WO2006062224A1 - Carboxamide derivative - Google Patents

Carboxamide derivative Download PDF

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Publication number
WO2006062224A1
WO2006062224A1 PCT/JP2005/022726 JP2005022726W WO2006062224A1 WO 2006062224 A1 WO2006062224 A1 WO 2006062224A1 JP 2005022726 W JP2005022726 W JP 2005022726W WO 2006062224 A1 WO2006062224 A1 WO 2006062224A1
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hz
1h
echiru
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PCT/JP2005/022726
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French (fr)
Japanese (ja)
Inventor
Kohji Fukatsu
Jun Kunitomo
Yasuhiko Kawano
Toshiro Yamashita
Tomoko Yamauchi
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Takeda Pharmaceutical Company Limited
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Priority to JP2004-354598 priority Critical
Priority to JP2004354598A priority patent/JP2008007405A/en
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2006062224A1 publication Critical patent/WO2006062224A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/101,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36One oxygen atom
    • C07D263/40One oxygen atom attached in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/061,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/101,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D285/00Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01Five-membered rings
    • C07D285/02Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/121,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

An SGLT inhibitor comprising a compound of the formula: (|) wherein the ring A is an optionally substituted ring; R1 is an optionally substituted hydrocarbon group, etc.; each of R2 and R3 independently is a hydrogen atom, an optionally substituted hydrocarbon group, etc.; R4 is an optionally substituted hydrocarbon group, etc.; and X is a bivalent chain group whose main chain consists of 1 to 6 atoms. This SGLT inhibitor is useful as a preventive/therapeutic agent for diabetes mellitus, obesity, hypertension, hyperlipemia, etc.

Description

Specification

Karubokisami de derivatives

Technical field

The present invention contain carboxamide derivatives, diabetes, obesity, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, useful sodium-dependent glucose transporter in the prevention and treatment of such metabolic syndrome (herein among, sometimes abbreviated as SGLT) for inhibitors and glucose uptake inhibitors.

In addition, the present invention relates to the usefulness of the new Karubokisami de derivatives as SGLT inhibitors your Yopi glucose uptake inhibitors.

BACKGROUND

Ingested carbohydrate as diet is absorbed after being digested into monosaccharides in the small intestine. At that time, SGLT and glucose transporters (herein sometimes to be abbreviated as GLUT) is that is known to function as a monosaccharide transporter proteins. GLUT is involved in the absorption of Fourques toast, to the absorption of glucose SGLT are involved.

Currently, at least six § isoforms are known in S GLT. Among them, SGLT 1 and SGLT homolog to glucose intake Ij¾ in the small intestine (also SGL T4 called) that is involved is revealed. Therefore, rapid glucose absorption through SGLT 1 and SGLT homolog in diabetic patients, is likely to elicit a postprandial hyperglycemia. Postprandial hyperglycemia not only exacerbates diabetes resulting in rapid low under the insulin secretion, resulting in failure of the vascular endothelial cells may also be a risk factor for developing atherosclerosis. In addition, from the fact that postprandial hyperglycemia is being in the possibilities Akira et al force to elicit a myocardial infarction, and postprandial hyperglycemia has had a significant adverse effect on the progress of developing your Yopi condition of lifestyle-related diseases General Conceivable.

In STZ (streptozotocin) rats is type 1 diabetes model animals enhanced expression of SGL T 1, the glucose absorption from the small intestine has been reported to increase (Metaporizumu (Metabolism), 990 pp., 2000) . Further, the Wistar fatty rats is type 2 diabetes' fertilizer Mitsurusho model animals expressing the SGLT homolog is known you to 亢 (WO 2004/039405 Patent brochure). From the above, in patients with diabetes or obesity, grayed by increased expression of these proteins -. Increased glucose absorption leads to such 墙大 of energy absorbed increases and the body of the blood glucose level, even worse pathologies possibility to can be considered.

Thus, curbing the excessive absorption of glucose through the SGLT 1 and SGLT homolog, or inhibition of rapid absorption of transient diabetes, it is assumed to contribute to the treatment of obesity or arteriosclerosis of any lifestyle . That is, selective inhibitor SGLT 1 and SGLT homolog, induced diabetes in postprandial hyperglycemia, obesity, to lead to therapeutic agents against metabolic syndrome is a condition in which integrated the like hyperlipidemia or hypertension it is expected that.

On the other hand, the Karubokisami de derivatives have been reported following compounds.

1) as an intermediate of Suruhoniumu compounds that bind to Guanin bases of DNA, and it is reported under compounds (Shinre' preparative (Synlett), 59 pp., 1992).

2) as CCR3 antagonists, the following formula compounds have been reported (WO 03/082861 Patent Pas Nfure' g).

Wherein the heteroaryl R 1 is to the substituted or unsubstituted, Y one (CRnaRnb) n- (Rna and Rnb hydrogen atom or independently - 6 alkyl, n is an integer of 0 to 5) the, R 2 is a Ariru or substituted or unsubstituted to the Te Roariru substituted or unsubstituted, R 3, R 4, R 7 and R 8 are hydrogen atoms independently or (:. Bok 6 alkylene - shows the Le ]

3) copper catalyst is reported that produced the formula compound new solid phase synthesis method using Rereru (Jananore-Saibu Organic 'Chemistry (Journal of Organic Chemistry), 67, pp. 3057, 2002 ). .

4) as the MCH receptor antagonists have been reported following formula compounds (WO 02/057233 Patent brochure).

Wherein, Ar 1 is a Ariru or heteroaryl group; Ar 2 is Ariru, etc. Heteroari Lumpur or Ararukiru group; Ar 3 is Ariren or to a heteroarylene group; X is an 0, S or N-CN; Y is a bond or 4 alkylene group; indicates the hydrogen atom or a C _ 6 alkyl]; R 1 is thiazole Lumpur, Ariru, Heteroariru etc.

5) HIV integrase (integrase) 'inhibitors that have been reported under compounds (WO 0V035076 No. brochure).

[Wherein, R 1, R 2 and R 4 are independently hydrogen, - 6 alkyl, etc., R 3 is a hydrogen atom or a C ^ - shows the 6 alkyl]

6) as the VLA-4 antagonist, has been reported under compounds (Bio-Organic '§ command-Medishinanore' ChemStation Doo Lee 'Letters (Bioorganic & Medicinal Chemistry Letters), 12 Certificates, 137 pp., 2002).

While the force, these compounds are not reported to have an inhibitory effect or glucose-up Write-inhibitory effect SGLT.

Disclosure of the Invention

The present invention aims to provide diabetes, obesity, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, the SGLT inhibitor and Dar course uptake inhibitors useful in the prevention and treatment of such metabolic syndrome to.

Furthermore, the present invention aims at providing a usefulness novel Karubokisami de derivative as SGLT inhibitors and glucose uptake inhibitors.

The present inventors have found that Karubokisami de derivatives having a substituent containing a Ami de bond in the side chain, on the basis of its specific chemical structure, have excellent SGLT inhibitory activity and Darco one scan uptake inhibitory activity , which resulted in the completion of the present invention based on these findings.

That is, the present invention is as follows.

(1 set

Wherein the ring A may be substituted ring, +

R 1 may be substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group or an optionally substituted arsenide Dorokishi group, R 2 and R 3 are independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a substituted optionally be also an amino group or a substituted Moyoihi Dorokishi group,

R 4 may be substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group optionally or箧换hydroxy group,, X is having 1 to atoms of the main chain a divalent chain group of 6. Compound is also properly its salt represented by] (herein sometimes to be abbreviated as compound (I)) or a SGLT inhibitor comprising the Purodo drag.

(2) Compound (I) or a Purodora'. Glucose uptake inhibitor comprising a grayed.

(3) SGLT inhibitor for the manufacture, use of compound (I) or a prodrug thereof.

(4) for the production of glucose uptake inhibitors, use of compound (I) or its flop port drag.

(5) Compound (I) or a prodrug thereof which comprises administering to a mammal, SGLT inhibition method in the mammal.

(6) Compound (I) or a prodrug thereof which comprises administering to a mammal, glucose uptake inhibition method in the mammal.

(7)

[In the formula, the ring Ab,

R lb is optionally substituted C 1. The Arukinore group,

R 3 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group or an optionally substituted hydroxy group,

R 4 b is 1 to 3 alkyl group optionally substituted by a halogen atom, 0 WINCH 6 alkoxy group, optionally substituted with 1 to 3 substituents selected from Shiano group Contact Yopi halogen atom It represents an Bibuwe two drill group. However, when the ring A is,

R 1 b is 3- (IH - Imidazoru - 1 - I) propyl group, (RS) - 2-morpholino - 3-Fueno Kishipuropiru group, (RS) - 2 - (Jimechiruamino) -3 - phenylpropyl group or 2 - not (1, 3 - - dihydro 2H- isoindol-2-I le) Echiru group. A compound represented by or a salt thereof] (herein sometimes to be abbreviated as compound (lib)).

(8) ring Ab force S

In a compound (lib).

(9) R 1 b force S

(I) human Dorokishi group,

(ii) C 6 _ 14 aromatic hydrocarbon Okishi group,

(iii) 1 to 3 substituents are 0 may be 6 alkyl group by a halogen atom, arsenic Dorokishi group, CI_ 6 alkoxy group, Okiso group, a halogen atom and C 6 - 14 aromatic hydrocarbon group (said C 6 _ i 4 aromatic hydrocarbon group may be substituted with 1 to 3 halogen atoms - 6 alkyl group, hydroxy group, 1 selected from 6 alkoxy Contact Yopiha androgenic atom to three substituents in substituted 1 Bareru selected from may also) have to three may be substituted with a substituent non-aromatic heterocyclic group,

(Iv) to 1 selected from a halogen atom Contact Yopi hydroxy group which may optionally be substitution in 3 substituents C - 6 alkoxy group,

(V) 1 to 3 of Mo optionally substituted with also an alkyl group with a halogen atom Roh or di-optionally substituted force Rubamoiruokishi group,

(vi) - 6 alkyl group (the C 6 alkyl group is a halogen atom, hydroxy group, a force Rupokishiru group, C 6 alkoxy group, to 1 selected from C 6 alkoxy one Karuboyuru group and Cal Bamoiru groups with 1-3 substituents optionally substituted), C 3 _ 1. Cycloalkyl group, an alkyl Ichiriki Ruponiru groups and C 6 _ 14 aromatic hydrocarbon group (said C 6 _ i 4 aromatic hydrocarbon group one to three may be substituted with a halogen atom 〇 6 alkyl group, hydroxy group, 0, - 6 alkoxy and halogen atom: - be mono- or di-substituted by one to three location substituent being selected from may also) be substituted with a substituent selected from the child an amino group,

(vii) 1 to 3 substituents which may be C 6 alkyl group by a halogen atom, arsenic Dorokishi group, 〇 6 alkoxy group, a halogen atom Contact Yopi 〇 6 14 aromatic hydrocarbon group (said C 6 - i 4 aromatic hydrocarbon group one to three optionally substituted _ 6 alkyl group by a halogen atom, is unsubstituted Dorokishi group, 1 selected from alkoxy groups Contact Yopi halogen atom to three substituents 1 a stone 3 substituents aromatic heterocyclic group which may be substituted with a group and selected from and each may be a)

(viii) C 7 _ 13 non-aromatic may be substituted by Ararukiru group heterocyclic Karupamoi Le group

1 may be substituted with 3 substituents selected from - an alkyl radical compound (lib).

(10) Ring A b is not less,

R lb is optionally substituted with 1 to 3 halogen atoms C DOO 6 alkyl group, arsenate Dorokishi group, C ^ 6 alkoxy group, a halogen atom Contact Yopi 〇 6 _ 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbon group may be substituted with 1 to 3 halogen atoms. preparative 6 alkyl group, arsenate Dorokishi group, to 1 selected from C doctor 6 alkoxy group Contact Yopi halogen atom 3 1 a stone three Yo Le be substituted with a substituent selected from may also be) substituted with a substituent, a condensed aromatic heterocyclic group

In compound is an alkyl group substituted (lib).

(1: 1) ring Ab is

N- 0

^ L, and

N

R 1 b is ^ alkyl group (wherein 0 I 6 alkyl group is a halogen atom, arsenic Dorokishi group, a carboxyl group, flicking 6 alkoxy group, CI_ 6 alkoxy - to 1 selected from carbonyl groups Contact Yopika Rubamoiru group 3 may be substituted with a substituent), C 3 ^. Cycloalkyl group, 0 I 6 alkyl one group Contact Yopi C 6 - 14 aromatic Sumyi匕- hydrogen group (said C i 4 aromatic hydrocarbon group be left at 1 to 3 halogen atoms good - 6 alkyl group, arsenate Dorokishi group, be mono- or di-substituted with a substituent selected from selected may be substituted with 1 to 3 substituents) from 〇 Bok 6 alkoxy group and a halogen atom . an amino group

In compounds which are substituted CI_ 6 alkyl group (lib).

(1 2) 2- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Jifuweniru Amino) Echiru] -1, 3-Okisazoru - 4 Karubokisami de,

2 - [2 - [(4 - bi Hue lily Luca Lupo - Le) Amino] Echiru] - N - (2 - morpholino - 3 Fueno Kishipuropiru) - 1, 3-Okisazoru 4 Karubokisami de,

5- [2 - [(4-bi Hue lily ylcarbonyl) Amino] Echiru] - N-[2-[(3- Mechirufue two Le) (phenyl) amino] Echiru] -1, 3, 4 - Okisajiazo Ichiru - 2 - Karubokisami de, 5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-[- phenyl - 1H-benz Imidazoru - 2 - I) methyl] -1, 2, 4- Okisajiazoru 3 Karubokisami de, 3- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-[(1-phenyl - 1H-benz Imidazoru - 2 - I) methyl] - 1, 2, 4-Okisajiazoru - 5-Karubokisami de,

3 - [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N - [(3 - Hue sulfonyl - 1 Benzofu run 2-I) methyl] - 1, 2, 4-Okisajiazoru - 5-Karubokisami de,

3- [2 - [[(4 - Full O lobby phenylalanine 4-I le) carbonyl] amino] Echiru] - N-(2-mol Horino - 3 phenoxyethanol propyl) - 1,2, 4 - Okisajiazo Ichiru - 5-Karubokisami de,

5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-[(1-Hue - Le - 1H-benz Imidazoru - 2-I) methyl] - 1, 3, 4 - Okisajiazoru - 2 - Karubokisami de, 1 - [2- [(4-Bifue two Rirukarubo - Le) Amino] Echiru]-N-r2- (Jifueniruamino) E chill]-1H-pyrazole - 4 - Karubokisami de,

5- [2 - [(4 - Bifuwe two Lil carbonyl) amino] Echiru] - N - [2 - (Jifuweniruamino) E chill] -1, 3, 4 Okisajiazoru - 2 Karubokisami de,

3- [2- [(4-bi Hue lily Luca Lupo -) amino] Echiru] - N-(2-morpholino - 3 - Fueno Kishipuropiru) - 1, 2, 4-Okisajiazoru - 5 Karubokisami de, and

5 - [2- [(4-Biff We lilies Luke Lupo sulfonyl) amino] Chill] - N-[2 - (Jifueniruamino) E chill] -1, 2, 4-Okisajiazoru 3- force Rupokisami selected from de compound or its compound which is a salt (lib).

(1 3) Compound (lib) or a prodrug thereof.

(14) Compound (lib) or medicine comprising the prodrug thereof.

(1 5) -

[Symbols in the formula are as defined above (7) wherein. Compound or a salt thereof represented by, the formula

R 4b - COOH

Wherein, R 4b is as defined above (7) wherein. ] Wherein the compound or the reaction of a salt thereof, process for the preparation of compounds (lib).

SGLT inhibitors Contact Yopi glucose uptake inhibitor of the present invention, diabetes, obesity, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, is useful for the prophylaxis or treatment of such meta Po Rick syndrome.

Further, Karubokisami de derivative of the present invention are useful as SGLT inhibitors Contact Yopi glucose preparative interrupt inhibitor.

BEST MODE FOR CARRYING OUT THE INVENTION

Described in detail below definition of each symbol used herein.

In this specification, "halogen atom", unless otherwise specified, refers to fluorine, chlorine, bromine Oyopi iodine.

Herein, ". ^ 6 alkyl group", unless otherwise specified, methyl, Echiru, propyl, isopropyl, Puchinore, Isopuchiru, sec- heptyl, tert- Puchinore, pentyl, isopentyl, neopentyl, 1 Echirupuropiru, hexyl hexyl, isohexyl, 1, -1-dimethyl-heptyl, 2, 2-dimethyl-heptyl, 3, 3-dimethylcarbamoyl Rupuchiru, such as 2 _ Echirubuchiru. meaning.

As used herein, "0 ^ 6 alkoxy group", unless otherwise specified, refers main butoxy, E butoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy sheet, and tert- butoxy. , Herein, "〇 I 6 alkoxy one carbonyl group", otherwise stated the a long as main Tokishikanorepo two Honoré, ethoxycarbonyl, propoxycarbonyl Kano repo sulfonyl, means such as tert- butoxide Kishikaruboeru.

Represented by R 1 as "hydrocarbon group" of the "optionally substituted hydrocarbon group", for example, Ji! . Alkyl groups, C 2 - i. Alkenyl group,. Alkynyl group, C 3. Cycloalkyl, Cs-i. Cycloalkenyl group. . Cycloalkanols diethyl two Le group, C 6 - 14 aromatic hydrocarbon group, C 7 _ 13 Ararukiru group, C 8 - 13 aromatic hydrocarbon § Luque - le group, C 3 - 0 cycloalkyl one C - 6 Arukiru group and the like.

As the "C i. Alkyl group", for example, methyl, Echiru, propyl, isopropoxy Ropinore, Puchinore, Isopuchinore, sec- Puchinore, tert- Buchinore, Penchinore, isopentyl, neopentyl, 1 _ Echirupuropiru, hexyl, isohexyl hexyl, 1, 1 - dimethyl-heptyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 2-E Chirubuchiru, heptyl, Okuchiru, nonyl, decyl and the like.

The - "i alkenyl C 2.", For example, Eteyuru, 1-propenyl, 2-Purobe - le, 2-methyl-1 _ propenyl, 1-butenyl, 2-Buteyuru, 3- Buteyuru, 3- Mechinore one 2-Buteninore, 1 one-pentenyl, 2-pent two Honoré, 3- Penteninore, 4- Penteninore, 4- Mechinore 3 Penteninore, 1 one to Kiseninore, cyclohexenyl 3, to 5-hexenyl, 1 one Heputeyuru, such as 1-Okuteniru and the like.

The - "C 2 !. alkynyl group", for example, Echiniru, 1 Purobyuru, 2 Puropini / Les, 1 one Buchininore, 2-Petit two Honoré, 3-Petit two Honoré, 1-pentyl two Honoré, 2 - pliers two Norre, 3-pentyl two Honoré, 4-pentyl two Honoré, 1 one to Kishunore, carboxymethyl to 2 Enore, to 3-Kishunore, Kishunore to 4, Kishininore to 5, Petit two to 1- Honoré, 1 Okuchiniru and the like.

"C 3. Cycloalkyl group" includes, for example, cyclopropyl, Shikuropuchi Le, cyclopentyl Honoré, cyclohexyl, the cycloalkyl heptyl, Shikurookuchi / Les, vicinal black [2.2.1] heptyl, bicyclo [3. 1.1] heptyl, bicyclo [2.2.2] Okuchiru, bicyclo [3.2.1] Okuchiru, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] Noel, bicyclo [4. 2.1] Noyuru, vicinal - black [4.3.1] decyl, and the like Adamanchiru. j

. Shikuroaruke - The Le group ", for example, 2-cyclopenten one 1 one Inore, 3-cyclopentene one 1- Inore, 2-cyclopropyl hexene one 1 Inore, such as hexene one 1 Iru to 3-cyclo thereof.

The "C 4 ^. Cycloalkadienyl group", for example, 2, 4-cyclopenta Gen one 1- Inore, 2, 4-cycloheteroalkyl Kisajen one 1 Inore, 2, into 5-cyclopropyl Kisajen 1 I Le etc. and the like.

The "C 6 _ 14 aromatic hydrocarbon group", for example, phenyl, naphthyl, Ant Lil, Fuenantoriru, Asenafuchireniru, etc. Bifue two drill and the like.

The "c 7 _ 13 Ararukiru group", for example, benzyl, phenethyl, phenyl-propyl, naphthylmethyl, and the like Bifue two Rirumechiru. ,

The "c 8 _ 13 aromatic hydrocarbon Arukeeru group", for example, styryl and the levator up. .

As - "C 3. I cycloalkyl ten preparative 6 alkyl group", for example, such as key Shirumechiru the like cyclohexylene.

The above ". C cycloalkyl group", "c 3 - 10 cycloalkenyl group", ". C 4 -i cycloalkadienyl group" each may be condensed with a benzene ring, such fused ring as the base, for example, indanyl, dihydronaphthyl, tetra human Doronafuchiru, etc. Furuoreniru the like.

Illustrated i as "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Alkyl group,. Alkenyl, and C 2 -. Alkynyl group has 1 to 5 at substitutable positions, preferably may have 1 to 3 substituents, when the number of substituents is 2 or more, respective substituents may be the same or different by Les,. As such substituents, for example,

(1) one to three which may be optionally CI- 6 alkyl group substituted with a halogen atom, arsenic Dorokishi group, to 1 selected from alkoxy groups and halogen atoms may be substituted with 1-3 substituents C 3. Cycloalkyl group (e.g., cyclopropyl, cyclohexyl, bicyclo [3.1.1] heptyl); (2) 1 to which may be substituted with 1-3 halogen atoms C - 6 alkyl group, Dorokishi group, ! 1 a) to 3 is substituted with a substituent which may C 6 _ 1 4 aromatic hydrocarbon group (eg selected from 〇 DOO 6 alkoxy group and a halogen atom, Hue - Le, naphthyl, Bifue two Lil);

(3) C 6 _ 1 4 aromatic hydrocarbon group (e.g., phenyl, naphthyl) mono- or di-substitution is optionally also an amino group, may be substituted with 1 to 3 halogen atoms - 6 alkyl group, arsenate Dorokishi group, 〇 I 6 alkoxy group, a halogen atom and C 6 1 4 aromatic hydrocarbon group (e.g., Hue - Le, naphthyl) (wherein C 6 4 aromatic hydrocarbon group one to three alkyl group which may be substituted by a halogen atom, arsenic Dorokishi group, 〇 6 1 to 3 substituents to 1 selected from alkoxy groups and halogen atoms substituted with 3 substituents selected from may also be) is an aromatic Hajime Tamaki optionally (eg substituted by groups, thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, Okisazoriru, thiazolyl, tetrazolyl, Okisajiazoriru, Pila Jiniru, Imidazo Lil, monocyclic aromatic heterocyclic group such as Isookisazoriru; reluctant Honoré, Indorinore, Benzofura two Honoré, Benzoche two Honoré, pyromellitic port Pirijininore, benz imidazolyl, benzo tri § benzisoxazolyl, fused aromatic heterocyclic group such as indazolyl);

(4) C 6 _ 1 4 aromatic hydrocarbon group (eg, Fuweniru, naphthyl) mono- or di-substitution is an amino group which may be, one to three is 6 may be substituted with a halogen atom group, human Dorokishi group, an alkoxy group, Okiso group, Ji halogen atom Contact Yopi 6 _ 1 4 aromatic hydrocarbon radical '(e.g., phenyl, naphthyl) (wherein C 6 _ 1 4 aromatic hydrocarbon group from 1 3 halogen atoms which may be substituted aralkyl kill group, arsenate Dorokishi group, 1 to 3 atoms selected from to 1 selected from alkoxy groups and halogen atoms may be substituted with 1-3 substituents) of is non-aromatic Hajime Tamaki may have (eg substituted with a substituent, tetrahydrofuryl, Moruho Rininore, thiomorpholinyl, Piberiji -, pyrrolidinyl, piperidines Rajuru, di- O Kisoriru, Jiokisorani , Dihydric mud benzofuranyl, Chiazorijeeru, Ben Zojiokisoraniru, dihydric mud benzodioxanyl O key sur, dihydric Doroi Soki quinolinyl, Te Torahi mud benz § Ze Bulle, Tetorahi Dorokinoriniru, Tetorahi Doroisokino Riniru);,

(5) 〇 6 alkyl group (the - 6 alkyl group is a halogen atom, arsenic Doroki group, forces Rupokishiru group, C i _ 6 alkoxy, to 1 selected from C i _ 6 alkoxy one carbonyl group and cull Pamoiru group 3 number of which may be substituted with a substituent), C 3 _ i. Cycloalkyl group (e.g., cyclopropyl, cyclohexyl), C 6 - 1 4 aromatic carbon hydrocarbon group (e.g., phenyl, naphthyl) (wherein C 6 - 1 4 aromatic hydrocarbon group one to three good d _ 6 alkyl group optionally substituted by a halogen atom, arsenic Dorokishi group, may be substituted with 1 to 3 substituents selected from C i _ 6 alkoxy Contact Yopi Ha port plasminogen atoms) , an aromatic Hajime Tamaki (e.g., aromatic heterocyclic group represented by R 1 described later), 6 alkyl one carbonyl group (e.g., Asechiru, Isobutanoiru, iso Pentanoiru) alkoxy - carbonyl group and C 6 - 1 4 aromatic family hydrocarbon one carbonyl group (eg, Benzoiru) (wherein c 6 - 1 4 aromatic hydrocarbon one carboxymethyl sulfonyl group

1 to 3 halogen atoms substituted by C i _ 6 optionally alkyl group, hydroxycarboxylic group, be to 1 selected from alkoxy groups Contact Yopi halogen atom substituted with 3 location substituent an amino group which may be mono- or di-substituted with a substituent selected from good);

(6) C i - e alkylsulfonyl § amino group (e.g., methylsulfonyl § Mino);

(7) amidino group;

(8) 1 may be substituted by three halogen atoms. Preparative 6 alkyl one local port - Le group (eg, Asechiru, Isobutanoiru, Isopentanoiru);

(9) one to three may be substituted with a halogen atom 〇 I 6 alkoxy Ichiriki Norebo; ^ Honoré;

(10) 1 to be 'good substituted with 3 halogen atoms - 6 alkylsulfinyl Ho - Le group (e.g., methylsulfonyl);

(11) one to three may be substituted with a halogen atom 〇 I 6 alkyl group ^ Roh or di-optionally substituted Karupamoiru group;

(12) one to three may be substituted with a halogen atom - 6 alkyl mono- or di-optionally substituted Chiokarubamoiru group group;

(13) one to three may be substituted with a halogen atom 〇 I 6 alkyl mono- or di-optionally substituted sulfamoyl group group;

(14) force Rupokishiru group;

(15) Non-Dorokishi group;

(16) to 1 selected from a halogen atom Contact Yopihi Dorokishi group may be replacement by 3 substituents - 6 alkoxy group;.

(17) 1 to 3 substituents which may be C 2 _ 6 Arukeniruo alkoxy group with a halogen atom (e.g., Eteyuruokishi);

(18). Cycloalkyl O alkoxy group (e.g., cyclohexylene Kishiruokishi);

(19) 〇 7 - 13 Ararukiruokishi group (eg, Benjiruokishi);

(20) C 6 - 14 aromatic hydrocarbon Okishi group (eg, Fueniruokishi, Nafuchiruoki sheet);

(21) 〇 6 alkyl Ichiriki Ruponiruokishi group (eg, Asechiruokishi, tert- butyl Luca Lupo Nino les oxy);

(22) thiol group;

(23) 1 to 3 substituents which may be an alkylthio group with a halogen atom (e.g., methylthio, Echiruchio);

(24) 〇 7 _ 13 Ararukiruchio group (e.g., benzylthio);

(25) C 6 - 14 aromatic hydrocarbon Chio group (e.g., phenylene thio, naphthylthio);

(26) a sulfo group;

(27) Shiano group;

(28) azide group;

(29) a nitro group;

(30) nitroso group;

(31) a halogen atom;

(32) - 6 alkylsulfinyl group (e.g., methylsulfinyl);

(33) a halogen atom and - 6 1 to 3 substituents C 6 _ 14 aromatic substituted with a substituent a hydrocarbon sulfonyl group selected from an alkyl group (e.g., Fuenirusuru Honiru);

(34) non-aromatic heterocyclic ten I 6 alkylsulfamoyl group (e.g., Tetorahi Dorofu (35) alkylsulfonyl O carboxymethyl group (e.g., methylsulfonyl O carboxymethyl) j;

(36) 1 to 3 substituents may Scarpa moil be mono- or di-substituted substituted by 0 may be collected by 6 alkyl group with a halogen atom O alkoxy group;

(37) C 7 - 13 Ararukiru group (e.g., benzyl, phenethyl, phenylpropyl) optionally substituted non-aromatic heterocyclic Karupamoiru group (eg, Piberiji - Rukaruba moil);

(38) 1 to 3 substituents which may be alkyl groups with a halogen atom, hydroxy group, to 1 selected from alkoxy groups and halogen atoms may be substituted with 1-3 substituents, the benzene ring fused which may have C 3 _ i. Shi Kuroarukeniru group (e.g., hexene one to 1-cyclopropyl 1 Inore, O Kuta hydro off Henin tolyl);

(39) alkyl group and C 6 - 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl Le) (wherein C 6 - 14 aromatic hydrocarbon group may be substituted with 1 to 3 halogen atoms 〇 it 6 alkyl group, hydroxy group, optionally substituted with C ^ 6 1 to 3 substituents selected from may also) have to 1 selected from alkoxy and halogen atom substituted with three substituents also an aromatic heterocyclic Chio group (eg, Kinokisa Riruchio, benzimidazolylthio, O hexa di § sledding thio);

(40) old Kiso group;

And the like.

"Aromatic heterocyclic group" of the "monocyclic aromatic heterocyclic group", the "condensed aromatic heterocyclic group" and "non-aromatic heterocyclic group", "substituted represented by R 1 described later It is mentioned the same ones as exemplified in the description also heterocyclic group "optionally.

Flip exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Cycloalkyl group, C 3 -. Cycloalkenyl group. Four . Shikuroa Rukajieniru group, C 6 - 14 aromatic hydrocarbon group, C 7 _ 13 Ararukiru group, C 8 _ 13 aromatic hydrocarbon alkenyl and. Cycloalkyl ten 6 alkyl group has 1 to 5 at substitutable positions, preferably rather it may also have 1 to 3 substituents, when the number of substituents is 2 or more, each substituent it may be the same or different. As such substituents, for example,

(1) the C 1. Substituent was exemplified as the substituent which may have an alkyl group;

(2) a halogen atom, a force Rupokishiru group, alkoxy Ichiriki Lupo - one to three may be substituted with a substituent 〇 DOO 6 alkyl group selected from the Le group and force Rupamoiru group;

(3) a halogen atom, a carboxyl group, one to three optionally substituted with a substituent C 2 _ 6 Arukeninore group (e.g. selected from alkoxy Ichiriki Ruponiru groups and force Rubamoiru group, Eteyuru, 1- Purobe - Le);

(4) 1 to which may be substituted with 1-3 halogen atoms C -! E alkyl group, arsenate Dorokishi group, to 1 selected from alkoxy groups and halogen atoms may be substituted with 1-3 substituents 〇 7 - 1 3 Ararukiru group (e.g., benzyl);

(5) one to three non-aromatic may be substituted by Okiso group heterocyclic one § alkyl group (e.g., thiomorpholinyl-methyl);

And the like.

Represented by R 1 in the "optionally substituted heterocyclic group" as the "heterocyclic group" include an aromatic Hajime Tamaki Contact Yopi nonaromatic Hayabusamotowa group.

As the "aromatic heterocyclic group", for example, nitrogen atom in addition to carbon atoms as ring atoms, to 1 heteroatoms selected from sulfur and oxygen atoms three, 5 to 7-membered containing 4 from 1 monocyclic aromatic heterocyclic group Oyopi bicyclic or tricyclic condensed aromatic heterocyclic group can be mentioned.

As the "monocyclic aromatic heterocyclic group", for example, furyl (e.g., 2-furyl, 3 - furyl), thienyl (e.g., 2-Choi, cycloalkenyl, '3-thienyl), pyridyl (e.g., 2 - pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidine sulfonyl, 4 one pyridinium Mijiniru, 5 _ pyrimidinyl, 6-pyrimidinyl), Piridajini Le (e.g., 3-pyridazinyl, 4-pyridazinyl), Birajiniru (eg, 2-Piraji yl), pyrrolyl (e.g., 1 one pyrrolyl, 2 _ pyrrolyl, 3-pyrrolyl), Imida Zoriru (e.g., 1 one imidazolyl, 2-imidazolyl, 4 f imidazolyl, 5-I imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazole Lil), thiazolyl (e.g., 2-thiazolyl, 4 one thiazolyl, 5-thiazolyl) -, isothiazoloxy Lil (e.g., 4-isothiazolyl), Okisazoriru (e.g., 2 - Okisazo Lil, 4 Okisazoriru, 5- Okisazoriru), Isookisazoriru (e.g., 5-I Sookisazoriru), Okisajiazoriru (e.g., 1, 2, 4 one Okisajiazo one Roux 5 - I le, 1, 3, 4 Okisajiazoru one-2-^ le, 1, 2, 5-Okisajiazo one rule 3 I le), thiadiazolyl (e.g., 1, 3, 4-thiadiazole - 2- I le) , Toriazoriru (e.g., 1, 2, 4-triazole-1-I le, 1, 2, 4-Toriazoru one 3- Inore, 1, 2, 3 Toriazonore one 1 one I le, 1, 2, 3 - Toriazoru one 2 - I le, 1, 2, 3 Toriazoru 4 one I le), Tetorazori Le (eg, tape Torazoru one 1 one I le, Te Torazoru one 5 _ I le), triazinyl (e.g., 1, 2, 4-triazine one 3 I le, 1, 2, 4-triazine one 5- I le, 1, 2, 4-Toriajin one 6- I le) and the like.

As the "condensed aromatic heterocyclic group", for example, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4 one quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-Isoki Noryl), quinazolyl (e.g., 2 - quinazolyl, 4 one quinazolyl), quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (e.g., 2-Ben Zofura two Honoré, 3- Benzofura two Honoré), Benzoche two Honoré column, 2-base Nzoche - Honoré , 3 Benzocheniru), benzo O hexa benzisoxazolyl (e.g., 2-base Nzookisazoriru), benzisoxazolyl O hexa benzisoxazolyl (e.g., 7-base Nzuiso 'Okisazoriru, 3-base Nzuisoo Kisazoriru), benzothiazolyl (e.g., 2- Nzochiazoriru), Benzuisochi Azoriru (e.g., 3-base lens benzisothiazolyl), benzimidazolyl (e.g., benz Imidazoru 1 Inore, base down Zi Mi imidazole-2-I le, base down Zi Mi Dazo Honoré 5-I le), benzotriazoles § benzisoxazolyl (e.g., 1 one 1, 2, 3-base Nzotoriazo rule 5- I le ), indolyl (e.g., Indoru one 1 one I le, Indoru one 2-I le, indole over 3 I le, indole one 5-I le, indole over 6 Inore), indazolyl (e.g., 1 .eta. Indazoru 3- I Le), Pirorobirajiniru (e.g., 1 .eta. pyro port [2, 3- b] pyrazin one 2-I le, 1 H- pyro port [2, 3- b] pyrazin-one 6 - I le), imidazopyridinyl (example, 1 H- imidazo [4, 5-b] pyridine one 2-I le, 1 H- imidazo [4, 5-c] pyridine one 2-I le, 2 H- imidazo [1, 2-a] pyridine one 3-I le), imidazopyrazinium Juru (eg, 1 H- imidazo [4, 5-b] pyrazin one 2 - I le), peak Zone outlet pyrid - le (Example, 1 H- pyrazole port [4, 3-c] pyridine, 3-I le), pyrazole port thienyl (e.g., 2 H- pyrazol port [3, 4-b] Chiofen one 2- I le) pyrazolo triazinyl (e.g., pyrazole port [5, 1 - c] [1, 2, 4] triazine - 3 - I le), and the like. -

As the "non-aromatic heterocyclic group", for example, nitrogen atom in addition to carbon atoms as ring atoms, to 1 heteroatoms selected from sulfur and oxygen atoms three, 5- to contain four one-stone 7-membered monocyclic non-aromatic heterocyclic group, such as bicyclic or tricyclic condensed aromatic heterocyclic group and 7 to 1 0-membered bridged heterocyclic ring group. As the "monocyclic non-aromatic heterocyclic group", for example, Tetorahi Dorofuriru, pyrosulfate lysinyl (e.g., 1 one pyrrolidine - le, 2-pyrrolidinyl, 3-pyrrolidinyl), pin Perijiniru (e.g., piperidino, '4 piperidinyl), morpholinyl (e.g., Moruho Reno), thiomorpholinyl (e.g., thiomorpholino), Kisamechiren piperazinyl (e.g., 1 over pin Perajiniru), hexamethylene iminyl (eg, hexamethylene imine-1 one I le to, Imin one 3-I-le), Okisazorijiniru (for example, Okisazorijin one 3 _ I Lumpur), thiazolidinyl '(for example, thiazolidine one 3-I-le, thiazolidine one 2 one I Lumpur), Imidazorijiniru (Italy!), Imidazorijin one 3 - I le), Birazorijini Le (eg, Birazorijin one 1 one I le), Jiokisoriru (e.g., 1, 3-di Taxol -4 one I le), Jiokisora ​​- Le (e.g., 1, 3- Jiokisoran _ 4 I le), dihydric mud O hexa di § benzisoxazolyl (e.g., 4, 5 dihydric mud one 1, 2, 4 one Okisajiazo one Lou 3 Niiru), Okisazorijiniru (e.g., 1, 3- Okisazorijin one 5- I le), Te Torahi Dorobiraniru (eg, 4 Tetorahi Dorobiraniru), and the like.

As the "fused non-aromatic heterocyclic group", for example, tetrahydro-base Nzofuraniru (eg, 4, 5, 6, 7-Tetorahi mud one benzofuran one 3-I le), Kuromeni Le (eg, 4 H- chromene one 2 f le, 2 H- chromen one 3-I le), dihydric Doroi Sokinoriniru (e.g., 1, 2-dihydrazide mud isoquinoline one 4 one I le), Tetorahi de ά isoquinolinyl (eg, 1, 2, 3, 4 Tetorahi mud isoquinoline one 4-I le), dihydric Dorofutarajuru (e.g., 1, 4-dihydrazide Dorofutarajin one 4-I le), dihydric de port isoindolyl (e.g., 1, 3- dihydric draw 2 .eta. isoindole one 2 - I le), tetrahydroquinolinyl (e.g., 1, 2, 3, 4-tetrahydroquinoline, 4-I -. le, 1, 2, 3, 4-tetrahydroquinoline one 3-I le), dihydrobenzo di O Kishuru (for example, 2 3-dihydro-1, 4 one benzodioxanyl O keys sur), Tetorahido port Benzuazepiniru (e.g., 2, 3, 4, 5 Tetorahi mud one 1 H- 1 Benzua Zepin one 1-I le), Tetorahi Doroindoriru (e.g., 4, 5, 6, 7-Tetorahi mud one 1 H- Indonore one 2-Inore), chromanyl (e.g., 2-chroma two Honoré), di hydro thiazolopyrimidinyl, such as hexa hydro Chio hexane Saturation Le and the like to. As the "bridged heterocyclic ring group", for example, quinuclidine one 3-I le, etc. 7 Azabi consequent opening [2.2.1] heptane one 3-I le can be mentioned.

"Heterocyclic group" of the "optionally substituted heterocyclic group" represented by R 1, 1 to 5 to a substitutable ability positions, even preferably have 1 to 3 substituents good, when the number of substituents is 2 or more, respective substituents may be the same or different. .

As such substituents, for example, exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such cycloalkyl substituent that may have such group.

As "optionally substituted amino group" represented by R 1, for example, their respective may be substituted. ,. Alkyl group,. Alkenyl group,. Cs- i. Sik opening alkyl group,. Cycloalkenyl group, c 6 - 14 aromatic hydrocarbon group, c 7 - 13 have been substituted with one or two substituents selected from such § La alkyl group Contact Yopi C 8 _ 13 aromatic hydrocarbon alkenyl group It includes an amino group optionally.

Here, 〇 door. Alkyl group,. Alkenyl group, Cg-i. Cycloalkyl group,

. The cycloalkenyl group, C 6 _ 14 aromatic hydrocarbon group, C 7 _ 13 Ararukiru groups and C 8 _ 13 aromatic hydrocarbon alkenyl group may be "substituted respectively represented by R 1 carbide those exemplified as the "hydrocarbon group" of the hydrogen groups "is Ru mentioned.

these. There. Alkyl group,. Alkenyl group,. 3. Cycloalkyl group, C 3. . Cycloalkenyl groups, C 6 _ 14 aromatic hydrocarbon group, C 7 _ 13 Ararukiru groups and C 8 - 13 aromatic hydrocarbon alkenyl groups can 1 at substitutable positions each have three substituents even if well, when the number of substituents is 2 or more, respective substituents may be different identical or.

As such substituents, for example,

(1) a halogen atom;

(2) alkoxy Ichiriki Ruponiru group;.

(3) 6 alkylcarbonyl group; -

(4) Shiano group;

(Five) . Alkyl group (e.g., methyl, Echiru, propyl, isopropyl, neo-pentyl) mono- or di-optionally substituted force Rubamoiru group;

(6) Non-Dorokishi group;

(7) a carboxyl group;

(8) C 6 14 aromatic hydrocarbon group (eg, off, naphthyl);

And the like.

As the "optionally substituted arsenide Dorokishi group" represented by R 1, for example, which may be their respective substituted C! I. Alkyl group,. 2. Alkenyl group, C 3 10 cyclo alkyl group, Ji! . Cycloalkenyl group, C 6 14 aromatic hydrocarbon group, C 7 _ 13 Ararukiru group, C 8 13 aromatic hydrocarbon alkenyl one force Lupo two Le group (e.g. 〇 I 6 alkyl, Asechiru, isobutanol. I le, Isopentanoiru), 5 or 6-membered aromatic Hajime Tamaki (e.g., furyl, thienyl, thiazolyl, Okisazoriru, imidazolyl, triazolyl, Birazoriru, pyrimidinyl), a fused aromatic Hajime Tamaki (e.g., India Lil) substituents selected from such in Ru include good heat Dorokishi group which may be substituted.

Here, C i. Alkyl group, C 2. Alkenyl group, C 3 i. Cycloalkyl group,. Cycloalkenyl group, C 6 _ 14 aromatic hydrocarbon group, C 7 13 Ararukiru group Oyo The beauty C 8 _ 13 aromatic hydrocarbon alkenyl group "optionally substituted hydrocarbon respectively represented by R 1 those exemplified as the "hydrocarbon group" of the group "Ru mentioned.

