl-6- [1-methyl-2- (4-pyridin-4-ylmethylpiperazin-1-carbonyl) -1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide dioxalate melting point: 117-120 ° C.

Example 567
3,4-Dichloro-N- {6- [2- (4-isobutylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} benzamide hydrobromide melting point : 251-254 ° C.

Example 568
N-methyl-N- (6- {1-methyl-2- [4- (5-methylisoxazol-3-ylmethyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl ) -4-Trifluoromethylbenzamide maleate Melting point: 112-115 ° C.

Example 569
N- (6- {1-methyl-2- [4- (5-methylisoxazol-3-ylmethyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide hydrobromide melting point: 220-223 ° C.

Example 570
N- (6- {2- [4- (5-cyanopyridin-2-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide dihydrobromide melting point: 211-215 [deg.] C.

Example 571
N- (6- {1-methyl-2- [4- (4- [1,2,3] thiadiazol-4-ylbenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridine-3- Yl) -4-trifluoromethylbenzamide melting point: 220.0-220.8 ° C.

Example 572
N- [6- (1-methyl-2- {4- [2- (4-trifluoromethylphenyl) thiazol-5-ylmethyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine-3 -Yl] -4-trifluoromethylbenzamide hydrobromide melting point: 218.9-220.8 [deg.] C.

Example 573
3,4-Dichloro-N-methyl-N- (6- {1-methyl-2- [4- (4- [1,2,3] thiadiazol-4-ylbenzyl) piperazine-1-carbonyl] -1H- Indol-6-yloxy} pyridin-3-yl) benzamide hydrobromide 1H-NMR (DMSO-d6) δ ppm:
3.27 (2H, s), 3.35 (3H, s), 3.45 (2H, s), 3.62 (4H, s), 3.74 (3H, s), 4.49 (2H) , S), 6.81 (1H, s), 6.82 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.22 −7.25 (1H, m), 7.29 (1H, d, J = 1.4 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.62 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.85 (1H, dd, J = 8.6 Hz, 2.7 Hz), 7.96 (1H, brs), 8. 28 (1H, d, J = 8.4 Hz), 9.73 (1H, s), 10.06 (1H, s).

Example 574
Preparation of N- {6- [2- (4-benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4,5-dichlorophthalamic acid [5 -(5-Aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] (4-benzylpiperazin-1-yl) methanone (1 g, 2.26 mmol) of 1,2-dichloroethane (22 ml) ) 4,5-dichlorophthalic anhydride (0.57 g, 2.62 mmol) was added to the solution and stirred at room temperature for 4 hours. The precipitated white precipitate was collected by filtration to obtain 1.5 g of the title compound.
Properties: White powder 1H-NMR (DMSO-d6) δ ppm:
2.59 (4H, brs), 3.68 (4H, brs), 3.77 (3H, s), 3.90 (2H, s), 6.63 (1H, s), 6.98 (1H) , D, J = 8.7 Hz), 7.03 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.25-7.45 (6H, m), 7.54 (1H, d, J = 8.7 Hz), 7.94 (1H, s), 8.05 (1H, s), 8.07 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1H, d, J = 2.4 Hz), 10.59 (1H, s).

  The following compounds were prepared in the same manner as in Example 574 using appropriate starting materials.

Example 575
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4 , 5-Dichlorophthalamic acid 1H-NMR (DMSO-d6) δ ppm:
2.56 (4H, brs), 3.68 (4H, brs), 3.77 (2H, s), 3.90 (3H, s), 6.00 (2H, s), 6.63 (1H) , S), 6.80 (1H, dd, J = 8.1 Hz, 1.5 Hz), 6.82-6.94 (2H, m), 6.98 (1H, d, J = 8.9 Hz) 7.02 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.32 (1H, d, J = 2.3 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.94 (1H, s), 8.05 (1H, s), 8.07 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.33 (1H, d, J = 2.7 Hz) ), 10.61 (1H, s), 13.10 (1H, brs).

Example 576
1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- (4- {5-[(4-trifluoromethylphenylamino) methyl] pyridin-2-yloxy} Preparation of -2,3-dihydroindol-1-yl) ethanone 1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [4- (5-hydroxymethylpyridine) 2-yloxy) -2,3-dihydroindol-1-yl] ethanone (0.671 g, 1.34 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (0.205 ml, 1.47 mmol) under ice cooling, Subsequently, methanesulfonyl chloride (0.114 ml, 1.47 mmol) was added and stirred at the same temperature for 1 hour. Dichloromethane was added to the reaction solution and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 0.778 g of a light brown amorphous. 0.389 g of the obtained powder was taken and 4-trifluoromethylaniline (0.252 ml, 2.01 mmol) was added thereto, followed by stirring at room temperature for 16 hours and further at 80 ° C. for 2 hours. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution (20 ml), ethyl acetate (30 ml) and THF (30 ml) were added and stirred. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain 0.060 g of the title compound.
Properties: Brown yellow amorphous powder 1H-NMR (CDCl3) δ ppm:
2.41-2.44 (4H, m), 2.84 (2H, t, J = 8.2 Hz), 3.40-3.52 (6H, m), 3.64 (2H, brs), 3.88 (2H, s), 4.27 (1H, brs), 4.32 (2H, s), 5.94 (2H, s), 6.29 (1H, d, J = 7.8 Hz) 6.44 (1H, d, J = 8.1 Hz), 6.63 (2H, d, J = 8.4 Hz), 6.74-6.76 (2H, m), 6.83-6. 87 (2H, m), 7.05-7.11 (1H, m), 7.40 (2H, d, J = 8.4 Hz), 7.64 (1H, dd, J = 8.4 Hz, 2 .3 Hz), 8.17 (1H, d, J = 2.1 Hz).