These. Alkyl group,. Alkenyl group, Cs i. Cycloalkyl group, C 3 ^. Cycloalkenyl group, C 6 14 aromatic hydrocarbon group, 〇 7 _ 13 Ararukiru group, C 8 _ 13 aromatic hydrocarbon alkenyl group, 0 I 6 alkyl - carbonyl group, 5- or 6-membered aromatic heterocyclic groups and fused aromatic heterocyclic group, each of 1 to a substitutable position -. may have teeth 3 substituents, when the number of substituents is 2 or more, respective substituents have the same or different it may be.

As such substituents, for example,

(1) a halogen atom; -

(2) Non-Dorokishi group;

(3) Shiano group;

(4) a halogen atom, a carboxyl group, 〇 preparative 6 alkoxy one carbonyl group and force Rubamoiru one or two optionally substituted with a substituent C i _ 6 alkyl group selected from the group;

(5) a halogen atom, a carboxyl group Contact Yopi 〇 bets 6 1 or 2 substituents alkoxy group optionally substituted by a group selected from alkoxy one carbonyl group;

(6) 6 alkylthio group (e.g., methylthio, Echiruchio);

(7) C 6 alkyl one carbonyl group (e.g., Asechiru, Isobutanoiru, Isopen Tanoiru);

(8) force Norebokishinore group;

(9) 0 bets 6 alkoxy one carbonyl group;

(Ten) . Alkyl group (e.g., methyl, Echiru, propyl, isopropyl, neo-pentyl) mono- or di-optionally substituted force Rubamoiru group;

(11). Alkyl group (e.g., methyl, Echiru, propyl, isopropyl, neo-pentyl) amino group which may optionally be mono- or di-substituted by;

(12) - 6 alkyl - carbonyl § amino group (e.g., Asechiruamino);

(13) alkyl group, a carboxyl group, an alkoxy one carbonyl group Oyo Pi Karupamoiru one to three optionally substituted with a substituent Fang aromatic Hajime Tamaki selected from the group (e.g., furyl, thienyl, Okisazoriru, thiazolyl, Isookisa Zoriru, tetrazolyl, Okisajiazoriru, thiadiazolyl, pyridyl);

(14) an alkylsulfinyl group (e.g., methylsulfinyl);

(15) 0 I 6 alkylsulfonyl group (e.g., methylsulfonyl);

And the like. R 1 is preferably an optionally substituted hydrocarbon group. Here, the hydrocarbon group is preferably Flip. An alkyl group Contact Yopi C 7 _ 13 Ararukiru group, good Mashiku to Kira. Is an alkyl group.

"Optionally substituted hydrocarbon group" represented by R 2, "but it may also be substituted heterocyclic group", "optionally substituted amino group" and "good substituted I-hydroxy the group ", for example, those exemplified as each of the R 1 can be mentioned up.

R 2 is preferably hydrogen atom.

"Optionally substituted hydrocarbon group" represented by R 3, "but it may also be substituted heterocyclic group", "optionally substituted amino group" and "good substituted I-hydroxy the group ", for example, those exemplified as each of the R 1 can be mentioned up.

R 3 is preferably hydrogen atom.

"Optionally substituted hydrocarbon group" represented by R 4, the "but it may also be substituted heterocyclic group" and "amino group which may be substituted", for example, their respective said R It includes those exemplified as 1.

The "substituted human Dorokishi group" represented by R 4, for example, the out of exemplified as R 1 'which may be substituted arsenide Dorokishi group "include groups other than human Dorokishi group.

R 4 is, CI_ preferably the "optionally substituted hydrocarbon group" and "optionally substituted amino group", more preferably, that may be replacement by "1 to 3 halogen atoms 6 alkyl group, hydroxy groups, C WINCH 6 alkoxy group, Xia amino group and one to three substituted C 6 _ 14 optionally aromatic hydrocarbon group substituted by a group selected from a halogen atom "," substituted it is substituted with a which may C 6 _ 14 aromatic hydrocarbon group optionally an amino group ".

'Among them, one to three which may be alkyl Le group substituted with a halogen atom, 〇 6 alkoxy group, optionally substituted with 1 to 3 substituents selected from Shiano group Contact Yopi halogen atom Yoi Bifueyuriru group is preferred.

As the "ring" of the "optionally substituted ring" for ring A, aromatic hydrocarbon ring, non-aromatic hydrocarbon ring, aromatic heterocyclic, non-aromatic heterocyclic ring.

As the "aromatic hydrocarbon ring", for example, benzene, naphthalene, Anne; Torase down, 'Fuenantoren, Asenafuchiren, like biphenyl.

As the "non-aromatic hydrocarbon ring", for example, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, butadiene cyclohexane, indene, indane, 1, 2, 3, 4 Tetorahi mud naphthalene , and the like Benzoshiku opening heptane.

As the "aromatic heterocycle", for example, ring-constituting atoms of nitrogen atom in addition to carbon atoms as, to 1 heteroatoms selected from sulfur and oxygen atoms 3, 1 to 5 to 7-membered containing four monocyclic aromatic heterocycle and a bicyclic or tricyclic ChijimigoKaoru aromatic heterocycles.

The "monocyclic aromatic heterocycle", for example, furan, Chiofen, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, Ji Azoru, Isochiazonore, old Kisazonore, I Soo hexa zone Honoré, Okisajiazo one Le (example, 1, 2, 4-Okisajiazoru, 1, 3, 4 one Okisajiazoru), thiadiazole (e.g., 1, 2, 4-thiadiazole, 1, 3, 4 Chiajiazo Le), Toriazoru (e.g., 1, 2, 4-triazole, 1, 2, 3 Toriazo Le), tetrazole, triazine (e.g., 1, 2, 4 one triazine), etc. furazane and the like.

The "condensed aromatic heterocycle", for example, quinoline, isoquinoline, Kinazori down, quinoxaline, benzofuran, Benzochiofuwen, Benzuokisazo one / Les, base lens isobutyl O benzoxazole, benzothiazole, naphtho [2, 3- b] Chiofen, benzimidazole, benzotriazole § tetrazole, India ^ Le, isoindole, 1 H- indazole, purine, 4 H- quinolizine, phthalazine, naphthyridine, cinnoline, carbazole, J8- carboline, Hue phenanthridine, Akurijin, Fuenajin, Buenochiajin, Fuenokisajin , Pirorobirajin (eg, 1 H- pyro port [2, 3 - b] pyrazine), imidazopyridine (e.g., 1 H- imidazo [4, 5-b] pyridine, 1 H- imidazo [4, 5-c] pyridine , 2 H- imidazo [1, 2-a] pyridine), Imidazopiraji down (Example, 1 H- imidazo [4, 5-b] pyrazine), pyrazole port pyridine (Example, 1 H- Pi Razoro [4, 3- c] pyridine), pyrazolopyridine Chio Fen (eg, 2 H- pyrazole port [3, 4 Ma - b] Chiofen) pyrazolo triazines (eg, pyrazole port [5, lc] [l, 2, 4] preparative "Riaji down), and the like.

As the "non-aromatic heterocycle", for example, nitrogen atom in addition to carbon atoms as ring atoms, to 1 heteroatoms selected from sulfur and oxygen atoms three, four 5 containing from 1 to 7 membered monocyclic non-aromatic heterocycle, such as bicyclic or tricyclic fused non-aromatic heterocyclic rings and 7 to 1 0-membered bridged heterocyclic ring.

As the "monocyclic non-aromatic heterocycle", for example, pyrrolidine, imidazoline, pin Razorijin, pyrazoline, piperidine, piperidines Rajin, hexamethylene I Min, I Midazorijin, Birazorijin, Jiokisoru, Jiokisoran, Jihidorookisaji Azoru ( example, 4, 5-dihydro-one 1, 2, 4-Okisajiazoru), Okisazori Jin (e.g., 1, 3 one Okisazorijin), tetrahydropyran, morpholine, Chio morpholine, Jiokisazoru, Okisazorijin, Okisajiazorin, thiazolidine down, thiadiazoline, Toriazorin, dithiazole and the like.

As the "fused non-aromatic heterocycle", for example, Tetorahi Dorobe Nzofuran (e.g.,

4, 5, 6, 7-tetrahydrobenzo furan), chromene (eg, 4 H- chromene, 2 H- chromene), dihydric mud isoquinoline (Example, 1, 2-dihydrazide Doroisokinori down), tetrahydroisoquinoline (e.g., 1, 2 , 3, 4-tetrahydroisoquinoline quinoline), dihydric Dorofutarajin (e.g., 1, 4-dihydro-phthalazine), dihydric Doroi Seo indole (example, 1, 3-dihydrazide chondroitinase 2 H- isoindole), Tetorahi mud quinoline ( example, 1, 2, 3, 4-tetrahydroquinoline), and the like.

The "bridged-hetero ring", for example, Kinutarijin, 7- Azabishikuro [2.2.1] heptane, and the like.

"Ring" indicated by the "ring which may be substituted" in the ring A, is preferably a 5-membered aromatic heterocyclic ring, more preferably furan, Chiofuwen, pyrrole, imidazole, Pirazonore, thiazole, Okisazonore, iso Okisazonore, Okisajiazo Lumpur (e.g., 1, 2, 4 one Okisajiazoru, 1, 3, 4 Okisajiazoru), thiadiazole (e.g., 1, 2, 4-thiadiazole, 1, 3, 4 Chiajiazo Le), Toriazoru (eg, 1, 2, 4 one Toriazoru, 1, 2, 3 Toriazo Le) and the like. Among them, pyrazole, Okisazoru and Okisajiazo Ichiru -

(Example, 1, 2, 4-Okisajiazoru, 1, 3, 4 Okisajiazo Ichiru); is favored arbitrariness.

Exemplified aromatic carbon hydrocarbon rings and aromatic heterocyclic rings as "ring" of the "optionally substituted ring" for ring A, 1 to 3 at substitutable positions, two preferably from 1 to it may have a substituent, and when the number of the substituents is 2 or more, respective substituents may be the same or different.

Such substituents include, for example, C 3 exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such substituents except Okiso group from cycloalkyl substituent which may have such group.

Non-aromatic hydrocarbon rings and non-aromatic heterocycles exemplified as the "ring" of the "optionally substituted ring" for ring A optionally has 1 to 5 at substitutable positions, and preferably contains 1 3 it may have substituents, and, when the number of substituents is 2 or more, each location substituent may be the same or different.

As such substituents, for example, exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such cycloalkyl substituent that may have such group.

As "divalent chain group of the main chain atoms of 1 to 6" represented by X, for example, C - 6 alkylene group (e.g., methylene, ethylene, one (CH 2) 3 -, -CH (CH 3) - CH 2 _, -CH 2 -CH (CH 3) one, - (CH 2) 4 one, -CH (CH 3) one (CH 2) 2 -, - (CH 2) 2 - CH (CH 3) one one C (CH 3) 2 -CH 2 -, one CH 2 -C (CH 3) 2 -); _CH in the 6 alkylene group 2 - is one O-, one NH- or a S- in substituted radicals; C 2 - 6 a ^ / Keniren group (e.g., vinylene, pro Bae ylene one C (CH 3) = CH-, -CH = C (CH 3) one, 2-butene one 1- Iren , hexene one 1- Iren) 4-penten one 1- Iren, to 5; said C 2 - 6 § Luque twenty-one in Ren groups CH 2 - is one O-, substituted in one NH- or a S- group; and the like are used.

Here, one CH 2 of 6 alkylene or C 2 _ 6 alkenylene group - is - O-, position to be substituted on one NH- or a S-, the end of the alkylene group or該A Luque two alkylene groups or it may be either in the chain. In addition, the - 6 alkylene group and C 2 - 6 alkenylene group, to 1 to a substitutable positions may have three substituents, and when the number of the substituents is 2 or more, each location substituent it may be the same or different.

As such substituents, for example, exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such substituent which may be optionally having an alkyl group.

X is preferably an ethylene group.

Compound (I) is preferably of formula

Wherein ring Aa is a 5-membered aromatic heterocyclic ring may be substituted,

R la is Ji may be substituted. Alkyl group, optionally substituted C 7 - 13 Ararukiru group, an optionally substituted amino group or an optionally substituted hydrin port alkoxy group,

R 2 a is Ji hydrogen atom, it may be substituted.13 Ararukiru group, - an alkyl group or an optionally substituted C 7

R 3 and R 4 are as defined above,

And X a represents an ethylene group which may be substituted. Or a salt thereof] is (herein, the compound (II) and is sometimes abbreviated).

Represented by R 1 a "may be substituted . Alkyl group ". The Al kill group ", for example, include those exemplified as the" hydrocarbon group "of the" optionally substituted hydrocarbon group "represented by R 1. "C 1 alkyl -. Group" optionally has 1 to 5 at substitutable positions, preferably may have have a 1 to 3 substituents, when the number of substituents is 2 or more, the substituents it may be the same or different.

As such substituents, for example, exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such substituent which may be possessed by the alkyl group.

The substituents are preferably

(I) human Dorokishi group,

(ii) C 6 _ 14 aromatic hydrocarbon Okishi group (preferably off Niruokishi),

(iii) 1 to 3 may be substituted with a halogen atom 〇 DOO 6 alkyl group, arsenate Dorokishi group, an alkoxy group, Okiso group, a halogen atom Contact Yopi C 6 _ 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (wherein C 6 - 14 aromatic hydrocarbon group 1 to 3 halogen atoms in Ji may be substituted alkyl groups, human Dorokishi group C i _ 6 alkoxy Contact Yopi Ha port Gen one to three one to three but it may also be substituted by a substituent non-aromatic Hajime Tamaki (preferably morpholinyl selected from also may) have been substitution with a substituent selected from the atoms, thiomorpholinyl pyrrolidin Le, Tetorahi Dorofuriru, piperidinyl, piperidines Rajuru, benzodioxanyl O key sky sulfonyl dihydric mud benzodioxanyl O key sur, dihydric Doroi Soki quinolinyl, Tetorahi Dorobe Nzua Zepiniru, Tet Human Dorokinoriniru, Tetorahi Doroi Soki quinolinyl)

(Iv) a halogen atom and 1 to 3 substituents in replacement which may be Ci-e alkoxy group selected from human Dorokishi group,

(V) 1 to 3 halogen atoms substituted by at which may be Arukiru group mono or di-optionally substituted force Rubamoiruokishi group,

(vi) C 6 alkyl group (the - 6 alkyl group is a halogen atom, arsenic Dorokishi group, forces Rupokishiru group, 6 alkoxy group, C ^ 6 alkoxy - to 1 selected from carbonyl groups Contact Yopi Cal Pamoiru group 3 may be substituted with a substituent), C 3 _ 10 cycloalkyl group (e.g., cyclopropyl, cyclohexyl), alkyl one carbonyl group (e.g., Asechiru, Isoputanoiru, Isopentanoiru) and C 6 - 14 aromatic hydrocarbon hydrogen group (e.g., off, naphthyl) (wherein C 6 _ 14 aromatic hydrocarbon group 1 to 3 substituents which may be alkyl groups with a halogen atom, human de proxy groups, C ^ e alkoxy group and one to three substituents optionally substituted) mono- or disubstituted amino group which may be substituents selected from-selected from a halogen atom,

(vii) 1 to 3 substituents which may be C 6 alkyl group by a halogen atom, arsenic Dorokishi group, 6 alkoxy group, a halogen atom and C 6 - 14 aromatic hydrocarbon, group (e.g., phenyl, naphthyl) selected 6 alkyl group, hydroxy group, a C physician 6 alkoxy group Contact Yopi Ha port Gen atom - (to the C 6 _ 14 aromatic hydrocarbon group is not 1, may be substituted by pieces of wafer androgenic atoms one to three one to three optionally substituted with a substituent an aromatic double ring group (e.g. selected from substituted or may be) with a substituent, thienyl, furyl, Okisazoriru, thiazolyl, pyrazolyl , pyridyl, pyrazinyl, Imidazoriru, monocyclic aromatic heterocyclic group such as Isookisazoriru; indolyl, benzofuranyl, Benzocheniru, pyro port pyrid - le, reluctant alkenyl, Benzui Dazoriru, benzotriazolyl, fused aromatic heterocyclic groups such Indazoriru)

(viii) C 7 _ 13 7 aralkyl group (e.g., benzyl, phenethyl, phenylpropyl) which may also be a non-aromatic heterocyclic force Rubamoiru group (eg, Piperijinirukaru Bamoiru) substituted with the like.

R 1 as "C 7 _ 13 § aralkyl group" of the "optionally substituted C 7 _ 13 Ararukiru group" represented by a, for example, the R 1 'may carbonization substituted represented by those exemplified as the "hydrocarbon group" of the hydrogen groups ". The "C 7 - 13 § La alkyl group" optionally has 1 to 5 at substitutable positions, preferably may have 1 to 3 substituents, when the number of substituents is 2 or more, each substituents may be different from one identical or. Further, these substituents may be substituted on any of the aromatic hydrocarbon group Contact Yopi alkyl group constituting the "C 7 _ 13 Ararukiru group".

Such substituents include, for example, illustrated C 3 _i as "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such cycloalkyl substituent that may have such group.

The substituents are preferably

(I) a halogen atom,

(Ii) human Dorokishi group,

(Iii) amino group,

(iv) a halogen atom, a force Rupokishiru group, 〇 6 alkoxy one carbonyl group and to 1 selected from Karupamoiru group 3 substituents substituted 6 may be an alkyl group with a group,,

(v) 1 to 3 alkyl optionally substituted by halogen atom, arsenic Dorokishi group, to 1 selected from alkoxy groups Contact Yopi halogen atoms which may be substituted with 1-3 substituents C 6 _ 14 aromatic hydrocarbon group (preferably phenylene Le), ■

(vi) 1 to 3 of which may be an alkyl group substituted with a halogen atom, arsenic Dorokishi group, to 1 selected from alkoxy groups and halogen atoms may be substituted with 1-3 substituents C 7 _ 13 Ararukiru group (preferably benzyl),

(vii) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, 0 6 alkoxy group, a halogen atom Contact Yopi C 6 _ 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (the C 6 14 aromatic hydrocarbon group one to three C androgenic atoms optionally substituted 〇 DOO 6 alkyl group, 'human Dorokishi group, a C ^ alkoxy group Contact Yopi Ha port Gen atoms one to three one to three optionally substituted with a substituent an aromatic double ring group (e.g. selected from substituted or may be) with a substituent selected, thienyl, furyl, Okisazoriru, thiazolyl , pyrazolyl, pyridyl, Pirajuru, Imidazoriru, monocyclic aromatic heterocyclic group such as Isookisazoriru; indolyl, benzofuranyl, Benzocheniru, pyrosulfate port pyridinyl, reluctant alkenyl, Benzuimi Zoriru, benzotriazolyl, fused aromatic heterocyclic groups such Indazoriru)

(viii) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, CI_ 6 alkoxy group, Okiso group, a halogen atom and C 6 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (the C 6 - 14 aromatic hydrocarbon group 1 to 3 halogen atoms in Ji may be substituted alkyl groups, human Dorokishi group, 1 to 3 substituents selected from an alkoxy group and a halogen atom in to 1 selected from substitution may be) of three but it may also be substituted by a substituent non-aromatic Hajime Tamaki (preferably morpholinyl, thiomorpholinyl, pyrrolidine -. le, Tetorahi Dorofuriru, Piperi Jiniru , piperidines Rajuru, benzodioxanyl O key Sola sulfonyl, dihydric Dorobe Nzojiokishiniru, dihydric Doroi Soki quinolinyl, Tetorahi Dorobe Nzua Zepiniru, Tetorahi Dorokinoriniru, Tetorahi Doroi Soki quinolinyl), and the like 1 to 3 substituents in replacement by 〇 may DOO 6 alkoxy group selected from (ix) a halogen atom Contact Yopihi Dorokishi group.έ

R "optionally substituted amino group" and "substituted Moyoihi Dorokishi group" represented by 1 a, those exemplified as each of the R 1 are found using. .

R 1 a is preferably "optionally substituted C 1. Alkyl group" or "substitution which may be C 7 _ 13 Ararukiru group", more preferably it may be "substituted. it is an alkyl group ".

The "optionally substituted c ^. Alkyl group", preferably,

(I) human Dorokishi group,

(ii) c 6 - 14 aromatic hydrocarbon Okishi group (preferably Fueniruokishi),

(iii) 1 to may be substituted by 3 halogen atoms - 6 alkyl group, arsenate Dorokishi group, 〇 I 6 alkoxy group, Okiso group, a halogen atom and C 6 _ 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (wherein C 6 _ 14 aromatic hydrocarbon group 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, a C! _ 6 alkoxy group Contact Yopi halogen atom one to three one to three but it may also be substituted by a substituent non-aromatic Hajime Tamaki (preferably morpholinyl selected from also may) have been substitution with a substituent selected, thiomorpholinyl, pyrrolidin Le, Tetorahi Dorofuriru, Piberiji - Le, piperazinyl, benzodioxanyl O key Sola sulfonyl, dihydric mud benzodioxanyl O key sur, dihydric Doroi Soki quinolinyl, Tetorahi Dorobe Nzua Zebyuru, Torahi Dorokinori cycloalkenyl, 'Tetorahi Doroi Soki quinolinyl)

(iv) to 1 selected from a halogen atom Contact Yopihi Dorokishi group may be replacement by 3 substituents - 6 alkoxy group,

(V) 1 to 3 may be substituted with a halogen atom 〇 I 6 alkyl group mono or di-optionally substituted force Rubamoiruokishi group,

(vi) alkyl groups (said C 6 alkyl group is a halogen atom, arsenic Dorokishi group, forces Rupokishiru group, CI_ 6 alkoxy group, C! to 1 selected from -e alkoxy one carbonyl group Contact Yopi Cal Bamoiru group 3 may be substituted with a substituent), C 3 _ 10 cycloalkyl group (e.g., cyclopropyl, cyclohexyl), 〇 β alkyl - Karuboeru group (eg, Asechiru, Isoputanoiru, Isopentanoiru) and C.-

6 _ 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (wherein c 6 _ 14 aromatic Sumyi hydrogen groups 1 to 3 of which may be substituted with a halogen atom 0 I 6 alkyl group, human de proxy group, one to three mono-Rui with a substituent selected from may) be substituted with a substituent amino group which may optionally be disubstituted selected from alkoxy groups Contact Yopi halogen atom,

(vii) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, an alkoxy group, a halogen atom and C 6 _ 14 aromatic hydrocarbon group (eg, off, naphthyl) (the C 6 14 aromatic hydrocarbon group one to three C androgenic may be substituted with atoms 〇 Bok 6 alkyl group, one to three human Dorokishi group, selected from C 6 alkoxy group Contact Yopi halogen atom substituents substituted by 1 selected from may also) have to three optionally substituted with a substituent an aromatic double ring group (e.g., thienyl, furyl, Okisazoriru, thiazolyl, pyrazolyl, pyridyl, Pirajuru, imidazolyl, monocyclic aromatic heterocyclic group such as Isookisazoriru; Indorinore, Benzofura two / Les, Benzoche two Honoré, pyromellitic port Pirijininore, reluctant alkenyl, Benzui Imidazolyl, benzotriazolyl, fused aromatic heterocyclic groups such Indazoriru) and,

(viii) C 7 _ 13 Ararukiru group (e.g., benzyl, phenethyl, phenylpropyl) non-aromatic and may be substituted by a heterocyclic force Rubamoiru group (eg, Piperijinirukaru Roh Moinore)

It 1 selected from a three may be substituted with a substituent ^ alkyl group.

The "optionally substituted C 7 _ 13 Ararukiru group", preferably,

(I) a halogen atom,

(Ii) human Dorokishi group,

(Iii) amino group,

(iv) a halogen atom, a carboxyl group, 〇 6 alkoxy - carbonyl group Contact Yopi force Rubamoiru one to three substituted with a substituent which may be Ji 6 alkyl group selected from the group, three to (v) no 1 optionally substituted alkyl group with a halogen atom, heat -. Dorokishi group, C i _ 6 alkoxy group and one to three optionally substituted with a substituent C 6 _ 1 4 selected from halogen atoms aromatic hydrocarbon group (preferably phenylene Le),

(vi) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, 〇 6 alkoxy to 1 selected from group and a halogen atom 3 may be substituted with a substituent 〇 7 _ 1 3 Ararukiru group (preferably benzyl),

(vii) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, an alkoxy group, a halogen atom and C 6 1 4 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (the 4 aromatic hydrocarbon group one to three C androgenic alkyl group which may be substituted with atoms, human Dorokishi group, - 1 selected from 6 alkoxy group Contact Yopi Ha port gen atom to three substituents 1 to 3 substituents in the optionally substituted aromatic double heterocyclic group (e.g. selected from may also) be substituted with a group, thienyl, furyl, Okisazoriru, thiazolyl, pyrazolyl, pyridyl, Pirajuru, imidazolyl, monocyclic aromatic heterocyclic group such as Isookisazoriru; Indorinore, Benzofura - Le, Benzoche two Honoré, pyromellitic port Pirijininore, reluctant Interview Le, benz I Mi Dazo Lil, benzotriazolyl, condensed aromatics such Indazoriru complex ring group),

(vii i) 1 to 3 may be substituted with a halogen atom 〇 6 alkyl group, arsenate Dorokishi group, C 6 alkoxy group, Okiso group, a halogen atom Contact Yopi C 6 _ 1 4 aromatic hydrocarbon group (eg, Hue - Le, naphthyl) (wherein C 6 1 4 aromatic hydrocarbon group 1 to 3 substituents C 6 alkyl group optionally substituted by a halogen atom, arsenic Dorokishi group, C ^ e alkoxy group and one to three to 1 selected from may be substitution) substituents three but it may also be substituted by a substituent non-aromatic Hajime Tamaki selected from a halogen atom (preferably morpholinyl , thiomorpholinyl, pyrrolidin Le, Tetorahi Dorofuriru, piperidinyl, piperidines Rajuru, benzodioxanyl O key Sola sulfonyl, dihydric mud benzodioxanyl O key sur, dihydric mud isoquinolizinyloxy linear Honoré, Tetorahi Dorobe Nzua Zepieru, Torahi Dorokinoriniru, Tetorahi Doroi Soki quinolinyl) and

(Ix) optionally substituted with 1 to 3 substituents in replacement has been Also good Ci-s alkoxy group, 1 selected from to 3 substituents selected from halogen atom and human Dorokishi group a C 7 _ 13 Ararukiru group.

R 2 represented by a "optionally substituted Ci i. Alkyl group" include and "may be substituted. 7 _ 13 Ararukiru group", for example, as illustrated each said R 1 a thing, and the like.

R 2 a may preferably be a hydrogen atom or a substituent. Alkyl group, more preferably a hydrogen atom.

Represented by ring Aa as "5-membered aromatic heterocycle" of the "optionally substituted 5-membered aromatic heterocyclic ring", the represented by ring A of the "optionally substituted ring", "ring" and it was among the exemplified aromatic heterocyclic ring, is used as a 5-membered ring.

In Formula (II), the partial structural formula

It is, preferably,

It is.

"5-membered aromatic heterocycle" of the "optionally substituted 5-membered aromatic heterocycle" for ring A a is to 1 at substitutable positions may have two substituents , when the number of substituents is two, the respective substituents may be the same or different.

'As such substituents, for example, illustrated C 3 _ i as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such substituents except Okiso group from cycloalkyl substituent which may have such group.

"Ethylene group" of X gamma optionally substituted ethylene group represented by a "may have 1 to 3 substituents at substitution possible positions, the number of the substituents is two or more. - in the case, the substituents may be the same or different. ¾ As such substituents, eg, C 1 exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R 1. Such substituent which may be optionally having an alkyl group. -

X a is preferably an ethylene group.

As preferable examples of compound (II) include the following compounds.

R 1 a is

(1) (i) human Dorokishi group,

(ii) C 6 _ 1 4 aromatic hydrocarbon Okishi group (preferably Fueniruokishi),

(iii) 1 to 3 may be substituted with a halogen atom 〇 6 alkyl group, arsenate Dorokishi group, C ^ e alkoxy group, Okiso group, a halogen atom and C 6 _ 1 4 aromatic hydrocarbon group (eg , phenyl, naphthyl) (wherein C 6 - 1 4 aromatic hydrocarbon group one to three alkyl group which may be substituted by a halogen atom, human Doroki sheet group, to 1 selected from alkoxy groups and halogen atoms 1 selected from the three may be substituted with a substituent) to three optionally substituted with a substituent non-aromatic Hajime Tamaki may be (preferably morpholinyl, thiomorpholinyl, pyrosulfate Rijininore, Tetorahi Dorofurinore, piperidinyl , Piperajininore, Benzojiokiso Ranil, dihydric mud benzodioxanyl O key sur, dihydric Doroi Soki quinolinyl, Tetorahi mud Benzuazebyuru Tetorahi Dorokinoriniru, Tetorahi Doroi Soki quinolinyl)

(Iv) 1 to 3 substituents alkoxy group which may be substituted with a group selected from a halogen atom Contact Yopihi Dorokishi group,

(V) 1 to 3 halogen atoms may be substituted - 6 alkyl group mono- or di-optionally substituted force Rubamoiruokishi group,

(vi) C Bok 6 alkyl group (the alkyl group is a halogen atom, arsenic Dorokishi group, and a carboxyl group, an alkoxy group, optionally substituted with 1-3 substituents to 1 selected from alkoxy Ichiriki Ruponiru groups and force Rubamoiru group ^ may also be), C 3. Cycloalkyl group (e.g., cyclopropyl, cyclohexyl), 6 alkyl Le Ichiriki Ruponiru group (eg, Asechiru, Isobutanoiru, Isopentanoiru) and C 6 _ 1 4 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (the c 6 1 4 aromatic hydrocarbon group 1 to 3 substituents which may be C i _ 6 alkyl / group by a halogen atom, arsenic Dorokishi group, to 1 selected from alkoxy groups Contact Yopi halogen atom 3 substituents in substituted with a substituent selected from may also) have mono- or di-optionally substituted amino group, -

(vii) 1 to 3 may be substituted with a halogen atom 〇 DOO 6 alkyl group, arsenate Dorokishi group, 0 WINCH 6 alkoxy group, a halogen atom Contact Yopi 〇 6 _ 1 4 aromatic hydrocarbon group (eg , off, naphthyl) (wherein C 6 - 1 4 aromatic hydrocarbon group 1 to 3 halogen atoms which may be substituted d 6 alkyl group, arsenate Dorokishi groups, C physician 6 alkoxy group Contact Yopi it 1 selected from a halogen atom 3 to 1 selected from may) be substituted with a substituent three optionally substituted with a substituent aromatic Hajime Tamaki (e.g., thienyl, furyl ,, Okisazoriru, thiazolyl, pyrazole Le, pyridyl, Pirajuru, Imidazoriru, monocyclic aromatic double heterocyclic group such Isookisazoriru; indolyl, Benzofuraeru, Benzocheniru, pyrosulfate port pyridinyl, key Noriniru, Ben Imidazoriru, benzotriazolyl, fused aromatic heterocyclic groups such Indazoriru) and

(viii) C 7 _ 1 3 Ararukiru group (e.g., benzyl, phenethyl, Fuenirupuropi Le) non-aromatic and may be substituted by a heterocyclic force Rubamoiru group (e.g., piperidinyl Karupamoinore)

One to three may be substituted with a substituent 〇 I 6 alkyl group selected from; or

(2) (i) a halogen atom,

(Ii) human Dorokishi group,

(I ii) amino group,

(iv) a halogen atom, a carboxyl group, 〇 6 alkoxy one carbonyl group Contact Yopi Karupamoiru one to three optionally substituted with a substituent C 6 alkyl group selected from the group, -

(V) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, 1 to 3 substituents may be substituted with a group c 6 _ 14 selected from alkoxy groups and halogen atoms aromatic hydrocarbon group (preferably Hue Le), ¾

(Vi) 1 to 3 optionally substituted ^ alkyl group with a halogen atom, arsenic Dorokishi group, - 1 selected from 6 alkoxy Contact Yopi halogen atom to be substituted with 1-3 substituents which may C 7 - 13 7 aralkyl group (preferably base Nji Le),

(vii) 1 to 3 may be substituted with a halogen atom 〇 DOO 6 alkyl group, arsenate Dorokishi group, 〇 6 alkoxy group, a halogen atom and C 6 14 aromatic hydrocarbon group (e.g., phenyl, naphthyl) (the C 6 _ 14 aromatic hydrocarbon group one to three which may be an alkyl group substituted with a halogen atom, arsenic Dorokishi group. preparative 6 to 1 selected from alkoxy Contact Yopi Ha port Gen atoms 3 to 1 selected from may) be substituted with a substituent three optionally substituted with a substituent aromatic Hajime Tamaki (e.g., thienyl, furyl, Okisazoriru, thiazolyl, pyrazolyl, pyridyl, Pirajuru, Imidazoriru, monocyclic aromatic double heterocyclic group such Isookisazoriru; indolyl, benzofuranyl, Benzocheniru, pyrosulfate port pyridinyl, key Noriniru, Benzui Imidazolyl, benzotriazolyl, fused aromatic heterocyclic groups such Indazoriru).

(viii) 1 to 3 halogen atoms which may be substituted alkyl group, human Dorokishi group, an alkoxy group, Okiso group, a halogen atom Contact Yopi C 6 _ 14 aromatic hydrocarbon group (eg, full sulfonyl , naphthyl) (selected from the C 6 _ 14 aromatic hydrocarbon group 1 to 3 substituents C ^ e alkyl group optionally substituted by a halogen atom, hydroxycarboxylic group, CI- 6 alkoxy group and a halogen atom one to three to 1 selected from substituted or may be) at location substituent three may be substituted with a substituent non-aromatic Hajime Tamaki (preferably morpholinyl are, Chiomoruhorieru, pin Rorijiniru, Tetorahi Dorofuriru, piperidines lysinyl, piperazinyl, Benzojioki Soraniru, dihydric mud benzodioxanyl O key sur, dihydric Doroi Soki quinolinyl, Tetorahi de port base Nzuazepiniru, tetra Human Dorokinoriniru, Tetorahi Doroi Soki quinolinyl) and

(ix) substituted with 1 to 3 substituents substituted with a substituent C! 6 alkoxy group, 1 selected from to 3 substituents selected from halogen atoms Contact Yopihi Dorokishi group which may C 7 _ 13 Ala Rekiru group;

R 2 a is a hydrogen atom;

R 3 is a hydrogen atom; -

R 4 is 1 to 3 substituents which may be alkyl groups with a halogen atom, an alkoxy group, one to three optionally substituted with a substituent Bifuwe two drill group selected from Shiano group and a halogen atom;

Partial structural formula

There or

And, X a is an ethylene group;

The compound is.

Compound (I) and compound (II), more preferably formula

I picture U Roh

[In the formula, ring Ab is

R lb is an optionally substituted C. An alkyl group,

R 3 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group or an optionally substituted hydroxy group,

R 4 b is 1 to 3 are 〇 may 6 alkyl group substituted with a halogen atom, an alkoxy group, to 1 selected from Shiano group and a halogen atom 3 -. May be substituted with a substituent It shows the Bifuweniriru group.

However, when the ring A is,

R 1 b is 3- (1H-Imidazoru - 1-I) propyl group, (RS)-2-morpholino - 3-Fueno Kishipuropiru group, (RS) -2- (Jimechiruamino) - 3-phenylpropyl group or 2 - not (1, 3 - dihydric mud - 2H-isoindole - - 2 I le) Echiru group. A compound or a salt thereof].

Represented by R lb 'may be substituted.. Alkyl group "include the

Those exemplified as R 1 a and the like.

"No 1 represented by R 4 b to three may be substituted with a halogen atom Ji 6 alkyl group, alkoxy group, substituted by 1 to 3 substituents selected from Shiano group Contact Yopi halogen atom the Bifuwe two Lil group "may be, it includes those exemplified as the R 4.

Among also compound (lib), the following compounds are preferred.

1) ring Ab is.

In a compound (lib).

2) R lb force S

(I) human Dorokishi group,

(ii) C 6 _ 14 aromatic hydrocarbon Okishi group (preferably off Niruokishi),

(iii) 1 to may be substituted by 3 halogen atoms - 6 alkyl group, arsenate Dorokishi group, C ^ e alkoxy group, Okiso group, a halogen atom Contact Yopi C 6 _ 14 aromatic hydrocarbon group ( the C 6 _ i 4 aromatic hydrocarbon group 1 to 3 substituents which may be alkyl groups with a halogen atom, hydroxy group, 〇 Bok 6 to 1 selected from alkoxy and C androgenic atoms 3 substituents morpholinyl), one to three rather non-aromatic Hajime Tamaki (preferably which may be substituted with a substituent barrel selected from may also) be substituted with a group,

(iv) a halogen atom and one to three still at location based conversion which may be optionally 〇 6 alkoxy group selected from human Dorokishi group,

(V) 1 to 3 of Mo optionally substituted with also an alkyl group with a halogen atom Roh or di-optionally substituted force Rubamoiruokishi group,

(vi) 〇 bets 6 alkyl group (the - 6 alkyl group is a halogen atom, arsenic Dorokishi group, forces Rupokishiru group, 6 alkoxy group, - 1 selected from 6 alkoxy one carbonyl group and cull Pamoiru group to three substituents in may be substituted), C 3 _ i. Cycloalkyl group, an alkyl one carbonyl group and C 6 _ 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbon group 1 to 3 substituents C ^ e alkyl group optionally substituted by a halogen atom , human Dorokishi group, one to three optionally substituted with a substituent mono location substituent selected from may also be) or di-substituted by an amino group which may be selected from alkoxy and halogen atom,

(vii) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, an alkoxy group, a halogen atom Contact Yopi 〇 6 _ 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbons hydrogen group one to three optionally substituted 〇 I 6 alkyl group by a halogen atom, arsenic Dorokishi group, optionally substituted with 1-3 substituents to 1 selected from alkoxy groups Contact Yopi halogen atom Yo Le optionally substituted by 1 a stone 3 substituents selected from good), aromatic Hajime Tamaki (preferably base Nzofu Rael, benzimidazolyl) and

(viii) C 7 _ 13 non-aromatic may be substituted by Ararukiru group heterocyclic Karupamoi Le group

1 to be substituted with 1-3 substituents also 'a good 〇 I 6 alkyl group compound selected from (lib).

3) ring Ab is

R lb is 1 to 3 may be substituted with a halogen atom 〇 6 alkyl group, arsenate Dorokishi group, an alkoxy group, a halogen atom and C 6 - 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbon group of 1 to 3 substituted with a halogen atom .- may CI- 6 alkyl group: human Dorokishi group, 〇 6 alkoxy and halogen; with 1 to 3 substituents selected from the emissions atoms it is 1 a stone 3 substituents in the optionally substituted fused aromatic Hajime Tamaki optionally (preferably Ben Zofuraeru substituted with benzimidazolyl) 〇 6 alkyl group selected from substituted or may be) compound (lib).

4) a ring A Waga '

R 1 b is.6 alkyl group (the C 6 alkyl group is a halogen atom, arsenic Dorokishi group, a carboxyl group, CI_ 6 alkoxy group, 〇 6 alkoxy - substituted by 1 to selected from the group Contact Yopika Rubamoiru group 3 substituents may be), C 3 -. 1Q cycloalkyl group, 0 6 alkyl - group Contact Yopi C 6 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbon group 1 to 3 halogen it may be substituted with atoms - 6 alkyl group, arsenate Dorokishi groups, C WINCH 6 1 to 3 substituents selected from the may be) substituted with a substituent selected from alkoxy groups Contact Yopi halogen atom in mono- or compounds is 0 6 Al kill group substituted with di-optionally substituted Amino group (lib).

5) 2- [2- [(4-Bifue two Rirukaruponiru) Amino] Echiru] - N - [2 - (Jifueniruami Bruno) Echiru] -1, 3-Okisazoru 4- Karubokisami de (Example 161),

2- [2- [(4-Bifue two Lil carbonyl) amino] Echiru] - N-(2-morpholino - 3 - Fueno Kishipuropiru) - 1, 3-Okisazoru 4- Karubokisami de (Example 162),

5- [2 - [(4-Bifue two Lil carbonyl) Amino '] Echiru] - N - [2-[(3 - Mechirufue two Le) (Fuweniru) Amino] Echiru] -1, 3, 4 Okisajiazoru - 2 - Karubokisami de (example 163),

5- [2- [(4-Biff We two Riruka Lupo sulfonyl) amino] Echiru] -N - [(l - phenyl - 1H-benz Imidazoru - 2-I) methyl] - 1, 2, 4-Okisajiazoru -3 - Karubokisami de (example 164),

3- [2- [(4-Biff We lily ylcarbonyl) Amino] Echiru] - N- phenyl - 1H-benz Imidazoru - 2-I) methyl] -1, 2, 4-Okisajiazo Ichiru - 5- Karubokisami de -

(Example 165), 3 - [2- [(4-bi Hue lily Luke Lupo yl) Amino] Echiru]-N-[(3 - phenyl - 1 - base Nzofu run - 2-I) methyl] -1, 2, 4 - Okisajiazo Ichiru - 5- Karubokisami de (example 166), -

3- [2- [[(4 '- Full O lobby off We sulfonyl - 4 - I le) force Ruponiru] Amino] Echiru] - N-(2 mol Horino -3 - off We Roh hydroxypropyl) - 1, 2, 4-Okisajiazo Ichiru - 5 - Karubokisami de (example 167),

5 - [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[(1 - phenyl - 1H-benzimidazole - 2-I) methyl] -1, 3, 4 Okisajiazoru 2- Karubokisami de (example 169),

1- [2- [(4 - Bifuwe two drill force Lupo sulfonyl) amino] Echiru] - N-[2 - (Jifuweniruamino) E chill]-1H-pyrazol-4 Karubokisami de (Example 60),

5 - [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2 - (Jifuweniruamino) E chill] -1, 3, 4 Okisajiazoru - 2- Karubokisami de (Example 50),

3 - [2- [(4 - Biff We lily Luke Lupo sulfonyl) amino] Echiru] - N - (2-morpholino - 3 - Fueno Kishipuropiru) - 1, 2, 4-Okisajiazoru - 5- Karubokisami de (Example 43), and

5- [2- [(4-Bifuwe two Rirukarubo - Le) Amino] Echiru] - N- from 3- Karubokisami de (Example 36) - [2 - (Jifuweniruamino) E chill] -1, 2, 4- Okisajiazoru chosen compound or a salt thereof (lib).

When the compound (I) (Compound (II) and. Similarly the compound (lib)) is a salt, the salt, preferably a pharmacologically acceptable salt thereof, and such a salt , for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids.

Preferable examples of the salts with inorganic bases include sodium salts, Al force Li metal salts such as potassium salt; and the like Anmoyuumu salts; calcium salts, alkaline earth metal salts such as magnesium salts; aluminum two © unsalted .

Preferable examples of salts with organic bases, Torimechiruamin, Toryechiruamin, pyridine, picoline, ethanolamine § Min, diethanol § Min, triethanol - Amin, tromethamine [tris (human Dorokishimechiru) Mechiruamin], T§rt- flop Chiruamin, Kishiruamin cyclohexane, Benjiruamin, Kishiruamin dicyclohexyl, N, N, salts with such over dibenzylethylenediammonium § Min.

Preferable examples of the salt with an inorganic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and salts with etc. phosphoric acid.

Preferable examples of salts with organic acids, formic acid, acetic acid, Torifuruoro acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, Kuen acid, succinic acid, malic acid, methane sulfonic acid, benzenesulfonic acid salts with p- toluenesulfonic acid, and the like can be mentioned up.

Preferable examples of the salt with basic amino acid, arginine, lysine, and salts with such Ol two chin.

Preferable examples of the salt with acidic amino Asuparagin acid include salts and glutamic acid.

Salts with salt Contact Yopi organic acids and inorganic acids among the salts mentioned above are preferred, the hydrochloride salt, Torifuruoro acetate, and fumaric acid salts.

Prodrugs of compound (I) compound by reaction due to an enzyme, gastric acid under the physiological condition in the living body compound which is converted to (I), i.e. enzymatic oxidation, reduction, hydrolysis etc. caused by Compound (I) a compound which is converted to, gastric acid is a compound that converts to compound undergo such hydrolytic (I) and the like. The Purodo lugs of the compound (I), Amino groups Ashiru of the compound (I), alkylated, phosphorylated compounds (e.g., Amino groups Eikosanoiru of the compound (I), Araniru reduction, Bae Nchirua Minokarubo sulfonyl reduction, (5-methyl ^ 2 Okiso one 1, 3-Jiokisoren 4 I le) method butoxy carbonylation, tetrahydrofuranyl reduction, Pirorijirumechi Le of, Pipa Roi Ruo carboxymethyl methylated, tert- butylated and like compounds); compound (hydroxyl group Ashiru of I), alkylation, phosphorylation, borated compounds (e.g., compound (I) hydroxyl groups Asechiru of, Palmi toyl reduction, Puropanoiru reduction, Pibaro I Le of illusion - Le reduction, fumaryl reduction, Araniru reduction, dimethylaminomethyl Cal port alkylsulfonyl of compounds, etc.); carboxyl group of the compound (I) Esterification, Ami de of compounds (e.g., carboxyl group Echiruesuteru of the compound (I), off -. Eniruesuteru, carboxymethyl ester, dimethyl § amino methyl ^ ester le of, Pipa Roi Ruo carboxymethyl ester reduction, ethoxy Kano repo sulfonyl O key shell chill E esterification, phthalidyl esterification, (5-methyl-one 2- Okiso one 1, 3-Jioki Soren one 4- Inore) methylcarbamoyl Honoré esterification, Kishinore old to Shi 'black Kishikarubo - Noreechiru esterification, etc. Mechiruami de of compounds), and the like. These I spoon compounds can be produced from compound (I) by a method known per se.

In addition, the prodrug of compound (I), Hirokawa Shoten 1 9 9 0 annual "Development of pharmaceuticals" as described from the Vol. 7, Design of Molecules, 1 6 3 page 1 9 8 page, under physiological conditions it may be one that converts to compound (I).

Further, Compound (I), an isotope (eg, 3 H, "C, 3 5 S, 1 such as 2 5 I) may be labeled with a..

Further, compound (I) may be anhydrous, or may be a hydrate.

Compound (I) or a prodrug thereof (hereinafter, simply and abbreviated child as the compound of the present invention) has low toxicity, as, or in such a mixed pharmaceutically acceptable carrier and pharmaceutical compositions by a mammal (e.g., human, mouse, rat, Usagi, I j, cat, © shea, © Ma, descriptors, monkey, etc.) with respect to, it is used as a prophylactic or therapeutic agent which will be described later various diseases can.

Here, as the pharmacologically acceptable carrier, which, each species organic or inorganic carrier substances in common is used as a preparation material, an excipient, a lubricant, binding agent, disintegrating agent; liquid formulations solvent in, solubilizing agents, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations. If necessary, preservatives, antioxidants, can also be used wearing colorant, formulation additives such as sweeteners. '

Preferable examples of the excipient include lactose, sucrose, D- mannitol, D- sorbitol Le, starch, starch, dextrin, crystalline cellulose, low substituted hydro Gishipuropinorese loin, Kano levo Kishime Chino receptacle Honoré loin sodium, Arabiago arm, pullulan, light anhydrous Kei acid. synthesis Kei aluminum, and the like magnesium aluminometasilicate.

Preferable examples of lubricant include magnesium stearate, calcium stearate © beam, talc and colloidal silica. Preferred examples of the binder, arsenide starch, sucrose, gelatin, Arabi r rubber, methylcarbamoyl Roh receptacle Honoré loin, Kano levo Kishime Chino receptacle Honoré loin, Kano repo Kishime Chino receptacle Honoré loin sodium, crystalline cellulose, white sugar , D- Man -. tall, trehalose, dextrin, Punoreran, hydroxycarboxylic pro Pinot receptacle Norerosu, human Dorokishipuropi / Remechinore cellulose, poly Bierupirori pyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose port over scan, Kano levo Kishime Chino receptacle Honoré loin Kano Residencial © beam cross Kano Leme loin sodium, carboxymethyl starch sodium, light anhydrous Kei acid , and a low-substituted arsenide Dorokishipu port pills cellulose.

Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol Konore, polyethylene glycol, sesame oil, corn oil, old leave oil, cottonseed oil, and the like.

Preferable examples of dissolution aids include polyethylene glycol, propylene glycol, D- mannitol, trehalose, benzyl benzoate, ethanol, triethanolamine Suaminometan, cholesterol, triethanolamine § Min, carbonate sodium, sodium click E phosphate, sodium salicylate, and sodium acetate. Preferable examples of the suspending agent include stearyl triethanolamine § Min, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, Benzarukoniumu chloride, downy chloride Nzetoniumu, surfactants such as glycerol monostearate; for example, poly Biel polysorbate DOO acids; Anorekonore, poly Byurupirori pyrrolidone, Kano repo carboxymethyl cell Honoré loin na tri um, methylcarbamoyl Roh receptacle Honoré loin, hydrophilic polymer arsenide mud Kishime Chino receptacle Honoré loin, human Dorokishechinore cellulose, such as hydroxypropylcellulose polyoxyethylene E Ji Ren hydrogenated castor oil and the like.

Preferable examples of the isotonicity agent include sodium chloride, glycerin, D- mannitol Le, D- sorbitol, glucose and the like.

Preferable examples of the buffer, re. Emissions, acetate, carbonate, and the like buffer solution such as Kuen salt.

Preferable examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative, Paraokishi benzoic acid esters, click port Robutano one .- Le, benzyl alcohol, full energy Chill alcohol, de human mud acid, Soruhi; etc. phosphate and the like.

Preferable examples of antioxidant include sulfite, Asukorubin acid salts. Preferable examples of coloring agent include water-soluble edible tar dyes (e.g., food red No. 2 and No. 3, Food Color Yellow No. 4 and No. 5, Food dyes such as Food Blue No. 1 Contact Yopi No.2), water-insoluble lake dye (e.g., aluminum salt of the aforementioned water-soluble edible tar pigment), natural color element (eg, J3- carotene, chlorophyll, red iron oxide) and the like.

Preferable examples of sweetening agent include saccharin sodium, glycyrrhizin dipotassium potassium © beam, aspartame, stevia and the like.

As the dosage form of the pharmaceutical composition, e.g., tablets (sublingual tablets, including-free intraoral disintegrating 壌錠), (including soft capsules and microcapsules) capsules, granules,. Powders, lozenges, syrups , emulsions, oral preparations such as suspensions; and injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external preparations (e.g., transdermal preparations, ointments), suppositories (e.g., rectal suppository, vaginal suppository), pellets, nasal preparations, pulmonary agents (inhalants), include parenteral preparations such as eye drops, have they have a respective orally It may be administered parenterally safely.

These formulations may be rapid release preparation or sustained release formulation a controlled release formulation such as (e.g., sustained-release microcapsules).

The pharmaceutical compositions, a method conventionally used in the field of pharmaceutical preparation, for example, can be produced by a method described in the Japanese Pharmacopoeia.

Incidentally, the content of the present compound in the pharmaceutical composition, dosage form, varies depending upon etc. The dosage of the present compound, for example, about 0.1 to 1 0 0 wt%.

In making the oral dosage is necessary, for the purpose of masking taste, enteric property or durability, may be performed coatings.

'As the coating base used in the coating, for example, sugar coating base, water-soluble film coating base, an enteric film coating base include sustained release buoys Rumuko one computing base.

As the sugar coating base, sucrose is used, furthermore, talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, one or selected from like Karunaparou - may be used in combination of two or more.

The water-soluble film coating base, for example, hydroxycarboxylic propyl cellulose, hydroxycarboxylic pro Pinot Leme Chino receptacle Honoré loin, human de Loki Chez Chino receptacle Honoré loin, cellulose polymers such as Mechiruhi de Loki Chez chill cellulose; poly Byuruase tar Jefferies chill § amino, aminoalkyl meth § methacrylonitrile rates copolymer E [OY Doragi' preparative E (trade name), Romufuaruma Inc.], synthetic polymers such as poly Byurupirori pyrrolidone; and polysaccharides such as pullulan.

As the enteric film coating base, for example, hydroxypropyl methylate Rusenorerosu phthalate, hydroxycarboxylic pro Pinot Leme Chino receptacle Honoré loin acetate succinate, carboxymethyl E chill cellulose, which cellulose such as cellulose acetate phthalate polymers; methacrylic acid copolymer L [Eudragit L (trade name), Romubuaruma Ltd.], methacrylic acid copolymer LD [Eudragit L - 3 0 D 5 5 (trade name), Romufuaruma Ltd.], methacrylic acid copolymer S [OY Doragitto S (trade name), like natural products such as shellac; Romufuaruma Inc.] acrylic high content child such.

The sustained-release film coating base, for example, cellulose polymers such as E chill cellulose; § aminoalkyl meth § methacrylonitrile rates copolymer RS ​​[OY de Ragitto RS (trade name), Romufuaruma Ltd.], acrylic acid E Chiru methacrylic methyl copolymer suspension [Eudragit NE (trade name), Romufuaruma Corporation] and the like Akuriru acid polymer such.

The above-mentioned coating bases may be used after mixing with two or more kinds thereof at an appropriate ratio. For coating, for example, titanium oxide, may be used a light-shielding agent such as ferric oxide.

The present invention compound has an excellent SGLT inhibitory activity. Here, Ho as SGLT, SGLT 1, SGLT 2, such as SGLT homologs fist up. The present invention compound has a selective inhibitory effect on SGLT 1 and SGLT homolog. The compound of the present invention, the excellent glucose uptake inhibitory effect, specifically with glucose uptake inhibitory activity in the small intestine. The compounds of the present invention, toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, Kokorodoku - resistance, carcinogenicity) is low, side effects less, mammals (e.g., human, © shea horses, I j , cats, monkeys, mice, rats, relative particularly humans), can be used as an SGLT inhibitor Contact and glucose uptake inhibitors.

The compounds of the present invention, specifically, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational sugar urine disease), obesity, hypertension, 髙脂 hyperlipidemia (e.g., high triglycerides Dochisho, high cholesterol hyperlipidemia, low HDL cholesterolemia, postprandial hyperlipemia), heart failure, diabetic cardiomyopathy, may be used as a prophylactic or therapeutic agent for metabolic syndrome Rick syndrome.

For the criterion of diabetes, new diagnostic criteria from the Japan Diabetes Society has been reported in 1 999 years.

According to this report, diabetes is a condition showing a fasting blood glucose level (glucose concentration in venous plasma) is 1 26 mg / d 1 or more, 75 g after Robudou glucose tolerance test (75 gOGT T) 2 h level (glucose concentration in venous plasma ) is 20 Omg / d 1 or more, the glucose concentration in the marrow blood sugar value (venous plasma) of not either 20 OnigZd 1 or more. A condition not falling under the above-mentioned diabetes and different from "a fasting blood glucose level less than (static glucose concentration in pulsating plasma) 1 1 Omg / d 1 or 75 g oral flop de © glucose tolerance test (75 gOGTT) .2 hours value the state (glucose concentration in venous plasma) is not in the state "(normal type) showing less than 14 OmgZd 1, a" borderline type "call

^^.

As for the criterion of diabetes, the ADA to 1 997 (American Diabetes Association), by WHO to 1 998, and new diagnostic criteria were reported.

According to these reports, diabetes is a fasting blood glucose level (Darko over scan concentration in venous plasma) is 1 26 mg / d 1 or more, 'and, 75 g after Robudou glucose tolerance test 2 h level (venous plasma glucose concentration) in is state showing a 20 OmgZd 1 or more.

'Furthermore, according to the above reports, impaired glucose tolerance, fasting blood glucose level (glucose concentration in venous plasma) is less than 1 26 mg / d 1, and, 75 g after Robudou sugar load test 2 h level ( glucose concentration) in venous plasma of not less 2 0 OmgZd less than one or more 140mgZd l. Furthermore, according to the report of ADA, a condition referred to as a fasting blood glucose level (glucose concentration in venous plasma) 1 1 O m g / d 1 or 1 2 6 mg, the state of less than dl IFG (Impaired Fasting Glucose). One; ¾, according to the report of WH O, among the IFG (Impaired Fasting Glucose), 7 5 g through Robudou glucose tolerance test 2 h level (glucose concentration in venous plasma) is 1 less than 4 0 mg Z d 1 a condition referred to as the IFG (Impaired Fasting Glycemia).

The compounds of the present invention, diabetes is determined by the new criteria mentioned above, borderline type, impaired glucose tolerance, also used as a prophylactic 'therapeutic agent of IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia). Furthermore, the compounds of the present invention, borderline, 而Otono failure, Ru can also prevent the development of the IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

The compound of the present invention, for example, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, cataracts, macroangiopathy, osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infection disease, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, lower limb infection), diabetic gangrene, xerostomia, decreased hearing, cerebrovascular disorder, peripheral blood circulation disorder], osteoporosis, cachexia ( examples, cancerous cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia 幫 or cachexia due to acquired immunodeficiency syndrome), fatty liver , polycystic ovary syndrome, kidney disease (e.g., diabetic Neff port PASSY, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscle Soo trophy, myocardial infarction, narrow heart disease, cerebrovascular disorders (eg, cerebral infarction , Stroke), Al Hhaima disease, Parkinson's disease, anxiety, dementia, insulin resistance syndrome, shea Ndoromu X, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer), 'irritable bowel syndrome, acute or chronic under diarrhea, inflammatory diseases (e.g., rheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, inflammation after surgery or trauma, swelling, neuralgia, laryngeal, cystitis (including Hia alcohol steatohepatitis) hepatitis (including inflammatory bowel disease) pneumonia, 滕炎, enteritis, inflammatory bowel disease, ulcerative colitis, gastric mucosal injury (aspirin including)) of gastric mucosal injury caused by, small intestinal mucosa injury, malabsorption, testis dysfunction, visceral obesity syndrome, use as a prophylactic or therapeutic agent such as sarcopenia Rukoto can. The compounds of the present invention, the above-mentioned various diseases (e.g., such as myocardial infarction cardiovascular events) of -

Used in secondary prevention and suppression of progression.έ dose of the compound of the present invention, administration subject, administration route, target disease, varies in cowpea like symptoms, for example, when administered orally to diabetic patients adult, about as normal single dose 0.0 1~:.. 1 0 O mg / kg body weight, preferably from 0 0 5~3 0 mg _ kg body weight, more preferably 0 1 to 1 O mg Bruno kg body weight, this amount once a day to it is desirable to administer three times.

The compounds of the present invention, for the purpose reducing and dose of enhancing or said compound of action of that compound, therapeutic agent for diabetes, therapeutic agents for diabetic complications, antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics agents, drugs such as anti-thrombotic agents (hereinafter combination drug abbreviated) can be used by the combination. In this case, timing of administration of the present invention and the combination drug compound is not limited, to these administration subject, may be administered simultaneously, or may be administered in a staggered manner. Further, the present compound and the concomitant drug include each active ingredient

It may be administered as two formulations may be administered as a single preparation containing both active ingredients.

The dose of the combination drug can and appropriately selected child the dose employed clinically as a reference. The mixing ratio of the present invention and the combination drug compound, administration subject, can be appropriately selected depending on such administration route, target disease, condition, combination. For example, if the dosing target is a human, the compound of the present invention 1 part by weight, the concomitant drug 0. 0 1 may be used 1 0 0 parts by weight.

As the antidiabetic agents, for example, insulin preparations (e.g., © shea, animal insulin preparations extracted from Katsu臓 pig; using Escherichia coli or Isuto, genetic engineering synthesized human insulin preparation; Insurin zinc; protamine insulin zinc; fragment or derivative of insulin (e.g., INS - 1), oral insulin preparation), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably rather hydrochloride salt), rosiglitazone or a salt thereof (preferably maleate), leg Rikisan (Reglixane) (JTT-501), netoglitazone (netoglitazone) (MCC- 555), DRF- 2593, KRP - 297, R - 119702, rivoglitazone (rivoglitazone) (CS- 011), FK- 614, W099Z58510 compound according to (e.g. (E) - 4- [4- (5-methyl-2 - phenyl - 4-O Kisazorirume butoxy) Benjiruo Shiimino] -4-phenyl-butyric acid), a compound of .- described in W001 / 38325, tesaglitazar (Tesaglitazar) (AZ-242), Ragagu Taza Lumpur (Ragaglitazar) (NN - 622), muraglitazar (Muraglitazar) (BMS- 298585), 0N0-5816, Edaguritazon (Edaglitazone) (BM- 13- 1258), LM- 4156, MBX- 102, naveglitazar (naveglitazar) (LY- 519818), MX- 6054, LY- 510929, rose glitazones (Balaglitazone) (丽 - 2344), T - 131, or a salt thereof, Thr- 0921), PPARy Agonisu DOO, PPARy antagomir two be sampled, PPAR gamma / alpha Deyuaruagoni be sampled, alpha-Darukoshidaze inhibitors (e.g., voglibose, Akarubosu, Miguri DOO Lumpur, Emidariteto), Biguanai de agent (e.g., phenformin, main Tohorumin, buformin or salts thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogues [ Ruhoniruurea agents (eg, Toruputamido, Daribe Nkurami de, gliclazide, Kurorupuropami de, Torazami de, Kisami de to Aseto, Darikuropi Lami de, Gurimepiri de, Daripizaido, etc. Daribuzoru), repaglinide, Se Nagurinido, nateglinide, mitiglinide or calcium salt thereof hydrate], GPR40 Agonisu bets, GLP 1 receptor Agonisu preparative [example, GLP- 1, GLP- 1MR agent, ΝΝ- 2211, AC- 2993 (exendin- 4), BIM- 51077, Aib (8, 35) hGLP- 1 (7, 37) NH physician CJC- 1131], § Mirinagonisu bets (e.g., pramlintide), Fosufochi port Shinfo scan Fatah one peptidase inhibitors (eg, sodium Panajin acid), di peptidyl peptidase IV inhibitors ( examples, NVP- DP P- 2 78, PT_ 1 0 0, Ρ 3 2 9 8, Vuidadaripuchi emissions (Vidagliptin) (L AF- 237), P 9 3 Bruno 0 1, TS_021, MK- 431 , Sakusadari leptin (Saxagliptin) (BMS- 477118), etc. T-6666), 3 Agonisu bets (e.g., AJ - 9 6 7 7, AZ 40 1 4 0), gluconeogenesis inhibitors (e.g., da Ricoh Gen phosphoryl error peptidase inhibitors, glucose one 6-phosphatase inhibitors, glucagon antagonists), 110-1 arsenide de Loki systemic Roi de dehydrogenase inhibitors (e.g., BVT-3498), Ajiponeku Chin or agonist, IKK inhibitors (e.g., AS-2868 ), Rebuchin resistance-improving agents, Seo Ma Tosutachin receptor agonists (e.g., W001 / 25228, W003 / 42204, W098 / 44921, W098 / 45285 and W099 / twenty-two thousand seven hundred and thirty-five compounds described), Darko kinase activator (e.g., Ro - 28 - 1675) and the like.

As the therapeutic agents for diabetic complications include aldose reductase inhibitors (e.g., Torr Resutatsuto, perilla Noreresutatsuto, Zenaresutatsuto, zo port Honoré less Tatsuto, Minarere .- Sutatsu DOO, Fidaresutatsu bets, CT- 1 1 2, Raniresutatsu Doo ( AS-3201), neurotrophic factors and increasing drugs thereof (e.g., NGF, NT- 3, BDNF, WO 0 1 /

Neuro DOO port fin production-secretion promoters described in 14372 (e.g., 4- (4 one black port phenyl) Single 2- (2-methyl-1 one-imidazolyl) one 5- [3- (2-Mechirufuwenokishi) propyl] Okisazoru)), nerve regeneration promoting drugs (eg, Y- 1

28), PKC inhibitors (e.g., Rubokishisutauri emissions mesylate (ruboxistaurin mesylate; LY- 33 3 53 1)), AGE inhibitors (e.g., ALT946, pimagedine, Biratokisachin, N- Hue without Lucia sledding © beam Puromai de (ALT766) , ALT- 711, EX0-226, pyridinium polyhedrin (Pyridorin), pyridinium Dokisamin), active oxygen scavengers (e.g., Chioku DOO acid), cerebral vasodilators (e.g., Chiapuri de, mexiletine), Somatosutachi emissions receptor agonists (example, BIM23190), apoptosis signaling Honoré regulating kinase -1 (ASK - 1) inhibitors.

The antihyperlipidemic 痺剤 include statin compounds (eg, bra pasta Chin, Shin Pasutachin, Ronoku statins, § Torupasutachin, Funorebasutachin, Itapasutachi down, Rosupasutachin, Pitapa statin or a salt thereof (e.g., sodium salt, force Rushiumu salt)), squalene synthase inhibitors (e.g., compounds described in W097 / 10224, for example, N- [[(3 R, 5 S) - 1- (3- Asetokishi one 2, 2-di-methylpropyl) Single 7-black opening one 5- (2, 3-dimethyl Tokishifueniru) Single 2 O Kiso one 1, 2, 3, 5-Tetorahi mud one 4, 1 one base Nzookisazepin one 3-I le] Asechiru] piperidine one 4-acetate), Fuiburato compounds (eg, Bezafibura over preparative, Kurofuiburato, Shimufuiburato, clino Fi Prato), ACAT inhibitors (e.g., avasimibe (Avasimib e) Efurushimaibu (Eflucimibe)), anion exchange resins (e.g., colestyramine), Puropukoru, nicotinic acid drugs (f column Nikomonore (nicomol), Niseri Toronore (Niceritrol)), Ikosapento acid Echiru, phytosterols (e.g. , soysterol (soysterol), Ganmaorizano "Norre (γ- oryzanol)), and the like ..

Examples of the antihypertensive agents, for example Angi O Tianjin converting enzyme inhibitors (e.g., captopril, Enarapuriru, delapril), Angi O tensin II antagonists (e.g., candesartan cilexetil, mouth Sultan, Epurosarutan, valsartan, telmisartan, -. Irubesarutan, tasosartan, 1 one [[2, one (2, 5-dihydrazide draw 5; ¾ Kiso 4 H - 1, 2, 4 one Okisajiazoru one 3-I le) Bifue two rules 4 I le] methylate

, Le] - 2-ethoxy one 1 H- base lens imidazole over 7 force carboxylic acid), Karushiu beam antagonists (e.g., manidipine, Two Fuejipin, amlodipine, efonidipine, two force Rujipin), potassium channel openers (e.g., levcromakalim, L- 27152, AL 0671, NIP- 121), include clonidine.

Anti-obesity agents, for example, central antiobesity drugs (e.g., dexfenfluramine, full Enfururamin, phentermine, sibutramine, Anfuepuramon, Dekisan Fuetamin, Majindonore, phenylene zone les prop NO / Reamin, Kurobe Nzorekku scan; MCH receptor antagonists (eg, SB- 568849; SNAP- 7941; compounds described in W001 / 01/82925 and W001 / 87834); neuropeptide Y antagonists (e.g., CP- 422 935); mosquito N'nabinoido receptor antagonists (e.g., SR- 141716, SR-147778); ghrelin antagonists; 11 over heat Dorokishisuteroi Dodehi dehydrogenase inhibitors (e.g., BVT-3498)), the knee lipase inhibitors (e.g., Orurisutatsuto, ATL-962), 3 Agonisu Doo ( examples, AJ- 9677, AZ40140), Asechiru CoA carboxylase inhibitors (e.g., CP_610431, CP- 640186) peptidic anorectics (e.g., Rebuchin CNTF (ciliary neurotrophic factor)), Koreshi strike quinine § Gore Marianist (for example, lintitript, FP physicians 15849), feeding inhibitors (for example, P - 57), and the like.

The diuretic include xanthine derivatives (eg, sodium salicylate Theo bromine, calcium salicylate Theo pro Min), thiazide preparations (e.g., Echia disilazide, cyclopenthiazide thiazide, trichlormethiazide, human Dorokuro port thiazides inhibit mud Furume thiazide, Benchiruhi Dorokuro port thiazides, Penfuruchijido, Porichi azide, methyclothiazide), anti-aldosterone preparations (e.g., Supironoraku tons, triamterene), carbonate dehydratase inhibitors (e.g., Asetazorami de), chlorine base Nze Shisuruhon'ami de-based formulation (e.g., Kurorutari Don , mefruside, Indapami de), Azosemi de, isosorbide, ethacrynic acid, Pireta - de, Pumetanido include Furosemi de.

As the antithrombotic agents, for example, heparin (e.g., heparin sodium, heparin force Rushiumu, such as dalteparin sodium (dalteparin sodium)), Warufuarin .- (e.g., Warufua Li Nkari um), anti collected by filtration Nbin drugs ( examples, Arugato p pan (argatroban)), thrombolytic agents (e.g., Urokinaze (urokinase;), tisokinase (tisokinase) Arutepurase (alteplase), Natepuraze (Nateplase), Monte Puraze (montepl ase), pamiteplase (pamiteplase)), platelet aggregation inhibitors (for example, hydrochloric acid tick Russia Pidgin (ticlopidine hydrochloride), cilostazol cilostazol), Ikosapen Bokusan Echiru, Berapurosu Bokunaboku! ; © beam (beraprost sodium), hydrochloric Sarupodarera Bok (sarpogrelate hydrochloride)) et al mentioned force S is like.

For producing the present compound will be described below.

Compound (I) can be produced by a known method per se, for example according to the compound ([pi) METHOD manufacturing method or analogous thereto, which will be described in detail below.

Compound (II) can be accordance connexion produced in the methods or method analogous thereto represented by the following reaction formula 1.

Compounds The compounds used in the preparation of (II) (III), (V) and (IX) are readily available as 巿 Commercially available products, also to the method known per se or a method analogous thereto therefore be produced it can.

Each symbol in Scheme 1, as defined above unless otherwise. Each starting material compound used in the preparation of compounds (II) may form a salt, the salt, those similar to the salt in the compound (I).

The solvent to be used in the production method of the present invention compounds, the acid and base will be described below. The "alcohols", for example, methanol, ethanol, 1 one propanol methylphenol, 2-propanol, tert - like Puchiruaruko Le is used.

The "ethers", for example, Jefferies chill ether, diisopropyl ether, Jifue two Noreeteru, as tetrahydrofuran, 1, 4-Jiokisan, 1, 2-dimethyl Tokishetan is used.

The "hydrocarbons", for example, benzene, toluene, xylene, key San cyclohexane, etc. hexane is used.

The "Ami earths", such as N, N-dimethyl formamidine de, N, N-dimethyl Chiruasetoami de, etc. to hexa methylphosphonate Holic Toriami de is used. .- As "halogenated hydrocarbons", for example dichloromethane, Kurorohoremu, carbon tetrachloride, 1, 2 Jikuroroetan is used.

Examples of the "nitrile compound", is needed use for example Asetonitoriru, such as propionic nitrile is. -

The "ketones", for example, acetone, etc. E chill methyl ketone Ru is used.

As the "esters", for example, acetic Echiru is used.

The "sulfoxides", for example, dimethyl sulfoxide is used. The "organic acids", for example formic acid, acetic acid, propionic acid, Torifuruoro acetic acid, methanesulfonic acid.

The "mineral acids", for example, hydrochloric acid, sulfuric acid is used.

As the "Lewis acids", for example, boron trichloride, bromide and the like boron Ru is used.

The "inorganic bases", for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide.

The "basic salts", for example sodium carbonate, potassium carbonate, Seshiu beam, sodium bicarbonate, 'sodium acetate, acetic Anmoniumu is used.

As the "aromatic Amin such", for example pyridine, lutidine is used. The "tertiary Amin such" eg Toryechiruamin, tripropylamine § Min, Toribuchiruamin, diisopropyl E chill § Min, hexyl dimethyl Amin cyclohexane, 4-dimethyl § amino pyridine, N, N _-dimethyl § aniline, N- Mechirupipe lysine, N- methylpyrrolidine, etc. N- methylmorpholine is used.

The "alkali metal hydrides", such as hydrogenated Natoriumu, such as hydrogenated force Li © beam is used.

The "metal Ami earths", such as sodium Ami de, lithium diisopropylate Ruami de, etc. hexa hexamethyldisilazide to lithium is used.

"Alkyl metals", for example heptyl lithium, sec- butyl lithium, tert- heptyl lithium is used. The "Ariru metals", such as Hue - butyllithium and the like are used. - The "metal alkoxides", Natoriumume Tokishido, Natoriu Etoki Sid, sodium tert- butoxide, potassium tert- butoxide Ru is used.

Scheme 1 '

R-COOH (V) deprotection

Wherein the R a may be substituted hydrocarbon group, an R 4 a may be substituted hydrocarbon group, an optionally substituted heterocyclic group or a substituted hydroxy group. ]

As the "optionally substituted hydrocarbon group" represented by R a, include those for example exemplified for the aforementioned R 1. ,

Represented by R 4 a "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" and "substituted human Dorokishi group", those shown examples of the R 4 and the like, respectively.

Compound (IV) can be produced by subjecting compound (III) to deprotection reaction. This reaction is a method known per se, for example Protective Groups in Organic Synthesis, Third Edition (1999), can be carried out according to the "method described in such as a chapter of Protection for the Amino GroupJ, or a method analogous thereto. Deprotection the reaction is, for example, acid, base, ultraviolet light, hydrazine, Hue - Le hydrazine, sodium N- methyl Jichio force Rubamin acid, tetra Petit Ruan monitor © beam fluorimeter de, acetic palladium, trialkylsilyl payment de (eg, trimethylsilyl ® Jido production, methods of using such trimethyl silyl Promise de). compounds made by such reduction method (VI) is the compound (IV) with the compound (V) or a reactive derivative thereof can be reaction can do.

As the reactive derivative of compound (V), for example, acid halides (e.g., acid chloride, acid bromide), acid Ami de (e.g., pyrazole, imidazole, acid amine de between etc. benzotriazole), acid anhydrides (eg., acetic anhydride, propionic anhydride, 6 aliphatic carboxylic acid anhydrides such as anhydrous acid), acid azides, active esters (e.g., diethoxy 'phosphate esters, Jifuenokishirin ester, p- nitrophenyl ester, 2 , 4 Jinitorofue two Noreesutenore, Xia Roh methyl ester, pentachlorophenol phenylene Noreesute ^ /, N- hydroxycarboxylic succinimidyl de and the Esutere, N- human Dorokishifu data ^^ I Mi de and the Esutenore 1- arsenide de b carboxymethyl Este / Les the benzotriazole § zone Honoré, 6 - black port one 1 over hydroxycarboxylic Esutenore the benzotriazole § zone Honoré, 1- arsenide Roxy

1 H- 2-ester of pyridone) activity Chioesuteru (e.g., 2-pyridylthio ester, 2-base emission zone benzothiazolylthio ester), such as isocyanate ester is Kobushige.

The compound (VI) can be prepared even cowpea to be reacted directly compound (IV) with the compound (V) in the presence of a suitable condensing agent. Examples of the "condensing agent", for example N, hexyl Cal positive imide to N'- dicyclohexyl, N, N'- diisopropyl Rukarupojiimi de, 3- (3-dimethylaminopropyl § amino propyl) 1 - Echirukarupojii -. Bromide or its hydrochloride N, such as salts, N'- disubstituted Karubojiimi earths; N, Azoraido such as N one local board El diimidazole; 2- Etokishi one N- Etokishikarubo sulfonyl one 1, 2-dihydroquinoline, Okishi phosphorus chloride, alkoxyacetylene dehydrating agent such as, iodide 2-chloromethyl-pyridinylcarbonyl © beam, such as iodide 2- Furuoro 1- main Chirupirijiniumu 2- halogeno-pyridinylmethylsulphinyl © unsalted; Shiano phosphate Jechiru, phosphoric acids such as azide diphenyl phosphoryl and esters can be used. These, when using a condensing agent, the reaction is when to proceed via a reactive derivative of the compound (V) considered Erareru.

Compound (V) or a reactive derivative thereof, compound (IV) usually about relative to 1 mole of 1.0 to 5.0 mol, preferably used about 1.0 to 2.0 mol.

When using an acid halide as the reactive derivative of the compound (V), the hydrogen halide that will be released in order to remove from the reaction system, the reaction can be carried out in the presence of an acid acceptor. Such acid acceptor, such as basic salts, aromatic Amin acids, and tertiary Amin acids preferred. These deoxidizing agents, compound (V) usually about relative to 1 mole of 1.0 to 20.0 mol, preferably used about 1.0 to 10.0 mol.

Wherein as a condensing agent N, Nyu'- disubstituted Karupojiimi case of using the earth, response Ji by suitable condensation accelerator required (eg, 1 over human Dorokishi one 7- Azabe benzotriazole, 1 over human Dorokishi benzotriazoles § tetrazole, Nyu- arsenate Dorokishi succinic acid imide, it is possible to improve the reaction efficiency by using a Nyu- human mud Kishifutaruimi de).

In the case of using the phosphoric acid ester as a condensing agent, it is possible to improve the reaction efficiency by adding ordinary aromatic Amin acids, and tertiary amines. These condensation accelerator, aromatic Amin compounds, the amount of such tertiary Amin compound is usually 0.1 to 10 molar equivalents relative to compound (IV), preferably 0.3 to 3 molar equivalents.

The reaction of the compound (IV) with the compound (V) or a reactive derivative thereof, is advantageously carried out using the inert property to solvent. Such solvent is the reaction is not particularly limited as long you progress, such as ethers, hydrocarbons, Ami earth, halogen hydrocarbons, nitriles, sulfoxides, water, etc. in a solvent or their etc. are preferred solvents mixed. While the reaction time varies depending on the reagent and solvent to be used, usually 30 minutes to 24 hours, preferably - 30 minutes to 4 hours. The reaction temperature is usually 0 to 100 ° C, is preferably 0 to 70 ° C |.

Compound (VII) can manufacturing child by subjecting the compound (VI) to hydrolysis reaction. The reaction is usually carried out using an acid or a base. It is the said "acid", for example mineral acids, Lewis acids, and organic acids and the like. And with the "base", for example, inorganic bases, basic salts, metal alkoxides, aromatic Amin compounds, such as tertiary Amin acids and the like. These acids Contact Yopi base, compound (VI) usually about 0.1 5 relative to 1 mole: 10 moles, preferably used about 0.5 to 6 moles.

This reaction is carried out using a solvent inert to the reaction if desired. Is in such a solvent is not particularly limited as long as the reaction proceeds, for example alcohols, ether acids, hydrocarbons, Ami de, halogenated hydrocarbons, nitriles, ketones, organic acids , etc. or a mixed solvent thereof and the like water.

Usually 10 minutes to 60 hours and the reaction time is preferably 10 minutes to 12 hours. The reaction temperature is passing Tsuneichi 10 to 200 ° C, preferably 0 to 120 ° C.

Compound (VIII) can it to produced by subjecting compound (III) to a hydrolysis reaction. This reaction is carried out in the same manner as in the hydrolysis reaction of the compound (VI). Compound (Ila) can be manufacturing by reacting the compound (Πί) and compound (IX).

Compound (IX), the compound (III) 1 mol 对 usually about 1. 0: 10.0 mol, preferably used about 1.0 to 5 0 mol..

The reaction can be carried out optionally in the presence of a base. It is in such a base, such as basic salts, aromatic Amin acids, and tertiary Amin acids preferred. These bases are the compounds (III) 1 mol of generally about 1.0 to 20.0 mol, preferably used about 1.0 to 10.0 mol.

This reaction is advantageously carried out using a solvent inert to the reaction. Is in such a solvent is not particularly limited as long as the reaction proceeds, for example ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles such, or a mixed solvent thereof and the like sulfoxides and the like are preferable.

While the reaction time varies depending on the reagent and solvent to be used, usually 12 hours to 120 hours, rather preferably is 12 to 60 hours. The reaction temperature is usually 60 to 200 ° C, preferably 60;. In L50 ° C - Mel

Compound (Ila) can be prepared even cowpea in reacting the compound (VIII) or a compound with a reactive derivative thereof (IX). This reaction is carried out in the same manner as the reaction of the compound (IV) with the compound (V) or a reactive derivative thereof.

Compound (IX) is generally about the compound (VIII) or 1 mole of a reactive derivative thereof from 1.0 to 5.0 mol, preferably used about 1.0 to 2.0 mol.

The reaction can be carried out optionally in the presence of deoxidizing agent. Such acid acceptor, such as basic salts, aromatic Amin acids, and tertiary Amin acids preferred. These deoxidizing agents, compounds (VIII) 1 mol of generally about 1.0 to 20.0 mol, preferably used about 1.0 to 10.0 mol.

Compound (X) can manufacturing child by subjecting the compound (Ila) to deprotection reaction. This reaction is carried out in the same manner as the deprotection reaction of the compound (III).

Compound (II) may be the compound (X) with the compound (V) or a reactive derivative thereof to produce by reaction. This reaction is carried out in the same manner as the reaction of the compound (IV) with the compound (V) or a reactive derivative thereof.

Compound (II) can be prepared even cowpea to reacting the compound (VI) with the compound (IX). This reaction is carried out in the compound (III) and reacting the same way with the compound (IX).

Compound (II) can also be prepared by reacting the compound (VII) with the compound (IX). This reaction is carried out in the same manner as in the reaction of the 'compound (VIII) or a compound with a reactive derivative thereof (IX).

Compound (lib) can be thus produced in a method or a method analogous thereto represented by the following reaction scheme 2. Further, the method shown in Scheme 2 may be carried out in the same manner as in the method shown in Scheme 1 above.

Compounds The compounds used in the production of (lib) (Ilia), (Va) and (IXa) are commercially easily available, and can be prepared according to methods known per se or a method analogous thereto.

Each symbols in the reaction scheme 2 has the same significance as described above unless otherwise. Each starting material compound used in the preparation of compounds (lib) may form a salt, the salt, those similar to the salt in the compound (I). , Scheme 2

(IVa) (lie)

R 4b - COOH (Va) Deprotection

(IXa)

Compounds thus obtained (I), (II), (lib) are known means, eg if solvent extraction, liquid conversion, redissolution, crystallization, recrystallization, single Te cowpea like chromatography it can be separated and purified. - - The compounds (I), (Π), each raw material compound used for the production of (lib), which can be isolated and purified by such a similar known means, without the isolation child it may be subjected as a starting material in the next step as it is as the reaction mixture. . .. The solvent used in the crystallization, for example, water, alcohols, er, ethers hydrocarbons, Ami de, halogenated hydrocarbons, nitriles, ketones, ester le, sulfoxides , such as organic acids, and the like. These solvents, to alone used may Rukoto, an appropriate ratio of two or more solvents, for example 1: 1 to 1: may be used in combined mixed in 10 ratio.

I 匕合 product (I), when present as (II), (lib) is configurable formic Yoo relational Rua iso mer (SEQ 置異 material elements), Jiasutereoma, such conformers, isolating each by means known can do. The compound (I), may be separated + form, together with (II), (lib) is when an optically active compound, conventional optical resolution means racemates.

Compound (I), and (Π), (lib) 1 optical isomers, stereoisomers, positional isomers, if they contain a rotamer, these are also compounds (I), (II), (lib) while it is contained Te, known synthetic techniques can be respectively the obtained as separately separation method.

For example, as a optical resolution method, methods known per se, eg fractional recrystallization method, Kiraruka ram method and Jiasutereoma method is used.

1) fractional recrystallization methods: racemate and an optically active compound (e.g., (+) - mandelic acid, (-) - mandelic acid, (+) - tartaric acid, (-) - tartaric acid, (+) - 1-off Nechiruamin, (-) - 1 one Fuenechiruamin, cinchonine, (-) - cinchonidine, is 开成 salts brucine, etc.), which is separated by a fractional recrystallization method, if desired, the free optical isomers of through neutralization step how to get the body.

2) Chiral Column Method: racemate or method for separating the salt thereof is a column for optical isomer separation (chiral Rukaramu). For example, in the case of liquid chromatography, ENALTI0-0VM (Torso manufactured one company) or by adding a mixture of a chiral column for optical isomers such as manufactured by Daicel Chemical Industries, Ltd. CHIRA I Nrizu, water, various buffers (eg, Li down acid buffer), an organic solvent (e.g., ethanol, methanol, isopropanol, § Seth - tolyl, Torifuruoro acetate, by deploying Jechiruamin) alone or mixed with solvent liquid, to separate the optical isomers. Also, for example, in the case of gas chromatography Matogurafi one, CP- Chirasi DeX CB (manufactured by GL Sciences Inc.). Use of .. chiral column such as to separate. ,

3) Jiasutereoma Method: A mixture of racemic mixture of by connexion Jiasutereoma the chemical reaction with an optically active reagent, single substance through such this conventional separation means (e.g., fractional recrystallization, chromatography, etc.) after the process of obtaining the optical isomers by separating the optically active reagent moiety by hydrolysis reaction of any chemical treatment. For example, Compound (I), ([pi), human Dorokishi group or the primary to (lib) is a molecule, if a secondary amino group, the compound and an optically active organic acid (e.g., MTPA [0; - main butoxy - alpha - (triflate Ruo b methyl) phenyl acetic acid], (-) - by subjecting to condensation reaction menthoxyacetic such as acetic acid) and the like, Jiasutereoma each ester or ami de thereof is obtained. On the other hand, Compound (I), (Π), (lib) force when it has a S carboxyl group, by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction, Jiasute Reoma each Ami de body or ester thereof It is obtained. Separated Jiasutereoma, by subjecting to an acid hydrolysis or basic hydrolysis reaction, it is converted to an optical isomer of the original compound.

Example

Reference Example The following, Examples, Formulation Examples and Experimental Examples, the present invention will be described more specifically, but not the by connexion present invention which is limited.

The following Reference Examples, "%" in the examples means% by weight unless otherwise specified.

NMR spectrum was used de tetramethyl silane as an internal standard. Showing the δ value in ppm.