Example 577
2- (6- {1- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2-oxoethyl] -1H-indol-5-yloxy} pyridine-3- Yl) -1- (4-trifluoromethylphenyl) ethanone fumarate 1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [5- (5- Bromopyridin-2-yloxy) -indol-1-yl] ethanone (0.3 g, 0.55 mmol) in toluene (10 ml) under a nitrogen atmosphere, tris (dibenzylideneacetone) dipalladium (25 mg, 0.03 mmol) ) And 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (38 mg, 0.07 mmol), and after stirring at room temperature for 5 minutes, 4 ′-(trifluoromethyl) acetophenone (0.15 g, 0.82 mmol) and potassium hexamethyldisilazide (0.16 g, 0.82 mmol) were added, and the mixture was stirred at 70 to 90 ° C. for 1.5 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 → 3: 1), equimolar amount of fumaric acid was added, ethanol azeotroped, and then crystallized with acetone-diethyl ether. It was collected by filtration. After drying under reduced pressure, 0.14 g of the title compound was obtained.
Property: Light brown powder 1H-NMR (DMSO-d6) δ ppm:
2.18-2.54 (4H, m), 2.88-3.76 (6H, m), 4.48 (2H, s), 5.16 (2H, s), 5.98 (2H, s), 6.39 (1H, d, J = 3.0 Hz), 6.76 (1H, dd, J = 7.9 Hz, 1.4 Hz), 7.25 (1H, d, J = 2.3 Hz) ), 7.29 (1H, d, J = 3.0 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.67 (1H, dd, J = 8.5 Hz, 2.3 Hz) 7.93 (2H, d, J = 8.2 Hz), 7.99 (1H, d, J = 2.1 Hz), 8.24 (2H, d, J = 8.2 Hz).

  The following compounds were prepared in the same manner as in Example 577 using appropriate starting materials.

Example 578
1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- (5- {5- [2- (3,4-dichlorophenyl) -2-oxoethyl] pyridine-2 -Yloxy} indol-1-yl) ethanone fumarate 1H-NMR (DMSO-d6) δ ppm:
2.23-2.68 (4H, m), 3.08-3.61 (6H, m), 4.45 (2H, s), 5.18 (2H, s), 6.00 (2H, s), 6.42 (1H, d, J = 3.1 Hz), 6.62 (2H, s), 6.73-6.81 (1H, m), 6.83-6.97 (4H, m), 7.26 (1H, d, J = 2.3 Hz), 7.31 (1H, d, J = 3.1 Hz), 7.35 (1H, d, J = 8.7 Hz), 7. 66 (1H, dd, J = 8.4 Hz, 2.3 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.99 (1H, d, J = 2.4 Hz), 8.01 (1H, dd, J = 8.4 Hz, 1.9 Hz), 8.27 (1H, d, J = 1.9 Hz).

Example 579
1- {6- [2- (4-Benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3- (3,4-dichlorophenyl) -1- Preparation of ethylurea hydrobromide (4-benzylpiperazin-1-yl) [5- (5-ethylaminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] methanone (280 mg, 0.6 mmol) in THF (6 ml) was added 3,4-dichlorophenyl isocyanate (112 mg, 0.6 mmol) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 50) to obtain 240 mg of the desired free form as a white powder. Ethanol and 47% hydrobromic acid (42 μl, 0.36 mmol) were added to the obtained free form, the solvent was distilled off, and the obtained solid was recrystallized from ethyl acetate to obtain 155 mg of the title compound.
Property: White powder Melting point: 171-277 ° C (decomposition).

  The following compounds were prepared in the same manner as in Example 579 using appropriate starting materials.

Example 580
1- {6- [2- (4-Benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -1-ethyl-3- (4-trifluoromethyl) Phenyl) urea hydrobromide melting point: 224-230 ° C.

Example 581
1- {6- [2- (4-Benzylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3- (3,4-dichlorophenyl) -1- Ethylthiourea hydrobromide melting point: 163-168 ° C.

Example 582
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -1 -Ethyl-3- (4-trifluoromethylphenyl) urea hydrobromide melting point: 176-179 [deg.] C.

Example 583
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 -(3,4-dichlorophenyl) -1-ethylurea hydrobromide melting point: 224-228 [deg.] C.

Example 584
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 -(3,4-dichlorophenyl) -1-ethylthiourea hydrochloride melting point: 152-160 ° C.

Example 585
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 -(3,4-dichlorophenyl) -1-methylurea hydrochloride melting point: 240-243 [deg.] C.

Example 586
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -1 -Methyl-3- (4-trifluoromethylphenyl) urea hydrochloride melting point: 230-233 [deg.] C.

Example 587
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -3 -(3,4-dichlorophenyl) -1-methylthiourea hydrochloride 1H-NMR (DMSO-d6) δ ppm:
2.98-3.25 (2H, m), 3.24-3.65 (4H, m), 3.57 (3H, s), 3.80 (3H, s), 4.25 (2H, brs), 4.41 (2H, brs), 6.07 (2H, s), 6.75 (1H, s), 6.99 (1H, d, J = 8.0 Hz), 6.96-7 0.08 (2H, m), 7.07 (1H, dd, J = 9.1 Hz, 2.2 Hz), 7.24 (1H, s), 7.32 (1H, dd, J = 8.8 Hz, 2.2 Hz), 7.37 (1 H, d, J = 2.2 Hz), 7.54 (1 H, d, J = 8.8 Hz), 7.57 (1 H, d, J = 8.8 Hz), 7.61 (1H, d, J = 2.5 Hz), 7.83 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.12 (1H, d, J = 2.8 Hz), 9 20 (1H, s).