Abbreviations used in other text represent the following meanings.

s: Shinguretsu door (singlet)

d: Daburetsuto (doublet)

t: triplets (triplet)

q: Karuatsu Bok ^ quartet)

m: Manorechipuretsu door nultiple't)

brs: broad singlet peaks door (broad singlet)

J: cup! .) Tank constant (.coupling constant) Hz: Hertz (Hertz) CDCl,: heavy chloroform, DMS0-d 6: dimethyl sulfoxide - d 6

Room temperature, usually from about 10 ° C shows the range of 35 ° C, it is not particularly strictly limited. .

Herein, the melting point, for example, micromelting point measuring apparatus (Yanako, MP- 500D type or may Bu chi, B- 545 type) or DSC (differential run 查熱 weight analysis) apparatus (SE I KO, EXSTAR6000) etc. It means a melting point as measured with a.

In general, the melting point may vary depending on measurement apparatuses, measurement conditions and the like. Honmyo crystals in Saisho, as long as it is within general error range may be a crystal show a different melting point described herein.

The compound obtained in Reference Example 74 to 144 and Examples 61 to 160 may form a salt with formic acid.

Reference Example 1 5- [2- [(tert- butoxycarbonyl) Amino] Echiru] - 1, 2, 4 - Okisajia 3-carboxylic acid Echiru

Boc-] 3- Aranin (13.6 g, 72.0 mmol) N in as tetrahydrofuran (0.99 mL) solution of, N, - carbo - give added portionwise Le Jie Mi Dazo Honoré (11.7 g, 72.0 mmol) at 0 ° C the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue Amino (human Dorokishiimino) acetate Echiru (7.96 g, 60.0 mmol) was heated to reflux and pyridine (100 mL) is obtained the mixture was added 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the residue was diluted with acetic acid Echiru. The resulting solution of 0.5 M hydrochloric acid, washed with saturated sodium bicarbonate aqueous solution Contact Yopi saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. After it made fine with the residue by silica gel column chromatography (hexane / acetic acid Echiru = 2/1 to), to which was crystallized from hexane / acetic acid Echiru to give the title compound (12.2 g, 71% yield).

Mp 60- 61 ° C.

J H NMR (CDCI3) δ 1.43 (9Η, s), 1.45 (3Η, t, J = 7.1 Hz), 3.19 (2H, t, J = 6.2 Hz), 3.65 (2H, q, J = 6.1 Hz), 4.52 (2H, q, J = 7.1 Hz), 5.00 (1H, brs) reference example 2 5- (2-Aminoechiru) -. 1, 2, 4-Okisajiazoru - 3-carboxylic acid chill salt -. salt έ

5- [2- [(tert- script butoxycarbonyl) amino] Echiru] -1,2, 4-Okisajiazo Ichiru - 3-carboxylic acid Echiru (2.85 g, 10.0 mmol) in acetic acid Echiru (15 mL) solution of 4 N salts hydrogen acetate Echiru solution (15 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with acetic acid Echiru to give the title compound (2.05 g, 92% yield).

J H negation R (DMS0-d 6) δ 1.33 (3H, t, J = 7.1 Hz), 3.27-3.33 (2H, m), 3.40

(2H, t, J = 7.0 Hz), 4.42 (2H, q, J = 7.1 Hz), 8.27 (3H, brs).

Reference Example 3 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] -1, 2, 4-Okisaji Azoru 3-force carboxylic acid Echiru

5- (2-Aminoechiru) -1,2, 4_ Okisajiazoru - 3-carboxylic acid Echiru hydrochloride (2.05 g, 9.23 mmol) and Toriechiruamin (2.58 mL, 18.5 mmol) as tetrahydrofuran (35 mL) suspension chloride solution of 4-Biff sulfonyl carbonyl (2.00 g, 9.23 mmol) was added portionwise at room temperature, and the resulting mixture was stirred for 30 minutes. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue f was recrystallized from hexane / acetic acid Echiru to give title compound (3.13 g, 93% yield).

Mp 158- 159 ° C.

JH negation R (CDC1 3) δ 1.45 ( 3H, t, J = 7.1 Hz), 3.36 (2H, t, J = 6.0 Hz), 4.01 (2H, q, J = 6.0 Hz), 4.52 (2H, q, J = 7.1 Hz), 6.87 (1H, t, J = 5.7 Hz), 7.37-7. 1 (1H, ra), 7.45-7. 9 (2H, m), 7.59-7.62 (2H, ra), 7.65 -7.68 (2H, m), 7.82-7.85 (2H, m).

Reference Example 4 2- (2 - heat Dorokishi - 3 phenoxyethanol propyl) - 1H-Lee predisposition Doll - 1, 3 (2H) - dione

Glycidyl phenylpropyl ether (11.5 mL, 85.0 mmol), Futaruimi de (12.5 g, 85.0 mmol) and potassium carbonate. (1 · 17 g, 8.50 mmol) in ethanol (100 mL) suspension was heated to reflux overnight. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization from hexane / acetic acid Echiru fart the residue the title compound -

Was obtained (19.9 g, 79% yield). ; Mp 116- 117 ° C.

X H NMR (CDC1 3) 5 2.85 (1H, d, J = 6.1 Hz), 3.96 (1H, dd, J = 4.2, 14.4 Hz), 4.01-4.09 (3H, m), 4.26-4.35 (1H, m ), 6.90-6.94 (2H, m), 6.95-6.99 (1H, ra), 7.26-7.31 (2H, m), 7,72-7.77 (2H, m), 7.85-7.90 (2H, m).

Reference Example 5 triflumizole Ruo b Methanesulfonic acid [2- (1, 3-dihydrazide mud - 1,3 - Jiokiso - 2H-isoindole-2 - I le) - 1 - (Fuwenokishimechiru) Echiru]

2- (2-heat Dorokishi - 3 phenoxyethanol propyl)-1H-Isoindoru - 1, 3 (2H) - dione (8.92 g, 30.0 ramol) and pyridine (2.91 mL, 36.0 mmol) in dichloromethane (100 mL) anhydrous triflic solution Ruo b methanesulfonic acid (5.55 mL, 33.0 mmol) was added dropwise at -78 ° C, the resulting mixture was warmed to 0 ° C. The reaction mixture is washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue fart from hexane / acetic acid Echiru was crystallized to give the title compound (12.5 g, 97% yield).

Mp 105- 106 ° C.

! H NMR (CDC1 3) δ 4.09 (1Η, dd, J = 3.8, 15.0 Hz), 4.25 (1H, dd, J = 6.0, 11.1 Hz), 4.32-4.39 (2H, m), 5.46-5.51 (1H , ra), 6.90-6.94 (2H, m), 7.00- 7.04 (1H, m), 7.29-7.34 (2H, m), 7.76-7.80 (2H, m), 7.89-7.94 (2H, m). reference example 6 2- (2-Moruhori Bruno -3 - phenoxyethanol propyl) - 1H-Isoindoru - 1, 3 (2H) - dione

Triflate Ruo b methanesulfonic acid [2 - (1,3-dihydrazide mud - 1, 3-Jiokiso - 2H-Isoin Doll - 2 - I le) -1 - (Fuenokishimechiru) Echiru] (12.0 g, 27.9 mmol) and carbonated water N elementary Natoriumu (3.52 gra 41.9 mmol), N- dimethyl formamide ami de (100 mL) suspension of morpholine (3.65 mL, 41.9 mmol) was added dropwise at 0 ° C, the resulting mixture at room temperature 1.5 and the mixture was stirred time. The reaction solution was diluted with acetic acid Echiru, twice with water, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After purification the residue silica gel column chromatography (hexane / acetate Echiru = 2/1) and recrystallized from hexane / acetic acid Echiru to give the title compound (4.88 g, 48% yield).

XH NMR (CDC1 3) δ 2.52-2.57 (2Η, m), 2.93-2.98 (2Η, ra), 3.37-3. 3 (1Η, m), 3.49-3.57 (4H, m), 3.77 (1H, dd , J = 5.7, 14.0 Hz), 4.03-4.10 (2H, .. m), 4.15 (1H, dd, J = 5.7, 9.8 Hz), 6.86- 6, 91 (2H, m), 6.94-6.98 ξΙΗ, m): 7.25-7.31 (2H, m), 7.71-7.76 (2H, m), 7.84-7.89 (2H, m).

Reference Example 7 2 - morpholino - 3-phenoxyethanol propyl § Min

2 - (2 - morpholino - 3 - phenoxyethanol propyl) - 1H-Isoindoru - 1, 3 (2H) - dione (4.87 g, 13.3 mmol), hydrazine monohydrate (3.23 mL, 66.5 mmol) Oyo a mixture of Pi E ethanol (100 mL) was heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure of 2 M hydroxide Natoriumu solution and 28% aqueous ammonia solution was added to the residue, and extracted with Jechiruete Le. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (7.63 g, 96% yield) as an oil.

X H NMR (CDC1 3) δ 1.05-1.57 (2Η, brs), 2.57-2.66 (2H, m), 2.80-2.90 (5H, m), 3.64-3.77 (4H, m), 3.93-4.00 (1H, m), 4.08-4.15 (1H, ra), 6.87-7.00 (3H, m), 7.25-7.33 (2H, ra).

Reference Example 8 2 - morpholino - 3 full Roh propyl § Min dihydrochloride

2- (2-morpholino - 3 - phenoxyethanol propyl) - 1H-Isoindoru - 1, 3 (2H) - dione (4.87 g, 13.3 mmol), hydrazine monohydrate (3.23 mL, 66.5 mmol) Oyo a mixture of Pi E ethanol (100 mL) was heated to reflux for 1 hour. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with brine and 1 M sodium hydroxide aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure.

The resulting residue 10% hydrogen chloride methanol solution (20 mL) was added to the resulting mixture was concentrated under reduced pressure. The residue was ethanol grounds recrystallized to give the title compound (3.96 g, yield

96% was obtained).

Mp 236_237 ° C.

Reference Example 9 1-Amino - 3 - phenoxy - 2 - propanol

In the same manner as in Reference Example 7, 2 - (2 - morpholino - 3 - phenoxyethanol propyl)-1H-isoindole - 1, 3 (2H) - 2 instead dione - (2 - heat Dorokishi - 3- Fuenokishipuro pills) - 1H-Isoindoru - 1, 3 (2H) - was used to obtain the title compound dione. 77% yield, mp 146- 147 ° C (recrystallized from acetic acid Echiru).

NMR (CDC1 3) δ 1.83 ( 3Η, brs), 2.84-2.88 (1Η, ra), 2.96-3.00 (1Η, m), 3.93-4.02 (3H, m), 6.90-6.98 (3H, m), 7.26 -7.32 (2H, m).

Reference Example 1 0 [2- [3 - [[(2 - heat Dorokishi - 3 phenoxyethanol propyl) Amino]; ¾ Lupo two Le] - 1, 2, 4-Okisajiazoru - 5-I le] Echiru] Karupamin acid tert- heptyl

5- [2 - [(tert - script butoxycarbonyl) amino] Echiru] - 1, 2, 4-Okisajiazoru - 3-carboxylic acid Echiru 1- Amino (285 mg, 1.00 mraol.) - 3- phenoxy - 2- propanol (167 mg, 1.00 ramol) and N, N- diisopropyl E chill § Min (129 mg, 1.00 mmol) in toluene (5 mL) solution was heated to reflux for 16 hours under a nitrogen atmosphere. Cold 却後, the reaction was concentrated under reduced pressure, the residue was purified by (g / acetic acid Echiru = 1/4 to) silica gel column chromatography to give the title compound (260 mg, 64% yield) as an oil It was.

J H NMR (CDC1 3) S 1.43 (9H, s), 2.96 (1H, brs), 3.17 (2H, t, J = 6.0 Hz) 3.60-3.67 (3H, ra), 3.84-3.90 (1H, m) , 3.97-4.01 (1H, m), 4.06-4.10 (1H, m), 4.22-4.30 (1H, ra), 5.01 (1H, brs), 6.92 (2H, d, J = 8.0 Hz), 6.99 (1H , t, J = 7.2 Hz), 7.28-7.32 (2H, m), 7.46 (1H, brs).

Reference Example 1 1 [2 - [3 - [[(2-morpholinoethyl) Amino] carbonyl] - 1, 2,4 Okisa Jiazoru 5 I le] Echiru] force Rubamin acid tert- butyl

In the same manner as in Reference Example 10, 1 - Amino - 3-phenoxy-2 instead N-(2-aminoethyl) propanol using morpholine to give the title compound as an oil. 51% yield.

JH NMR (CDCI3) δ 1.43 (9Η, s), 2.50-2.52 (4H, m), 2.60 (2H, t, J = 6.0 Hz), 3.17 (2H, t, J = 6.0 Hz), 3.56-3.60 ( 2H, m), 3.62-3.67 (2H, m), 3.72-3.75 (4H, m), 5.02 (1H, brs), 7.43 (1H, brs).

Reference Example 1 2 2 [3 - phenoxy - 2- (1-pyrrolidinyl) propyl] - 1H-Isoindo Le - 1, 3 (2H) - dione

In the same manner as in Reference Example 6 to give the title compound as an oil using pyrrolidine instead of morpholine. Yield 40 ° /. .

J H NMR (CDCI3) δ 1.68-1.82 . (4Η, m), 2.76-2.90 (4H, m), 3.26-3.35 (1H, m), 3.95-4.17 (4H, m), 6.77-7.00 (3H, . m), 7.18-7.31 (2H, m), 7.68-7.73 (2H, m), 7.80-7.85 (2H, m) reference example 13 [3 - phenoxy - 2- (1-Pirorijieru) flop port propyl] Amin - in the same manner as in reference example 7, 2- (2-morpholino - 3 - phenoxyethanol propyl) - IH - isoindole - 1,3 (2Η) - instead of dione 2- [3- phenoxy - 2- (1 - pyrrolidin) propyl]-1H-Isoindoru - 1, 3 (2Η) - was used to obtain the title compound dione. This compound was used in the next reaction without purification (Example 1 9).

Reference Example 14 2- (2-heat Dorokishi - 3 Isopuropokishipu port pills) - 1H-Isoindoru - 1, 3 (2Η) - dione

In the same manner as in Reference Example 4 to give the title compound as an oil with a glycine Jill isopropyl ether in place of glycidyl phenylpropyl ether. 86% yield. X H NMR (CDC1 3) δ 1.15 (6H, d, J = 4.5 Hz), 2.70 (1H, d, J = 4.8 Hz), 3.44 (1H, dd, J = 3.8, 7.1 Hz), 3.54 (1H, dd, J = 2.9, 7.4 Hz), 3.55- 3.64 (1H, m), 3.80 (1H, dd, J = 3.2, 7.7 Hz), 3.92 (1H, dd, J = 5.7, 10.5 Hz), 4.01-4.09 (1H, m), 7.68-7.77 (2H, ra), 7,82-7.90 (2H, m).

Reference Example 1 5 triflumizole Ruo b Methanesulfonic acid [2- (1,3 - dihydric mud - 1,3 - Jiokiso - 2H - Isoindonore - 2-I le) -1 - (I Seo Provo carboxymethyl) Echiru]

In the same manner as in Reference Example 5, 2 - (2-heat Dorokishi - 3 - phenoxyethanol propyl) - IH - isoindole - 1, 3 (2H) - 2 instead of dione - (2-heat Dorokishi - 3 - Isopuropokishi propyl) - 1H-Isoindoru - 1, 3 (2H) - it was dione using obtained as an oil the title compound. 97% yield.

JH NMR (CDC1 3) δ 1.17 (6Η, dd, J = 1.4, 4.7 Hz), 3.57-3.72 (2H, ra), 3.77 (1H, dd, J = 2.7, 8.4 Hz), 3.94 (1H, dd, J = 2.7, 11.1 Hz), 4.23 (1H, dd, J = 6.3, 11.1 Hz), 5.20-5.29 (1H, m), 7.76 (2H, dd, J = 2.3, 4.1 Hz), 7.90 (2H, dd , J = 2.3, 4.1 Hz);

Reference Example 1 6 2- (3-Isopuropokishi 2-morpholinopropyl) - 1H-Isoindoru - 1, 3 (2H) - dione

In the same manner as in Reference Example 6, triflumizole Ruo b methanesulfonic acid [2 - (1, 3 - dihydric de port - 1, 3-Jiokiso - 2H-Isoindo Ichiru -. 2 I Le) - 1- (Fuenokishimechiru) Echiru] Alternatively triflate Ruo b methanesulfonic acid [2- (1,3-dihydrazide mud - 1, 3-Jiokiso - 2H-I Soindoru - 2 - I le) -1-(I Seo Provo carboxymethyl) Echiru] the title compound was obtained as an oil using. 56% yield., X H NMR (CDCL) δ 1.17 (6H, dd, J = 4.5, 8. Hz), 2.44-2.53 (2H, m), 2.83-2.92 (2H, m), 3.07-3.16 (1H, m), 3.44-3.61 (7H, m), 3.67 (1H, dd, J = 4.5, 10.5 Hz), 3.89 (1H, dd, J = 7.1, 10.4 Hz), 7.72 (2H, dd, J = 2.4, 5.2 Hz) , 7.85 (2H, dd, J two 2.1, 5.2 Hz).

Reference Example 1 7 3 Isopuropokishi 2-morpholinopropyl § Min

In the same manner as in Reference Example 7, 2- (2-morpholino - 3-phenoxyethanol propyl) - 1H-isoindole - 1, 3 (2H) - instead of dione 2- (3-Isopuropokishi - 2- morpholino propyl) - 1H-Isoindoru - 1,3 (2H) - it was dione using obtained as an oil the title compound. 79% yield.

^ Negation R (CDC1 3) δ 1.15 ( 6Η, t, J = 5.2 Hz), 1.48 (2H, brs), 2.50-2.60 (3H, ra), 2.65-2.83 (4H, m), 3.36 (1H, dd , J = 5.2, 7,2 Hz), 3.47-3.60 (2H, m), 3.62-3.75 (4H, m).

Reference Example 1 8 5 - [2- [[(4 - Bifuwe - Riruamino) carbonyl] amino] Echiru] - 1,2, 4-Okisajiazoru - 3-carboxylic acid Echiru

5- (2 - Aminoechiru) -1,2, 4 - Okisajiazoru - 3-carboxylic acid Echiru hydrochloride (200 mg, 0.902 mmol) and Toriechiruamin (0.240 mL, 1.72 mraol) suspension of tetra human Dorofuran (10 mL) Nigoeki the isocyanate 4 Bifue - Lil (190 mg, 0.973 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with acetic acid Echiru, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Residue was recrystallized from acetic acid E chill, to give the title compound (290 mg, 84% yield).

Melting point 188- 189 ° (:.

J H NMR (CDC1 3) δ 1.45 (3Η, t, J = 7.6 Hz), 3.27 (2H, t, J = 6.0 Hz), 3.25-3.35 (2H, m), 4.50 (2H, q, J = 7.2 Hz), 6.30 (1H, t, J = 6.0 Hz), 7.32-7.65 (9H, m), 8.23 ​​(1H, s).

Reference Example 1 9 2- [2- [(2 - main Tokishechiru) (methyl) Amino] - 3-Fuenokishipuropi le] - 1H-Isoindoru - 1, 3 (2H) - dione

In the same manner as in Reference Example 6, instead of morpholine - by using the (2 main Tokishechiru) methylcarbamoyl Ruamin give the title compound as an oil. 44% yield. NMR (CDCI3) δ 2.45 (3H, s), 2.74-2.91 (2H, m), 3.14 (3H, s), 3.25- 3.38 (2H, in), 3.51-3.61 (1H, m), 3.77 (1H, dd, J = 4.8, 10.2 Hz) ,, 3.94- 4.06 (2H, m), 4.15 (1H, dd, J = 4.4, 7.4 Hz), 6.80-6.86 (2H, m), 6.93 (1H, t, J = 5.6 Hz), 7.24 (2H, t, J = 5.9 Hz), 7.67-7.74 (2H, m), '7.80- 7.86 (2H, m)..

Reference Example 20 N 2 - (2-menu Tokishechiru) - N 2 - methyl - 3 - phenoxyethanol propane - 1, 2-di Amin

In the same manner as in Reference Example 7, 2- (2 - morpholino - 3 - phenoxyethanol propyl) - 1H-isoindole - 1, 3 (2H) - 2 instead of dione - [2- [(2 - Main Tokishechiru) (methyl) Amino] - 3 - phenoxyethanol propyl] - 1H-isoindole - 1, 3 (2H) - to give dione using the title compound as an oil. 97% yield.

J H NMR (CDClg) δ 1.54 (2H, brs), 2.44 (3Η, s), 2.70-2.86 (3H, m), 2.88- 3.03 (2H, m), 3.36 (3H, s), 3.41-3.54 ( 2H, m), 3.91 (1H, dd, J = 4.2, 7.2 Hz), 4.09 (1H, dd, J = 4.5, 7.2 Hz), 6.87-6.98 (3H, m), 7.24-7.31 (2H, m) .

Reference Example 21 2- (3-Benjiruokishi - 2-hydroxycarboxylic propyl) - 1H-Isoindoru - 1, 3 (2H) - dione

In the same manner as in Reference Example 4 to give the title compound as an oil with benzyl glycidyl ether in place of Gurishijirufue two Rue one ether. 77% yield.

JH NMR (CDCI3) δ 2.69 (1Η, d, J = 4.8 Hz), 3.52 (1H, dd, J = 3.9, 7.2 Hz), 3.60 (1H, dd, J = 3.2, 7.4 Hz), 3.82 (1H, dd, J = 3.3, 10.5 Hz), 3.93 (1H, dd, J = 5.7, 10.8 Hz), 4.07-4.15 (1H, m), 4.56 (2H, s), 7.26- 7.36 (5H, m), 7.69 -7.75 (2H, m), 7.82-7.88 (2H, m).

Reference Example 22 triflumizole Ruo b methanesulfonic acid [1-benzyl O carboxymethyl - 2- (1, 3 - dihydric mud - 1, 3-Jiokiso - 2H - isoindole - 2 - I le) Echiru]

In the same manner as in Reference Example 5, 2- (2 - heat Dorokishi - 3 phenoxyethanol propyl) - IH - isoindole - 1, 3 (2H) - instead of dione 2- (3-Benjiruokishi - 2- human Dorokishi propyl) - 1H-Isoindoru - 1, 3 (2H) - was dione using obtained as an oil the title compound. 100% yield.: H丽R (CDClg) δ 3.72-3.85 (2H , ra), 3.93 (1H, dd, J = 2.3, 11.3 Hz) 4.27 (1H, dd, J = 6.2, 11.0 Hz), 4.59 (1H, d, J = 9.0 Hz), 4.63 (1H, d, J = 9.0 Hz), 5.26-5.36 (1H, m), 7.26-7. 0 (5H, m), 7.72-7.80 (2H, ra), 7.86-7.94 (2H, m).

Reference Example 23 2- (3 - Benjiruokishi - 2-morpholinopropyl)-1H-Isoindoru - 1, 3 (2H) - dione

In the same manner as in Reference Example 6, triflumizole Ruo b Methanesulfonic acid [2- (1,3 - dihydric de B - 1, 3-Jiokiso - 2H - Isoindoru - 2-I le) - 1- (Fuenokishimechiru) Echiru] of instead triflates Ruo b methanesulfonic acid [1 - benzyl O carboxymethyl - 2- (1,3-dihydrazide mud - 1, 3-Jiokiso - 2H-Isoindoru - 2-I le) Echiru] was used to obtain the title compound . This compound was used in the next reaction without purification.

Reference Example 24 3 - base Njiruokishi - 2-morpholinopropyl § Min

In the same manner as in Reference Example 7, 2- (2-morpholino - 3 - off We Roh hydroxypropyl) - 1H-isoindole - 1, 3 (2H) - instead of dione 2- (3-Benjiruokishi - 2- morpholino propyl) - 1H-isoindole - 1,3 (2H) - it was dione using obtained as an oil the title compound. 46% yield (triflate Ruo b methanesulfonic acid [1-benzyl O carboxymethyl - 2- (1,3-dihydrazide mud - 1, 3 - Jiokiso - 2H-isoindole - 2-I le) Echiru] yield from ) (! H NMR (CDCI3) δ 1.47 (2Η, brs), 2.50-2.58 (2H, m), 2.59-2.67 (1H, m), 2.69-2.81 (4H, m), 3.44 (1H, dd, J = 4.1, 7.4 Hz), 3.59-3.75 (5H, m), 4.50 (2H, s), 7.26-7.40 (5H, m).

Reference Example 25 2- (3 - phenoxy - 2-Ji ^ morpholinopropyl) - IH - Isoindoru - 1, 3 (2H) - dione

In the same manner as in Reference Example 6 to give the title compound as an oil using thiomorpholine instead of morpholine. 28% yield.

XH NMR (CDCI3) δ 2.47 (4Η, t, J = 3.8 Hz), 2.73-2.83 (2H, m), 3.17-3.26 (2H, m), 3.38-3.47 (1H, m), 3.71 (1H, dd , J = 4.1, 10.8 Hz), 4.00-4.17 (3H, m), 6.85-6.99 (3H, ra), 7.24-7.32 (2H, m), 7.70-7.76 (2H, m), 7.82- 7.89 (2H , m).

In the same manner as 2-thiomorpholinopropyl § Min Reference Example 7, 2 - - Reference Example 26 3-phenoxy (2 - morpholino - 3 full We Roh hydroxypropyl) - IH isoindole - 1, 3 (2H) - instead 2- dione (3 - phenoxy - 2 - Chiomono Horino propyl) - IH - Isoindoru - 1, 3 (2H) - was dione using obtained as an oil the title compound. Yield 99%.

NMR (CDC1 3) δ 1.64 ( 2H, brs), 2.58-2.74 (4Η, m), 2.74-2.94 (5H, m), 3.10-3.22 (2H, m), 3.89 (1H, dd, J = 3.9, 7.2 Hz), 4.09 (1H, dd, J = 4.5, 7.2 Hz), 6.86-7.01 (3H, m), 7.28 (2H, t, J = 5.9 Hz).

Reference Example 27 - tert (2-morpholino 2-Fueniruechiru) Karupamin acid heptyl

(2 - human Dorokishi 2 Fueniruechiru) Karupamin acid tert- butyl (9.49 g, 40.0 mmol) and Toryechiruamin (6.13 mL, 44.0 mmol) acetic acid Echiru (250 mL) was added methanesulfonyl chloride (3.41 mL, 40.0 mmol) and It was added dropwise at room temperature, and the resulting mixture was stirred for 15 min. The reaction mixture is washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.

Obtained residue and Monorehorin (7.85 mL, 90.0 mmol) was heated at reflux for 4 hours as tetrahydrofuran (100 mL) suspension of. After cooling, the reaction was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (hexane / acetic acid Echiru = 1/1 to), and recrystallized from hexane / acetic acid Echiru to give the title compound (5.24 g, 43% yield).

Melting point of 106-107 ° (:.

! H NMR (CDC1 3) δ 1.42 (9H, s), 2.37- 2, 48 (4Η, ra), 3.32-3.38 (1H, m), 3.42 (1H, t, J = 6.5 Hz), 3.64-3.73 (5H, m), 4.69 (1H, t, J = 5.1 Hz), 7.21-7.24 (2H, ra), 7.27-7.37 (3H, m).

Reference Example 28 2-morpholino - 2 - phenylpropyl E chill § Min

(2-morpholino - 2 Fueniruechiru) force Rubamin acid tert- heptyl (4.99 g, 16.3 mmol) in dichloromethane (50 mL) was added Torifuruoro acetate (25 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with Jikurorome Tan. Aqueous 1 M sodium hydroxide solution obtained and dried in wash Les ,, sodium sulfate and saturated brine, and concentrated under reduced pressure to give the title compound (3.11 g, 92% yield) as an oil.

J H NMR (CDCI3) δ 1.12 (2H, s), 2.39-2.47 (4H, ra), 2.98 (1H, dd, J f = 6.6, 13.0 Hz), 3.10 (1H, dd, J = 5.6, 13.0 Hz ), 3.28 (1H, t, J = 6.1 Hz),

3.64-3.75 (4H, m), 7.25-7.30 (3H, m), 7.31-7.37 (2H, m).

Reference Example 29 (3,4-dihydrazide Dorokinorin - 1 (2H) - I le) Asetonitoriru

1,2,3,4 Tetorahi Dorokinorin (3.77 mL, 30.0 Yuzuru ol), Promo acetonitrilate Le (4.18 mL, 60.0 mraol) and carbonate Kariumu (8.29 g, 60.0 mmol) N of, N- di-methyl formamidine de and the (50 mL) suspension is stirred for 4 hours at 60 ° C. After cooling, the reaction was diluted with acetic acid Echiru, twice with water, washed once with saturated brine, dried over. Magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / acetate Echiru = 5/1) to give the title compound (4.74 g, 92% yield) oil.

: H NMR (CDCI3) δ 2.02-2.08 (2H, m), 2.80 (2Η, t, J = 6.5 Hz), 3.29-3.31 (2H, m), 4.16 (2H, s), 6.67 (1H, d, J = 8.3 Hz), 6.78 (1H, dt, J = 1.0, 7.5 Hz), 7.01-7.04 (1H, m), 7.12-7.16 (1H, m).

Reference Example 30 2 - (3, 4 dihydric Dorokinorin - 1 (2H) - I le) Echiruamin dihydrochloride 'lithium aluminum hydride (1.14 g, 30.0 mmol) chloride GETS chill ether (30 mL) suspension of aluminum (4.00 g, 30.0 mmol) the oxygenate chill ether (30 mL) solution was added dropwise at room temperature. After 5 minutes, the reaction solution (3, 4 - dihydric Dorokinorin - 1 (2H) - I le) Asetonitoriru (4.74 g, 27.5 mmol) Jefferies chill ether (30 mL) was added dropwise and the resulting mixture 30 min It stirred. The reaction was quenched by adding water little by little to dissolve the insoluble matter further added 8 M aqueous sodium hydroxide. The resulting mixture was extracted 3 times with Jeffrey chill ether, washed the combined organic layers with saturated brine, dried over sulfate Natoriumu, and concentrated under reduced pressure.

The resulting residue 10% hydrogen chloride methanol solution (50 mL) was added to the resulting mixture was concentrated under reduced pressure. The residue was washed with ethanol, and recrystallized from methanol to give the 'title compound (4.27 g, 62% yield).

Mp 213-214 ° C.

X H NMR (DMS0 - d 6 ) δ 1.84-1.90 (2H, m), 2.68 (2H, t, J = 6.4 Hz), 2.89- 2.97 (2H, m), 3.25-3.28 (2H, m), 3.51 (2H, t, J = 7.1 Hz), 6.53 (1H, t ,, J = 7.3 Hz), 6.90 (1H, d, J = 8.1 Hz), 6.90 (1H, d, J = 7.3 Hz) ,, 6.96 - 7.00 (1H, m), 8.18 (3H, s).

Reference Example 3 1 (2, 3, 4, 5 Tetorahi mud - IH - 1 - Benzuazepin - 1-I le) Asetonito drill.

In the same manner as in Reference Example 29, 1,2, 3, 2 instead of 4 Tetorahi Dorokinorin, 3, 4, 5-tetrahydro - IH - using 1 Benzuazepin give the title compound as an oil. 57% yield.

J H NMR (CDC1 3) δ 1.60-1.66 (2Η, m), 1.77-1.83 (2H, m), 2.77-2.80 (2H, m), 3.08-3.11 (2H, m), 4.06 (2H, s) , 6.97 (1H, dt, J = 1.0, 7.3 Hz), 7.07 (1H, dd, J = 1.0, 7.8 Hz), 7.14 (1H, dd, J = 1.5, 7.3 Hz), 7.20 (1H, dt, J = 1.5, 7.8 Hz).

Reference Example 3 2 2- (2, 3, 4, 5 Tetorahi mud - IH-1 - Benzuazepin - 1-I le) Echirua Min

Lithium aluminum hydride (0.474 g, 12.5 mmol) Jefferies chill ether (10 mL) suspension of aluminum chloride (1.67 g, 12.5 mmol) of the oxygenate chill ether (10 mL) solution was added dropwise at room temperature. After 5 minutes, the reaction solution (2,3,4,5-tetrahydro - 1H-1-Ben Zuazepin - 1-I le) Asetonitoriru (2.10 g, 11.3 mmol) was added dropwise oxygenate chill ether (10 mL) solution of the resulting mixture was stirred for 1 hour. Reaction stopped Water was added One not a little reaction to dissolve the insoluble matter further added 8 M hydroxide Natoriumu solution. The resulting mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column inlet Mato chromatography (acetate Echiru / as tetrahydrofuran = 1 / 0-0 / 1) to give the title compound (1.92 g, 89% yield) as an oil.

JH NMR (CDCI3) δ 1.31 (2H, brs), 1.58-1.64 (2Η, m), 1.70-1.75 (2H, ra), 2.78-2.81 (2H, ra), 2.82-2.85 (2H, m), 2.90 -2.93 (2H, ra), 3.20-3.23 (2H, m), 6.88 (1H, dt, J = 1.1, 7.4 Hz), 6.94-6.98 (1H, m), 7.11-7.16 (2H, m). reference example 33 5- [3- [(tert- butoxycarbonyl) Amino] propyl] - 1, 2, 4-Okisa Jiazoru - in the same manner as 3-carboxylic acid Echiru reference example 1, Boc-instead of Aranin 4- (N-tert butoxy -. Shikarubo - Ruamino) with acid to give the title compound as an oil. Yield 50%.

NMR (CDC1 3) δ 1.44 ( 3H, t, J = 7.2 Hz), 1.44 (9H, s), 2.02-2.10 (2H, m), 3.03 (2H, t, J = 7.6 Hz), 3.15-3.28 ( 2H, m), 4.51 (2H, q, J = 7.2 Hz), 4.63 (1H, brs),.

Reference Example 34 5- (3-Aminopuropiru) - 1, 2, 4-Okisajiazoru 3-carboxylic acid E Chi le hydrochloride

In the same manner as in Reference Example 2, 5-[2-[(tert - script butoxycarbonyl) Amino] E Chi le] - 1,2, 4-Okisajiazoru - 3 5_ instead of the carboxylic acid Echiru [3_ [( tert- butoxycarbonyl) amino] propyl] - 1, 2, 4-Okisajiazoru - the title compound was obtained using 3-carboxylic acid E Ji Le.

Mp 144_145 ° C (recrystallized from acetic acid Echiru / ethanol).

Reference Example 35 5- [3- [(4-Bifue - Lil carbonyl) Amino] propyl] - 1,2,4-O key Sajiazonore - 3-force Rupon acid Echiru

In the same manner as in Reference Example 3, 5- (2 - aminoethyl) - 1,2,4 Okisajiazo Ichiru -

3-carboxylic acid Echiru instead 5- (3-aminopropyl) hydrochloride -1, 2, the title compound was obtained using 4-Okisajia 3-carboxylic acid Echiru hydrochloride.

Mp 158- 159 ° C (recrystallized from acetic acid Echiru).

NMR (CDC1 3) δ 1.43 ( 3H, t, J = 6.8 Hz), 2.15-2.28 (2H, m), 3.13 (2H, t, J = 7.2 Hz), 3.57-3.66 (2H, m), 4.49 ( 2H, q, J = 7.2 Hz), 6.53 (1H, brs), 7.33-7.48 (3H, m), 7.57-7.72 (4H, m), 7.82-7.88 (2H, m).

Reference Example 36 [(2 - morpholino - 3 - phenoxyethanol propyl) Amino] (Okiso) acetate E Ji Le

2-morpholino - 3 - phenoxyethanol propylamine (390 mg, 1.65 mmol), oxalic acid Jechiru (265 mg, 1.82 mmol) in ethanol (5 mL) was added 20% sodium E butoxide in ethanol (122 mg, 0.36 mmol) was added and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, followed by extraction with acetic acid Echiru. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / acetate Echiru = 1/1) to give the title compound (400 mg, 72% yield) as an oil.

! H NMR (CDC1 3) δ 1.40 (3H, t, J = 7.2 Hz), 2.61-2.66 (2H, m), 2. ¾2-2.87 (2H, m), 3.03-3.07 (1H, m), 3.36 -3.43 (1H, m), 3.68-3.76 (5H, m), 4.01- 4.05 (1H, m), 4.11-4.17 (1H, m), 4.37 (2H, q, J = 7.2 Hz), 6.90 (2H , d, J = 8.0 Hz), 6.98 (1H, t, J = 7.2 Hz) ,. 7.28-7.32 (2H, m), 7.80 (1H, brs) reference example 3 7 2-arsenide Dorajino -. N - ( 2 - morpholino - 3 - phenoxyethanol propyl) - 2-Okiso Asetoami de

[(2 - morpholino - 3 - phenoxyethanol propyl) Amino] (Okiso) acetate Echiru (3 80 mg, 1.13 mmol) in ethanol (5 mL) was added hydrazine monohydrate (85 mg, 1.69 mmol) It was added and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was crystallized from diisopropyl ether to give the title compound (348 mg, 96% yield).

Mp 148- 149 ° C.

] H NMR (CDCI3) δ 2.61-2.66 (2Η, m), 2.81-2.86 (2Η, ra), 3.02-3.05 (1Η, m), 3.37-3.44 (1H, m), 3.64-3.77 (5H, m ), 3.96 (2H, d, J = 4.8 Hz), 4.01-4.05 (1H, m), 4.13-4.17 (1H, m), 6.90 (2H, d, J = 8.4 Hz), 6.98 (1H, t, J = 7.6 Hz), 7.28-7.32 (2H, m), 7.96 (1H, brs), 8.47 (1H, brs).

Reference Example 38 [2- (methylcarbamoyl) Echiru] Karupamin acid tert- butyl

N-(tert script butoxycarbonyl) - J3- Aranin (1.89 g, 10.0 mmol) and 1H- benzotriazol § tetrazole - 1- Ino Les yloxytris (dimethylamino) Hosuhoniumu to hexa full O b phosphite Fay preparative (4.42 g, Asetonitoriru of 10.0 mol) (20 raL) was added 40 ° /. Methyl § Min methanol solution (2.33 g, 30.0 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the residue sodium bicarbonate aqueous solution was added, followed by extraction with acetic acid Echiru. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (1.10 g, 54% yield).

J H NMR (CDCI3) δ 1.43 (9H, s)., 2.39 (2Η, t, J = 5.6 Hz), 2.65 (3H, d, J

= 9.6 Hz), 3.38-3.43 (2H, m), 5.18 (1H, brs), 5.76 (1H, brs).

Reference Example 39 [2- (methylthio force Rubamoiru) Echiru] force Rubamin acid tert- heptyl [2 - (methyl Kalpa carbamoyl) Echiru] force Rubamin acid tert- butyl (600 mg, 3.0¾ mraol) and Lawesson's reagent (607 mg, under a nitrogen atmosphere as tetrahydrofuran (10 ^ L) dissolved solution of 1.50 mmol), and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane / acetic acid Echiru = 6/4 to), Table title compound (660 mg, 100% yield) of an oil and. To give It was.

X H NMR (CDC1 3) δ 1.43 (9H, s), 2.87 (2H, t, J = 5.6 Hz), 3.19 (3H, d, J = 4.8 Hz), 3.52-3.57 (2H, m), 5.08 ( 1H, brs), 7.99 (1H, brs).

Reference Example 40 [2- [4-methyl-5 - [[(2-morpholino-3-phenoxyethanol propyl) Amino] carbonylation Honoré] - 4H - 1, 2, 4-Toriazoru _3 - Inore] Echiru] Karupamin acid tert - heptyl

[2- (methylthio Kalpa carbamoyl) Echiru] Karupamin acid tert- butyl (109 mg, 0.500 mmol) the mixture under a nitrogen atmosphere and methyl iodide (5 mL), and 16 hours stirred at room temperature. The reaction solution was concentrated under reduced pressure, the residue aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with acetic acid E chill. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.

The resulting residue and 2 - heat Dorajino - N-(2 - morpholino - 3 - off We Roh hydroxypropyl) - 2 - O Kisoasetoami de (161 mg, 0.500 mmol) nitrogen Kiri囲 vapor toluene (10 mL) solution of lower and stirred for 16 h at 100 ° C. The reaction solution was concentrated under reduced pressure, the residue sodium hydrogen carbonate aqueous solution was added, and the mixture was extracted with acetic acid Echiru. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue fart from hexane / acetic acid Echiru was crystallized to give the title compound (173 rag, 71% yield).

Mp 135- 136 ° C.

lH NMR (CDCI3) δ 1.42 (9Η, s), 2.65-2.69 (2Η, m), 2.86-2.94 (4H, m), 3.07-3.11 (1H, m), 3.45-3.53 (1H, m), 3.65 -3.83 (7H, m), 3.92 (3H, s), 4.03-4.07 (1H, m), 4.16-4.20 (1H, m), 5.35 (1H, brs), 6.92 (2H, d, J = 8.0 Hz .), 6.98 (1H, t, J = 7.2 Hz), 7.28-7.32 (2H, m), 7.99 (1H, brs) reference example 41 N-(2-Shianoechiru) biphenyl - 4 power Rupokisami de

3 § Mino propiononitrile (7.38 mL, 100 mmol) and Toriechiruamin a (13.9 mL, 100 mmol) in as tetrahydrofuran (400 mL) was added chloride 4 Bifue two ylcarbonyl (21.7 g, 100 ramol) at room temperature in added portionwise, and the resulting mixture was stirred for 30 minutes. The reaction mixture 'was diluted with acetic acid Echiru, water and washed with saturated brine, dried over sulfate mug. Neshiumu, and concentrated under reduced pressure. The residue was wash with hexane / acetate Echiru (1 /) to give the title compound (24.4 g, 97% yield).

Mp 170- 171 ° C.

XH NMR (CDC1 3) δ 2.78 (2Η, t, J = 6.2 Hz), 3.75 (2H, q, J = 6. Hz), 6.67 (1H, t, J = 5.0 Hz), 7.38-7.42 (1H, m), 7.45-7.50 (2H, m), 7.60- 7.63 (2H, ra), 7.66-7.69 (2H, m), 7.85-7.88 (2H, in).

Reference Example 42 N - [3- Amino - 3 - (arsenate Dorokishiimino) propyl] biphenyl - 4 - Power Lupo Kisami de

N-(2 - Shianoechiru) Bifue sulfonyl - 4- Karubokisami de (11.8 g, 47.3 mmol), human Dorokishiruamin hydrochloride (4.93 g, 71.0 mmol) and sodium acetate (5.82 g, 71.0 mmol) ethanol (0.99 mL) of the suspension was heated to reflux for 18 hours. After cooling, pour the reaction solution into water, the resulting crystals were collected by filtration. The filtrate was extracted three times with acetic Echiru, after the organic layer combined and dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with acetic acid Echiru, just in conjunction with collected by filtration crystals were recrystallized from methanol to give the title compound (6.10 g, 46% yield).

Mp 239- 240 ° C.