Example 588
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -1 -Ethyl-3- (4-trifluoromethylphenyl) thiourea hydrochloride 1H-NMR (DMSO-d6) δ ppm:
1.15 (3H, t, J = 7.1 Hz), 3.00-3.22 (2H, m), 3.23-3.49 (2H, m), 3.54 (1H, brs), 3.80 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 4.27 (2H, s), 4.41 (1H, brs), 4.65 (2H, brs) , 6.07 (2H, s), 6.74 (1H, s), 6.95-7.07 (2H, m), 7.04 (1H, d, J = 8.7 Hz), 7.07 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.24 (1H, s), 7.38 (1H, d, J = 2.3 Hz), 7.51 (2H, d, J = 8.6 Hz), 7.58 (1 H, d, J = 8.9 Hz), 7.62 (2 H, d, J = 8.6 Hz), 7.79 (1 H, dd, J = 8.7 Hz, 2 .8 Hz), 8.08 (1 , D, J = 2.8Hz), 9.13 (1H, s).

Example 589
1- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -1 -Methyl-3- (4-trifluoromethylphenyl) thiourea hydrochloride melting point: 202-207 [deg.] C.

Example 590
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N -Preparation of ethyl-4-trifluoromethylbenzamide hydrobromide {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazine-1-carbonyl) -1-methyl-1H- Indol-5-yloxy] pyridin-3-yl} ethylcarbamic acid t-butyl ester (290 mg, 0.47 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml) under ice cooling and stirred at room temperature for 1 hour. did. The reaction solution was concentrated under reduced pressure, and the residue was made alkaline by adding water and 5M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was dissolved in dichloromethane (2 ml) and ice-cooled. Triethylamine (0.1 ml, 0.72 mmol) was added to the solution, and then 4- (trifluoromethyl) benzoyl chloride (0.09 ml, 0.61 mmol) was added dropwise. After stirring the reaction solution for 1 hour, water was added for liquid separation, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain 230 mg of white amorphous powder. This was dissolved in ethanol (2 ml), 47% hydrobromic acid (0.04 ml, 0.35 mmol) was added, and the mixture was stirred for 1 hour. The solvent was distilled off and the residue was recrystallized from ethanol-dichloromethane to give 190 mg of the title compound.
Properties: White powder melting point: 192-195 ° C.

Example 591
2-hydroxy-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-tri Preparation of fluoromethylbenzamide hydrobromide 2-Methoxymethoxy-4-trifluoromethylbenzoic acid (530 mg, 2.12 mmol) in dehydrated dichloromethane (2 ml) in oxalyl chloride (0.22 ml, 2.52 mmol) and dehydrated DMF (2 drops) was added and stirred for 1 hour. The solvent was distilled off, and the residue was dissolved by adding ethyl acetate (4 ml), of which 2 ml was [5- (5-aminopyridin-2-yloxy) -1-methyl-1H-indol-2-yl] [4 -(4-Methoxybenzyl) piperazin-1-yl] methanone (400 mg, 0.848 mmol) and triethylamine (0.15 ml, 1.076 mmol) in ethyl acetate (2 ml) were added dropwise under ice cooling and stirred for 1 hour. . Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was partitioned, and extracted with dichloromethane and then ethyl acetate. Each organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: acetone = 10: 1). The obtained product was dissolved in dichloromethane (2 ml), trifluoroacetic acid (2 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was stirred and separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: acetone = 8: 1) to obtain 120 mg of white amorphous powder. This was dissolved in ethanol (2 ml), 47% aqueous hydrobromic acid solution (0.016 ml, 0.14 mmol) was added, and the mixture was stirred for 1 hour. The precipitate was recrystallized from ethanol to obtain 80 mg of the title compound.
Property: White powder.
Melting point: 218-221 ° C. (decomposition).

  The following compounds were prepared in the same manner as in Example 591 using appropriate starting materials.

Example 592
2-Hydroxy-N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide oxalate melting point: 171-173 [deg.] C.

Example 593
N- [6- (2- {4-[(4-methoxybenzyl) methylamino] piperidin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -N-methyl Preparation of -4-trifluoromethylbenzamide oxalate (4-methoxybenzyl) methyl (piperidin-4-yl) amine dihydrochloride (390 mg, 1.27 mmol) in DMF (2 ml) solution with triethylamine (0.45 ml, 3.23 mmol) and stirred for 30 minutes, then 1-methyl-5- [5- (4-trifluoromethylbenzoylamino) pyridin-2-yloxy] -1H-indole-2-carboxylic acid (480 mg, 1. 05 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (310 mg, 1.62 mmol) and 1-hydroxybenzotriazole monohydrate (210 mg, 1.39 mmol) were added and stirred overnight. The solvent was distilled off, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue for liquid separation. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane: methanol = 40: 1). The obtained product was dissolved in dehydrated DMF (4 ml) under an argon atmosphere and ice-cooled. Methyl iodide (0.05 ml, 0.803 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) were added for 1 hour. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: acetone = 10: 1) to obtain 170 mg of white amorphous powder. This was dissolved in ethyl acetate (2 ml), oxalic acid dihydrate (31 mg) was added, and the mixture was stirred for 1 hr. The reaction solution was crystallized by adding diethyl ether-acetone. The crystals were collected by filtration and dried to give 140 mg of the title compound.
Property: White powder.
Melting point: 121-123 ° C.

  The following compounds were produced in the same manner as in Reference Example 255 using appropriate starting materials.

Example 594
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -2-hydroxy-N- Methyl-4-trifluoromethylbenzamide oxalate melting point: 155-160 ° C.