X H NMR (DMS0 - d 6 ) δ 2.28 (2H, t, J = 7.4 Hz), 3.44-3.49 (2H, m), 5.43 (2Η, 's), 7.39-7.43 (1H, m), 7.48- 7.52 (2H, m), 7.72-7.75 (2H, m), 7.75- 7.78 (2H, m), 7.92-7.95 (2H, m), 8.49 (1H, t, J = 5.5 Hz), 8.86 (1H, . s) reference example 43 3- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] -1, 2, 4-Okisa Jiazoru - 5-carboxylic acid Echiru

N - [3- Amino - 3- (arsenate Dorokishiimino) propyl] Bifue Le - 4- Karubokisami de (2.83 g, 10.0 mmol) in pyridine (30 mL) was added black port Okiso acetate Echiru (1.68 mL, 15.0 mmol) It was added dropwise at room temperature, and the resulting mixture was stirred for 30 min at 90 ° C. After cooling, the reaction solution was concentrated under reduced pressure, the residue was diluted with acetic acid Echiru. The resulting solution water, 1 M hydrochloric acid, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography grayed roughy (acetic Echiru), and recrystallized from acetic acid Echiru to give the title compound (2.54 g, 70% yield). , Mp 140- 141 ° C.

JH NMR (CDC1 3) δ 1.47 (3H, t, J = 7.1 Hz), 3.22 (2H, t, J = 6.1 Hz), 3.96 (2H, q, J = 6.1 Hz), 4.54 (2H, q, J = 7.1 Hz), 6.75 (1H, t, J = 5.0 Hz), 7.37-7.41 (1H, m), 7.45-7.48 (2H, m), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.83-7.86 (2H, m).

Reference Example 44 N- [2- (1H- tetrazol-5-I le) Echiru] biphenyl - 4 Karubokisa Mi de,

N-(2 - Shianoechiru) Bifue sulfonyl - 4- Karubokisami de (2.50 g, 10.0 negation ol), § di trimethylsilylcyanide (2.65 mL, 20.0 ramol) and oxidation n- dibutyltin (IV) (0.747 g, 3.00 negation ol toluene (50 mL) suspension of) was heated under reflux for 3 hours under a nitrogen atmosphere. After cooling, the reaction mixture was poured into aqueous 1 M sodium hydroxide, washed with acetic acid Echiru and acidified aqueous layer with 6 M hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from ethanol to give the title compound (1.99 g, 68% yield).

Melting point 251- 252 ° (:.

X H NMR (DMSO- d 6) δ 3.18 (2H, t, J = 7.0 Hz), 3.63-3.68 (2H, m), 7.39- 7.43 (1H, m), 7.47-7.52 (2H, m), 7.71 -7.74 (2H, m), 7.75-7.79 (2H, m), 7.90-7.93 (2H, m), 8.73 (1H, t, J = 5.6 Hz).

Reference Example 45 5- [2 - [(4-Bifue two Lil carbonyl) Amino] Echiru] - 1,3,4 - Okisa Jiazoru - 2-carboxylic acid Echiru

N - [2- (1Η - tetrazol-5-I le) Echiru] biphenyl - 4 Karubokisami de (2.93 g, 10.0 ramol) and Toriechiruamin (4.18 mL, 30.0 mmol) Tetorahi Dorofura emissions (100 mL) of suspension Nigoeki the black hole Okiso acetate Echiru (3.35 mL, 30.0 mmol) was added dropwise at room temperature, and the resulting mixture was stirred for 2 hours at 60 ° C. After cooling, the reaction was diluted with acetic acid Echiru, washed with water, saturated aqueous sodium hydrogen carbonate solution Contact Yopi brine, dried over sulfate Ma Guneshiumu, and concentrated under reduced pressure. The residue was recrystallized from acetic acid Echiru to give the table title compound (1.99 g, 54% yield).

Mp 145- 146 ° C.

J H NMR (CDC1 3) δ 1.45 (3H, t, J = 7.1 Hz), 3.29 (2H, t, J = 5.9 Hz), 4.03 (2H, q, J = 6.1 Hz), 4.52 (2H, q, J = 7.1 Hz), 6.99 (1H, t, J = 5.6 .. Hz), 7.37-7.41 (1H, m), 7.44-7.49 (2H, m), 7.59-7.62 (2H, m), 7.6,4 -7.67 (2H, m), · 7.83-7.86 (2H, m).

Reference Example 46 (3-arsenide Dorajino - 3 Okisopuropiru) force Rubamin acid tert - butyl

Boc-/ 3- § La Nin E chill ester (21.3. G, 98.0 mmol) was heated under reflux with ethanol (200 mL) of hydrazine monohydrate (23.8 mL, 490 mmol) solution for 24 hours. Cold 却後, and the reaction mixture was concentrated under reduced pressure, washed with residue fart hexane / acetic acid Echiru (2/1), and recrystallized from acetic acid Echiru to give the title compound (16.3 g, 82% yield) .

Mp 105-106 ° C.

XH NMR (CDC1 3) δ 1.44 (9Η, s), 2.39 (2Η, t, J = 5.9 Hz), 3.42 (2H, q, J = 6.1 Hz), 3.90 (2H, d, J = 3.9 Hz), 5,10 (1H, brs), 7.02 (1H, brs).

Reference Example 47 [Ν'- [3 - [(tert - butoxycarbonyl - Le) Amino] propionate - le] arsenide Dora Ho] Okiso acetate Echiru

(3 heat Dorajino - 3 Okisopuropiru) Karupamin acid tert- butyl (10.0 g, 49.2 mmol) and Toriechiruamin (6.86 mL, 49.2 mmol) as tetrahydrofuran (200 mL) was added black port Okiso acetate Echiru (5.50 mL of was added dropwise at room temperature 49.2 mmol), the resulting mixture was stirred for 1 hour. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (12.2 g, 81% yield) as an oil.

ι NMR (CDCI3) δ 1.40 (3H, t, J = 7.2 Hz), 1.43 (9H, s), 2.56 (2H, t, J = 5.9 Hz), 3.47 (2H, q, J = 6.3 Hz), 4.39 (2H, q, J = 7.2 Hz), 5.13 (1H, brs), 8.89 (1H, brs), 9.31 (1H, brs).

Reference Example 48 5- [2- [(tert- butoxycarbonyl) Amino] Echiru] -l, 3, 4 - Chiajia-2- force Rupon acid Echiru

[N, _ [3 - [(tert- butoxycarbonyl) Amino] propionate - le] arsenide Dorajino] Okiso acetate Echiru (12.1 g, 40.0 mmol) and Lawesson's reagent (16.2 g, 40.0 mmol) § Se Tonitoriru (200 mL of ) was stirred at room temperature for 24 hours. The reaction mixture was diluted with acetic acid Echiru, once with water, six times with saturated aqueous sodium bicarbonate, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / acetate Echiru = 1/1) to give the title compound (.6.57 g, .- 55% yield) as an oil.

XH NMR (CDC1 3) δ 1.43 (9Η, s), 1.46 (3H, t, J = 7.1 Hz), 3.38 (2H, t, J = 6.2 Hz), 3.63 (2H, q, J = 6.1 Hz), 4.51 (2H, q, J = 7.1 Hz), 5.05 (1H, brs)..

Reference Example 49 5- [2- [(4-Bifue - Lil carbonyl) amino] Echiru] -1, 3, 4 - Chiaji § zone one / Les - 2-carboxylic acid Echinore

5- [2 - [(tert - butoxycarbonyl) Amino] Echiru] - 1, 3, 4-thiadiazole - 2 - carboxylic acid Echiru (6.54 g, 21.7 mmol) acetic acid Echiru (50 mL) of the solution to 4 N hydrogen chloride acetate Echiru solution (50 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with acetic acid Echiru, 5 - (2-aminoethyl) -1, to obtain a 3,4-thiadiazole-2-carboxylic acid Echiru hydrochloride as a hygroscopic crystals.

The resulting hydrochloride salt as tetrahydrofuran (0.99 mL) and mixed solution chloride 4- Biff We sulfonyl carbonyl of saturated sodium hydrogen carbonate solution (150 mL) (4.70 g, 21.7 mmol) was added portionwise at room temperature, the resulting the mixture was stirred for 1 hour. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (black port Holm / methanol = 10/1), and recrystallized from as tetrahydrofuran, to give the title compound (6.02 g, 73% yield).

Mp 13 5-136 ° C

J H NMR (CDCI3) δ 1.45 (3Η, ΐ, J = 7.1 Hz), 3.51 (2Η, t, J = 6.0 Hz), 4.03 (2H, q, J = 6.0 Hz), 4.51 (2H, q, J = 7.1 Hz), 7.10 (1H, t, J = 5.6 Hz), 7.37-7.41 (1H, m), 7.45-7.49 (2H, m), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.84-7.87 (2H, m).

Reference Example 50 1- (4-bi Hue lily Luke Lupo sulfonyl) aziridine

. '2 Promo E chill § Min hydrobromide (6.15 g, 30.0 mmol), Tetorahi Dorofu orchid (0.99 mL) and 1 M carbonate Na Toriumu aqueous 4 chloride in a mixed solution of (0.99 mL) - Bifueeru carbonyl (6.50 g, 30.0 mmol) was added portionwise at room temperature, the resulting mixture was stirred for 18 hours. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over sulfate Maguneshiumu, and concentrated under reduced pressure. The residue was purified by silica gel column chroma - was purified by preparative chromatography (hexane / acetate Echiru = 2 / 1-1 / 1) to give the table compound (5.17 g, 77% yield).

Mp 123- 124 ° (:.

: H NMR (CDC1 3) δ 4.09 (2Η, t, J = 9.5 Hz), 4.46 (2H, q, J = 9.5 Hz), 7.36-7.40 (1H, m), 7.44-7.48 (2H, m), 7.61-7.67 (4H, m), 8.00-8.03 (2H, m).

Reference Example 5 1 1- [2- [(4-Bifue two Rirukarubo - Le) Amino] Echiru] - 1H-Pirazo 4carboxylate Echiru

1- (4-Bifue two Lil carbonyl) aziridine (4.96 g, 22.2 mmol) and 1H- pyrazole Lumpur - 4- carboxylic acid Echiru (3.11 g, 22.2 mmol) between toluene (30 mL) solution of 7 days of heating under reflux did. After cooling, the reaction solution was purified by silica gel column chromatography (key San / acetic Echiru = 1 / 1-0 / 1) and recrystallized from acetic acid Echiru, the title compound (1.04 g, 13% yield) It was obtained.

Melting point 144- 145 ° (:.

X H NMR (CDCI3) δ 1.33 (3Η, t, J = 7.2 Hz), 3.93-3.97 (2H, m), 4.29 (2H, q, J = 7.2 Hz), 4.39-4.42 (2H, m), 6.89 (1H, t, J = 5.4 Hz), 7.37-7.42

(1H, m), 7.45-7.49 (2H, m), 7.59-7.62 (2H, m), 7.65-7.68 (2H, ra), 7.80-

7.83 (2H, m), 7.92 (1H, s), 7.99 (1H, s).

Reference Example 5 1- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] -1Ita- Pirazo Le - 4- carboxylic acid '

1- [2- [(4-Bifue two Rirukaruponiru) Amino] Echiru] - IH - pyrazole-phosphate Echiru (909 mg, 2.50 mmol), 1 MzK oxide Natoriumu solution (7.5 mL), Te Torahidoro furan mixed solution of (7.5 mL) and ethanol (7.5 mL) was stirred final night at room temperature. The reaction mixture was poured into water, was added of 1 M hydrochloric acid (7.5 mL). The precipitated crystals were collected by filtration and recrystallized from methanol to give the title compound (775 mg, 92% yield). Melting point of 242-243 ° (:.

! H NMR (DMS0-d 6 ) δ 3.69 (2Η, q, J = 5.9 Hz), 4.35 (2H, t, J = 6.1 Hz), 7.39-7.43 (1H, ra), 7.47-7.52 (2H, m ), 7.71-7.74 (2H, m), 7.75-7.78 (2H, ra), 7.82 (1H, s), 7.88-7.91 (2H, ra), 8.24 (1H, s), 8.64 (1H, t, J = 5.4. Hz), 12.30 (1H, brs)..

Reference Example 5 3 [2 - [3 - [[(2 - morpholino - 3 - phenoxyethanol propyl) amino] carbonylation Le] - 1, 2, 4-Okisajiazoru - 5-I le] Echiru] tert Karupamin acid butyl

In the same manner as in Example 1, 5- [2- [(4-Bifue two Lil carbonyl) Amino] E chill] - 1, 2, 4-Okisajiazoru - 5 in place of 3-carboxylic acid Echiru [2- [(tert - flop Tokishikaruponiru) amino] Echiru] - 1, 2, 4 - Okisajiazoru 3-carboxylic acid E Chi le, 2, 2 - diphenyl E chill § Min instead 2 - morpholino - 3- Fuenokishipuro It was used to obtain the title compound Piruamin. 77% yield.

Mp 107 - 108 ° C (crystallized from acetic Echiru / diisopropyl ether).

X H NMR (CDC1 3) δ 1.43 (9H, s), 2.62-2.72 (2H, ra), 2.83-2.93 (2H, m), 3.06-3.23 (3H, m), 3.45-3.55 (1H, m) , 3.59-3.80 (6H, m), 3.82-4.92 (1H, m), 4.06 (1H, dd, J = 4.1, 7.4 Hz), 4.18 (1H, dd, J = 4.2, 7.2 Hz), 5.01 (1H , brs), 6.92 (2H, t, J = 5.7 Hz), 6.99 (1H, t, J = 5.6 Hz), 7.30 (2H, t, J = 6.0 Hz), 7.70 (1H, brs).

Reference Example 5 4 5- (2 - Aminoechiru) -N_ (2-morpholino - 3 off enoki Cipro pull) - 1,2, 4-Okisajiazoru 3- Karubokisami de

[2- [3- [[(2 - morpholino - 3-phenoxyethanol propyl) Amino] carbo sulfonyl] - 1, 2, 4-O Kisajiazoru - 5-I le] Echiru] force Rubamin acid tert- butyl ( 2.50 g, dichloromethane (20 mL) was a solution in Torifuruoro acetate (10 mL) was added a 5.26 mmol), the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with Jikurorome Tan. The solution was washed with brine and 1 M hydroxide Natoriumu aqueous, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.87 g, 95% yield).

Melting point 93- 94 ° (.

J H NMR (CDCI3) δ 1.44 (2Η, brs), 2.64-2.69 (2H, m), 2.85-2.90 (2H, m), 3.09-3.15 (3H, m), 3.25 (2H, t, J = 6.5 Hz), 3.50 (1H, ddd, J = 3.7, 9.3: 13.9 Hz), 3.68-3.78 (4H, ra), 3.86 (1H, ddd, J = 5: 7, 6.7, 13.9 Hz), 4.06 (1H, dd, J = 5.4, 9.8 Hz ), 4.18 (1H, dd, J = 5.4, 9.8 Hz), 6.90-6.94 (2H; m), 6.97-7.01 (1H, m), 7.28-7.33 (2H, in) , 7.73 (IH, brs), example 55 5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] -. N-(2 Morehori Bruno - 3- phenoxyethanol propyl) - 1, 2 , 4 Okisajiazoru - 3 - power Rupokisami de

In the same manner as in Example 5 below, 4'Echirubifueniru - to give the title compound using instead 4- Bifue two Rukarubon acid 4-carboxylic acid. 54% yield.

Mp 168- 169 ° C (crystallized from acetic Echiru).

^ NMR (DMS0-d 6) δ 2.53-2.63 (2Η, m), 2.69-2.79 (2H, m), 3.05-3.15 (1H, m), 3.29 (2H, t, J = 5.1 Hz), 3.33- 3.59 (6H, ra), 3.73 (2H, q, J = 4.7 Hz), 4.02 (1H, dd, J = 3.6, 7.8 Hz), 4.12 (1H, dd, J = 4.5, 7.8 Hz), 6.89-6.98 (3H, ra), 7.24-7.32 ( 2H, m), 7.41 (1H, t, J = 5.4 Hz), 7.49 (2H; t, J = 5.7 Hz), 7.20 (2H, d, J = 5.7 Hz) , 7.76 (2H, d, J = 6.3 Hz), 7.90 (2H, d, J = 6.3 Hz), 8.77 (1H, t, J = 4.4 Hz), 8.81 (1H, t, J = 4.4 Hz). reference example 56 [[3- [[(2-morpholino - 3 full We Roh hydroxypropyl) Amino] carbonyl] - 1, 2, 4 - O hexa di § zone Honoré - 5 - Inore] methyl] Karupamin acid tert- butyl

5 - [[(tert-butoxycarbonyl) Amino] methyl] - 1, 2, 4-Okisajiazoru - 3 - carboxylic acid Echiru (1,36 g, 5.00 mmol), 2_ morpholino - 3-phenoxyethanol propyl Amin ( 1.18 g, 5.00 mmol) and N, N- diisopropyl E chill § Min (1.74 mL: the Asetonitoriru (10 mL) solution of 10.0 mmol) was heated under reflux for 10 hours under a nitrogen atmosphere. After cooling, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane / acetic acid Echiru = 1 / 4-0 / 1) to give the title compound (1.67 g, 72% yield) .

Amorphous.

• J H NMR (CDC1 3) δ 1.46 (9H, s), 2.64-2.69 (2H, m), 2.85-2.90 (2H, m), 3.07-3.14 (1H, m), 3.47-3.54 (1H, m ), 3.68-3.78 (4H, m), 3.83-3.89 (1H, ra), 4,06 (1H, dd, J = 5.4, 9,8 Hz), 4.17 (1H, dd, J = 5.4, 9.8 Hz ), 4.66 (2H, d, J = 5.1 Hz), 5.23 (1H, brs), 6.90-6.93 (2H, m), 6.97-7.01 (1H, m), 7.29-7.33 (2H, m), 7.69 ( 1H, brs).

Reference Example 57 5- [[3 - (4 - Bifuwe two Lil) Urei de] methyl]-N-(2-morpholino - 3 off Enokishipuropiru) - 1, 2, 4 - Okisajiazoru - 3- Karubokisami de [[3 - [[(2 - morpholino - 3 - phenoxyethanol propyl) Amino] force Ruponiru] - 1, 2, 4 - O key .. Sajiazoru 5 I le] methyl] Karupamin acid tert- heptyl (462 mg, 1.00 dichloromethane (4 m L) was added Torifuruoro acetate (2 mL) added mmol), a mixed-obtained was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane, washed with a 2 M hydroxide isocyanatomethyl Riumu aqueous saturated sodium chloride solution, dried over sulfate Na. Toriumu, and concentrated under reduced pressure. The resulting residue as tetrahydrofuran (3 mL) was added isocyanate 4- Bifuweyuri Le (195 mg, 1.00 mmol) was added at room temperature, and the resulting mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration and washed with hexane / as tetrahydrofuran (2/1) to give the title compound (443 mg, 80% yield).

Mp 217- 218 ° C.

J H NMR (DMSO- d 6) δ 2.56-2.61 (2H, m), 2.73-2.78 (2H, m), 3.08-3.14 (1H, m), 3.38-3.45 (1H, m), 3.49-3.62 ( 5H, m), 4.02 (1H, dd, J = 4.8, 10.4 Hz), 4.13 (1H, dd, J = 6.0, 10.4 Hz), 4.68 (2H, d, J = 5.6 Hz), 6.91- 6.96 (4H , m), 7.26-7.32 (3H, ra), 7.41-7.45 (2H, m), 7.49-7.52 (2H, m), 7.55-7.58 (2H, ra), 7.61-7.63 (2H, m), 8.84 (1H, t, J = 5.6 Hz), 9.06 (1H, s).

Reference Example 58 5- [2- [(3-Bifue - Rirukarubo - Le) Amino] Echiru] - N-(2 Moruhori Bruno - 3- phenoxyethanol propyl) - 1,2, 4-Okisajiazo Ichiru - 3 - power Rupokisami de

In the same manner as in Example 4, the title compound was obtained using 3-Bifuweyu Rukarubon acid in place of 4- (2-thienyl) benzoic acid. 34% yield.

Amorphous.

X H NMR (CDC1 3) δ 2.60-2.65 (2H, m), 2.81-2.86 (2Η, m), 3.03-3.10 (1Η, m), 3.36 (2Η, t, J = 6.2 Hz), 3.48 (1H , ddd, J - 3.4, 9.3, 13.9 Hz), 3.64-3.73 (4H, m), 3.84 (1H, ddd, J = 5.6, 6.6, 13.9 Hz), 3.99-4.05 (3H, ra), 4.15 (1H , dd, J = 5.4, 9.8 Hz), 6.91-6.98 (3H, m), 6.96-7.00 (1H, m), 7.27-7.32 (2H, m), 7.35-7.40 (1H, m), 7.43-7.51 (3H, m), 7.59-7.62 (2H, m), 7.67-7.74 (3H, m), 7.99 (1H, t, J = 1.6 Hz).

Reference Example 59 5- [2- [(4-Bifuwe - Lil carbonyl) Amino] Echiru] - N-(Jifuweniru methyl) - 1, 2, 4-Okisajiazoru - in the same manner as 3-Karubokisami de Example 2, 3, 3-diphenyl We sulfonyl propyl § Min Ziv instead of the E alkenyl methylamine to give the table compound with p- xylene instead of Asetonitoriru. 58% yield.

Mp 193 - 194 ° C (recrystallized from acetic acid Echiru).

JH NMR (CDC1 3) δ 3.33 (2H, t, J = 6, 1 Hz), 3.97 (2H, q, J = 6.1 Hz), 6. 6 (1H, d, J = 8.6 Hz), 6.84 (1H , t, J = 6.0 Hz), 7.27-7.41 (11H, m), 7.45-7.51 (3H, m), 7.57-7.60 (2H, m), 7.61-7.64 (2H, m), 7.80-7.83 (2H , m).

Reference Example 60 5- [2 - [(Jifue two Ruasechiru) Amino] Echiru] - N-(2 - morpholino - 3 - phenoxyethanol propyl) - 1, 2, 4-Okisajiazoru - 3 Karubokisami de '

[2 - [3- [[(2 - morpholino - 3 - off enoki Cipro pull) Amino] carbo sulfonyl] - 1, 2, 4-O Kisajiazoru - 5-I le] Echiru] Karupamin acid tert- butyl (190 mg, 0.400 Yuzuru ol) in dichloromethane (2 mL) was added Torifuruoro acetate (1 mL) added and the resulting et be mixture was stirred for 30 minutes at room temperature. The reaction was diluted with dichloromethane, washed with 1 M aqueous oxidation Natoriumu solution and saturated brine, dried over sulfate Natoriumu, and concentrated under reduced pressure.

Obtained residue and Toriechiruamin (61.3 μΐ, 0.440 mmol) Tetorahi Dorofu run (3 mL) was added chloride diphenyl § cetyl (113 mg, 0.440 mmol) of was added portionwise to low at room temperature, the resulting mixture 30 minutes and the mixture was stirred. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (acetic Echiru) to give the title of compound a (134 mg, 59% yield).

Amorphous. -

^ NMR (CDC1 3) δ 2.64-2.69 (2H, m), 2.84-2.89 (2H, m), 3.07-3.13 (1H, m), 3.22 (2H, t, J = 6.2 Hz), 3.48-3.55 ( 1H, m), 3.67-3.89 (7H, m), 4.07 (1Ή, dd, J = 5.5, 9.9 Hz), 4.18 (1H, dd, J = 5.5, 9.9 Hz), 4.90 (1H, s), 6.08 (1H, t, J = 6.2 Hz), 6.90-6.94 (2H, m), 6.97-7.01 (1H, m), 7.18- 7.33 (11H, m), 7.59-7.62 (2H, in).

Reference Example 6 1 5 - [2- [(3, 3-diphenyl We sulfonyl propionitrile two Honoré) Amino] Echiru] - N-(2 Moruho Reno - 3- phenoxyethanol propyl) - 1,2, 4 - Okisajiazoru - 3 in the same manner as carboxamide example 4, 4- - was (2-Choi Le) with 3, 3-chome Jifue Nirupuropion acid in place of benzoic acid to give the title compound. 45% yield.

Amorphous.

l NMR (CDC1 3) δ 2.65-2.70 (2Η, m), .2.86-2.91 (6H, ra), 3.09-3.15 (1H, m), 3.51-3.57 (1H, m), 3.61 (2H, q, J = 6.1 Hz), 3.69-3.78 (4H, m), 3.88 (1H, td, J = 6.2, 13.7 Hz), 4.08 (1H, dd, J = 5.4, 9.8 Hz), 4.19 (1H, dd, J = 5.4, 9.8 Hz), 4.51 (1H, t, J = 7.9 Hz), 5.91 (1H, t, J = 6.1 Hz), 6.91-6.94 (2H, ra), 6.97-7.01 (1H, ra), 7.11 -7.15 (2H, m), 7.17-7.24 (8H, m), 7.28-7.33 (2H, m), 7.64-7.66 (1H, m).

Reference Example 62 5- (4-Bifuwe two Riruamino) - 5- Okiso valeric Echiru

4 Bifue two Rirukarupamin acid tert- butyl (2.15 g, 8.00 mmol) acetic acid Echiru (25 mL) was added 4 N hydrogen chloride acetate Echiru solution (25 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, after the alkali resistance with 1 M sodium hydroxide solution and extracted with acetic acid Echiru. The organic layer was washed with saturated brine, dried over sulfate mug Neshiumu, and concentrated under reduced pressure.

Obtained residue and Toriechiruamin (1.15 mL, 8.00 mmol) in tetrahydrofuran (35 mL) was added 5-black port - 5 Okiso valeric Echiru (1,25 mL, 8.00 mmol) was added dropwise at room temperature the resulting mixture was stirred for 30 minutes. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / as tetrahydrofuran = 1/1), and recrystallized from hexane / as tetrahydrofuran to give the title compound

It was obtained (2.32 g, 93% yield).

Mp 133_134 ° C.

JH NMR (CDC1 3) δ 1.28 (3Η, t, J = 7.2 Hz), 2.08 (2H, quintet, J = 7.1 Hz), 2.44-2.48 (4H, m), 4.16 (2H, q, J = 7.2 Hz ), 7.31-7.35 (1H, m), 7.41-7.45 (2H, m), 7.50 (1H, brs), 7.55-7.61 (6H, m).

Reference Example 63 5- (4 - Bifuwe two Riruamino) _5- Okiso valerate

In the same manner as in Reference Example 52, 1- [2 - [(4-Bifuwe two Lil carbonyl) Amino] Echiru] -1Ita- pyrazole - 5 instead of 4-carboxylic acid Echiru (4 Bifue - Riruami. - Roh) -5 - was used to obtain the title compound Okiso valerate Echiru. Yield 98%.¾ mp 205 - 206 ° C (recrystallized from acetic acid Echiru).

X H NMR (DMS0 - d 6 ) δ 1.82 (2H, quintet, J = 7.3 Hz), 2.29 (2H, t, J = 7.3 Hz), 2.38 (2H, t, J = 7.3 Hz), 7.30 ^ 7.34 ( 1H, m), 7.42-7.46 (2H, m), 7.59-7.65 (4H, m), 7.67-7.71 (2H, m), 10.00 (1H, s), 12.10 (1H, brs). reference example 64 5 - [4- (4 - Bifuwe two Riruamino) - 4 - Okisopuchiru] -1, 2, 4-Okisajia Zonore - 3-force Norepon acid Echinore

In the same manner as in Reference Example 1, Boc - β - instead of Aranin 5- (4-Bifue two Lil Amino) using 5-Okiso valeric acid to give the title compound. 29% yield.

Mp 152 - 153 ° C (recrystallized from acetic acid Echiru).

J H NMR (CDC1 3) δ 1.45 (3Η, t, J = 7.1 Hz), 2.32 (2H, quintet, J = 7.2 Hz), 2.54 (2H, t, J = 7.2 Hz), 3.15 (2H, t, J = 7.2 Hz), 4.51 (2H, q, J = 7.1 Hz), 7.31-7.35 (1H, m), 7.41-7.45 (2H, m), 7.35-7.62 (7H, m).

Reference Example 65 5- [4 - (4-Bifue two Riruamino) - 4 - Okisopuchiru] - N - (2-morpholino - 3 - phenoxyethanol propyl) - 1, 2, 4_ Okisajiazoru - 3 - Karubokisami de

In the same manner as in Example 3, 5- [2- [(4 - Bifue two Lil carbonyl) Amino] E Chinore] - 1, 2, 4-Okisajiazo one Honoré - 5 in place of 3-carboxylic acid Echiru [ 4- (4-Bifuwe two Riruamino) - 4-Okisobuchiru] - 1,2, 4-Okisajiazoru 3-carboxylic acid Echiru, 4, 4 - Ziv We instead of 2-morpholino nil butyl § Min hydrochloride - 3 - give the tables compound with phenoxy Puropiruamin'ni hydrochloride. 58% yield.

(Crystallized from hexane / acetic acid Echiru to) mp 117- 118 ° C.

J H NMR (CDC1 3) δ 2.32 (2H, quintet, J = 7.2 Hz), 2.57 (2H, t, J = 7.2 Hz), 2.63-2.68 (2H, m), 2.84-2.89 (2H, m), 3.07-3.15 (3H, m), 3.50 (1H, ddd, J = 3.7, 9.3, 14.0 Hz), 3.68-3.78 (4H, m), 3.84 (1H, td, J = 6.1, 14.0 Hz), 4.05 ( 1H, dd, J = 5.4, 9.8 Hz), 4.16 (1H, dd, J = 5.6, 9.8 Hz), 6.90-6.93 (2H, m), 6.96-7.00 (1H, m), 7.28-7.34 (3H, m), 7.40-7.44 (2H, m), 7.54-7.58 (4H, m), 7.60-7.63 (2H, m), 7.68 (1H, brs), 7.74 (1H, dd, J = 2.9, 4.6 Hz) . reference example 66 N- [2- (2- thienyl) Echiru] biphenyl - 4 Karubokisami de.

2- (2-aminoethyl) Chiofen (3, 18 g, 25.0 mmol) and Toryechiru Min (3.48 mL, 25.0 mmol) as tetrahydrofuran (75 mL) was added chloride 4 Bifue two ylcarbonyl (5.42 g of, 25.0 mmol ) was added portionwise at room temperature, and the resulting mixture was stirred for 30 minutes. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over sulfate Ma Guneshiumu, and concentrated under reduced pressure. And washed with residue fart hexane / acetic acid Echiru (1/1) to give the title compound (7.40 g, 96% yield).

Mp 164- 165 ° C.

J H NMR (CDC1 3) δ 3,18 (2H, t, J = 6.6 Hz), 3.77 (2H, q, J = 6.4 Hz), 6.31 (1H, t, J = 4.9 Hz), 6.90 (1H, dd, J = 1.2, 3.4 Hz), 6.98 (1H, dd, J = 3.4, 5.1 Hz), 7.20 (1H, dd, J = 1.2, 5.1 Hz), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.59-7.62 (2H, ra), 7.63-7.66 (2H, m), 7.79-7.82 (2H, m).

Reference Example 6 7 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] Chiofen - 2 - carboxylic acid

N- [2- (2- Choi - Le) Echiru] biphenyl - 4 Karubokisami de (7.38 g, 24.0 mmol) and Ν, Ν, Ν ', Ν'- tetramethyl ethylene § Min (7, 97 mL, 52.8 mmol) Te Torahi Dorofuran (100 mL) of the solution to 1.6 M n - hexane solution (33,0 mL to butyl lithium, 52.8 mmol) and - added dropwise at 78 ° C, the resulting mixture was stirred for 20 min. Di to the reaction solution - tert - butyl (12.6 mL, 55.0 mmol) and - 78 ° was added in C, and the resulting mixture was warmed to room temperature. The reaction solution was diluted with acetic acid Echiru, 0.5 M hydrochloric acid, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and reduced pressure concentrated.

The resulting residue in dichloromethane (100 mL) was added Torifuruoro acetate (50 mL) was added and the resulting mixture was stirred at room temperature for 64 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with acetic acid Echiru. The precipitated crystals were collected by filtration and dissolved in tetrahydrofuran. The resulting solution was treated with activated carbon,. And concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran to give the title compound (1.66 g, 20% yield).

Mp 223- 224 ° (:. '\ {NMR (DMSO- d 6) δ 3.13 (2H, t, J = 6.8 Hz), 3.56 (2H, q, J = 6.4 Hz) ,. 7.00 (1H, d, J = 3.7 Hz), 7.39-7.43 (1H, m), 7.48-7.52 (2H, m), 7.58 (IE d, J = 3.7 Hz), 7.72-7.75 (2H, m), 7.77-7.80 (2H, m), 7.92-7.95 (2H, m), 8.71 (1H, t, J = 5.5 Hz), 12.92 (1H, brs).

Reference Example 68 5- [2- [(4 - Bibuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3 - phenoxyethanol propyl) Chiofen - 2 - Karubokisami de

In the same manner as in Example 59, 1- [2- [(4-Biff two Lil carbonyl) Amino] Echiru] - 5 instead of 1H- pyrazol-4-force carboxylic acid [2- [(4- Bifue two Rirukarubo yl) Amino] Echiru] Chiofen - using 2-carboxylic acid the title compound was obtained. Yield 55%

Mp 178 - 1 79 ° C (recrystallized from acetone).

NMR (CDC1 3) δ 2.63-2.68 ( 2H, m), 2.85-2.90 (2Η, m), 3.07-3.13 (1Η, m), 3.20 (2Η, t, J = 6.6 Hz), 3.41 (1H, ddd , J = 3.2, 9.5, 13.7 Hz), 3.67-3.83 (7H, m), 4.05 (1H, dd, J = 5.1, 9.9 Hz), 4.16 (1H, dd, J = 5.6; 9.9 Hz), 6.38 ( 1H, t, J = 5.7 Hz), 6.77 (1H, dd, J = 2.7, 6.1 Hz), 6.88- 6.92 (2H, m), 6.96-7.00 (1H, ra), 7.28-7.32 (2H, m) , 7.37-7.41 (2H, m), 7. 5-7.49 (2H, m), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.80-7.83 (3H, m).

Reference Example 69 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Jifue Niruamino) Echiru] Chiofen - 2 - Karubokisami de

In the same manner as in Example 5 9 1- [2 - [(4 - Bifue two Lil carbonyl) amino] Echiru] - 5 instead of 1H- pyrazol-4-force Rupon acid [2- [(4- Bifue two Rirukarupo sulfonyl) amino] Echiru] Chiofen - 2 - force the carboxylic acid, 2 - morpholino - 3 - N instead of phenoxy-propylamine dihydrochloride, N- Jifuweniruetan - 1, the title using 2-diamine hydrochloride to give compound. 68% yield.

Mp 228 - 229 ° C (recrystallized from acetic acid Echiru).

ln NMR (DMSO- d 6) δ 3.09 (2H, t, J = 6.8 Hz), 3.39-3.44 (2H, m), 3.54 (2H, q, J = 6.6 Hz), 3.79-3.83 (2H, m) , 6.91-6.95 (3H, m), 7.02-7.05. (4H; m), 7.24-7.30 (4H, m), 7.39-7 3 (1H, m), 7.48-7.52 (3H, m), 7.72- 7.75 (2H, ra), 7.76-7.80 (2H, m), 7.92-7.95 (2H, m), 8.55 (1H, t, J = 5.7 Hz), ._ 8.70 (1H, t, J = 5.5 Hz) ., reference example 70 2- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] thiazole _4- carboxylic acid Echiru

In the same manner as in Reference Example 3, 5 - (2-aminoethyl) - 1,2,4 Okisajiazo Ichiru - 3 - 2- (2-aminoethyl) instead of force carboxylic acid Echiru hydrochloride thiazol-4 - to give the title compound with carbonic phosphate Echiru hydrochloride. 56% yield.

Mp 124- 125 ° C (recrystallized from hexane / acetic acid Echiru to).

^ NMR (CDC1 3) δ 1.42 (3Η, t, J = 7.2 Hz), 3.38 (2H, t, J = 6.0 Hz), 3.95 (2H, q, J = 6.0 Hz), 4.44 (2H, q, J = 7.2 Hz), 7.28-7.33 (1H, m), 7.37-7 2 (1H, m), 7.46 (2H, t, J = 7.5 Hz), 7.60-7.63 (2H, m), 7.66 (2H.: d, J = 8.2 Hz), 7.91 (2H, d, J = 8.2 Hz), 8.09 (1H, s).

Reference Example 7 1 2- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] thiazole - 4- carboxylic acid

In the same manner as in Reference Example 52, 1- [2 - [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - 1H-pyrazol - 2 instead of 4-carboxylic acid Echiru [2- [(4- Bifueyuriru carbo - was used to obtain the title compound le) Amino] Echiru] thiazole-4-carboxylic acid Echiru. 97% yield.

Mp 219- 220 ° C (recrystallized from hexane / acetic acid Echiru to).

JH NMR (CDC1 3 + DMSO- d 6) δ 3.40 (2H, t, J = 6.5 Hz), 3.86 (2H, q, J = 6.5 Hz), 7.38 (1H, t, J = 7.3 Hz), 7.45- 7.48 (2H, ra), 7.62 (2H, d, J = 7.8 Hz), 7.65 (2H, d, J = 7.8 Hz), 7.95 (2H, d, J = 8.3 Hz), 8.10 (1H, s), 8.18-8.21 (1H, m).

Reference Example 72 2- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3- phenoxyethanol propyl) thiazol - 4 - Karubokisami de

In the same manner as in Example 59, 1- [2 - [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - 1H-pyrazol - 2 instead of 4-carboxylic acid [2- [(4- Bifuwe two It was used to obtain the title compound le) Amino] Echiru] thiazole-4-carboxylic acid - Lil force Lupo. Yield 96% mp 14 3 - 144 ° C (recrystallized from hexane / acetic acid Echiru to).

! H NMR (CDCI3) δ 2.57-2.65 (2H, m), 2.78-2.86 (2H, m), 3.06-3.1, (1H, m), 3.37 (2H, t, J = 6.4 Hz), 3.48-3.57 (1H, in), 3.61-3.70 (4H, m), 3.76-3.83 (1H, m), 3.95 (2H, q, J = 6.1 Hz), 4.03 (1H, dd, J = 5.1, 9.8 Hz), 4.10-4.16 (1H, m), 6.67-6.71 (1H, m), 6.90 (2H, d, J = 8.1 Hz), 6.97 (1H, t, J = 7.5 Hz), 7.26-7.30 (2H, m) , 7.37-7.41 (1H, m), 7.45 (2H, t, J = 7.5 Hz), 7.59 (2H, d, J = 7.5 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.90-7.95 (1H, m), 8.03 (1H, s).

Reference Example 73 2- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Jifuwe Niruamino) Echiru] thiazol-4 - Karubokisami de

In the same manner as in Example 5 9, 1 - [2 - [(4-Bifue two Lil carbonyl) Amino] Echiru] - 1H-pyrazol - 4 instead of the carboxylic acid 2- [2- [(4-bi Fueyurirukarupo

- a) amino] Echiru] thiazole-4-carboxylic acid, 2 - morpholino-3-phenoxy Puropiruamin'ni hydrochloride N instead of, N- Jifuweniruetan - 1, the title compound was obtained using 2-Jiamin hydrochloride. Yield 75 ° /. .

Mp 169_170 ° C (recrystallized from hexane / acetic acid Echiru to).

NMR (CDCI3) δ 3.29-3.33 (2H, m), 3.47-3.52 (2Η, in), 3.69 (2Η, q, J =

6.6 Hz), 3.82-3.85 (2H, m), 6.93 (2H, t, J = 7.3 Hz), 7.07 (4H, d, J =

7.8 Hz), 7.27 (4H, t, J = 7.9 Hz), 7.41 (1H, t, J = 7.3 Hz), 7.49 (2H, t, J = 7.6 Hz), 7.71 (2H, d, J = 7.3 Hz ), 7.77 (2H, d, J = 8.6 Hz), 7.93

(2H, d, J = 8.3 Hz), 8.14 (1H, s), 8.60 (1H, t, J = 6.1 Hz), 8.75 (1H, t,

J = 5.6 Hz).

Reference Example 74 to: 131

5- (2-Aminoechiru) -N - (2-morpholino - 3 off enoki Cipro pull) -1, 2, 4 - Okisa Jiazo Ichiru - 3 Karubokisami de of 0.06 M dichloromethane solution (500 zL) with various power 0.09 MN of carboxylic acid reagent, N - dimethylformamidine de solution (1 in a mixture of 500Myuupushiron - Echiru - 3 - (3 - dimethyl § amino propyl) Karupojiimi de hydrochloride (0.045 mmol) and 1 - hydroxycarboxylic benzotriazole (0.045 mmol) the mixture was dichloromethane solution (500 ^ L) was added and stirred for 18 hours at room temperature. dichloromethane (2 mL), and extracted by adding 5% carbon hydrogen aqueous sodium (2 mL), the upper layer of alkaline the aqueous layer was removed, and. Ranimizu the (2 mL) was washed by adding. phase CEP (Whatman) to remove water layer had to distill off the organic layer, dimethylsulfoxide residue sulfoxide / methanol = 1 / 1 was dissolved in (500 / x L), preparative HPLC As eluents to give the desired compound with a purity of 80% (LC / MS analysis)..

Reference Example 1 3 2-1 4 4

5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - 1, 2, 4-Okisajiazo Ichiru - 3- 0. 06 M propionic nitrile solution of carboxylic acid Echiru (500 Mr.) and various Amin 0. 18 Micromax propionic nitrile solution reagent (500 / z L) was added and the mixture was heated at reflux for 18 hours, then evaporated organic layer, the residue of dimethyl sulfoxide / methanol = 1/1 (500 / i L) It was dissolved in and purified using preparative HPLC, to give the desired compound with a purity of 80% (LC / MS analysis).

LC / MS analysis of Reference Example 7 4-1 4 4 was carried out under the following conditions.

A measuring device: Waters LC / MS system

HPLC part: Agilent HP1100

MS part: micro mass Inc. ZMD

Column: CAPCELL PAK cl8UG120 S-3 μ ra s 1. 5 X 35 mm ( manufactured by Shiseido)

Solvent: A solution; 0.05% Torifuruoro aqueous acetic acid solution, B solution: 0.04% Torifuruoro acetate Aseto nitriles solution

Gradient cycle: 0 min (A solution / B solution = 90/10), 2.00 min (A solution / B solution = 5/95), 2. 75 minutes (A fluid / B solution = 5/95), 2.76 min (A solution / B solution = 90/10), 3. 60 minutes (A fluid / B solution = 90/10) injection volume: 2 Les flow rate: 0. 5 mL / min, detection method: UV 220 nm

MS conditions ionization method: ESI '

Purification by preparative HPLC of Example 7 4-1 4 4 was carried out under the following conditions.

Equipment: Gilson high-throughput purification system

Garam: YMC CombiPrep 0DS - A S-5 μ 50 X 20 mm

Solvent: A solution; 0.1% aqueous formic acid, B solution; 0.1% formic acid Asetonitoriru solution

Gradient cycle: 0 min (A solution / B solution = 95/5), 1.00 min (A solution / B solution = 95/5), 5.20 min (A solution / B solution = 5/95), 6.40 min (A solution / B solution = 5/95), 6.50 min (A solution / B solution = 95/5), 6.60 min (A solution / B solution = 95/5)

Flow rate: 20 mL / min, detection method: shown in Table 1 to Table 5 data structure Contact Yopi Masusu Bae spectrum of the compound obtained in UV 220 nm ^ Reference Example 7 4 to 1 3 1.

Reference Example No. R 4 MS (m / Z)

Reference Example number R4 MS (m / Z)

Table 5

Reference Example No. R 4 MS (m / Z)

The data of structure and Masusu Bae spectrum of the compound obtained in Reference Example 1 3 2-1 4 4 shown in Table 6.

TOT

Z.ZZO / SOOZdf / X3d tm90 / 900Z OAV Reference Example 145 [2 - [(2 - Aminofueniru) (full We -) amino] - 2-Okisoechiru] force -. Rubamin acid base Njiru

N - Hue - Le - 1,2 Hue - Renjiamin (4.79 g, 26.0 mmol), Z- glycine (5.98 g, 28.6 mmol), 1- [3- (Jimechiruamino) propyl] - 3-Echirukarubojii bromide hydrochloride ( 5.98 g, 31.2 mmol) and 4- (Jimechiruamino) pyridine (3.81 g, N of 31.2 mmol), N- dimethylformamide (50 mL) solution was stirred at room temperature for 24 hours. The reaction solution was diluted with acetic acid Echiru, twice with water, washed once with saturated brine, dried over sulfate Maguneshiu arm, and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (hexane / acetic acid Echiru = 1/1 to), and crystallized from hexane / acetic acid Echiru to give the title compound (7.21 g, 74% yield).

Mp 90- 92 ° C.

¾ NMR (CDC1 3) δ 3.92 (2Η, d, J = 5.9 Hz), 5.06 (2H, s), 5.21 (1H, brs), 5.58 (1H, brs), 6.75 (2H, d, J = 7.3 Hz ), 6.87 (1H, t, J = 7.5 Hz), 7.10-7.26 (5H, m), 7.30-7.38 (5H, in), 7.92-7.94 (1H, m), 8.14 (1H, brs). reference example 146 [(1 Hue - Le -1H- benzimidazole - 2-I) methyl] Karubami phosphate base Njinore

[2- [(2 - Aminofuweniru) (Fuweniru) amino] - 2-Okisoechiru] Karupamin acid base Njiru (7.02 g, 18.7 mmol) and the acetic acid (50 mL) solution of was stirred for 1 hour at 100 ° C. Cold 却後, the reaction was concentrated under reduced pressure, the residue was dissolved in acetic acid Echiru. The solution was washed with water, saturated sodium hydrogen Natoriumu solution and saturated brine, after Drying over anhydrous sulfate Maguneshiumu, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexa on / acetic Echiru: 1 / 2-0 / 1) to afford the title compound (6.58 g, 98% yield).

Oil.

¾ NMR (CDC1 3) δ 4.52 (2H, d, J = 4.9 Hz), 5.10 (2H, s), 5.97 (1H, brs), 7.16 (1H, d, J = 7.8 Hz), 7.22-7.39 (9H , m), 7.51-7.59 (3H, m), 7.78 (1H, d, J = 8.1 Hz).

Reference Example 147 [(1-phenyl - 1H-benz I Mi imidazole-2-I) methyl] amine

[(1-phenyl - 1H-benz I Mi indazole - 2-I) methyl] base Karupamin acid Njiru (6.43 g, 18.0 mmol) in acetic acid (15 mL) was added 25% hydrogen bromide acetic acid solution (15. mL ) and - added and the solution was stirred for 30 minutes at room temperature. The reaction was diluted with water and washed 3 times with black port Holm. The aqueous layer was Al force re resistance in 8 M hydroxide Natoriumu solution and extracted with black port Hol beam. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetra hydrofuran = 2 / 1-0 / 1) to give the title compound (3.47 g, 86% yield). Oil.

¾ NMR (CDC1 3) δ 1.70 (2Η, brs), 3.99 (2H, s), 7.15-7.18 (1H, m), 7.21- 7.25 (1H, m), 7.28-7.32 (1H, m), 7.39- 7.42 (2H, m), 7.51-7.55 (1H, ra), 7.57-7.62 (2H, m), 7.79-7.81 (1H, m).

Reference Example 1 4 8 N - (2 - Shianoechiru) -4 '_ full O robin off We sulfonyl - 4 Karubokisami de 4, _ full O lobby phenylalanine - 4- carboxylic acid (168 mg, 0.500 mmol), 3- Aminopuro Piononitoriru (4.36 mL, 59.1 mmol), 1 - [3 - (Jimechiruamino) propyl] - 3 - Chirukarubojiimi de hydrochloride (12.3 g, 64.4 mmol) and 1-arsenide Dorokishibenzo Toriazoru (9.86 g, 64.4 mmol) N of N - dimethyl formamidine de (100 mL) dissolved was stirred at room temperature overnight. The reaction solution was diluted with acetic acid Echiru, twice with water, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After purification residue was purified by basic silica force gel column chromatography (tetrahydrofuran), and recrystallized from acetic acid E chill, to give the title compound (13.8 g, 95% yield).

Mp 173- 174 ° C.

NMR (CDC1 3) δ 2.77-2.80 ( 2Η, m), 3.73-3.77 (2H, m), 6.64 (1H, t, J = 5.1 Hz), 7.13-7.19 (2H, m), 7.55-7.60 (2H , ra), 7.61-7.64 (2H, m), 7.84- 7.87 (2H, m).

Reference Example 1 4 9 N- [3 - Amino - 3- (arsenate Dorokishiimino) propyl] - 4'Furuorobifu Weniru - 4- Karubokisami de

N - (2-Shianoechiru) -4 - Full O lobby phenylalanine - 4- Karubokisami de (13.5 g, 50.3 mmol), hydroxylamine § Min hydrochloride (5.25 g, 75.5 mmol) and acetic acid isocyanatomethyl Riumu (6.19 g, 75.5 ethanol (200 mL) suspension of mmol) was heated at reflux for 18 hours. After cooling, the reaction mixture was poured into water and extracted three times with acetic acid Echiru. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. Residue was recrystallized from methanol -. To give the title compound (7.74 g, 51% yield).

Mp 243-245 ° C.

¾ NMR (DMS0-d 6) δ 2.26-2.30 (2H, m), 3.43-3.48 (2H, m), 5.44 (2H, s), 7.29-7.35 (2H, m), 7.74-7.81 (4H, m ), -7.91-7.94 (2H, m), 8.49 (1H, t, J = 5.5 Hz), 8.86 (1H, s).

Reference Example 1 50 3- [2- [[(4 - Full O lobby phenylalanine - 4-I le) carbonyl] Amino] E chill] - 1, 2, 4-Okisajiazoru - 5-carboxylic acid Echiru

N - [3- Amino - 3 - (arsenate Dorokishiimino) propyl] - 4 - Furuorobifue sulfonyl - 4 - local Bokisami de (7.53 g, 25.0 mmol) pyridine (50 mL) of the solution to black port Okiso acetate Echiru (3.35 mL, and 30.0 mmol) was added dropwise at room temperature, and the resulting mixture was stirred for 30 minutes at 60 ° C. After cooling, the reaction solution was poured into water, the precipitated crystals were collected by filtration and recrystallized from Tetorahi Dorofu run to give the title compound (6.13 g, 64% yield).

Mp 184- 185 ° C.

¾ NMR (CDC1 3) δ 1.47 (3Η, t, J = 7.1 Hz), 3.20-3.23 (2H, m), 3.93-3.98 (2H, ra), 4.54 (2H, q, J = 7.1 Hz), 6.74 (1H, t, J = 5.5 Hz), 7.12-7.18 (2H, m), 7.54-7.62 (4H, m), 7.82-7.85 (2H, m).

Reference Example 1 5 1 methyl N - (tert butoxycarbonyl) yl -] 3 § oxiranylmethyl Seri inert N-(tert script butoxycarbonyl) _I3- Arayun (10.0 g, 52.9 mmol) and Toryechi Ruamin (14.6 mL , N of 105 mmol), N-dimethylformamidine de (0.99 mL) was added L - serine methyl ester hydrochloride (8.22 g, 52.9 mmol), 1- Echiru 3- (3-dimethylcarbamoyl Ruaminopuropiru) Karupojiimi de hydrochloride (11.2 g, 58.2 thigh ol) Oyopi Bokuhi mud carboxymethyl benzotriazole (7.86 g, 58.2 mmol) at room temperature and the mixture was stirred for 14 hours. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over sulfate magnesium © beam, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetic Echiru) to give the title compound (3.98 g, 26% yield) as an oil. -

J H NMR (CDC1 3) δ 1.61 (9Η, s), 2.45-2.55 (2Η, ra), 2.81-2.87 (1Η, m), 3.37-3.45 (1Η, ra), 3.46-3.53 (1H, m) , 3.80 (3H, s), 3.93-4.00 (2H, m), 4.64-4.67 (1H, m), 5.11 (1H, brs), 6.60 (1H, brs)., reference example 1 52 2- [2- [(tert - butoxycarbonyl) Amino] Echiru] -1, 3-Kisazo Lumpur - 4 - power carboxylic acid methyl

Methyl N-(tert - butoxide deer Lupo sulfonyl) -. J3- § oxiranylmethyl Seri diisocyanate (3.98 g, 13.7 mmol) in dichloromethane (6 0 mL) solution of Jechiruamino sulfur trifluoride (2.4 mL, 16.5 ramol) was added and the mixture the - mixture was stirred for 1 hour at 78 ° C. The reaction solution was warmed to 0 ° C, 1,8 - Jiazabishikuro [5.4.0] - 7-Undesen (7.2 mL, 48.0 mmol) and blanking opening mode trichloromethane (4.7 mL, 48.0 mmol) was added to the and the mixture was stirred for 2 hours at a temperature. The reaction was diluted with dichloromethane, washed with saturated chloride Anmoniumu solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column inlet Mato chromatography (to from hexane / acetic acid Echiru = 2/3 0/1) to give the title compound (2.38 g, 64% yield) as an oil.

NMR (CDC1 3) δ 1.42 ( 9Η, s), 3.01 (2H, t, J = 6.2 Hz), 3.53-3.64 (2H, m), 3.91 (3H, s), 5.01 (1H, brs), 8.18 ( 1H, s).

Reference Example 1 53 2 - (2-Aminoechiru) -1, 3-Okisazoru - 4 - Power carboxylic acid methyl hydrochloride

Acetate Echiru solution (15 mL) - 2_ [2- [(tert- script butoxycarbonyl) amino] Echiru] -1, 3-Okisazoru 4 Cal Bonn acid methyl (1.48 g, 5.48 ramol) 4 N hydrogen chloride in It was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain washed with Jeffrey chill ether to give the title compound (1.04 g, 78% yield).

Negation R (DMS0-d 6) δ 3.10-3.27 (4Η, 'ra), 3.78-3.81 (3H, m), 8.20 (3H, brs) 8.84-8.85 (1H, m).

Reference Example 1 54 2- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - 1,3 Okisa tetrazole -4 - force carboxylic acid methyl

2- (2-aminoethyl) -1, 3 - Okisazoru 4-carboxylate hydrochloride (1.04 g, 4.11 mmol) and Toriechiruamin (1.15 mL, 8.23 ​​mmol) as tetrahydrofuran (30 mL) suspension chloride 4-Biff sulfonyl carbonyl (892 mg, 4.11 mmol) was added portionwise at room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with acetic acid Echiru, washed with water and saturated Japanese brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting solid was collected by filtration to give the title compound was washed with acetic acid Echiru a (1.22 g, 85% yield). , X H NMR (CDC1 3) δ 3.17 (2Η, t, J = 6.1 Hz), 3.92 (3H, s), 3.97 (2H, q, J = 6.1 Hz), 7.08 (1H, brs), 7.36-7.41 (1H, m), 7.44-7. 9 (2H, m), 7.59- 7.62 (2H, m), 7.64-7.68 (2H, m), 7.84-7.88 (2H, m), 8.19 (1H, s) .

Reference Example 1 5 5 2- [2- [(4-Biff Yeah Lil carbonyl) Amino] Echiru] -l, 3- Okisa Zonore - 4 Power Norebon acid

2 - [2- [(4-Bifue two Rirukarubo - Le) Amino] Echiru] -1, 3-Okisazoru 4 Cal Bonn methyl (1.12 g, 3.20 mmol) in the same manner as in Reference Example 52 from to give the table title compound (920 mg, 85% yield) as a white solid.

! H NMR (DMSO- d 6) δ 3.07 (2H, t, J = 7.0 Hz), 3.65 (2H, q, J = 6.8 Hz), 7.38-7.43 (1H, m), 7.48-7.53 (1H, in ), 7.71-7.74 (2H, m), 7.76-7.80 (2H, m), 7.90-7.94 (2H, m), 8.67 (1H, s), 8.72 (1H, t, J = 5.6 Hz), 12.99 ( 1H, brs).

Reference Example 1 56 [2 - [(3-methylphenyl) (phenyl) Amino] - 2 - Okisoechiru] force Rubamin acid base Njiru

3-methyl - N - phenylene Ruanirin (5.00 g, 27.3 mmol) N of, N- Jimechiruaseta mi de (50 mL) was added (2-chloro - 2 Okisoechiru) force Rubamin acid base Njiru (14.9 g,

N of 65.6 mmol), added N- dimethyl § Seto ami de (20 mL) solution at room temperature, the mixture

And the mixture was stirred for 1 hour. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over sulfate Ma Guneshiumu, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (to from hexane / acetic acid Echiru = 3/7 3/5) to give the title compound (10.7 g, 99% yield) as an oil.

NMR (CDC1 3) δ 2.34 ( 3Η, brs), 3.88 (2H, d, J = 4.6 Hz), 5.09 (2H, s),

5.69 (1H, brs), 7.02-7.47 (14H, m).

Reference Example 1 57 [2- [(3 - methylphenyl) (Fuweniru) Amino] Echiru] Karupamin benzyl

[2- [(3 - methylphenyl) (Hue -) amino] - 2-Okisoechiru] base Karupamin acid Njiru (10.7 g, 28.5 mmol) borane as tetrahydrofuran (60 mL) solution of - Te Torahi Dorofuran complex of Te Torahi Dorofuran solution (1.0 M, 38.5 mL, 38.5 mmol) was added portionwise at room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with acetic acid Echiru, washed with 1 N aqueous sodium hydroxide and brine, dried over sulfate mug Siumu, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from hexane / acetic acid Echiru = 3/17 3/7) to give the title compound (6.49 g, 63% yield) as an oil. -

J H NMR (CDC1 3) δ 2.28 (3Η, s), 3.43 (2H, q, J = 6.3 Hz), 3.87 (2H, t, J = 6.4 Hz), 4.92 (1H, brs), 5.10 (2H, s), 6.79-7.02 (6H, m), 7.13-7.28 (3H, m), 7.30-7.40 (5H, m).

Reference Example 1 58 N-(3- Mechirufue sulfonyl) - N- Fuweniruetan - 1, 2- Jiamin

[2- [(3-methylphenyl) (phenyl) amino] Echiru] carbamate base Njiru (6.46 g, 17.9 mmol) and palladium on carbon (10 ° N 1.90 g, 1.79 mmol) methanol in (50 mL) suspension under hydrogen atmosphere the solution was stirred for 50 minutes at room temperature. The reaction solution over, and the filtrate was concentrated under reduced pressure. The resulting residue was used in the next reaction without purification (3.46 g, 74% yield) (Example 1 63).

XH NMR (CDCI3) δ 2.29 (3H, s), 2.95 (2Η, t, J = 6.6 Hz), 3.78 (2H, t, J

= 6.6 Hz), 6.79-6.85 (2H, m), 6.92-6.95 (1H, m), 6.98-7.03 (2H, m),

7.14-7.18 (1H, m), 7.23-7.29 (2H, m), 7.36-7.38 (1H, m).

Reference Example 1 59 2- [(3-phenyl - benzofuran - 2-I) methyl] - 1H-Isoindo Lumpur - 1, 3 (2H) - dione

3-phenyl - benzofuran - 2-carboxylic acid Echiru (2.00 g, 7.51 mmol) City Ruen (30 mL) of diisobutylaluminum hydride in toluene to a solution (1.5 M, 15 mL, 22.5 mmol) under ice-cooling in added portionwise and the mixture was stirred for 1 hour. Sodium sulfate to the reaction mixture decahydrate (7.25 g, 22.5 tiimol) was added and the mixture was stirred for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. Obtained residue and Futaruimi de (1.33 g, 9.01 mmol), triphenyl phosphine (2.37 g, 9.01 mmol) Te Torahi Dorofuran (30 mL) in toluene solution Azojikarubon acid Jechiru (40%, 3.9 mL, 9.01 mmol ) was added portionwise at room temperature and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, the resulting solid was washed with acetic acid Echiru to give the title compound (1.94, 88% yield) as a white solid material.X H NMR (CDCI3) δ 5.11 (2H, s), 7.30-7.24 (1H, m), 7.25-7.30 (1H, m) ,, 7.35-7.40 (1H, m), 7. 4 (1H, d, J = 8.3 Hz), 7.48-7.55 ( 3H, m) H 7.68- 7.73 (4H, m), 7.86 (2H, dd, J = 5.4, 3.2 Hz).

Reference Example 160 1- (3-phenyl - benzofuran - 2-I le) Metanamin

2- [(3-Hue - Le - 1 - base Nzofuran - 2 - I) methyl]-1H-Isoindoru - 1, 3 (2H) - dione (1.97 g, 5.57 mraol) in ethanol (20 mL) solution of hydrazine monohydrate (1.2 mL, 22.3 mraol) was added at room temperature, the mixture was heated to reflux for 1.5 hours. The reaction solution was filtered, the filtrate diluted with acetic acid Echiru, washed with brine, dried over sulfate magnesium © beam, and concentrated under reduced pressure. The residue (1.29 g, 99% yield) was used in Rukoto without subsequent reaction to purification (Example 166).

J H NMR (CDCI3) δ 4.06 (2Η, s), 7.23-7.27 (1H, m), 7.29-7.34 (1H, m), 7.37-7.43 (1H, m), 7.48-7.53 (5H, ra), 7.59-7.62 (1H, m).

Example 1 5- [2 _ [(4_ Bifuwe two Lil force Ruponiru) Amino] Echiru] - N-(2,2-Jifuwe - Ruechiru) - 1, 2, 4-Okisajiazoru - 3- Karubokisami de

5- [2- [(4 - bi Hue lily ylcarbonyl) amino] Echiru] - 1, 2, 4-Okisajiazo Ichiru - 3-carboxylic acid Echiru (201 mg, 0.550 mmol), 2, 2 - Jifueniruechiru Amin (109 rag, 0.550 mmol) and N, N- diisopropyl E chill § Min (0.192 mL, 1.10 mmol) and Asetonitoriru (2 mL) solution of was 24 hours under heating to reflux under a nitrogen atmosphere. After cooling, crystals were collected by filtration and recrystallized from as tetrahydrofuran, to give the title compound (132 mg, 46% yield).

Mp 223- 224 ° C.

J H NMR (DMS0 - d 6 ) δ 3.24 (2H, t, J = 6.6 Hz), 3.68 (2H, q, J = 6.4 Hz), 3.91 (2H, dd, J = 6.1, 7.6 Hz), 4.44 ( 1H, t, J = 8.1 Hz), 7.15-7.20 (2H, m), 7.26-7.34 (8H, m), 7.40-7.43 (1H, m), 7.48-7.52 (2H, m), 7.72-7.75 ( 2H, m), 7.76-7.79 (2H, m), 7.87-7.90 (2H, m), 8.74 (1H, t, J = 5.6 Hz), 8:97 (1H, t, J = 5.9 Hz).

Example 2 5- [2- [(4-Biff We Yuri Luca Lupo two Honoré) Amino] Echiru] - N-(3, 3 Jifuwe two Rupuropiru) - 1, 2, 4-Okisajiazoru - 3- Karubokisami de

5 - [2- [(4 - Bifue two Lil carbonyl) Amino] Echiru] -1, 2, 4-Okisajiazoru - 3 - Power carboxylic acid Echiru (201 mg, 0.550 mmol) and 3, 3-diphenyl sulfonyl propyl § Mi - (349 mg, 1.65 mmol) and the Asetonitoriru (3 mL) solution under a nitrogen atmosphere) was heated to reflux for 24 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the residue fart was crystallized from hexane / acetic acid Echiru to give the title compound (268 mg, 92% yield).

Mp 133- 134 ° C. -

X H NMR (CDC1 3) δ 2.38-2.43 (2Η, m), 3.32 (2Η, t, J = 6.1 Hz), 3.43-3.48 (2H, ra), 3.96-4.02 (3H, m), 6.80 (1H , t, J = 6.1 Hz), 6.84 (1H, t, J = 6.0 Hz), 7.15-7.20 (2H, m), 7.22-7.31 (8H, m), 7.37-7.41 (1H, m), 7.44- 7.48 (2H, m), 7.56-7.61 (2H, m), 7.63-7.67 (2H, m), 7.81-7.84 (2H, m). example 3 5- [2- [(4-Bifue two drill carbonyl ) Amino] Echiru] - N-(4,4-Jifue two Rubuchiru) - 1, 2, 4-Okisajiazoru - 3 - Karubokisami de

5 - [2 - [(4-Bifue two Rirukarupoeru) amino] Echiru] - 1, 2, 4-Okisajiazo Ichiru - 3-carboxylic acid Echiru (183 rag, 0.500 mmol), 4, 4-diphenyl-butyl § Min hydrochloride (393 mg, 1.50 mmol) and N, N- diisopropyl E chill § Min (0.261 mL, 1.50 mmol) and Asetonitoriru (2 mL) suspension of the heating for 24 hours under reflux under a nitrogen atmosphere. After cooling, the reaction was diluted with acetic acid Echiru, water and washed with saturated brine, dried over sulfate mug Neshiumu, and concentrated under reduced pressure. The residue was recrystallized from acetic acid Echiru to give the title compound (227 mg, 82% yield).

Mp 183- 184 ° C.

JH NMR (CDCI3) δ 1.54 - 1.63 (2Η, m), 2.12 (2H, ddd, J = 5.5, 7,9, 10.3 Hz), 3.32 (2H, t, J = 6.1 Hz), 3.49 (2H, d , J = 7.1 Hz), 3.91 (1H, t, J = 7.9 Hz), 3.98 (2H, q, J = 6.1 Hz), 6.79-6.85 (2H, m), 7.14-7.18 (2H, m), 7.21 -7.29 (8H, ra), 7.37-7.42 (1H, m), 7.45-7. 9 (2H, m), 7.58-7.61 (2H, m), 7.63-7.66 (2H, m), 7.80-7.83 ( 2H, m).

Example 4 N_ (2-morpholino - 3 full We Roh hydroxypropyl) - 5- [2 - [[4 - (2 - thienyl) Baie Nzoiru] Amino] Echiru] -1, 2, 4-Okisajiazoru - 3- Karupokisami de

[2 - [3 - [[(2 - morpholino - 3 off Nokishipuropiru) Amino] force Lupo sulfonyl] - 1, 2, 4-O Kisajiazoru - 5-I le] Echiru] Karupamin acid tert- heptyl (238 mg dichloromethane (2 mL) was added Torifuruoro acetate (1 mL) was added a 0.500 mmol), the resulting et be mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane, washed with 1 M hydroxide of Natoriumu solution and saturated brine, dried over sulfate Natoriumu and intimidating enrichment.

The resulting residue, 4 - (2 - thienyl) benzoic acid (102 mg, 0. 500 mraol), 1- [3 - (dimethyl Chiruamino) propyl] -3-E chill carbo di imide hydrochloride (105 mg, 0. 550 mmol) and 1 - hydroxycarboxylic benzotriazole (84. 2 mg, 0. 550 mraol) of N, N - dimethylol Ruhorumuami de (4 mL) the solution was stirred for 3 hours at room temperature. The reaction solution was diluted with acetic acid Echiru, twice with water, washed once with saturated brine, dried over magnesium sulfate, followed by vacuum enrichment. After purification the residue was purified by basic silica gel column chromatography (hexane / tetra arsenide Dorofuran = 1/2) and crystallized from hexane / as tetrahydrofuran to give the title compound (172 mg, 61% yield) .

Mp 157- 158 ° C.

'Η NMR (DMSO- d 6) δ 2. 55-2. 60 (2H, m), 2. 72-2. 77 (2H, m), 3. 07-3. 13 (1H, m), 3 . 29 (2H, t, J = 6. 6 Hz), 3. 39-3. 45 (1H, m), 3. 47-3. 57 (5H, m), 3. 69-3. 74 (2H , m), 4. 02 (1H, dd, J = 4. 6, 10. 2 Hz), 4. 12 (1H, dd, J = 6. 4, 10. 2 Hz), 6. 91-6. 98 (3H, m), 7. 18 (1H, dd, J = 3. 9, 4. 9 Hz), 7. 25- 7. 31 (2H, m), 7. 63-7. 64 (2H, m), 7. 73-7. 77 (2H, m), 7. 83-7. 86 (2H, m), 8. 75 (1H, t, J = 5. 6 Hz), 8. 81 (1H , t, J = 5. 7 Hz).

Example 5 5- [2- [[(4 '- E Chill biphenyl - 4-I le) carbonyl] Amino] Echiru] - N-(2 - morpholino - 3_ phenoxyethanol propyl;) - 1, 2, 4 Okisajiazo Ichiru - 3 - power Rupoki Sami de

[2- [3 - [[(2-morpholino - 3 - phenoxyethanol propyl) amino] carbonyl] -1, 2, 4 - O Kisajiazoru - 5-I le] Echiru] force Rubamin acid tert- butyl (190 mg , 0. 400 mmol) in dichloromethane (1. 5 mL) solution was added to Torifuruoro acetate (1 mL), the resulting mixture was stirred for 10 minutes at room temperature. The reaction was diluted with dichloromethane, washed with 1 M hydroxide Natoriumu solution and saturated brine, dried over sulfate Natoriumu to give a residue under reduced pressure concentrated. -

4 '- Echirubifueniru - 4- carboxylic acid (103 mg, 0. 440 mmol) Tetorahi Dorofu run (3 mL) carbonate solution New, New' - disuccinimidyl succinimidyl (§ 2. 8 mg, 0. 440 mmol ) pressurized example and the resulting mixture was stirred at room temperature for 1 hour. To the reaction solution, the residue Tetorahi -. Dorofuran (1.5 Ral) was added, and the mixture was stirred at room temperature for a further 5 hours. The reaction solution washed with 1 M hydroxide Natoriumu solution and saturated brine, dried over sulfate Natoriumu, and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (acetic Echiru / methanol = 100 / 01-98 / 2), and crystallized from acetic acid Echiru / Jefferies chill ether to give the title compound (100 mg, 43% yield) Obtained.

Mp 177- 178 ° C.

X H NMR (DMSO- d 6) δ 1.21 (3H, t, J = 5.7 Hz), 2.53-2.61 (2H, ra), 2.65 (2H, q, J = 5.7 Hz), 2.70-2.79 (2H, m ), 3.05-3.14 (1H, ra), 3.29 (2H, t, J = 5.0 Hz), 3.36-3.58 (6H, m), 3.72 (2H, q, J = 4.8 Hz), 4.02 (1H, dd, J = 3.5, 7.6 Hz), 4.12 (1H, dd, J = 4.5, 7.8 Hz), 6.90-6.97 (3H, m), 7.28 (2H, t, J. = 6.0 Hz), 7.33 (2H, d, J = 6.3 Hz), 7.64 (2H, d, J = 6.0 Hz), 7.74 (2H, d, J = 6.3 Hz), 7.88 (2H, d, J = 6.0 Hz), 8.75 (1H, t, J = 4.2 Hz), 8.81 (1H, t, J = 4.4 Hz).

Example 6 5- [2- [[(4, - Furuorobifue - Le - 4-I le) carbonyl] Amino] E Chi le] - N-(2-morpholino - 3-phenoxyethanol propyl) - 1,2 , 4 - Okisajiazoru -3 - Cal Bokisami de

In the same manner as in Example 5, 4'Echirubifueniru - 4- carboxylic 4 instead of acid, - by using the 4-carboxylic acid to give the title compound - Full O lobby off We chloride. Yield 72 ° N mp 156- 157 ° C (crystallized from acetic Echiru / Jefferies chill ether).

J H NMR (DMSO - d 6 ) δ 2.53-2.62 (2Η, m), 2.70-2.79 (2H, m), 3.05-3.14 (ΙΗ 'm), 3.29 (2Η, t, J = 5.0 Hz), 3.37 -3.58 (6H, m), 3.72 (2H, q, J = 4.5 Hz), 4.02 (1H, dd, J = 3.6, 7.8 Hz), 4.12 (1H, dd, J = 4.8, 7.5 Hz), 6.89- 6.97 (3H, m), 7.23-7.37 (4H, m), 7.71-7.80 (4H, m), 7.89 (2H, d, J = 6.3 Hz), 8.77 (1H, t, J = 4.1 Hz), 8.81 (1H, t, J = 4.4 Hz).

Example 7 5- [2- [[(4, - Shianobibuweniru - 4-I le) carbonyl] Amino] Echiru] - N-(2-morpholino - 3 - phenoxyethanol propyl) -1,2, 4- Okisajiazoru - 3 - carboxyl Sami de

In the same manner as in Example 5, 4'Echirubifueniru - 4 'instead of 4-carboxylic acid - Shianobifueniru - the title compound was obtained using 4-carboxylic acid. 73% yield. , Mp 184- 185 ° C (crystallized from acetic Echiru / Jefferies chill ether).s

J H NMR (DMSO- d 6) δ 2.53-2.62 (2H, m), 2.69-2.79 (2H, m), 3.05-3.14 (1H, m), 3.30 (2H, t, J = 5.0 Hz), 3.37 -3.58 (6H, m), 3.73 (2H, q, J = 4.6 Hz), 4.01 (1H, dd, J = 3.5, 8.0 Hz), - 4.12 (1H, dd, J = 4.7, 7.7 Hz),

6.88- 6.97 (3H, m), 7.28 (2H, t, J = 5.9 Hz), 7.86 (2H, d, J = 6.3 Hz),

7.89- 7.99 (6H, m), 8.76-8.86 (2H, m).

EXAMPLE 8 N-(2 - morpholino - 3 - off We Roh hydroxypropyl) - 5 - [2 _ [[[4 '- (Torifuruoro methyl) Bifue 4- I le] carbonyl] Amino] Echiru] -1 , 2, 4-Okisajiazo Le - 3- Karubokisami de

In the same manner as in Example 5, 4'Echirubifueniru - 4 4 instead of the carboxylic acid '- was the title compound with 4-carboxylic acid - (triflate Ruo ii methyl) Bifuweniru. Yield 15%.

Mp 189- 190 ° C (crystallized from acetic Echiru / Jefferies chill ether).

l NMR (DMS0-d 6) δ 2.53-2.62 (2Η, m), 2.69-2.79 (2Η, m), 3.06-3.16 (1Η, m), 3.30 (2Η, t, J = 5.0 Hz), 3.37- 3.58 (6H, m), 3.74 (2H, q, J = 4.7 Hz), 4.02 (1H, dd, J = 3.5, 7.7 Hz), 4.13 (1H, dd, J = 4.7, 7.7 Hz), 6.88-6.98 (3H, m), 7.28 (2H, t, J = 6.0 Hz), 7.85 (4H, d, J = 6.3 Hz),

7.90- 7.98 (4H, m), 8.76-8.86 (2H, m).

EXAMPLE 9 5- [2- [[(4, - Mechirubifueniru - 4 - I le) carbonyl] Amino] Echiru] - N-(2 - morpholino - 3 - phenoxyethanol propyl) - 1,2, 4-Okisajiazoru - 3-carboxy Sami de

In the same manner as in Example 5, 4, - Echirubifueniru - 4 'instead of 4-carboxylic acid - was used to obtain the title compound Mechirubifuweniru 4-carboxylic acid. 36% yield.

Mp 175- 176 ° C (crystallized from acetic Echiru / Jefferies chill ether).

^ NMR (DMS0-d 6) δ 2.35 (3H, s), 2.53-2.61 (2H, m), 2.69-2.78 (2H, m), 3.05-3.14 (1H, m), 3.29 (2H, t, J = 5.0 Hz), 3.37-3.58 (6H , m), 3.72 (2H; q, J = 4.7 Hz), 4.01 (1H, dd, J = 3.6, 7.8 Hz), 4.12 (1H, dd, J = 4.8, 7.8 Hz), 6.88-6.98 (3H, m), 7.23-7.33 (4H, m), 7.62 (2H, d, J = 6.0 Hz), 7.73 (2H, d, J = 6.3 Hz), 7.87 (2H, . d, J = 6.3 Hz), 8.75 (1H, t, J = 4.1 Hz), 8.81 (1H, t, J = 4.2 Hz), example 1 0 5- [2 - [[(4 - black port Bifuweniru - 4 - I le) carbonyl] Amino] E Chi le] - N-(2-morpholino - 3-phenoxyethanol propyl) - 1,2, 4 - Okisajiazo Ichiru - 3-Cal Pokisami de - example 5 in the same manner as, 4 'instead of 4'Echirubifueniru 4-carboxylic acid - by using the 4-carboxylic acid to give the title compound - black port Bifuweniru. 52% yield.

Mp 184- 185 ° C (crystallized from acetic Echiru / Jefferies chill ether).

NMR (DMS0-d 6) δ 2.53-2.62 (2Η, ra), 2.68-2.78 (2H, m), 3.05-3.14 (1H, m), 3.30 (2H, t, J = 5.0 Hz), 3.36-3.59 (6H, m), 3.74 (2H, q, J = 4.7 Hz), 4.02 (1H, dd, J = 3.6, 7.8 Hz), 4.13 (1H, dd, J = 4.7, 8.0 Hz), 6.88-6.97 ( 3H, m), 7.28 (2H, t, J = 6.6 Hz), 7.55 (2H, d, J = 6.6 Hz), 7.76 (2H, d, J = 6.6 Hz), 7.77 (2H, d, J = 6.0 Hz), 7.91 (2H, d, J = 6.3 Hz), 8.75-8.85 (2H, ra).

Example 1 1 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3 - phenoxyethanol propyl) -1, 2, 4 - Okisajiazo Ichiru - 3 - Karubokisami de of optically active substance (retention time is small)

5- [2 - [(4 - Biff We two Riruka Lupo sulfonyl) amino] Echiru] -N - (2-morpholino-3-Hue Nokishipuropiru) - 1, 2, 4-Okisajiazoru 3- Karubokisami de (approximately 70 mg) the high performance liquid chromatography [column: CHIRALCEL AD, 50 (id) X500 (L) negation, Daicel chemical Industries, Ltd .; mobile phase: hexane / ethanol = 3/7; flow rate: 80 mL / min from 120 mL / rain; column temperature: 30 ° C; 1 implant dose: was collected with about 30 mg] min to obtain the title of compound a (28 mg, 49% yield). Optical purity of 99.7% ee.

Example 1 2 5- [2- [(4 - Bibuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3 - Fuenokishipuropi ^ /) - 1, 2, 4 - Okisajiazo Ichiru - 3- Karubokisami de of optically active substance (Univ retention time)

In the same manner as in Example 1 1., To give the title compound (36 mg, 36% yield). Optical purity of 99.3% ee.

'EXAMPLE 1 3 N- [2- [3 - [[(2- morpholino - 3 - phenoxyethanol propyl) Amino] carbonylation Le] - 1, 2, 4-Okisajiazoru -5_ I le] Echiru] - in the same manner as 6-phenylalanine nicotinamidine de example 5, 4 '- Echirubifueniru - 4 Karupon to Ri generations acid 6 - with phenylalanine nicotinic acid to give the title compound. 56% yield.

Mp 178- 179 ° C (crystallized from acetic Echiru / Jefferies chill ether).

XH NMR (DMS0-d 6) δ 2.53-2.62 (2Η, ra), · 2 · 69 - 2.78 (2Η, m), 3.05-3.14 (1H, m), 3.31 (2H, t, J = 5.1 Hz) , 3.38-3.59 (6H, m), 3.75 (2H, q, J = 4.7 Hz), 4.02 (1H, dd, J = 3.6, 7.8 Hz), 4.12 (1H, dd, J = 4.7, 7.7 Hz),

6.88- 6.98 (3H, m), 7.28 (2H, t, J = 5.9 Hz), 7.45-7.56 (3H, m), 8.08 (IE d, J = 6.6 Hz), 8.12-8.17 (2H, m), 8.23 (1H, dd, J = 1.7, 6.2 Hz), 8.82 (1H, t, J = 4.2 Hz), 8.95 (1H, t, J = 4.2 Hz), 9.04 (1H, d, J = 1.8 Hz). eXAMPLE 14 N-(2-morpholino - 3 - off We Roh hydroxypropyl) -5- [2 - [[4- (3 - thienyl) Benzoiru] Amino] Echiru] -1, 2, 4-Okisajiazoru - 3 - Karubokisami de

In the same manner as in Example 5, 4'Echirubifuweniru - 4 instead of 4-carboxylic acid - (3-thienyl) to give the title compound with benzoic acid. 48% yield.

Mp 163- 164 ° C (crystallized from acetic Echiru / Jefferies chill ether).

H NMR (DMS0-d 6) δ 2.53-2.63 (2Η, m), 2.69-2.79 (2Η, m), 3.04-3.15 (1H, m), 3.29 (2H, t, J = 5.0 Hz), 3.36- 3.59 (6H, m), 3.72 (2H, q, J = 4.6 Hz), 4.02 (1H, dd, J = 3.5, 7.7 Hz), 4.12 (1H, dd, J = 4.8, 7.8 Hz),

6.89- 6.98 (3H, m), 7.28 (2H, t, J = 5.9 Hz), 7.60-7.70 (2H, m), 7.82 (2H: d, J = 6.3 Hz), 7.85 (2H, d, J = 6.3 Hz), 8.01 (1H, s), 8.74 (1H, t, J =

4.1 Hz), 8.82 (1H, t, J = 4.2 Hz). '

Example 1 5 5- [2- [[4- (3-furyl) Benzoiru] Amino] Echiru] - N-(2 Moruhori Bruno - 3 - Fuenokishipu port pills) - 1, 2, 4 - Okisajiazoru -3 - power Rupokisami de

In the same manner as in Example 5, 4'Echirubifueniru - instead of 4-carboxylic acid 4- (3-furyl) with benzoic acid to give the title compound. 56% yield.

Mp 140- 141 ° C (crystallized from acetic Echiru / Jefferies chill ether).

XH NMR (DMS0-d 6) δ 2.54-2.63 - (2Η, ra), 2.70-2.78 (2H, m), 3.05-3.14 (1H, m), 3.28 (2H, t, J = 5.1 Hz), 3.37 -3.59 (6H, m), 3.71 (2H, q, J = 4.8 Hz), 4.02 (1H, dd, J = 3.6, 7.8 Hz), 4.12 (1H, dd, J = 4.5, 7.8 Hz), 6.88- 6.97 (3H, ra), 7.03 (1H, d, J = 0.6 Hz), 7.28 (2H, t, J = 5.9 Hz), 7.71 (2H, d, J = 6.3 Hz), 7.78 (1H, d, J = 0.6 Hz), 7.82 (2H, d, J = 6.3 Hz), 8.29 (1H, s), 8.72 (1H, t, J = 4.2 Hz), 8.81 (1H, t, J = 4.2 Hz). example 1 6 5 - [2 - [[4- [(2,2-dimethyl-propionyl) amino] Benzoiru] amino] Echiru] - N-(2 - morpholino-3-phenoxyethanol propyl) - 1, 2, 4 - Okisajiazo Ichiru -

3 - Karubokisami de

In the same manner as in Example 5, 4, - Echirubifuweniru - instead of 4-carboxylic acid

4 - [(2, 2-dimethyl-propionyl) Amino] to give the title compound with benzoic acid. Yield 46 ° /. .

Mp 193- 195 ° C (crystallized from acetic Echiru / Jefferies chill ether).

J H NMR (DMS0-d 6 ) δ 1.23 (9H, s), 2.54-2.63 (2Η, ra), 2.70-2.78 (2H, m), 3.04-3.14 (1H, m), 3.26 (2H, t, J = 5.0 Hz), 3.37-3.59 ( 6H, m), 3.69 (2H: q, J = 4.7 Hz), 4.02 (1H, dd, J = 4.1, 7.7 Hz), 4.12 (1H, dd, J = 4.5 , 7.5 Hz), 6.90-6.97 (3H, m), 7.28 (2H, t, J = 6.0 Hz), 7.73 (2H, d, J = 7.2 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.60 (1H, t, J = 4.4 Hz), 8.81 (1H, t: J = 4.4 Hz), 9.40 (1H, s).

Example 1 7 5- [2- [(4 - Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2-heat Doroki sheet - 3- phenoxyethanol propyl) - 1, 2, 4-Okisajiazoru - 3- Karubokisami de

[2- [3- [[(2-heat Dorokishi - 3 - phenoxyethanol propyl) Amino] carbo sulfonyl] - 1,2, 4 - O Kisajiazoru - 5-I le] Echiru] force Rubamin acid tert- butyl (170 mg, 0.418 mmol) was stirred for 1 hour at room temperature a mixture of 10% hydrogen chloride methanol solution (5 mL), and concentrated under reduced pressure reaction solution.

Obtained residue and Toriechiruamin (101 mg, 1.00 mmol) in Asetonitoriru (5 mL) was added chloride 4- Biff We sulfonyl carbonyl (91 mg, 0.418 mmol) was added, stirred for 1 hour and the resulting that mixture at room temperature did. The reaction mixture was concentrated under reduced pressure, water was added to the residue, followed by extraction with acetic acid Echiru. The organic layer was washed with water, dried over magnesium sulfate, followed by vacuum enrichment. The residue was crystallized from acetic acid Echiru to give the title compound (97 mg, 48% yield).

Mp 177- 178 ° (. X H NMR (CDCI3) δ 2.93 (1H, d, J = 4.4 Hz), 3.34 (2H, t, J = 5.6 Hz) ,, 3.61-3.67 (1H, m), 3.85- 3.89 (1H, m), 3.97-4.02 (3H, m), 4.06-4.1,0 (1H, m), 4.23-4.30 (1H, m), 6.84 (1H, brs), 6.90-6.92 (2H, m ), 6.98 (1H, t, J = 7.6 Hz), 7.27-7.31 (2H, m), 7.37-7.41 (1H, m), 7.44-7.48 (3H, m), 7.59-7.60 (2H, ra), 7.65 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz) example 1 8 5. [2 - [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-( 2 Moruhori aminoethyl) - 1, 2, 4-Okisajiazoru - 3- Karubokisami de

In the same manner as in Example 1 7, [2 - [3 - [[(2 - heat Dorokishi - 3 - Fuenokishipuropi Le) Amino] carbonyl] - 1, 2, 4-Okisajiazoru 5-I le] Echiru] Power instead of Rubamin acid tert- butyl [2- [3- [[(2-morpholinoethyl) Amino] Karuboeru] - 1, 2, 4-Okisajiazoru 5-I le] Echiru] using Karupamin acid tert- butyl to give the title compound. 49% yield.