Example 595
2-Hydroxy-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- Preparation of 6-yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide 2- {Methyl [6- (1-methyl-2- {4- [4- (2,2,2, 2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridin-3-yl] carbamoyl} -5-trifluoromethylphenyl ester (460 mg, 0.59 mmol) in methanol (5 ml) ) To the solution was added potassium carbonate (65 mg, 0.47 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1), diethyl ether and an equimolar amount of 47% hydrobromic acid were added, and the precipitate was collected by filtration. After drying under reduced pressure, 0.36 g of the title compound was obtained.
Properties: White powder 1H-NMR (DMSO-d6) δ ppm:
3.17 (3H, s), 3.05-3.55 (6H, m), 3.71 (3H, s), 4.37 (2H, s), 4.30-4.60 (2H, m), 4.82 (2H, q, J = 8.0 Hz), 6.73 (1H, d, J = 8.3 Hz), 6.80 (1H, s), 6.87 (1H, d, J = 8.9 Hz), 6.88 (1H, s), 7.05 (1H, d, J = 7.6 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.24 ( 1H, s), 7.37 (1H, d, J = 7.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.75 (1H, d, J = 8.9 Hz), 7.92 (1H, s), 9.98 (1H, brs).

Example 596
N- (6- {2- [4- (4-difluoromethoxybenzyl) -4-oxypiperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N- Preparation of methyl-4-trifluoromethylbenzamide N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine-3 To a solution of -yl) -N-methyl-4-trifluoromethylbenzamide maleate (470 mg, 0.577 mmol) in ethyl acetate (10 ml) was added saturated aqueous sodium hydrogen carbonate (10 ml), and the mixture was vigorously stirred for 10 minutes. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in dichloromethane (12 ml), and 3-chloroperbenzoic acid (75%, 139 mg, 0.604 mmol) was added under ice cooling, followed by stirring for 5 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 → 1: 3) to obtain 170 mg of the title compound.
Properties: Pale yellow amorphous powder 1H-NMR (CDCl3) δ ppm:
2.07 (2H, brs), 3.11 (2H, d, J = 10.2 Hz), 3.23-3.27 (2H, m), 3.47 (3H, s), 3.83 ( 3H, s), 4.09 (1H, brs), 4.39 (3H, s), 6.54 (1H, t, J = 72.9 Hz), 6.56 (1H, s), 6.84 (1H, d, J = 8.9 Hz), 7.04 (1H, dd, J = 8.9 Hz, 2.0 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.30 ( 1H, d, J = 2.0 Hz), 7.36-7.39 (4H, m), 7.50 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8) .6 Hz), 7.80 (1 H, s).

  The following compounds were prepared in the same manner as in Example 596 using appropriate starting materials.

Example 597
N- (6- {2- [4- (4-difluoromethoxybenzyl) -4-oxypiperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -2- Fluoro-N-methyl-4-trifluoromethylbenzamide melting point: 151.3-154.4 ° C.

Example 598
N-methyl-N- [6- (1-methyl-2- {4-oxy-4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] methanesulfonamide melting point: 153.4-155.5 [deg.] C.

Example 599
N-methyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Ill] -4-trifluoromethylbenzamide N- [6- (1-methoxymethyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl}- 1H-Indol-6-yloxy) pyridin-3-yl] -N-methyl-4-trifluoromethylbenzamide (0.24 g, 0.31 mmol) in methanol (12 ml) in veratrol (0.43 g, 3.1 mmol). ) 2N hydrochloric acid (6 ml) was added, and the mixture was heated to reflux for 7 hours. After cooling, the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.34 g of the title compound.
Properties: White powder 1 H-NMR (CDCl 3) δ ppm:
2.54 (4H, s), 3.47 (3H, s), 3.51 (2H, s), 3.91 (4H, s), 4.35 (2H, q, J = 8.1 Hz) 6.74 (1H, s), 6.84 (1H, d, J = 8.6 Hz), 6.85 (1H, dd, J = 8.6 Hz, 2.2 Hz), 6.92 (2H, d, J = 8.6 Hz), 7.15 (1H, s), 7.29 (2H, d, J = 8.6 Hz), 7.40 (3H, d, J = 7.8 Hz), 7. 50 (2H, d, J = 7.9 Hz), 7.60 (1 H, d, J = 8.6 Hz), 7.80 (1 H, s), 9.25 (1 H, s).
Pharmacological test 1
Collagen synthesis inhibitory action (in vitro)
A human hepatic stellate cell line (LI90) was seeded in a 12-well plate with DMEM (Dulbecco's modified easy medium) containing 10% fetal bovine serum, and a CO ₂ incubator (set temperature: 37 ° C., CO2 concentration: 5%). ) For 24 hours. The cultured cells were washed with D-PBS (Dulbecco's Phosphate Buffered Saline) and further cultured in MEM (Eagle's minimum essential medium) containing 0.1% fetal bovine serum for 3 days. Again, the cultured cells were washed with D-PBS and cultured with MEM containing 10 pM h-TGF-β1 (human-transforming growth factor-β1) and 0.1% fetal bovine serum together with the test compound. . Next, the cultured cells are washed with D-PBS, cultured for 24 hours in MEM containing 3H-proline as a radiolabeled compound and 0.25 mM ascorbic acid, and the produced collagen is labeled with RI (radioisotope). did. An acid-soluble fraction was extracted from the culture supernatant, radioactivity was measured, and the obtained measurement value was defined as collagen synthesis activity.

  Compared with the radioactivity in the supernatant cultured in the absence of the test compound (control) in the supernatant cultured in the presence of the test compound, the concentration that inhibits collagen synthesis by 50% [IC50 value (NM)].

  These results are shown in the following table.