Mp 181-182 ° C (crystallized from acetic Echiru).

1 H thigh (CDC1 3) δ 2.48-2.50 (4Η , ra), 2.59 (2H, t, J = 6.0 Hz), 3.35 (2H, t, J = 6.0 Hz), 3.56-3.60 (2H, m), 3.70-3.72 (4H, m), 3.98-4.01 (2H, m), 6.85 (1H, brs), 7.36-7,43 (2H, m), 7.45-7.48 (2H, m), 7,59-7.62 (2H, m): 7.66 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz).

Example 1 9 5 - [2- [(4-Bifue two Rirukarubo two Honoré) Amino] Echiru] - N-[3 - Fuenoki sheet - 2- (1-pyrrolidinyl) propyl] -1, 2, 4- Okisajiazoru - in the same manner as 3-Karubokisami de example 1, 2, 2 - diphenyl ^ / instead of Echiruamin with [3 off Wenokishi 2- (1-pyrrolidinyl) propyl] amine to give the title compound. 51% yield.

Mp 160- 161 ° C (crystallized from acetic Echiru / Jefferies chill ether).

JH NMR (DMSO- d 6) δ 1.65 (4H, brs), 2.60-2.73 (4H, m), 2.91-2.99 (1H, m): 3.28 (2H, t, J = 5.1 Hz), 3.42-3.52 ( 1H, m), 3.54-3.64 (1H , m), 3.72 (2H: q, J = 4.6 Hz), 4.00-4.11 (2H, m), 6.87-6.96 (3H, m), 7.26 (2H, t, J = 6.0 Hz), 7.41 (1H, t, J = 5.6 Hz), 7.49 (2H, t, J = 5.6 Hz), 7.72 (2H, d: J = 5.7 Hz), 7.76 (2H, d, J = . 6.6 Hz), 7.89 (2H, d, J = 6.3 Hz), 8.76 (1H, t, J = 4.4 Hz), 8.80 (1H, t, J = 4.2 Hz) example 20 5 - [2- [( 4 Bifue two Lil carbonyl) amino] Echiru] - N-(2, 3- dihydric de - b -1, 4 - base Nzojiokishin - 2 - Irumechiru) -1, 2, 4 - Okisajiazoru -3- force Rupoki Sami de

5- [2- [(4-Biff Eni Riruka Lupo yl) Amino] Echiru] -1, 2, 4-Okisajiazoru - 3-force Norebon acid Echinore (183 mg, 0.500 mmo-1), 2,3- dihydric mud - 1, 4-Benzojioki Shin - 2 - Irumechiruamin (124 rag, 0.750 mraol) and 20% sodium © Mue butoxy de ethanol solution (0.34 mL, 1.00 mmol) in ethanol / as tetrahydrofuran (2/2 mL) solution under a nitrogen atmosphere and stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue, followed by extraction with acetic acid Echiru. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. After the residue was crystallized from diisopropyl ether and recrystallized from hexane / acetic acid Echiru to give the title compound (130 rag, 54% yield).

Mp 174- 176 ° C.

X H NMR (CDC1 3) δ 3.34-3.37 (2Η, m), 3.65-3.75 (1Η, ra), 3.87-3.95 (1H, m), 3.99-4.04 (3H, m), 4.32-4.35 (1H, ra), 4.37-4.44 (1H, m), 6.78 (1H, brs), 6.83-6.90 (4H, m), 7.32 (1H, brs), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.59-7.61 (2H, m), 7.65 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz).

施例 2 1 Methanesulfonic acid [2- [[[5- [2- [(4-Bifuwe two Lil carbonyl) amino] Echiru] - 1, 2,4 Okisajiazo Ichiru - 3 - I le] carbonyl] amino] -1- (Fuwenoki Shimechiru) Echiru]

5- [2- [(4 - Bifue two Lil carbonyl) Amino] Echiru] - N - (2-arsenide Dorokishi 3 Hue Nokishipuropiru) _1,2, 4 Okisajiazoru - 3 Power Rupokisami de (250 mg, 0.514 pyridine mmol) (10 mL) was added methanesulfonyl chloride (59 mg, 0.514 mraol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, followed by extraction with acetic acid Echiru. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and recrystallized from acetic acid Echiru to give the title compound (180 m g, 62% yield).

Mp 150- 151 ° C. NMR (CDClg) δ 3.10 (3H, s), 3.26-3,35 (2H, m), 3.75-3.82 (1H, m), 3.90-4.10 (3H, m), 4.18-4.27 (2H, m), 5.14-5.20 (lH, m), 6.90 (2H, d, J = 8.4 Hz), 6.96 (1H, brs), 7.01 (1H, t, J = 7.6 Hz), 7.30 (2H, m), 7.38 (1H , t, J = 7.2 Hz), 7.46 (2H, m), 7.59-7.66 (5H, ra), 7.84 (2H, d, J = 8.0 Hz) -. example 22 5- [2- [(4- Bifue two Lil force Ruponiru) Amino] Echiru] - N - (3- isopropenyl epoxy-2-morpholino-propyl) - 1, 2, 4-Okisajiazoru - 3 - Karubokisami de example 1 and by the same method, 2, 2- instead of Ziff sulfonyl E chill amine with (3 I isopropoxy-2-morpholinopropyl) amine to give the title compound. Yield 35%

Mp 138- 139 ° C (Rooster 乍酸 Echiru / crystallized from Jeffrey chill ether).

JH NMR (DMSO- d 6) δ 1.07 (6H, t, J = 4.2 Hz), 2.44-2.54 (2H, m), 2.63- 2.71 (2H, m), 2.75-2.84 (1H, m), 3.24- 3.54 (11H, m), 3.73 (2H, q, J = 4.7 Hz), 7.41 (1H, t, J = 5.4 Hz), 7.50 (2H, t, J = 5.6 Hz), 7.73 (2H, d, J = 5.4 Hz), 7.77 (2H, d, J = 6.3 Hz), 7.90 (2H, d, J = 6.3 Hz), 8.60 (1H, t, J = 4.4 Hz), 8.77 (1H, t, J = 4.2 Hz).

Example 23 propyl force Rubamin acid [2- [[[5- [2- [(4-Bifuwe two Lil carbonyl) § amino] Echiru] -1, 2, 4 - Okisajiazo Ichiru - 3-I le] carbonyl] amino] - 1 - (Fueno Kishimechiru) Echiru]

5- [2 - [(4 - Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2-arsenide Dorokishi 3 Hue Nokishipuropiru) - 1,2, 4 - Okisajiazoru -3 - Karubokisami de (60 mg, 0.123 mmol) and New, Nyu- diisopropyl E chill § Min (16 mg, as tetrahydrofuran (10 mL) was added propyl isocyanate (160 mg of 0.123 mmol), 1.85 mmol) was added, the mixture obtained in 70 ° C 72 and the mixture was stirred time. The reaction solution was concentrated under reduced pressure, the residue aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with acetic acid Echiru. The organic layer was washed with water, dried over sulfate mug Ne 'Shiumu, and concentrated under reduced pressure. The residue fart from hexane / acetic acid Echiru was crystallized to give the title compound (51 mg, 73% yield).

Mp 157-158 ° C.

NMR (CDCI3) δ 0.87 (3Η, t, J = 7.6 Hz), 1.43-1.51 (2H, m), 3.08-3.13 (2H, m), 3.34 (2H, t, J = 2.4 Hz), 3.76-3.83 (1H, m), 3.95-4.07 (3H, m) ,, 4.16-4.17 (2H, ra), 4.87 (1H, brs), 5.23 (1H, brs), 6.92-6.99 (l, m), 7.26- 7.31 (2H, ra), 7.39 (1H, t, J = 7.2 Hz), 7.44-7.48 (2H, m), 7.60 (2H: d, J = 7.6 Hz), 7.65 (2H, d, J = 8.4 Hz ), 7.71 (1H, brs), 7.85 (2H, d, J = 8.4 Hz). ·

Example 24 5- [2- [3- (4-Bifuwe - Lil) Urei de] Echiru] - N-(2-morpholino - 3 - phenoxyethanol propyl) -1, 2, 4-Okisajiazo Ichiru - 3 - Karubokisami de

In the same manner as in Example 1, 5- [2 - [(4-Bifuwe two Lil carbonyl) Amino] E chill] - 1, 2, 4-Okisajiazoru - 5 in place of 3-carboxylic acid Echiru [2- [3- (4-Biff We two Lil) Urei de] Echiru] -1, 2, 4-Okisajiazoru - 3-carboxylic acid Echiru, 2, instead of (2-morpholino 2-diphenyl E naphthylamine - 3 - to give the title compound using the phenoxyethanol propyl) amine. 47% yield.

Mp 192 - 193 ° C (crystallized from acetic Echiru).

NMR (DMS0-d 6) δ 2.55-2.63 (2H, m), 2.70-2.79 (2H, m), 3.05-3.14 (1H, ra), 3.21 (2H, q, J = 5.0 Hz), 3.38-3.62 (8H, m), 4.02 (1H, dd, J = 3.5,

7.7 Hz), 4.13 (1H, dd, J = 4.7, 7.7 Hz), 6.45 (1H, t, J = 4.5 Hz), 6.89-

6.99 (3H, m), 7.24-7.33 (3H, m), 7.42 (2H, t, J = 5.7 Hz), 7. 6 (2H, d,

J = 6.3 Hz), 7.54 (2H, d, J = 6.3 Hz), 7.60 (2H, d, J = 5.4 Hz), 8.73

(1H, s), 8.84 (1H, t, J = 4.2 Hz).

EXAMPLE 25 5 - [2 - [(4 - Bifuwe two Lil carbonyl) Amino] Echiru] - N - [2 - [(2-Main preparative Kishechiru) (methyl) Amino] one 3 phenoxyethanol propyl] - 2, 4 - Okisajiazo one Lou

3 - Karubokisami de

In the same manner as in Example 1, 2, 2-diphenyl instead of Niruechiruamin N 2 - (2 - main Tokishechiru) - N 2 - methyl - 3-phenoxyethanol propane - title compound using 1,2 Jiamin It was obtained. Yield 60%.

Mp 91 - 92 ° C (crystallized from acetic Echiru / diisopropyl ether).

^ NMR (CDC1 3) δ 2.46 (3Η, s), 2.69-2.78 (1H, m), 2.96-3.06 (1H, m), 3.21-3.54 (9H, m), 3.92-4.06 (4H, m), 4.12 (1H, dd, J = 4.1, 7.4 Hz), 6.90 (2H, d, J = 5.7 Hz), 6.93-7.04 (2H, m), 7.29 (2H, t, J = 5.4 Hz), 7.39 (1H , t, J = 5.6 Hz), 7.46 (2H, t, J = 5.9 Hz), 7.60 (2H, d, J = 5.4 Hz), 7.65 (2H, d, J = 6.3 Hz), 7.84 (2H, d , J = 6.3 Hz), 8.12-8. ¾9 (1H, m).

EXAMPLE 26 N-(3 Benjiruokishi - 2-morpholino-propyl) - 5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] -1,2, 4-Okisajiazoru - 3 Karubokisami de Example 1 the same manner as the 2 to give the title compound using 2-Ziv instead enyl E chill § Min (3-base Njiruokishi 2-morpholinopropyl) amine. 21% yield.

Amorphous.

JH NMR (DMSO- d 6) δ 2.45-2.55 (2Η, ra), 2.63-2.72 (2H, ra), 2.87-2.96 (1H, m), 3.30 (2H, t, J = 5.0 Hz), 3.31- 3.54 (7H, m), 3.59 (1H, dd, J = 4.7, 7.7 Hz), 3.73 (2H, q, J = 4.7 Hz), 4.46 (2H, s), 7.24-7.37 (5H, m), 7.41 (1H, t, J = 5.4 Hz), 7.49 (2H, d, J = 5.7 Hz), 7.72 (2H, d, J = 6.0 Hz), 7.77 (2H, d, J = 6.3 Hz), 7.91 (2H , d, J = 6.0 Hz), 8.68 (1H, t, J = 4.2 Hz), 8.78 (1H, t, J = 4.2 Hz).

EXAMPLE 27 5 - [2- [(4-Bifuwe two Rirukarubo two Honoré) Amino] Echiru] - N-[3- [4 - (4-menu Tokishifueniru) pin piperidylpiperidine] propyl] - 1, 2, 4- Okisajiazoru - 3-Karubokisa Mi de,

In the same manner as in Example 2, 3, 3-Jifuwe - instead of Rupuropiruamin - using [3- [4- (4 main Tokishifue yl) piperidino] propyl] amine to give the title compound. 48% yield.

Mp 159- 160 ° C (recrystallized from hexane / acetic acid Echiru to).

J H NMR (CDC1 3) δ 1.73 - 2.18 (8Η, m), 2.44-2.54 (1H, m), 2.55-2.69 (2H, m), 3.05-3.20 (2H, ra), 3.28 (2H, t, J = 6.0 Hz), 3.64 (2H, q, J = 5.5 Hz), 3.77 (3H, s), 3.93 (2H, q, J = 6.0 Hz), 6.80-6.69 (3H, ra), 7.19- 7.22 ( 2H, m), 7.37-7.41 (1H, ra), 7.44-7.48 (2H, ra), 7.58-7.61 (2H, m), 7.62-7.65 (2H, m), 7.80-7.83 (2H, m), 9.47 (1H, brs).

Example 28 5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-[3- (3, 4-di-arsenide mud isoquinoline - 2 (IH) - I) propyl] -1, 2, 4 - Okisajiazoru - 3-carbonitrile Kisami de, in the same manner as in example 2, 3, 3 - Jifue - [3- (3 instead έ of Rupuropiruamin, 4 - dihydric mud isoquinoline - 2 (1 [Eta]) - I was used to obtain the title compound) propyl] amine. 51% yield.

Mp 151- 152 ° C (to from hexane / acetic acid Echiru. Recrystallization).

l NMR (CDC1 3) δ 1.85 - 1.91 (2Η, ra), 2.72-2.74 (2H, m), 2.76-2.79 (2H, m), 2.97 (2H, t, J = 6.0 Hz), 3.04 (2H, t, J = 6.0 Hz), 3.61-3.67 (4H, m), 3.72 (2H, q, J = 6.0 Hz), 6.56 (1H, brs), 6.96 (1H, d, J = 7.6 Hz), 7.05- 7.17 (3H, ra), 7.37-7.41 (1H, m), 7.44-7. 9 (2H, m), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.77-7.80 (2H , m), 9.06 (1H, brs).

Example 29 5- [2- [(4-Bifuwe two Rirukarubo two Honoré) Amino] Echiru] - N-(3 - Fuenoki sheet 2 thiomorpholinopropyl) - 1,2, 4 - Okisajiazoru - 3- Karubokisami de in the same manner as in example 1, 2, the title compound was obtained using 2-Ziv instead enyl E chill § Min (3-phenoxy-2-thiomorpholinopropyl) Amin. 52% yield.

Mp 136- 137 ° C (crystallized from acetic Echiru / Jefferies chill ether).

^ NMR (DMS0-d 6) δ 2.46-2.56 (4Η, ra), 2.76-2.85 (2H, m), 3.01-3.09 (2H, ra), 3.10-3.19 (1H, m), 3.30 (2H, t , J = 5.0 Hz), 3.33-3.41 (1H, m), 3. 6-3.56 (1H, m), 3.73 (2H, q, J = 4.7 Hz), 3.98 (1H, dd, J = 3.8, 7.7 Hz), 4.11 (1H, dd, J = 5.0, 7.7 Hz), 6.90-6.97 (3H, m), 7.24-7.32 (2H, m), 7.41 (1H, t, J = 5.6 Hz), 7.49 (2H , t, J = 5.7 Hz), 7.72 (2H, d, J = 5.1 Hz), 7.77 (2H, d, J = 6.6 Hz), 7.90 (2H, d, J = 6.3 Hz), 8.73-8.81 (2H , m).

EXAMPLE 30 N-(2-Benzyl - 3 - phenylpropyl) - 5- [2- [(4-Bifuwe two Rirukaru Poniru) Amino] Echiru] -1, 2, 4 - Okisajiazoru - 3 - Karubokisami de

In the same manner as in Example 3, 4, 2 instead of 4-diphenyl Petit Rua Min hydrochloride - benzyl -. 3 Fuwenirupuropiru was used to obtain the title compound Amin hydrochloride. 93% yield.

(Crystallized from hexane / acetic acid Echiru to) mp 127- 128 ° C.X H NMR (CDCI3) δ 2.28-2.38 (1H, m), 2.62 (2H, dd, J = 7.6, 13.9 Hz) ,. 2.71 (2H, dd, J = 6.6, 13.9 Hz), 3.31 (2H, t , J = 6.1 Hz), 3.44 (^ H, t, J = 6.1 Hz), 3.97 (2H, q, J = 6.1 Hz), 6.70 (1H, t, J = 6.1 Hz), 6.83 (1H, t, J = 6.0 Hz), 7.16-7.21 (6H, ra), 7.23-7.29 (4H, m), 7.37-7.41 (IE m), 7.43-7.48 (2H, m), 7.56-7.59 (2H ,. m) , 7.62-7.66 (2H, m), 7.81-7.85 (2H, m).

Example 3 1 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2-off: nil Echiru) -1, 2, 4-Okisajiazoru 3- force Rupokisami de

In the same manner as in Example 2, 3, the title compound was obtained using Hue Nechiruamin instead of 3-diphenyl-propyl § Min. 93% yield.

Mp 199- 200 ° C (crystallized from Asetonitoriru).

X H NMR (DMS0-d 6 ) δ 2.84 (2Η, t, J = 7.5 Hz), 3.28 (2H, t, J = 6.6 Hz), 3.46-3.51 (2H, m), 3.72 (2H, q, J = 6.3 Hz), 7.17-7.23 (3H, m), 7.26- 7.30 (2H, m), 7.39-7.43 (1H, m), 7.48-7.52 (2H, m), 7.72-7.74 (2H, m), 7.76-7.80 (2H, m), 7.89-7.92 (2H, m), 8.78 (1H, t, J = 5.5 Hz), 9.04 (1H: t, J = 5.6 Hz).

EXAMPLE 32 5 - [2- [(4 - Bifuwe two Lil carbonyl) Amino] Echiru] - N - (2-Fuweniru propyl) - 1, 2, 4-Okisajiazoru - 3- Karubokisami de

In the same manner as in Example 2, 3, instead of 3-diphenyl-propyl § Min - to give the title compound with methyl full phenethyl Rua Min. 89% yield.

Mp 159 - 160 ° C (recrystallized from acetic acid Echiru).

lH NMR (CDC1 3) δ 1.34 (3Η, d, J = 7.1 Hz), 3.02-3.10 (1H, m), 3.30 (2H, t, J = 6.1 Hz), 3.50 (1H, ddd, J = 5.4, '8.4, 13.6 Hz), 3.76-3.83 (1H, m) 3.96 (2H, q, J = 6.2 Hz), 6.77-6.83 (2H, m), 7.22-7.26 (3H, m), 7.31- 7.35 (2H , m), 7.37-7.41 (1H, m), 7.44-7.49 (2H, m), 7.59-7.62 (2H, m), 7; 64-7.67 (2H, ra), 7.80-7.83 (2H, m) .

EXAMPLE 33 5 - [2 - [(4 - Biff We lily ylcarbonyl) Amino] Echiru] - N-(2-Moruhori Bruno - 2 - Fueniruechiru) -1, 2, 4 - Okisajiazoru 3- Karubokisami de

In the same manner as in Example 2, 3, 2 instead of 3-diphenyl-propyl § Min - mode Ruhorino - the title compound was obtained using 2 full We sulfonyl E chill § Min. 63% yield. ., Mp 1 52 -1 53 ° C (crystallized from acetic Echiru).Four

NMR (CDC1 3) δ 2.39-2.47 ( 2H, m), 2. 8-2.53 (2Η, m), 3.34 (2Η, t, J = 6.1 Hz), 3.60 (1H, dd, J = 6.4, 7.3 Hz ), 3.65-3.73 (4H, m), 3.78 (1H, td, J = 5.9, 13.9 Hz), 3.90 (1H, ddd, J = 4.7, 7.7, 13.9 Hz), 3.99 (2H, q, J = 6.2 Hz), 6.81 (1H, t, J = 5.7 Hz), 7.21-7.41 (7H, m), 7.45-7.49 (2H, ra), 7.59-7.62 (2H, ra), 7.64-7.68 (2H, m) , 7.81-7.84 (2H, m).

Example 34 N - [2- [3 - [[(2 - morpholino - 3-phenoxyethanol propyl) Amino] carbonylation Le] - 1, 2, 4-Okisajiazoru - 5-I le] Echiru] -4- phenylalanine piperidine - 1-carboxylate Kisami de

[2 - [3- [[(2-morpholino - 3 full We Roh hydroxypropyl) Amino] carbo sulfonyl] - 1, 2, 4-O Kisajiazoru 5-I le] Echiru] Karupamin acid tert- heptyl ( 250 mg, 0.525 mmol) in dichloromethane (2 mL) was added Torifuruoro acetate (1 mL) added and the resulting et be mixture was stirred for 30 minutes at room temperature. The reaction was diluted with dichloromethane, washed with 1 M aqueous oxidation Natoriumu solution and saturated brine, dried over sulfate Natoriumu, and concentrated under reduced pressure.

The resulting residue and Ν, Ν- diisopropyl E chill § Min (0.101 mL, 0.578 mmol) carbonate New in Asetonitoriru (3 mL) solution of, Nyu'- disuccinimidyl I succinimidyl (148 rag, 0.578 mmol) to 0 ° It was added portionwise at C. After 1 hour, 4-phenylene Rubiperijin (93.2 mg, 0.578 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with acetic acid E Ji Le, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (acetic Echiru) to give the title compound (169 mg, 57% yield).

Amorphous.

XH NMR (CDC1 3) δ 1.58-1.69 (2H, m), 1.81-1.89 (2Η, m), 2.62-2.70 (3Η, m), 2.83-2.90 (4H, m), 3.07-3.13 (1H, m ), 3.25 (2H, t, J = 6.1 Hz), 3.48-3.55 (1H, ra), 3.68-3.80 (6H, m), 3.85 (1H, td, J = 6.1, 13.9 Hz), 4.03-4.08 ( 3H, ra), 4.17 (1H, dd, J = 5.5, 9.9 Hz), 5.13 (1H, t, J = 5.7 Hz), 6.90-6.93 (2H, m), 6.97-7.01 (1H, m), 7.18 -7.23 (3H, ra), 7.28-7.33 (4H, m), 7.68 (1H, dd, J = 3.4, 6.0 Hz), example 35 N- [2- [3- [[(2 -. morpholino - 3 Fuenokishipu port pills) Amino] force έ Lupo two Le] - 1, 2, 4-Okisajiazo Ichiru - 5-I le] Echiru] -4-phenylene Rubiperajin - 1- force Lupo Kisami de

In the same manner as in Example 34, 4-Hue. Using Bok phenyl piperazine instead of two Rubiperijin give the title compound. 72% yield.

Amorphous.

X H NMR (CDC1 3) δ 2.63-2.68 (2H, m), 2.84-2.89 (2Η, m), 3.07-3.20 (5H, ra), 3.25 (2H, t, J = 6.0 Hz), 3.48-3.55 (5H, m), 3.68-3.80 (6H, m), 3.85 (1H, td, J = 6.1, 13.9 Hz), 4.06 (1H, dd, J = 5.5, 9.9 Hz), 4.17 (1H, dd, J = 5.5, 9.9 Hz), 5.23 (1H, t, J = 5.9 Hz), 6.87-6.94 (5H, m), 6.97-7.01 (1H, m), 7.25-7.33 (4H, m), 7.69 (1H, dd, J = 3.3, 6.0 Hz).

Example 36 5- [2- [(4 - Bibuwe two Lil carbonyl) Amino] Echiru] - N-[(. Jifuwe Niruamino) 2 Echiru] -1, 2, 4_ Okisajiazoru - 3- Karubokisami de

In the same manner as in Example 3, 4, N instead of 4 Jifue two Rubuchiruamin hydrochloride, N- Jifuweniruetan - to give the title compound using 1,2 Jiamin hydrochloride. Yield 88 ° N mp 172- 173 ° C (hexane / Tetra. Recrystallization from human Dorofuran).

! H NMR (CDC1 3) δ 3.32 (2Η, t, J = 6.0 Hz), 3.73 (2H, q, J = 6.5 Hz), 3.95-4.01 (4H, m), 6.80 (1H, t, J = 6.0 Hz), .6.94-6.98 (1H, m), 7.02- 7.05 (4H, m), 7.11 (1H, t, J = 5.7 Hz), 7.23-7.28 (5H, m), 7.37-7.41 (1H: m ), 7.44-7.48 (2H, m), 7.58-7.60 (2H, m), 7.62-7.65 (2H, m), 7.80-7.83 (2H, ra).

Example 37 5- [2- [(4-Bifuwe two Lil force Ruponiru) Amino] Echiru] - N-(2, 3-Jifue Nirupuropiru) - 1,2, 4-Okisajiazoru - 3- Karubokisami de

In the same manner as in Example 3, 4,4-diphenyl We sulfonyl butyl § Min 2 instead of hydrochloride, the title compound was obtained using 3-diphenyl-propyl § Min hydrochloride. 83% yield.

Mp 179-180 ° C (crystallized from hexane / acetic acid Echiru to).

NMR (CDCI3) δ 2.94-3.04 (2H, m), 3.17-3.25 (1Η, m), 3.27 (2Η, t, J = 6.0 Hz), 3.61 (1H, ddd, J = 5.3, 8.8, 13.8 Hz) , 3.88 (1H, dd, J = 6.6, 13.2 Hz), 3.94 (2H, q, J = 5.8 Hz), 6.69 (1H, t, J = 5.7 Hz), 6.79 (1H t, J = 6.0 Hz), 7.07-7.08 (2H, m), 7.13-7.23 (6H, m), 7.27-7.31 (2H, m), 7.37-7.41 (1H, m), 7.45-7.49 (2H, m), 7.58-7.61 (2H , m), 7.64-7.67 (2H, ra), 7.79-7.82 (2H, m).

EXAMPLE 38 5 - [2 - [(4-Bifue two Lil carbonyl) Amino] Echiru]-N-[3 - [(methylation) (phenyl) Amino] propyl] - 1,2,4 Okisajiazoru - 3 - in a similar manner to that Karubokisami de example 2, 3, 3-diphenyl: instead of sulfonyl propylamine N- (3- Aminopuropiru) -N - Mechirua using diphosphorus give the title compound. Yield 95%. Mp 179- 180 ° C (recrystallized from hexane / acetic acid Echiru to).

XH NMR (CDC1 3 + DMS0 - d 6) δ 1.89-1.96 (2Η, m), 2.92 (3Η, s), 3.32 (2Η, t: J = 6.3 Hz), 3.41 (2H, t, J = 6.8 Hz ), 3.52 (2H, q, J = 6.8 Hz), 3.95 (2H, q, J = 6.3 Hz), 6.69-6.75 (3H, m), 7.20-7.24 (2H, m), 7.33 (1H, t, J = 5.7 Hz), 7.37-7.48 (4H, ra), 7.59-7.65 (4H, m), 7.85 (2H, d, J = 8.3 Hz).

Example 3 9 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N_ [2- (3, 4 - di arsenide Dorokinorin -1 (2H) - I le) Echiru] -1, 2 in the same manner as 4-Okisajiazoru 3 Karubokisami example 3, 4, 4-diphenyl We sulfonyl butyl § Min hydrochloride instead of 2- (3, 4 dihydric Dorokinorin - 1 (2H) - I le) It was used to obtain the title compound Echiruamin dihydrochloride. 51% yield.

Mp 129- 130 ° C (crystallized from hexane / acetic acid Echiru to).

lR NMR (CDC1 3) δ 1.92-1.98 (2H, m), 2.76 (2Η, t, J = 6.4 Hz), 3.30-3.34 (4H, m), 3.53 (2H, t, J = 6.5 Hz), 3.70 . (2H, q, J = 6.3 Hz), 3.97 (2H, q: J = 6.1 Hz), 6.60 (1H, dt, J = 1.0, 7.3 Hz), 6.68 (1H, d, J = 8.3 Hz), 6.79 (1H, t, J = 6.0 Hz), 6.94-6.97 (1H, m), 7.02-7.07 (1H, m), 7.12 (1H: t, J = 5.7 Hz), 7.37-7.41 (1H, m) , 7. 4-7.49 (2H, m), 7.58-7.61 (2H, ra), 7.64-7.67 (2H, m), 7.80-7.83 (2H, m).

Example 4 0 5- [2- [(4-Biff We lilies Luke Lupo sulfonyl) § Mi Bruno] Echiru] - N- [2- (2, 3, 4, 5- Tetorahi mud - IH-1-Benzuazepin-1- I le) Echiru] -1, 2, 4 - Okisaji Azoru - 3- Karubokisami de

In the same manner as in Example 2, 3, 3 - 2 to Ri jib E nil propylamine instead ¾ - (2, 3, 4, 5-Tetorahi mud - IH-1-Benzuazepin-1-Inore) using Echiruamin to give the table title compound. Yield 81%.

Mp 140_141 ° C (crystallized from acetic Echiru). -

J H NMR (CDC1 3) δ 1.57-1.63 (2H, m), 1.70-1.76 (2H, m), 2.83-2.86 (2H, m), 2.92-2.95 (2H, m), 3.30-3.34 (2H, m), 3.40 (2H, t, J = 5.9 Hz), 3.64 (2H, q, J = 5.5 Hz), 3.99 (2H, q, J = 6.1 Hz), 6.80 (1H, t, J = 6.0 Hz) , 6.92 (1H, dt, J = 1.2, 7.3 Hz), 6.97 (1H, dd, J = 1.2, 7.6 Hz), 7.12 (1H: dd, J = 1.5, 7.3 Hz), 7.16 (1H, dt, J = 1.5, 7.6 Hz), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.53 (1H, t, J = 4.9 Hz), 7.58-7.64 (4H, m), 7.78- 7.81 ( 2H, m).

Example 41 5_ [3- [(4-Bifuwe two Lil carbonyl) Amino] propyl] - N-(2-Moruho Reno - 3- phenoxyethanol propyl) - 1,2, 4 - Okisajiazo Ichiru - 3 - Power Rupokisami de

In the same manner as in Example 1, 5- [2- [(4 - Bifuwe two Lil carbonyl) Amino] E chill] -1,2, 4-Okisajiazoru - 5 in place of 3-carboxylic acid Echiru [3- [(4-Bifue two Lil carbonyl) Amino] propyl] -1, 2, 4 - the Okisajiazoru 3-carboxylic Sane chill, 2, instead of 2-diphenyl E chill § Min 2 - morpholino - 3 - Fuenokishipu to give the title compound using mouth Piruamin. Yield: 70%.

Amorphous.

J H NMR (DMS0-d 6 ) δ 2.01-2.12 (2Η, ra), 2.53-2.63 (2Η, m), 2.70-2.79 (2Η, m), 3.03-3.14 (3Η, ra), 3.36-3.46 ( 3Η, m), 3.47-3.58 (5H, ra), 4.02 (1H, dd, J = 3.3, 7.5 Hz), 4.13 (1H, dd, J = '4.7, 7.7 Hz), 6.89-6.97 (3H, m ), 7.23-7.31 (2H, m), 7.41 (1H, t, J = 5.6 Hz), 7.50 (2H, t, J = 5.7 Hz), 7.30 (2H, d, J = 5.7 Hz), 7.77 (2H , d, J = 6.3 Hz), 7.93 (2H, d, J = 6.3 Hz), 8.62 (1H, t, J = 4.2 Hz), 8.78 (1H, t, J = 4.4 Hz).

Example 42 5- [2 - [(4 - Bifuwe - Lil carbonyl) Amino] Echiru] - 4-methyl - N-(2-morpholino - 3 - phenoxyethanol propyl) - 4H - 1, 2, 4-triazole - 3-force Rupokisami de, in the same manner as in example 1 7, [2 - [3- [[(2 - heat Dorokishi - 3 - phenoxyethanol propyl) Amino] carbonyl] -1, 2, 4 - Okisajiazoru - 5-I le] Echiru] force Luba phosphate tert - [2-[4-methyl - 5- [[(2 - morpholino - 3 - Fuwenokishipuropi) amino] carbo sulfonyl] - instead of heptyl 4H-1 , 2, 4-Toriazoru - to give the title compound using 3-I le] Echiru] tert carbamate heptyl. 86% yield.

(Crystallized from hexane / acetic acid Echiru to) mp 157- 158 ° C.

X H NMR (CDC1 3) δ 2.65-2.69 (2Η, ra), 2.85-2.90 (2H, m), 3.04-3.15 (3H, m), 3.43-3.50 (1H, ra), 3.70-3.83 (5H, m), 3.94 (3H, s), 4.03-4.10 (3H, m), 4.16-4.19 (1H, m), 6.91 (2H, d, J = 8.0 Hz), 6.97 (1H, t, J = 7.6 Hz ), 7.27-7.31 (2H, m), 7.38-7.42 (2H, m), 7.44-7.48 (2H, m), 7.60 (2H, d, J = 7.6 Hz), 7.64 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 7.97 (1H, brs).

Example 4 3 3- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3- phenoxyethanol propyl) - 1, 2, 4_ Okisajiazo Ichiru - 5 - Karubokisami de

In the same manner as in Example 2, 5 - [2 - [(4 - Bifuwe two Lil carbonyl) Amino] E chill] -1, 2, 4-Okisajiazoru 3- force Rupon instead of acid Echiru 3- [2 - [(4-biphenyl two Rirukaruponiru) amino] Echinore] -1, 2, 4-Okisajiazoru - 5-carboxylic acid E Chi le, 3, 3 - diphenyl-propyl § Min instead 2 - morpholino - 3- It was used to obtain the title compound Fuenokishipu port Piruamin. Yield 97 ° / 0.

(Crystallized from hexane / acetic acid Echiru to) mp 155- 156 ° C.

^ NMR (CDC1 3) δ 2.62-2.67 (2Η, m), 2.83-2.88 (2H, m), 3.06-3.13 (1H, m), 3.21 (2H, t, J = 6.1 Hz), 3.48-3.55 ( 1H, m), 3.66-3.76 (4H, m), 3.85 (1H, ddd, J = 5.6, 6.5, 14.2 Hz), 3.96 (2H, q, J = '6.2 Hz), 4.06 (1H, dd, J = 5.6, 9.8 Hz), 4.18 (1H, dd, J = 5.1, 9.8 Hz), 6.88 (1H, t, J = 5.7 Hz), 6.89-6.93 (2H, m), 6.99 (1H, t, J = 7.3 Hz), 7.28-7.33 (2H, m), 7.37-7.41 (1H, m), 7.44-7.48 (2H, ra), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.79 -7.85 (3H, ra).

Example 44 3- [2- [(4 - Bibuwe two Lil carbonyl) Amino] Echiru] - N-(2, 2-Jifue two Ruechiru) - 1, 2, 4-Okisajiazoru - with 5 Karubokisami de Example 2 by the same method, 5- [2- [(4-Bifuwe - Lil carbonyl) Amino] -. chill] - 1, 2, 4 - Okisajiazoru-3 in place of the carboxylic acid Echiru 3- [2- [(4 - 4 biphen two Lil carbonyl) amino] Echiru] - 1, 2, 4-Okisajiazoru - 5 - forces carboxylic acid E Ji Honoré, 3, 3-Jifue two Le prop Honoré 2 instead of the amine, 2- Jifueninore It was used to obtain the title compound Echinoreamin. Yield 95%. -

Mp 196- 197 ° C (recrystallized from hexane / as tetrahydrofuran to).

XH NMR (CDC1 3) δ 3.11 (2H, t, J = 6.2 Hz), 3.89 (2H, q, J = 6.1 Hz), 4.10 (2H, dd, J = 6.1, 7.8 Hz), 4.30 (1H, t , J = 7.8 Hz), 6.63 (1H, t, J = 5.7 Hz), 6.99 (1H, t, J = 5.4 Hz), 7.22-7.27 (6H, m), 7.31-7.35 (4H, m), 7.37 -7.41 (1H, m), 7.45-7.49 (2H, m), 7.59-7.62 (2H, ra), 7.63-7.66 (2H, m), 7.78-7.82 (2H, m).

Example 45 3 - [2 _ [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N - (3, 3 - Jifue Nirupuropiru) -1, 2, 4-Okisajiazoru - 5 - Karubokisami de

In the same manner as in Example 2, 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] E chill] -1,2, 4-Okisajiazoru - 3 instead of 3-carboxylic acid Echiru [2- [(4-Bifue - Lil carbonyl) Ryo amino] Echiru] - 1, 2, 4-Okisajiazoru - was used to obtain the title compound 5-carboxylic acid E Ji Le. Rate of 90%.

Mp 134- 135 ° C (crystallized from hexane / acetic acid Echiru to).

J H NMR (CDCI3) δ 2.41 (2Η, q, J = 7.6 Hz), 3.15 (2H, t, J = 6.2 Hz), 3. 3-3. 8 (2H, ra), 3.93 (2H, t, J = 6.2 Hz), 3.99 (1H, t, J = 7.8 Hz), 6.65 (1H, t, J = 5.9 Hz), 6.96 (1H, t, J = 5.6 Hz), 7.16-7.20 (2H, m) , 7.23-7.30 (8H, m), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.59-7.61 (2H, m), 7.63-7.66 (2H, m), 7.81-7.84 ( 2H, m).

Example 46 3- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Jifuwe Niruamino) Echiru] -1,2, 4-Okisajiazoru - 5 - Power Rupokisami de

'In the same manner as in Example 3, 5- [2 - [(4 - Bifuwe two Lil carbonyl) Amino] E chill] -1,2, 4-Okisajiazoru - 3 instead of 3-carboxylic acid Echiru [2 - [(4-Bifue two Rirukarubo - Le) Amino] Echiru] - 1, 2, 4-Okisajiazoru 5-carboxylic acid E Ji Honoré, 4, 4 - diphenyl We sulfonyl Petit Rua Ν instead Min hydrochloride, Ν- Jifuweniruetan - to give the title compound using 1,2 Jiamin hydrochloride. 89% yield. - mp 180-181 ° C (recrystallized from acetic acid Echiru). s

X H NMR (CDC1 3) δ 3.15 (2Η, t, J = 6.2 Hz), 3.73 (2H, q, J = 6.4 Hz),

3.92 (2H, q, J = 6.1 Hz), 4.00 (2H, t, J = 6.5 Hz), 6.64 (1H, t, J = 6.0 Hz), 6.95-6.99 (2H, m), 7.01-7.04 (4H -, m), 7.22-7.29 (5H, ra), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.58-7.61 (2H, m), 7.62-7.65 (2H, m), 7.80- 7.83 (2H, m).

Example 47 3- [2 - [(4-Biff two Lil carbonyl) Amino] Echiru] - N-[2 - (3, 4-di heat Dorokinorin - 1 (2H) - I le) Echiru] - 1, 2 , 4 Okisajiazo Ichiru - 5 - Karubokisami de

In the same manner as in Example 3, 5 - [2 - [(4-Bifuwe two Lil carbonyl) amino] E chill] - 1, 2,4 Okisajiazoru - 3 instead of 3-carboxylic acid Echiru [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] -1, 2, 4-Okisajiazo Ichiru - 5-carboxylic acid E Chi le, 4, 4-diphenyl We sulfonyl Petit Rua Min 2 instead of hydrochloride - (3, 4 dihydric Dorokinorin - 1 (2H) _ I le) Echiruamin using dihydrochloride to give the title compound. Yield 81%.

Mp 140- 141 ° C (recrystallized from hexane / acetic acid Echiru to).

X H NMR (CDCI3) δ 1.92-1.98 (2Η, m), 2.76 (2H, t, J = 6.5 Hz), 3.14-3.17 (2H, m), 3.30-3.32 (2H, ra), 3.53 (2H, t, J = 6.5 Hz), 3.69 (2H, q, J = 6. Hz), 3.92 (2H, q, J = 6.3 Hz), 6.59-6.67 (3H, m), 6.94-6.97 (1H, m) , 7.02-7.06 (1H, m), 7.24-7.28 (1H, m), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.58-7.61 (2H, ra), 7.63-7.66 ( 2H, m), 7.80-7.83 (2H, m).

EXAMPLE 4 8 3- [2- [(4-Bifuwe two Lil carbonyl) § Mi Bruno] Echiru] - N- [2- (2, 3, 4,5- Tetorahi mud - IH-1 - Benzuazepin - 1 - I le) Echiru] - 1,2, 4 - Okisaji Azoru - 5- Karubokisami de

In the same manner as in Example 2, 5 - [2 - [(4 - Bifuwe two Lil carbonyl) Amino] E chill] - 1, 2, 4-Okisajiazoru - 3 instead of 3-carboxylic acid Echiru [2- [(4-Bifue two Rirukaruponiru) Ryo amino] Echiru] - 1, 2, 4-Okisajiazoru - 5-carboxylic acid E Chi le, 3,3-diphenyl-propyl § Min instead of 2- (2,3 , 4, 5 Tetorahi mud - the title compound was obtained using 1-I le) Echiruamin - 1H-1- Benzuazepin. 83% yield. Mp 126 - 127 ° C (recrystallized from hexane / acetic acid Echiru to).- J H NMR (CDCI3) δ 1.59 - 1.65 (2Η, ra), 1.71-1.76 (2H, m), 2.83-2.8,6 (2H, m), 2.93-2.95 (2H, m), 3.15-3.18 ( 2H, ra), 3.41 (2H, t, J = 5.9 Hz), 3.63 (2H, q, J = 5.5 Hz), 3.94 (2H, q, J = 6.1 Hz), 6.65 (1H, t, J = 5.9 Hz), 6.92-6.97 (2H, m), 7.13-7.19 (2H, m), - 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.58-7.65 (5H, ra), 7.79 -7.82 (2H, m).

Example 49 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3- phenoxyethanol propyl) - 1, 3, 4 Okisajiazoru - 2- Karubokisami de

In the same manner as in Example 3, 5 - [2 - [(4 - Bifuwe two Lil carbonyl) Amino] E chill] _1, 2, 4-Okisajiazoru - instead of 3-carboxylic acid Echiru 5- [2- [ (4 Bifue two Lil carbonyl) Amino] Echiru] - 1, 3, 4 Okisajiazoru-2-carboxylic acid E Chi le, 4,4-diphenyl We sulfonyl Petit Rua Min hydrochloride instead of 2-morpholino salt - 3 - to give the title compound using Fuenoki shea propyl § Min dihydrochloride. 59% yield.

Mp 137_138 ° C (crystallized from hexane / acetic acid Echiru to).