Pharmacological test 2
Anti-cancer action against cancer cells (in vitro)
The growth inhibitory effect on human hepatoma cells (HuH-7) was measured by the sulfoeerdamine B method according to the method of Skehan P et al. (J Natl Cancer Inst. 1990 Jul 4; 82 (13): 1107-12.). . Specifically, HuH-7 was seeded in a 96-well microplate in DMEM medium containing 10% fetal bovine serum, cultured at 37 ° C. in the presence of 5% carbon dioxide gas for 24 hours, and then a test compound was added. Cultured for 5 days. After the cultivation, trichloroacetic acid was added to a final concentration of 10%, and the cells were fixed by allowing to stand at 4 ° C. for 1 hour, then washed with water to remove the medium and trichloroacetic acid and air-dried. After air drying, it was stored at 4 ° C. until it was stained with sulferodamine B. A 1% aqueous acetic acid solution containing 0.4% sulfododamine B was added to each well and allowed to stand at room temperature for 20-30 minutes. After removing the supernatant, each well was washed with a 1% aqueous acetic acid solution, a 10 mM Tris (trishydroxyaminomethane) aqueous solution was added, and the mixture was stirred to elute the dye incorporated into the cells. Next, the OD value is measured at a measurement wavelength of 492 nm and a control wavelength of 690 nm, and the difference is taken. Further, the OD value of a control well containing no cells (difference between the measurement wavelength of 492 nm and the control wavelength of 690 nm) is subtracted, and cell growth in each well is performed. Active.

  The cell growth activity when the test compound was added was compared with the cell growth activity (control) not containing the test compound, and the concentration at which cell growth was inhibited by 50% (IC50 (nM)) was determined.

  The growth inhibitory effect on human pancreatic cancer cells (HPAC) was measured according to the above method. However, HPAC was used instead of HuH-7, and the medium was RPMI 1640 medium containing 10% fetal calf serum instead of DMEM medium containing 10% fetal calf serum.

  The growth inhibitory effect on human chronic myeloid leukemia cells (KU812) was measured by the WST-8 assay according to the method of Singh AK et al. (Cancer Lett. 1996 Oct 1; 107 (1): 109-15.). That is, KU812 was seeded in a 96-well microplate in RPMI 1640 medium containing 10% fetal calf serum, cultured at 37 ° C. in the presence of 5% carbon dioxide gas for 24 hours, and then the test compound was added for another 5 days. Cultured. 15 μL of 5 mM WST-8 (2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2,4-disulfophenyl) -2H-tetrazolium monosodium salt) after culture Was added and cultured for 2 hours. After 2 hours, 15 μL of 1% SDS (sodium dodecyl sulfate) was added, the OD value was measured at a measurement wavelength of 450 nm and a control wavelength of 630 nm, and the difference was taken. Further, the OD value of a control well containing no cells (measurement wavelength of 450 nm, The difference in control wavelength (630 nm) was subtracted to obtain the cell proliferation activity of each well.

  The cell growth activity when the test compound was added was compared with the cell growth activity (control) not containing the test compound, and the concentration at which cell growth was inhibited by 50% (IC50 (nM)) was determined.

  These results are shown in the following table.

Pharmacological test 3
Anticancer activity against liver cancer cells HuH-7 (in vivo)
Using human hepatoma cells HuH-7, these were transplanted into SCID mice (female, 6 mice per group), and the inhibitory action of the present invention on their proliferation was examined. That is, a cell suspension prepared by pre-culturing and adjusting the concentration to 2.5 × 10 7 cells / mL was injected subcutaneously into 0.2 mL of the right axilla to transplant cancer cells to prepare tumor-bearing mice. When the tumor diameter became 5 mm or more, grouping was performed based on the tumor volume. The test compound was orally administered as a 5% gum arabic suspension once a day for 9 days from the next day after grouping. The control group received 5% gum arabic. Tumor volume was measured the day after the last dose. The ratio of the tumor volume at the time of grouping and the tumor volume on the day after the end of administration was calculated to determine the relative tumor volume of each group. The ratio (T / C%) of the relative tumor volume in the control group and the relative tumor volume in the drug administration group was calculated and used as an effect index.

Relative tumor volume = tumor volume the day after the last administration / tumor volume T / C% at the time of grouping = (average value of relative tumor volume of drug administration group / average value of relative tumor volume of control group) × 100
These results are shown in the following table.

Pharmacological test 4
Inhibitory effect on IL-6-induced STAT3 phosphorylation in human myeloma cells (in vitro)
Modified Tochizawa S. Et al. (J Immunol Methods. 2006 Jun 30; 313 (1-2): 29-37), using IL-6 (interleukin-6) induced STAT3 (Signal Transducer and) in human myeloma cells (U266B1). Activator of Transcription-3) The inhibitory effect of the test compound on phosphorylation was examined. That is, U266B1 cells were seeded in a 12-well plate in RPMI 1640 medium containing 10% fetal bovine serum (FBS), added with a test compound, and cultured at 37 ° C. for 2 hours in the presence of 5% carbon dioxide gas. After the culture, IL-6 was added to 1 ng / mL, and the cells were cultured at 37 ° C. in the presence of 5% carbon dioxide for 15 minutes. Immobilization buffer containing formaldehyde (Lyse / Fix Buffer, BD Biosciences) was added, and the cells were fixed at room temperature for 10 minutes, centrifuged to remove the supernatant, and ice-cooled methanol was added to increase the permeability of the cell membrane. Treated for 10 minutes under ice cooling. After removing the methanol by centrifugation, the cells were washed twice with 2% FBS-containing D-PBS (Dulbecco's Phosphate Buffered Saline). Fluorescently labeled phosphorylated STAT3 (pSTAT3) antibody (Alexa Fluor 488 labeled antiphosphorylated STAT3 (Y705) antibody, BD Biosciences) was added and stained for 30 minutes under ice-cooling. After washing once with 2% FBS-containing D-PBS, the suspension was suspended with 2% FBS-containing D-PBS, and the fluorescence intensity was measured with a flow cytometer (FACS Sort, BD Biosciences). The difference between the geometric mean of the IL-6-induced fluorescence intensity of the control and the geometric mean of the pSTAT3 fluorescence intensity of the unstimulated control without adding IL-6 was taken as 100%, and the geometric mean of the fluorescence intensity of pSTAT3 at each concentration of the test compound T / C was calculated by the following formula from the difference between the fluorescence intensity and the non-stimulated control.
T / C (%) = (synergistic mean of pSTAT3 fluorescence intensity of compound-treated cells−synergistic mean of pSTAT3 fluorescence intensity of unstimulated control) / (synergistic mean of IL-6-induced pSTAT3 fluorescence intensity of control−unstimulated control) Of pSTAT3 fluorescence intensity) × 100
The concentration at which the test compound inhibits STAT3 phosphorylation by 50% (IC50; the concentration of the test compound at which T / C (%) corresponds to 50%) is used as an indicator of the inhibitory activity of the test compound. The T / C (%) was determined.

  These results are shown in the following table.

Claims (10)

General formula (1):

[Wherein R ¹ represents a group R ⁵ —B—N (R ⁶ ) —, a group R ⁵ —N (R ⁶ ) —B—, a group R ⁵ —N (R ⁷ ) —, and a group R ⁵ —N. ^{(R 8) -CO-N (} R 9) -, group ^{R 5 -N (R 10) -CS} -N (R 11) -, group _{^{R 5 -SO 2 -N (R 12}} ) -, ^the radicals ^{R 5} —CO—B ₁ —, group R ⁵ —B ₂ —CO—N (R ^12a ) —, group R ⁵ —B ₉ —SO ₂ —N (R ⁴⁷ ) —, or group R ⁵ —O—B ₁₀ —. SO ₂ -N ^{(R 48)} - shows the.
R ⁵ is a 5- to 15-membered monocyclic, binary or ternary saturated or unsaturated heterocyclic group having 1 to 4 nitrogen, oxygen or sulfur atoms (on the heterocyclic ring, oxo A group having 1 to 6 carbon atoms which may have a halogen atom as a substituent; a 1 to 6 alkyl group having a halogen atom as a substituent; a halogen atom; an alkylsulfonyl group having 1 to 6 carbon atoms; A phenyl group optionally having 1 to 6 carbon atoms having a halogen atom on the phenyl ring may be substituted; a 1 to 6 alkylthio group; a pyrrolyl group; a benzoyl group; an alkanoyl group having 1 to 6 carbon atoms ; 1 to 6 alkoxycarbonyl groups; 1 to 4 alkylenedioxy groups; pyridyl groups; and 1 to 6 alkyl groups and 1 to 6 alkanoyl groups as substituents. 1 to 3 groups selected from the group consisting of amino groups which may have a group may be substituted), a C 1-6 alkyl group which may have a halogen atom as a substituent, cycloalkyl group, consisting an amino group which may have a naphthalene ring on the number 6 alkyl group having a carbon halogen atoms and having 1 to 6 carbon atoms as a substituent alkyl group and a group selected from a C 1 -C 6 alkanoyl group the group consisting of carbon A naphthyl group or group optionally substituted by 1 to 3 groups selected from the group