! H NMR (CDCI3) δ 2.63-2.68 (2Η, m), 2.85-2.90 (2H, m), 3.07-3.14 (1H, m), 3.29 (2H, t, J = 5.9 Hz), 3.51 (1H, ddd, J = 3.5, 9.6, 13.8 Hz), 3.69-3.79 (4H, m), 3.85 (1H, ddd, J = 5.6, 6.6, 13.8 Hz), 4.00-4.08 (3H, m), 4.18 (1H, dd, J = 5.6, 9.8 Hz), 6.89-6.93 (2H, m), 6.97-7.00 (2H, m), 7.28-7.33 (2H, ra), 7.37-7.41 (1H, ra), 7.45-7.49 ( 2H, m), 7.59-7.62 (2H, m), 7.65-7.68 (2H, m), 7.80-7.87 (3H, m).

Example 50 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Jifuwe Niruamino) Echiru] - 1, 3, 4 - Okisajiazoru - 2- Karubokisami de

In the same manner as in Example 3, 5- [2 - [(4-Bifue two Lil carbonyl) Amino] E chill] -1,2, 4-Okisajiazoru - 5 in place of 3-carboxylic acid Echiru [2- [(4-Bifue Nirirukaruponiru) Amino] Echiru] - 1, 3, 4 Okisajiazoru-2-carboxylic acid E Chi le, 4, 4-diphenyl N instead of enyl butyl § Min hydrochloride, N- Jifueniruetan - 1, the title compound was obtained using 2-Jiamin hydrochloride. 89% yield.

Mp 203_204 ° C (recrystallized from acetic acid Echiru).

X H NMR (CDClg) δ 3.27 (2Η, t, J = 5.9 Hz), 3.73 (2H, q, J = 6.5 Hz), 3.98-4.02 (4H, m), 6.92-6.99 (3H, m), 7.02 -7.05 (4H, m), 7.25-7.30 (5H,. m), 7.37-7.41 (1H, m), 7.44-7.48 (2H, m), 7.58-7.61 (2H, m), 7.6 ^ -7.67 ( 2H, m), 7.82-7.86 (2H, m).

Example 5 1 5- [2- [(4 - bib; n two Lil carbonyl) Amino] Echiru] - N-(2, 2 - Jibuwe - Ruechiru) -1, 3, 4 Okisajiazoru - 2- Karubokisami de

In the same manner as in Example 2, 5 - [2- [(4-Bifuwe - Lil carbonyl) Amino] E chill] -1,2,4 Okisajiazoru - 5 in place of 3-carboxylic acid Echiru [2- [(4-Bifue two Rirukaruponiru) Amino] Echiru] _1, 3, 4 - Okisajiazo Ichiru - 2-carboxylic acid E Chi le, 3, 3-diphenyl-propyl § Min 2 instead of 2- Jifue two It was used to obtain the title compound Ruechiruamin. Yield 90%.

Mp 198- 199 ° C (recrystallized from hexane / as tetrahydrofuran to).

XH NMR (CDC1 3) δ 3.24 (2Η, t, J = 6.0 Hz), 3.98 (2H, q, J = 6.3. Hz), 4.11 (2H, dd, J = 6.0, 7.9 Hz), 4.29 (1H, t, J = 7.9 Hz), 6.90 (1H, t, J = 6.0 Hz), 7.00 (1H, t, J = 5.7 Hz), 7.22-7.28 (6H, m), 7.31-7.35 (4H, in), 7.37-7.41 (1H, m), 7.45-7.48 (2H, m), 7.58-7.61 (2H, m), 7.63-7.66 (2H, m), 7.81-7.84 (2H, m).

Example 52 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(3,3-Jifuwe Nirupuropiru) - 1, 3, 4 Okisajiazoru - 2- Karubokisami de

In the same manner as in Example 2, 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] E chill] -1,2, 4-Okisajiazoru - 3- force Rupon instead of acid Echiru 5- [2 - [(4-Bifue two Lil carbonyl) Amino] Echiru] - 1, 3, 4 - Okisajiazo Ichiru - 2 - using a force carboxylic acid E Chi le to give the title compound. The yield 95¾.

Mp 157- 158 ° C (crystallized from acetic Echiru). -

J H NMR (CDCI3) δ 2.41 (2H, q, J = 7.6 Hz), 3.27 (2H, t, J = 5.9 Hz), 3.44 (2H, q, J = 6.6 Hz), 3.98-4.02 (3H, m ), 6.92 (1H, t, J = 5.9 Hz), 7.00 (1H, t, J = 5.9 Hz), 7.16-7.21 (2H, m), 7.24-7.31 (8H, m), 7.37- 7.41 (1H, m), 7.44-7.48 (2H, ra), 7.59-7.61 (2H, m), 7.64-7.67 (2H, m), 7.83-7.86 (2H, m).

Example 5 3 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (3, 4 - di heat Dorokinorin - 1 (2H) - I le) Echiru] - 1, 3, 4 - Okisajiazoru - 2 - Karubokisami -. de, in the same manner as ί example 3, 5- [2 - [(4-Bifuwe two Lil carbonyl) Amino] E chill] - 1, 2, 4_ Okisajiazoru - 5 instead of 3-carboxylic acid Echiru [2- [(4-Bifue lily ylcarbonyl) amino] Echiru] - 1, 3, 4 Okisajiazoru - 2-carboxylic acid E Ji Le, 4, 4- Jifuwe 2 instead of Nirupuchiruamin hydrochloride - (3, 4 dihydric Dorokinorin - 1 (2Ita) - I le) to give the title compound using Echiruamin dihydrochloride. 71% yield.

Mp 173- 174 ° C (recrystallized from acetic acid Echiru).

^ NMR (CDC1 3) δ 1.93-1.99 (2H, m), 2.77 (2H, t, J = 6.4 Hz), 3.26-3.29 (2H, m), 3.31-3.34 (2H, m), 3.53 (2E, t, J = 6.5 Hz), 3.70 (2H, q, J =

6.4 Hz), 4.00 (2H, q, J = 6.0 Hz), 6.61 (1H, dt, J = 1.0, 7.3 Hz), 6.67

(1H, d, J = 8.3 Hz), 6.92-6.97 (2H, m), 7.03-7.07 (1H, m), 7.28 (1H, t,

J = 6.1 Hz), 7.37-7.41 (1H, m), 7.44-7.49 (2H, m), 7.59-7.62 (2H, m),

7.64-7.67 (2H, m), 7.82-7.85 (2H, m).

Example 5 4 5- [2 - [(4-Bifuwe two Lil carbonyl) § Mi Bruno] Echiru] - N-[2-

(2, 3, 4, 5 Tetorahi mud - IH-1-Benzuazepin-1-I le) Echiru] -1, 3, 4 Okisaji Azoru - 2- Karubokisami de

In the same manner as in Example 2, 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] E chill] -1,2, 4-Okisajiazoru 3-force Rupon acid Echiru Instead 5- [2 - [(4-biphenyl Yurirukaruponiru) Amino] Echiru] - 1, 3, 4 Okisajiazo Ichiru - 2 - a force carboxylic acid E Chi le, 3, instead of 3-diphenyl-propyl § Min 2- (2 , 3, 4, 5 Tetorahi mud - 1H-

1- Benzuazepin - using 1-I le) Echiruamin give the title compound. Yield 91 ° / 0. (Crystallized from hexane / acetic acid Echiru to) mp 136- 137 ° C.

'Η NMR (CDC1 3) δ 1.59-1.65 (2Η, m), 1.72-1.78 (2H, m), 2.85-2.88 (2H, m), 2.93-2.96 (2H, m), 3.25-3.28 (2H, m), 3.39-3.42 (2H, m), 3.63 (2H, q, J = 5.5 Hz), 4.00 (2H, q, J = 6.1 Hz), 6.92-6.97 (3H, ra), 7.14-7.19 (2H , m), 7.37-7.41 (1H, m), 7.44 7.48 (2H, m), 7.59-7.62 (3H, m), 7.63-7.67 (2H, m), 7.82-7.85 (2H, m).

Example 55 5_ [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3 - phenoxyethanol propyl) - 1,3, 4-thiadiazol-2 - Karubokisami de, in the same manner as in example 2, 5- [2- [(4-Bifue two Lil carbonyl) § Bruno] E chill] - 1, 2, 4-Okisajiazoru - 3- force instead of Rupon acid Echiru 5- [ 2- [(4-Bifue two Rirukaruponiru) Amino] Echiru] - 1, 3, 4-thiadiazole - 2- carboxylic acid Echiru, 3, 2 instead of 3-diphenyl-propyl § Min - morpholino - 3- Fuenokishipuro It was used to obtain the title compound Piruamin. Yield 81%.

Mp 165 - 166 ° C (recrystallized from acetic acid Echiru).

X H NMR (CDC1 3) δ 2.65-2.70 (2Η, m), 2.86-2.91 (2H, m), 3.09-3.15 (1H, m), 3.49-3.56 (3H, m), 3.70-3.80 (4H, m), 3.85 (1H, ddd, J = 5.6, 6.6, 13.9 Hz), 4.00-4.08 (3H, m), 4.19 (1H, dd, J = 5.4, 9.8 Hz), 6.91-7.00 (4H, ra) , 7.27-7.33 (2H, m), 7.37-7.41 (1H, m), 7.45-7.49 (2H, m), 7.59- 7.62 (2H, ra), 7.65-7.68 (2H, m), 7.84-7.87 ( 2H, m), 7.97 (1H, dd ,. J = 3.5, 6.0 Hz).

Example 56 5- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-(2, 2-Jifue two Ruechiru) - 1, 3, 4-thiadiazol-2-Karubokisami de

In the same manner as in Example 2, 5 - [2- [(4-Bifuwe two Lil carbonyl) Amino] E Chill] - 1,2, 4-Okisajiazo Ichiru - - instead of the carboxylic acid Echiru 5- [2 - [(4-Bifue two Rirukaruponiru) Amino] Echiru] - 1, 3, 4-thiadiazol-2-carboxylic acid Echiru, 3, 3-diphenyl 2 instead of enyl propylamine, 2-diphenyl E naphthylamine There use the to give the title compound. 96% yield.

Mp 223- 224 ° C (recrystallized from as tetrahydrofuran).

: H NMR (CDCI3) δ 3.45 (2H, t, J = 6.0 Hz), 3.97 (2H, q, J = 5.9 Hz), 4.11 (2H, dd, J = 6.1, 7.8 Hz), 4.31 (1H, t , J = 7.8 Hz), 6.91 (1H, t, J = 5.7 Hz), 7.21-7.29 (7H, m), 7.31-7.35 (4H, m), 7.37-7.41 (1H, m), 7.45-7.49 ( 2H, m), 7.59-7.62 (2H, m), 7.63-7.66 (2H, m), 7.81-7.84 (2H, m).

Example 57 5- [2 - [(4 - Bifuwe two Lil carbonyl) Amino] Echiru] - N-(3,3-Jifue Nirupuropiru) - 1, 3, 4-thiadiazol-2-Karubokisami de

In the same manner as in Example 2, 5- [2 - [(4 - Bifuwe two Lil carbonyl) Amino] E chill] - 1, 2, instead of 4 Okisajiazoru -3_ acid Echiru 5- [2- [(4, Bifue -. two Rirukaruponiru) Amino] Echiru] - 1, 3, 4-thiadiazole - the title compound was obtained using 2-carboxylic acid Echiru. 66% yield.

Mp 220 - 221 ° C (recrystallized from as tetrahydrofuran).

JH NMR (CDClg) δ 2.39-2.44 (2Η, m), 3.41-3.50 (4H, m), 3.97-4.04 (3H, m), 6.95 (1H, t, J = 6.0 Hz), 7.16-7.20 (2H , m), 7.24-7.31 (9H, m), 7.37-7.41 (1H, m), 7.44-7.49 (2H, m), 7.59-7.62 (2H, m), 7.64-7,67 (2H, m) , 7.83-7.86 (2H, m).

Example 58 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Jifuwe Niruamino) Echiru] -1, 3, 4 - thiadiazole-2-Karubokisami de

In the same manner as in Example 3, 5- [2- [(4 - Bifuwe two Lil carbonyl) Amino] E chill] - 1, 2, 4-Okisajiazoru - 3-carboxylic acid instead of 5 Echiru - [2_ [ (4 - Bifue two Lil carbonyl) Amino] Echiru] - 1, 3, 4 - thiadiazole-2-force Rupon acid Echiru, 4, 4-Jifue - N instead of Rubuchiruamin hydrochloride, N- Jifueniruetan - 1, the title compound was obtained using 2-Jiamin hydrochloride. 86% yield.

Mp 206 - 207 ° C (recrystallized from as tetrahydrofuran).

X H NMR (CDC1 3) δ 3.49 (2Η, t, J = 6.0 Hz), 3.73 (2H, q, J = 6.6 Hz), 3.98-4.02 (4H, m), 6.93-6.98 (3H, m), 7.03-7.06 (4H, m), 7.24-7.30 (4H, m), 7.37-7.41 (1H, m), 7. 5-7.50 (3H, ra), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.83-7.86 (2H, m).

EXAMPLE 59 1- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-(2 Moruhori Bruno - 3 - phenoxyethanol propyl)-1H - pyrazol - 4- Karubokisami de

1- [2- [(4-bib We two Lil carbo - Le) Amino] Echiru]-1H-pyrazol-4-force Lupo phosphate (168 mg, 0.500 mmol), 2- morpholino - 3-phenoxyethanol propyl Amin'ni salt salt (170 mg, 0.550 mmol), 1 - [3 - (Jimechiruamino) propyl] - 3-Echirukaru Pojiimi de hydrochloride (115 mg, 0.600 mmol), 1- hydroxycarboxylic benzotriazole (91.9 mg, 0.600 mmol) and Toryechiruamin (0.153 mL, N of 1.10 mmol), the N- dimethylformamidine de (3 mL) was stirred at room temperature for 2 hours. The reaction solution was diluted with acetic acid Echiru, twice with water, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After purification the residue was purified by basic silica gel column chromatography. (Tetra .- hydrofuran), and recrystallized from acetic acid Echiru to give the title compound 208 mg, 75% yield).

Mp 188-189 ° C.

XH NMR (CDC1 3) δ 2.62-2.67 (2Η, m), -2.84-2.89 (2Η, m), 3.04-3.10 (1Η, m), 3.40 (ΙΗ 'ddd, J = 3.2, 9.1, 13.7 Hz) , 3.65-3.80 (5H, m), 3.93-3.97 (2H, m), 4.04 (1H, dd, J = 5.0, 10.0 Hz), 4.15 (1H, dd, J = 5.6, 10.0 Hz), 4.40-4.43 (2H, m), 6.53 (1H, dd, J = 2.9, 6.1 Hz), 6.87-6.92 (3H, m), 6.96-7.00 (1H, m), 7.27-7.32 (2H, m), 7.37-7.41 (1H, m), 7.44-7.49 (2H, ra), 7.59-7.62 (2H, m), 7.64-7.67 (2H, m), 7.81-7.84 (3H, m), 7.85 (1H, s).

EXAMPLE 60 1- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2- (Hue Niruamino) Echiru] -1Ita- pyrazole - 4- Karubokisami de

In the same manner as in Example 59, 2_ morpholino - 3 - N instead of phenoxyethanol propylamine dihydrochloride, N- Jifueniruetan - 1, to give the title of compound using 2-diamine hydrochloride. 84% yield.

Mp 221 - 2 2 2 ° C (recrystallized from tetrahydrofuran down).

X H NMR (DMSO- d 6) δ 3.36-3.41 (2H, m), 3,66 (2H, q, J = 5.8 Hz), 3.76- 3.80 (2H, m), 4.33 (2H, t, J = 6.0 Hz), 6.90-6.94 (2H, m), 7.01-7.04 (4H, m), 7.23-7.28 (4H, m), 7.39-7.43 (1H, m), 7.47-7.51 (2H, m), 7.70 -7.73 (2H, ra), 7.74-7.77 (2H, m), 7.83 (1H, d, J = 0.5 Hz), 7.86-7.91 (2H, m), 8.11 (1H, s), 8.23 ​​(1H, t , J = 5.9 Hz), 8.64 (1H, t, J = 5.6 Hz).

Example 6 1-82

In the same manner as in Reference Example 74-1 3 1, to obtain the desired compound.

Example 83 to: 1 60

+ In the same manner as in Reference Example 1 32-144, to obtain the desired compound.

The structures of the compounds obtained in Examples 1 to 60 shown in Tables 7 to 1 3.



Example No. R 1a Xa R 4

(Optically active form: retention time is small) (optically active form: retention time Univ.)



0

141 Table 1 3

Example No. R 1a ring Aa Xa R 4

The data of structure Contact Yopi Masusu Bae-vector of the compound obtained in Example 6 1-8 2 shown in Table 1 4 Table 1 5.

Example No. R 4 MS (m / Z)

The data structures and Masusu Bae-vector of the resultant I compound in Example 8 3 to 6 0 shown in Table 1 6 Table 2 1.

¾16 7

Example Number R a MS (m / Z)

98 HOCH H 2 OCH 2 CH- 425.2

100 HO (CH 2) 6 - 437.2

441.2

8

Example No. R 1a MS (m / Z)

121 (CH 3 CH 2) 2 NCH, CH 2 - 436.2

9

Example No. R 1a MS (m / Z)

128 448.2

H 3 C ", Roh

129 450.2 130 (C 2 H 5 ) 2 N (CH 2) 3 - 450.2

134 [(CH 3) 2 CH ] 2 NCH 2 CH- 464.3

, CH 3

135 476.3

H 3 C

136 477.3

139 [CH 3 (CH 2) 3] 2 N (CH 2) 3 - 506.3

Table 2 1

Example 1 6 1 2- [2- [(4-Bifuyu two Lil carbonyl) Amino] Echiru] - N-[2- (diphenyl Eniruamino) Echiru] -1, 3-Okisazoru 4- Karubokisami de

2- [2- [(4-bi Hue lily Luke Lupo yl) Amino] Echinore] -1, 3-Okisazoru 4 - Chikararu Bonn acid (169 mg, 0. 500 mmol) and Toryechiruamin (77 ^ L, 0. 550 N of mmol), New to N- dimethylformamidine de (5 mL) solution, New - Jibuweniruetan _1, 2-Jiamin hydrochloride (131 mg, 0. 525 mmol), 1 - Echiru - 3 - (3 - Jimechirua Minopuropiru) Cal Pojiimi de hydrochloride (116 mg, 0. 600 mmol) and 1-hydroxycarboxylic benzotriazole Le (81. 1 mg, 0. 600 mmol) was added at room temperature, the mixture was stirred for 1 hour. The reaction was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and reduced pressure concentrated. Recrystallization from hexane / acetic acid Echiru fart the residue to give the title compound (214 mg, 81% yield).

lH NMR (CDCI3) δ 3.12 ( 2Η, t, J = 6.2 Hz), 3.68 (2H, q, J = 6.;: 6 Hz), 3.91 (2H, q, J = 6.3 Hz), 3.97 (2H, t, J = 6.7 Hz), 6.66 (1H, t, J = 5.4 Hz), 6.92-6.96 (2H, m), 7.02-7.08 (5H, ra), 7.21-7.28 (4H, m), 7.37-7.42 (1H, m), 7.44-7.49 (2H, m), 7.56-7.63 (4H, ra), 7.75-7.78 (2H, m).

Example 162 2- [2 - [(4-Biff: Two Lil carbonyl) Amino] Echiru] - N-(2 Moruho Reno - 3 - phenoxyethanol propyl) - 1, 3 - Okisazoru 4 Karubokisami de

2 - [2- [(4-Biff Eni Riruka Lupo sulfonyl) amino] Echiru] _1, 3- Okisazoru 4 Cal Bonn acid (169 mg, 0.500 mraol) and Toryechiruamin (77 mu L, 0.550 mmol) one N, N - dimethylformamidine de (5 mL) was added 2 - morpholino - 3-phenoxyethanol propyl Amin hydrochloride (163 mg, 0.525 mmol), 1- Echiru - 3 - (3-dimethyl § amino propyl Le) carbodiimide hydrochloride salt (116 mg, 0.600 mmol) and 1-arsenide Dorokishibe / zone preparative Riazor (81.1 mg, 0.600 mmol) at room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with acetic acid Echiru, water and washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue f was recrystallized from hexane / acetic acid Echiru to give the title compound (202 mg, 73% yield).

JH NMR (CDCI3) δ 2.61-2.66 (2Η, m), 2.81-2.86 (2H, m), 3.06-3.12 (1H, m), 3.16 (2H, t, J = 6. Hz), 3.45-3.53 ( 1H, m), 3.61-3.71 (4H, ra), 3.75-3.82 (1H, m), 3.95 (2H, q, J = 6.1 Hz), 4.05 (1H, dd, J = 9.9, 5.3 Hz), 4.16 (1H, dd, J = 9.9, 5.5 Hz), 6.72-6.76 (1H, m), 6.90-6.92 (2H, m), 6.97 (1H, t, J = 7.3 Hz), 7.28-7.31 (2H, m ), 7.37-7.41 (1H, m), 7. 4-7.49 (2H, ra), 7.52-7.57 (1H, m), 7.58-7.61 (2H, ra), 7.63-7.66 (2H, ra), 7.80 (2H, d, J = 8.3 Hz).

Example 163 5- [2 - [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[2-[(3 - Main Chirufueniru) (phenyl) amino] Echiru] -1, 3, 4 Okisajiazoru - 2-carboxy Sami de

N- (3- Mechirufue - Le) - N - Fueniruetan - 1,2 Jiamin (263 mg, 1.00 mmol) and 5 - [2 - [(4-Bifuwe two Lil carbonyl) Amino] Echiru] -1, 3, 4 Okisajia-2- carboxylic acid Echiru (183 mg, 0.500 mmol) using the same method as in example 1 from, to give the title compound (183 mg, 67% yield) as a white solid., J H NMR (DMS0 - d 6) δ 2.23 (3H, s), 3.20 (2H, t, J = 5.9 Hz), 3.4,6 - 3.53 (2H, m), 3.69 (2H, q, J = 6.0 Hz), 3.84 (2H, t, J = 6.8 Hz), 6.77 (1H, d J = 7.1 Hz), 6.82 (1H, d, J = 8.6 Hz), 6.87-6.95 (2H, m), 7.13-7.17 (1H, m), 7.23-7.31 (2H, m), 7.39-7.44 (1Η, · m), 7.46-7.53 (2H, m), 7.70-7.79 (4H, m), 7.86-7.94 (2H, m ), 8.69-8.76 (1H, m), 9.37 (1H, brs).

Example 1 64 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N - [(l - Hue sulfonyl - 1H-benz I Mi imidazole-2-I) methyl] -1, 2 , 4-Okisajiazoru - 3-Cal Pokisami de

In the same manner as in Example 2, 3, instead of 3-diphenyl-propyl § Min was used to obtain the title compound [(1-phenyl - 2-I le - 1H-benz I Mi imidazole) methyl] amine . 18% yield.

Mp 204- 205 ° C (recrystallized from acetic acid Echiru).

¾ NMR (CDC1 3) δ 3.24-3.27 (2Η, ra), 3.87-3.91 (2H, m), 4.77 (2H, d, J = 5.1 Hz), 7.17-7.31 (4H, m), 7.35-7. 0 (3H, m), 7.41-7.45 (2H, m), 7.52- 7.61 (7H, m), 7.73-7.78 (1H, m), 7.88-7.91 (2H, m), 9.26 (1H, t, J = 5.1 Hz).

Example 1 6 5 3- [2- [(4-Biff We lilies Luke Lupo yl) Amino] Echiru] - N - [(l - Hue sulfonyl - 1H-benz I Mi imidazole-2-I) methyl] - 1, 2, 4-Okisajiazoru - 5 Cal Bokisami de

In the same manner as in Example 2, 5 - L2- [(4 - Bifue two Lil carbonyl) amino] E chill] - 1, 2, 4-Okisajiazoru - instead of 3-carboxylic acid Echiru 3- [2- [ (4 Bifue two Rirukaruponiru) amino] Echiru] -1, 2, 4-Okisajiazoru - 5-carboxylic acid E Ji Le, 3, 3-diphenyl instead of phenylpropyl § Min [(1-phenyl - 1H- the Benzuimida-2- I) methyl] amine, the title compound was obtained using p- xylene instead of Asetonitoriru. Yield 81%.

Mp 224- 225 ° C (recrystallized from acetic acid Echiru).

¾ NMR (CDC1 3) δ 3.10-3.13 (2H, m), 3.81-3.85 (2H, m), 4.76 (2H, d, J = 5.1 Hz), 7.02 (1H, t, J = 5.9 Hz), 7.18 -7.23 (1H, m), 7.25-7.32 (2H, m), 7.34-7. 5 (5H, m), 7.54-7.62 (7H, m), 7.74-7.79 (1H, m), 7.86-7.89 ( . 2H, - m), 9.40 (1H, t, J = 4.4 Hz) i:

Example 1 6 6 3- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[(3 - Hue El - 1 - base Nzofuran - 2 Inore) methyl] -1, 2, 4 - Okisajiazoru - 5-Karubokisami de, -

1 - (3-phenylene Honoré - benzofuran - 2-I le) Metanamin (335 mg, 1.50 mmol) and 3- [2- [(4-bi Hue lily ylcarbonyl) Amino] Echiru] -1, 2, 4 - Okisajiazoru - 5-carboxylic acid Echiru (183 mg, 0.500 ramol) in the same manner as in reference example 59 from to give the title compound (187 mg, 69% yield) as a white solid.

H NMR (CDC1 3) δ 3.04-3.14 (2Η, m), 3,62-3.73 (2H, ra), 4.74 (2H, d, J = 4.4 Hz), 7.30-7.64 (10H, ra), 7.69- 7.76 (6H, m), 7.89 (2H, d, J = 8.1 Hz), 8.66 (1H, brs), 10.12 (1H, brs).

Example 1 6 7 3- [2- [[(4, - Furuorobifu - Le - 4-I le) carbonyl] Amino] E chill]-N-(2-morpholino-3-phenoxyethanol propyl) - 1, 2, 4 - Okisajiazo Ichiru -5 - power Norebokisami de

In the same manner as in Example 2, 5- [2- [(4-Bifuwe two Lil carbonyl) Amino] E chill] - 1, 2, 4-Okisajiazo Ichiru -? - force instead of carboxylic acid Echiru 3- [2- [[(4 - Full Orobifue sulfonyl - 4-I le) carbonyl] Amino] Echiru] -1, 2, 4-Okisajiazo Ichiru - 5 - Power Lebon the acid Echiru, 3, 3-diphenyl instead of phenylpropyl § Min 2 Moruhori Roh - 3 - to give the title compound using the phenoxyethanol propylamine. 89% yield.

Mp 139- 140 ° C (recrystallized from ethanol).

¾ NMR (CDC1 3) δ 2.62-2.67 (2H, m), 2.83-2.88 (2H, m), 3.07-3.13 (1H, m), 3.19-3.22 (2H, m), 3.48-3.55 (1H, m ), 3.67-3.76 (4H, m), 3.85 (1H, ddd, J = 5.5, 6.7, 14.0 Hz), 3.94-3.98 (2H, m), 4.07 (1H, dd, J = 5.4, 9.8 Hz), 4.18 (1H, dd, J = 5.4, 9.8 Hz), 6.88 (1H, t, J = 5.9 Hz), 6.89- 6.93 (2H, m), 6.97-7.01 (1H, m), 7.12-7.18 (2H, m), 7.28-7.33 (2H, m), 7.54-7.62 (4H, m), 7.79-7.84 (3H, m).

Example 1 6 8 3- [2- [[(4'Furuorobifu nil - 4-I le) carbonyl] Amino] E chill]-N-(2 - morpholino - 3 - phenoxyethanol propyl) - 1,2 , 4 - Okisajiazoru -5 - force Rupokisami de hydrochloride

3 - [2- [[(4, - Furuorobifue sulfonyl - 4-I le) carbonyl] Amino] Echiru] - N '(2-mode Ruhorino - 3 - off We Roh hydroxypropyl) - 1,2, 4 - Okisajiazo Ichiru - 5- Karubokisami de (1.49 g, 2.60 mmol) acetic acid Echiru (50 mL) was added 4 N hydrogen chloride acetate Echiru dissolved solution (5 mL) was added, ethanol and the mixture was concentrated under reduced pressure 'residue. after crystallized to give the title compound (1.54 g, 97% yield).

Mp 201- 202 ° C.

¾ NMR (DMS0-d 6) δ 3.09 (2Η, t, J = 7.0 Hz), 3.32-4.10 (13H, m), 4.34- 3.54 (2H, m), 6.99-7.03 (3H, m), 7.30- 7.35 (4H, ra), 7.74-7.80 (4H, m), 7.90-7.93 (2H, m), 8.73 (1H, t, J = 5.6 Hz), 9.79 (1H, brs), 10.97 (1H, brs) .

Example 1 6 9 5- [2 _ [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[(1-off We sulfonyl - 1H-benz I Mi indazole - 2-I) methyl] - 1, 3, 4 Okisajiazoru 2-Cal Bokisami de

In the same manner as in Example 2, 5- [2 - [(4 - Bifuwe two Lil carbonyl) Amino] E chill] -1, 2, 4-Okisajiazoru - 3-carboxylic acid instead of 5 Echiru - [2- [(4-Bifue two Rirukarupoeru) Amino] Echiru] - 1, 3, 4 Okisajiazoru - 2-carboxylic acid E Chi le, 3, instead of 3-diphenyl-propyl § Min [(1-phenyl -1H- the Benzuimida-2- I) methyl] amine, the title compound was obtained using p- xylene instead of Asetonitoriru. 73% yield.

Mp 213_214 ° C (recrystallized from acetone).

¾ NMR (CDC1 3) δ 3.18-3.22 (2Η, m), 3.87-3.92 (2H, m), 4.76 (2H, d, J = 4.9 Hz), 7.18-7.22 (2H, m), 7.25-7.29 ( 1H, m), 7.30-7.34 (1H, m), 7.35- 7.40 (1H, m), 7.40-7. 7 (4H, m), 7.53-7.64 (7H, m), 7.77-7.80 (1H, m ), 7.86-7.89 (2H, m), 8.98 (1H, t, J = 4.9 Hz).

The structures of the compounds obtained in Examples 161 to 169 shown in Table 22.

ı55 Formulation Example 1 (production of capsule)

1) Compound of Example 1 30 mg:

2) fine powder cellulose 10 mg

3) Lactose 1 9 mg

4) Magnesium stearate ■ 1 mg

B † 60 mg

1), 2), 3) and 4) are mixed and filled in gelatin capsules.

Formulation Example 2 (production of tablets)

1) Example 1 Compound 30 g

2) Lactose 50 g

3) Corn starch 1 5 g

4) carboxymethylcellulose calcium 44 g

5) Magnesium stearate 1 g

1000 tablets total 140 g

1), 2), 4) the total amount and 3 Og are kneaded with water 3), vacuum dried and granulated. 5) 4) and lg of the end resulting sized 14 g were mixed and tableted by a tableting machine. Thus, to obtain 1000 tablets containing Compound 3 Omg of Example 1 per tablet.

Measurement of glucose uptake inhibitory effect mediated Experimental Example 1 SGLT Homo port grayed

W0 using human SGLT homolog expressed CH0 cell line described in Example 1 of 04/39405, uptake experiments a -Methylglucose incorporated into Yotsute selectively intracellular SGLT, American Journal of Physiology, G833 pages, 1996 and Journal of Clinical Investigation, 397 pages, was carried out according to the method of 1994.

First, the human SGLT homolog expression CH0 (dhfr-) cells, 10% FBS, in a 96-well containing the nucleic acid added DMEM medium 100 Mr / Ueru CytoStar- T plates 3X10 4 cells / Ueru to (Amersham Bio Sa Iensu Inc.) were seeded so that, and cultured for 2 days at 37 ° C. Cells buffer after culture (125 mM N- methyl- D-glucamine , 1.2 mM KH 2 P0 4, 2.5 mM CaCl 2, 1.2 mM MgS0 4, 4 mM glutaraine, 10 mM HEPES (pH 7.2), 0,1 mg / mL BSA) 150; after three washes with uL, by further incubation for 1 hour with the same buffer to remove the glucose remaining in the cell.

Then, buffer was removed to examine the glucose uptake upon addition buffer 40 Les total sugar uptake ability or compounds in order to examine the independent sugar uptake in Na is, N - methyl - the buffer was replaced with D-glucamine in NaCl was added 40Mi. Et al., Added 5μί compound dilutions in order to determine the glucose uptake of 5-les compound when added dimethylsulfoxide dilution to examine the independent sugar uptake capacity or total sugar uptake in Na is, All Uweru 0.08 to 10 mM α-methylglucose containing ([14 C] a- methylglucose of丄(Amersham Biosciences) was 5μί添Ka卩, by 2 hours Inkyubeto at 37 ° C, shed - Methylglucose It was carried out of the uptake reaction.

Then, the supernatant was removed from each Ueru, the radioactivity of 14 C was measured by TopCount (Pakine luma one company). Na-dependent glucose uptake is a value obtained by subtracting the non-dependent glucose uptake in Na from the total glucose uptake. The compounds of Na-dependent glucose-up Write-ability upon addition, and calculates the ratio (% of control) for Na-dependent glucose uptake capacity during compound without additives, compound concentration (IC indicating a 50% sugar uptake 5. value) was calculated by dose-response curve or et Prism 3.0 (GraphPad software, Inc.).

As a result, reference examples 55 and 65 and Example 1, 2, 4, 6, 9: 1 2, 14, 19, 2 1, 24, 29, 36 ,, 37, 43 to 46, 49 to 52, 58-60, 1 14, 1 38, 14 1 and 1 6 1-1 6 compound obtained in 9, 0.5 or less of IC 5. It showed the value.

Industrial Applicability

SGLT inhibitors of the present invention, diabetes, obesity, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, is useful for the prevention 'treatment, such as metabolic syndrome. Further, Karubokisami de derivative of the present invention are useful as SGLT inhibitors Contact Yopi glucose preparative interrupt inhibitor.

'This application is based on application No. 2004-354598 filed in Japan,' the contents of which are incorporated herein.

Claims

The scope of the claims
Wherein the ring A may be substituted ring,
R 1 may be substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group or an optionally substituted hydroxy group, R 2 and R 3 are independently Te hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group optionally or substituted have been Moyoi hydroxy group,
R 4 may be substituted hydrocarbon group, an optionally substituted heterocyclic group, 'an optionally substituted amino group or a substituted hydroxy group,
X represents a divalent chain group having 1 to atoms of the main chain 6. SGLT inhibitor compound also is properly formed by salt thereof or a prodrug represented by].
2. formula
[Symbols in the formula are as defined claim 1. Compound or glucose uptake inhibitor comprising a salt or a prodrug represented by].
3. for the production of SGLT inhibitors of the formula
[Symbols in the formula are as defined claim 1. Compounds represented by or a salt thereof or a prodrug thereof in].
4. for producing glucose uptake inhibitors, formula
[Symbols in the formula are as defined claim 1. Compounds represented by or a salt thereof or a prodrug thereof in].
5. Equation
[Symbols in the formula are as defined claim 1. The compound or a salt thereof or a prodrug represented by] which comprises administering to a mammal, SGLT inhibition method in the mammal.
6. Expression
[Symbols in the formula are as defined claim 1. A compound represented by or a salt thereof, or]. Characterized by administering a prodrug thereof to a mammal, glucose uptake inhibition method in the mammal.
7. Expression
The R lb is substituted 0 Good C sheet 1 even if an alkyl group, R 3 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic - ring group, optionally substituted an amino group or an optionally substituted hydrocarbyl ^ shea group,
R 4 b is 1 to 3 halogen atoms which may be substituted C ^ e alkyl group, an alkoxy group, optionally substituted with 1 to 3 substituents selected from Shiano group and a halogen atom Bifuweyuriru a group.
However, when the ring A is,
R lb is 3- (1Η- imidazol - 1-I) propyl group, (RS) - 2-morpholino - 3 - Fuweno Kishipuropiru group, (RS) - 2- (Jimechiruamino) -3 - phenylpropyl group or 2 - not (1,3 - dihydric mud - 2H - - Isoindoru 2 I le) Echiru group. Or a salt thereof].
8. ring Ab force S
7. A compound according is.
9. R lb force S
(I) a hydroxy group,
(ii) C 6 _ 14 aromatic hydrocarbon Okishi group.,
(iii) 1 to 3 halogen atoms may be substituted 〇 bets 6 alkyl group, hydroxy group, 〇 6 alkoxy group, Okiso group, a halogen atom and C 6 _ 14 aromatic hydrocarbon group (said C 6 4 aromatic hydrocarbon group 1 to 3 substituents which may be alkyl groups with a halogen atom, hydroxy group, optionally substituted with 1 selected from 〇 6 alkoxy and c androgenic atoms to three substituents 1 Bareru 遴 from may also be) to three may be substituted with a substituent non-aromatic heterocyclic group,
(iv) 1 to 3 substituents in replacement which may be optionally 6 alkoxy group selected from a halogen atom Contact Yopi hydroxy group,
(V) 1 to 3 halogen atoms optionally substituted CI- 6 alkyl group mono or di-optionally substituted Scarpa moil O alkoxy group, - (vi) Ji Bok 6 alkyl group (the C 6 alkyl group is a halogen atom, human Doroki ^ group, forces Rupokishiru group, C ^ e alkoxy group, may be substituted by 1 to selected from C 6 alkoxy one carbonyl group and cull Pamoiru groups 3 substituents ), C 3 _ i. Cycloalkyl group, an alkyl one carbonyl group and C 6 _ 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbon group 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, one to three optionally substituted with a substituent mono location substituent selected from may also be) or di-substituted by an amino group which may be selected from alkoxy groups Contact Yopi halogen atom,
(vii) 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, C 6 alkoxy group, a halogen atom Contact Yopi 〇 6 - 14 aromatic hydrocarbon group (said C 6 - 14 aromatic family hydrocarbon group 1 to 3 substituents which may be C ^ e alkyl group with a halogen atom, hydroxy group, to 1 selected from alkoxy groups and halogen atoms may be substituted with 1-3 substituents 1 a stone three Yo Le be substituted with a substituent selected from), aromatic heterocyclic group and
(viii) C 7 _ 13 Ararukiru non-aromatic heterocyclic force Rubamoi Le group which may be substituted with a group.
1 to compound of claim 7 wherein there are three of which may be substituted with a substituent C Bok 6 alkyl group selected from.
Is 1 0. ring Ab force S,
R 1 b is 1 to 3 substituents which may be alkyl groups with a halogen atom, arsenic Dorokishi group, 6 alkoxy group, a halogen atom and c 6 - 14 aromatic hydrocarbon group (said C 6 _ 14 aromatic hydrocarbons hydrogen radical from 1 to 3 substituents which may be Ci-e alkyl group with a halogen atom, hydroxy group, - 1 selected from 6 alkoxy groups and halogen atoms may be substituted with 1-3 substituents stone for 1 selected from) three Yo Le be substituted with a substituent, a condensed aromatic heterocyclic group
The compound of claim 7, wherein in a substituted C i-6 alkyl group.
1 1. a ring A b force S,
R lb is C ^ e alkyl group (the alkyl group is a halogen atom, arsenic Dorokishi group, a carboxyl group, an alkoxy group, substituted by 1 to 3 substituents selected from C ^ alkoxy one carbonyl group and force Rupamoiru group may be), C 3 ^. Cycloalkyl group, 〇 6 alkyl Ichiriki Ruponiru groups and C 6 _ 14 aromatic hydrocarbon group (said C 6 - 14 aromatic hydrocarbon group one to three may be substituted with a halogen atom 〇 I 6 alkyl group, arsenate Dorokishi group, - 6 1 selected from alkoxy groups Contact Yopi to 3 halogen atoms of an amino optionally mono- or di-substituted with a substituent selected from which may be optionally) substituted with a substituent basis
The compound of claim 7, wherein in a substituted C 6 alkyl group.
12. 2- [2- [(4-Bifue two Rirukarubo - Le) Amino] Echiru] - N-[2- (diphenyl amino) Echiru] one three to Okisazoru - 4 - Karubokisami de,
2- [2- [(4-Bifuwe two Lil carbonyl) amino] Echiru] - N-(2 - morpholino - 3 - Fueno Kishipuropiru) - 1, 3-Okisazoru 4 - Power / Repokisami de,
5 - [2 - [(4-Bifue two Rirukaruponiru) Amino] Echiru] - N-[2- [(3- Mechirufue two Le) (Fuweniru) amino] Echiru] -1, 3, 4 Okisajiazoru - 2- Karubokisami de, 5 - [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[(1 - Hue sulfonyl - 1H-benz Imidazo Ichiru - 2-I) methyl] -1,2 , 4 Okisajiazoru - 3 - Karubokisami de, 3- [2- [(4-Bifue two Lil carbonyl) Amino] Echiru] - N-[(1-phenyl - 1H-benz Imidazoru - 2-I) methyl] - 1, 2, 4-Okisajiazoru 5 Karubokisami de,
3- [2- [(4-bi Hue lily ylcarbonyl) Amino] Echiru] - N-[(3 - phenyl - 1 Benzofu run 2-I) methyl] - 1, 2, 4-Okisajiazoru - 5 - Karubokisami de,
3- [2- [[(4'Full O lobby phenylalanine - 4 - I le) carbonylation Honoré] Amino] Echiru] -N - (2-mol Horino - 3 - phenoxyethanol propyl) - 1,2 , 4-Okisajiazoru - 5-Karubokisami de,
5- [2- [(4-Bifuwe two Lil carbonyl) Amino] Echiru] - N-[(1-Hue - Le - 1H-benz Imidazoru - 2-I) methyl] - 1,3, 4-Okisajiazoru - 2 - Karubokisami de,
1- [2 - [(4-Bifue - Lil carbonyl) Amino] Echiru]-N-[2 - (Jifuweniruamino) E chill] - 1H-pyrazol - 4-Karubokisami de,
5- [2 - [(4 - Bibuwe two Lil carbonyl) Amino] Echiru] - N-[2 - (Jifuwenirua Bruno) E chill] -1, 3, 4 Okisajiazoru - 2 Karubokisami de,
3- [2- [(4 - Bifue two Lil carbonyl) Amino] Echiru]-N-(2-morpholino - 3-Fueno Kishipuropiru) - 1, 2, 4-Okisajiazoru - 5 Karubokisami de, and
5 - [2- [(4 - Bifue two Lil carbonyl) Amino] Echiru] - N-[2 - (Jifuweniruamino) E chill] -1, 2, 4-Okisajiazoru 3- force Rupokisami selected from de compound or its 7. a compound according a salt.
1 3. Compound or prodrug thereof according to claim 7 wherein.
1 4. 7. A compound according or pharmaceutical agent comprising the prodrug thereof.
1 5. Equation
[Symbols in the formula are as defined claim 7, wherein. Compound or a salt thereof represented by, the formula
R 4 b - COOH
Wherein, R 4 b is as defined claim 7, wherein. Characterized by reacting a compound or its salt represented by 'the formula
[Symbols in the formula are as defined above. Table. The compound or preparation how its salt.
PCT/JP2005/022726 2004-12-07 2005-12-06 Carboxamide derivative WO2006062224A1 (en)

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