Indicates.
The monocyclic, binomial or tricyclic saturated or unsaturated heterocyclic group is pyrrolidinyl, piperidinyl
, Piperazinyl, morpholinyl, pyridyl, 1,2,5,6-tetrahydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 1,2,3, 4-tetrazolyl, thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, 2H-pyrrolyl, pyrrolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl, flazanyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl Quinazolidinyl Quinoxalinyl, cinnolinyl, phthalazinyl, carbazoyl, acridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydrobenzo [b] furyl, benzothienyl, phenoxathinyl, phenoxazinyl, 4H- Chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thiantenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, isothiazolyl, pyranyl, 2-thiazolinyl, 2-pyrazolinyl, quinuclidinyl, 1, 4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4- Nzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl, 1,4-dithiaphthale Nyl, dibenz [b, e] azepine, 6,11-dihydro-5H-dibenz [b, e] azepine or imidazo [2,1-b] thiazolyl group.
R ¹³ has a hydrogen atom, a hydroxyl group, a carboxy group, a halogen atom, a C 1-6 alkyl group which may have a halogen atom as a substituent, a halogen atom or a C 1-6 alkoxy group as a substituent. a number 6 alkoxy group having a carbon number of 1 to 6 alkanoyloxy group having a carbon number of 1-6 alkoxycarbonyl group having a carbon number of 1-6 alkoxycarbonyl group substituted having 1 to 6 carbon atoms alkyl group carbon atoms, a cyano group, a phenyl group, A pyrazolyl group, an oxazolyl group, or a pyrrolyl group that may have a nitro group, an alkanoylamino group having 2 to 6 carbon atoms , an alkylenedioxy group having 1 to 4 carbon atoms , a phenoxy group, or an alkyl group having 1 to 6 carbon atoms .
m shows the integer of 1-5. If m represents 2-5, 2-5 of ^{R 13} may be the same or different.
R ⁴⁷ and R ⁴⁸ each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁶ is a hydrogen atom, a C 1 -C 6 alkyl group having a carbon which may have a number-6 alkoxy group having a carbon as a substituent, a C 1 -C 6 alkanoyl group, a C 1 -C 6 alkylsulfonyl group or number phenyl carbon-carbon atoms 1-6 alkyl groups are shown.
B represents a group —CO— or an alkylene group having 1 to 6 carbon atoms .
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ¹² and R ^12a each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
B ₁ represents, each exhibit 1 -C 6 alkylene group having a carbon.
B ₂ represents a C 2-6 alkenylene group.
B ₉ represents a C 1-6 alkylene group or a C 2-6 alkenylene group.
B ₁₀ represents an alkylene group having 1 to 6 carbon atoms .
R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Y represents CH or N.
A ₁ represents a heterocyclic ring selected from the group consisting of an indolediyl group and an indolinediyl group.
The heterocyclic ring may have one or more substituents.
The T is bonded to the substitution position at the 1-position or 2-position of the indolediyl group or indolinediyl group; and
O is bonded to the substitution position at the 4-position, 5-position, 6-position or 7-position of the indolediyl group or indolinediyl group.
T represents a group —B ₅ —CO— or a group —CO— .
B ₅ represents a C 2-6 alkenylene group or a C 1-6 alkylene group which may have a hydroxyl group as a substituent .
R ³ and R ⁴ together with the nitrogen atom to which they are bonded form a piperidine ring or piperazine ring.
The piperidine ring or piperazine ring may have one or more substituents. ]
The pharmaceutical composition containing the heterocyclic compound or its salt represented by these. The pharmaceutical composition according to claim 1, which is used for suppressing the production of collagen. The pharmaceutical composition according to claim 1 or 2, which is used for treating and / or preventing a disease accompanied by fibrosis caused by excessive production of collagen. The pharmaceutical composition according to claim 3, wherein the disease accompanied by fibrosis is pulmonary fibrosis, liver fibrosis and / or glomerulosclerosis. The pharmaceutical composition according to claim 1, which is used for treating and / or preventing a tumor. The pharmaceutical composition according to claim 5, wherein the tumor is a malignant tumor. The pharmaceutical composition according to claim 6, wherein the malignant tumor is a solid tumor, lymphoma or leukemia. At least one childhood brain tumor selected from the group consisting of astrocytoma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, and ependymoma; glioma, glioma, meningioma, pituitary gland At least one adult brain tumor selected from the group consisting of adenomas and schwannomas; at least one selected from the group consisting of maxillary sinus cancer, pharyngeal cancer, laryngeal cancer, oral cancer, lip cancer, tongue cancer, and parotid gland cancer Species head and neck cancer; at least one breast cancer and tumor selected from the group consisting of small cell lung cancer, non-small cell lung cancer, thymoma and mesothelioma; esophageal cancer, liver cancer, primary liver cancer, gallbladder cancer, bile duct Cancer, stomach cancer, colon cancer, colon cancer, rectal cancer, anal cancer, pancreatic cancer and pancreatic endocrine tumor, at least one digestive cancer and tumor selected from the group consisting of: penile cancer, renal pelvis / ureteral cancer, renal cell cancer, Testicular cancer, prostate cancer, bladder cancer, Wilms tumor and urinary tract At least one urological cancer and tumor selected from the group consisting of skin cancer; vulvar cancer, cervical cancer, endometrial cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, breast cancer, ovarian cancer and ovary At least one gynecological cancer and tumor selected from the group consisting of germ cell tumors; adult and pediatric soft tissue sarcomas; at least one bone tumor selected from the group consisting of osteosarcomas and Ewing tumors; adrenocortical carcinoma and thyroid Cancer and tumor of at least one endocrine tissue selected from the group consisting of cancer; malignant lymphoma, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, plasma cell tumor, acute myeloid leukemia, acute lymphocytic leukemia, adult T At least one malignant lymphoma and leukemia selected from the group consisting of cellular leukemia lymphoma, chronic myelogenous leukemia and chronic lymphocytic leukemia; chronic myeloproliferative disorder, malignant melanoma The pharmaceutical composition according to claim 6 or 7 which is metastases the tumors and cancers; of squamous cell carcinoma, at least one cancer and tumors of the skin selected from the group consisting of basal cell carcinoma and mycosis fungoides. 4, N-dimethyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] benzenesulfonamide,
3,4-dichloro-N- (2- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl)- N-methylbenzenesulfonamide,
N- [6- (2- {4-[(4-methoxybenzyl) methylamino] piperidin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -4-tri Fluoromethylbenzamide,
2-chloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide,
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -N-methyl-4-trifluoromethoxybenzamide,
N- [6- (2- {4-[(E) -3- (4-methoxyphenyl) allyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl ] -4-trifluoromethylbenzamide,
N- (2- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide;
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide,
N- (6- {2- [4- (6-Isopropoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-Isopropylbenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethoxybenzamide,
N- {6- [2- (4-isobutylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide;
N- [6- (1-methyl-2- {4- [2- (4-trifluoromethylphenyl) thiazol-5-ylmethyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine-3 -Yl] -4-trifluoromethylbenzamide,
4-methoxy-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide,
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide,
N- (6- {2- [4- (4-Ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -2-methylpyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-Ethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide,
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -N-methyl-4- Trifluoromethylbenzamide,
N- (6- {1-methyl-2- [4- (4- [1,2,3] thiadiazol-4-ylbenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridine-3- Yl) -4-trifluoromethylbenzamide,
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -N-methyl-4-trifluoromethylbenzamide,
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -2-methyl-4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide,
N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-5 Yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide,
N- (6- {2- [4- (5-ethoxypyridin-2-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide,
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide,
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl)- N-methylbenzenesulfonamide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzene Sulfonamide,
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine- 3-yl) -4, N-dimethylbenzenesulfonamide,
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4 -Trifluoromethylbenzamide,
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide ,
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N -Methyl-4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide;
N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide,
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide,
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide,
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine- 3-yl) -N-methyl-4-trifluoromethylbenzamide,
2-chloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethoxybenzamide,
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- N-methyl-4-trifluoromethoxybenzamide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide ,
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethoxybenzamide,
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide,
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide;
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide ,
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide ,
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 4-trifluoromethylbenzamide,
N- [2- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyrimidin-5-yl]- N-methyl-4-trifluoromethylbenzamide,
as well as,
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide
The pharmaceutical composition as described in any one of Claims 1-8 containing the heterocyclic compound or its salt selected from the group which consists of. 4, N-dimethyl-N- [6- (2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine- 3-yl] benzenesulfonamide,
3,4-dichloro-N- (2- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl)- N-methylbenzenesulfonamide,
N- [6- (2- {4-[(4-methoxybenzyl) methylamino] piperidin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl] -4-tri Fluoromethylbenzamide oxalate,
2-chloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4- Trifluoromethylbenzamide hydrobromide,
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -N-methyl-4-trifluoromethoxybenzamide hydrobromide,
N- [6- (2- {4-[(E) -3- (4-methoxyphenyl) allyl] piperazin-1-carbonyl} -1-methyl-1H-indol-5-yloxy) pyridin-3-yl -4-trifluoromethylbenzamide methanesulfonate,
N- (2- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide;
N- (6- {2- [4- (4-difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide maleate,
N- (6- {2- [4- (6-Isopropoxypyridin-3-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide maleate,
N- (6- {2- [4- (4-Isopropylbenzyl) piperazin-1-carbonyl] -1,4-dimethyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4 -Trifluoromethylbenzamide hydrobromide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide hydrobromide,
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethoxybenzamide hydrobromide,
N- {6- [2- (4-isobutylpiperazine-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4-trifluoromethylbenzamide;
N- [6- (1-methyl-2- {4- [2- (4-trifluoromethylphenyl) thiazol-5-ylmethyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine-3 -Yl] -4-trifluoromethylbenzamide hydrobromide,
4-methoxy-N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole- 6-yloxy) pyridin-3-yl] benzenesulfonamide hydrochloride,
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate,
N- (6- {2- [4- (4-Ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} -2-methylpyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide hydrobromide,
N- (6- {2- [4- (4-Ethylbenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide oxalate,
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -N-methyl-4- Trifluoromethylbenzamide hydrochloride,
N- (6- {1-methyl-2- [4- (4- [1,2,3] thiadiazol-4-ylbenzyl) piperazine-1-carbonyl] -1H-indol-6-yloxy} pyridine-3- Yl) -4-trifluoromethylbenzamide,
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -N-methyl-4-trifluoromethylbenzamide hydrobromide,
N- [6- (2- {4- [4- (2-Fluoro-1-fluoromethylethoxy) benzyl] piperazine-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridine-3- Yl] -2-methyl-4-trifluoromethylbenzamide hydrochloride,
N- (6- {2- [4- (4-cyanobenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide hydrobromide,
N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4-tri Fluoromethylbenzamide maleate,
N-methyl-N- [6- (1-methyl-2- {4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indole-5 Yloxy) pyridin-3-yl] -4-trifluoromethylbenzamide maleate,
N- (6- {2- [4- (5-ethoxypyridin-2-ylmethyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl -4-trifluoromethylbenzamide maleate,
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide hydrobromide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide hydrobromide,
3,4-dichloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl)- N-methylbenzenesulfonamide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4, N-dimethylbenzene Sulfonamide,
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridine- 3-yl) -4, N-dimethylbenzenesulfonamide hydrochloride,
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -4 -Trifluoromethylbenzamide hydrobromide,
N- (2- {2- [4- (4-Isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyrimidin-5-yl) -4-trifluoromethylbenzamide Hydrochloride,
N- {6- [2- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-carbonyl) -1-methyl-1H-indol-5-yloxy] pyridin-3-yl} -N -Methyl-4-trifluoromethylbenzamide hydrobromide,
N- (6- {2- [4- (4-methoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Acid salt,
N- (6- {2- [4- (4-ethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrides,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide maleate,
N-methyl-N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-tri Fluoromethylbenzamide maleate,
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethylbenzamide hydrobromide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) Pyridin-3-yl] -4-trifluoromethylbenzamide dihydrobromide,
N- (6- {2- [4- (2,2-difluorobenzo [1,3] dioxol-5-ylmethyl) piperazine-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridine- 3-yl) -N-methyl-4-trifluoromethylbenzamide oxalate,
2-chloro-N- (6- {2- [4- (4-isopropoxybenzyl) piperazine-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N- Methyl-4-trifluoromethylbenzamide hydrobromide,
N-methyl-N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) Pyridin-3-yl] -4-trifluoromethoxybenzamide hydrobromide,
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- N-methyl-4-trifluoromethoxybenzamide hydrobromide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide,
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-5-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide hydrobromide,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -N-methyl-4- Trifluoromethoxybenzamide hydrobromide,
N- [6- (1-methyl-2- {4- [4- (2,2,2-trifluoroethoxy) benzyl] piperazine-1-carbonyl} -1H-indol-6-yloxy) pyridine-3- Yl] -4-trifluoromethylbenzamide hydrobromide,
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydrides,
N- (6- {2- [4- (4-Isopropoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide,
N- (6- {2- [4- (4-Difluoromethoxybenzyl) piperazin-1-carbonyl] -1-methyl-1H-indol-6-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide Hydrobromide,
N- [6- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyridin-3-yl]- 4-trifluoromethylbenzamide hydrobromide,
N- [2- (2- {4- [4- (2,2-difluoroethoxy) benzyl] piperazin-1-carbonyl} -1-methyl-1H-indol-6-yloxy) pyrimidin-5-yl]- N-methyl-4-trifluoromethylbenzamide hydrochloride,
as well as,
N- (6- {1-methyl-2- [4- (4-propoxybenzyl) piperazin-1-carbonyl] -1H-indol-5-yloxy} pyridin-3-yl) -4-trifluoromethylbenzamide odor Hydride
The pharmaceutical composition as described in any one of Claims 1-8 containing the heterocyclic compound chosen from the group which consists of.