CN101646666A

CN101646666A - Tricyclic compounds

Info

Publication number: CN101646666A
Application number: CN200880010285A
Authority: CN
Inventors: 柳泽新; 洼山刚之; 荒武诚士; 边见和辉; 上野公久; 铃木道彦; 松原正浩; 矢尾幸三; 滨口晃规; 九十九透仁
Original assignee: Kyowa Hakko Kirin Co Ltd
Current assignee: Kyowa Kirin Co Ltd
Priority date: 2007-02-07
Filing date: 2008-02-07
Publication date: 2010-02-10

Abstract

The present invention provides a PPAR gamma agonist comprising, as an active ingredient, a tricyclic compound represented by the formula (I) (wherein R1 represents lower alkyl optionally having substituent(s) or the like, R2 and R3 are the same or different and each represents lower alkyl optionally having substituent(s) or the like, R4 and R5 are the same or different and each represents a hydrogen atom or the like, Q1-Q2-Q3 represents CH-CH-CH-CH or the like, Y represents a single bond or the like, Z1-Z2 represents C-CR13 (wherein R13 represents a hydrogen atom or the like), or the like, andA represents -COOH or the like), or a pharmaceutically acceptable salt thereof and the like.

Description

Tricyclic compounds

Technical field

The present invention relates to contain peroxisome proliferation sensitization acceptor (PPAR) gamma agonist of tricyclic compounds as effective constituent.In addition, relate to tricyclic compounds, it has PPAR γ agonist activity, as for example, type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.) etc. to treat and/or prevent agent useful.

Background technology

PPAR γ is one of nuclear internal hormone receptor superfamily, plays an important role in the differentiation of adipocyte.Cytokine--the TNF-α or the free fatty acids of the adipocyte of hypertrophyization a large amount of secretions causing insulin resistance, the thiazoline derovatives of pioglitazone, rosiglitazone etc. is by making the PPAR gamma activityization, the adipocyte of hypertrophyization is owing to apoptosis reduces, and then by promoting to be divided into small-sized adipocyte with normal function by Preadipocyte In Vitro, improve insulin resistance ((J.Biol.Chem.), nineteen ninety-five, the 270th volume, 12953 pages; (J.Med.Chem.), 1996, the 39th volume, 665 pages etc.).The PPAR γ excitomotor of pioglitazone and rosiglitazone as remedy for diabetes clinical use (spy opens clear 61-267580, the spy opens flat 1-131169 etc.).

PPAR γ excitomotor is useful as treatment of diseases such as diseases associated with inflammation, inflammatory bowel diseases such as the impaired glucose tolerance of the metabolism syndrome beyond the diabetes, obesity, preceding diabetic disease states and other insulin resistance syndrome, hypertension, atherosclerosis, hyperlipidaemia, psoriasis and/or preventive.

On the other hand, angiotensin-ii receptor makes vasoconstriction and makes increased blood pressure by the angiotensin-ii receptor Class1 on the cytolemma.Thereby what angiotensin II receptor antagonists became circulation system disease such as hypertension effectively treats and/or prevents agent ((J.Med.Chem.),, the 39th volume, 625 pages in 1996).The angiotensin II receptor antagonists of losartan, Candesartan, telmisartan, valsartan, Olmesartan etc. is used for clinical (spy opens flat 4-364171, the spy opens flat 5-783228 number etc.) as depressor.

About 60% concurrent impaired glucose tolerance or type ii diabetes (insulin resistance) among the known hyperpietic.Although the depressor of various excellences is arranged, such patient's blood pressure management still is bad, in addition, does not implement positive blood sugar management.

Thus, medicine with PPAR γ agonist activity and angiotensin-ii receptor antagonistic activity can be used as and these two kinds of diseases that mechanism is relevant, type ii diabetes for example, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), the neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.), arteriosclerosis, heart trouble, cerebral apoplexy, the circulation system disease of kidney disease etc. etc., particularly type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia etc. to treat and/or prevent agent useful.Reported the angiotensin II receptor antagonists that shows the effect of insulin resistant property improvement, but its mechanism of action not clear and definite (with reference to patent documentation 1 and 2) as yet.In addition, known unite the therapy of using thiazoline derovatives with PPAR γ agonist activity and angiotensin II receptor antagonist with hypertension as the arteriosclerosis of complication or follow in the treatment of obesity etc. of diabetes effectively (with reference to patent documentation 3 and 4).And then, the report (non-patent literature 1, patent documentation 5) of the angiotensin II receptor antagonists that shows PPAR γ agonist activity is arranged, do not increase the risk of floating secondary, floating second month in a season of lung of the fluid retention, the tip that bring out by PPAR γ excitomotor or ischemia heart failure with the compound of PPAR γ agonist activity and angiotensin-ii receptor antagonistic activity, expectation is used for treatment of diseases and/or the prevention (patent documentation 5) that type ii diabetes, metabolic syndrome and other and PPAR γ excitomotor react.

On the other hand, the compound of known following formula (A) expression as tricyclic compounds with and derivative have excellent hypotensive effect (with reference to patent documentation 6 and 9) based on the angiotensin-ii receptor antagonistic action.

[Chemical formula 1]

In addition, the compound of known following formula (B) expression with and the material (with reference to patent documentation 7 and 8) that transmits as the signal that suppresses GPR4 of derivative.

[Chemical formula 2]

[patent documentation 1] international brochure that discloses No. 2003/047573

[patent documentation 2] international brochure that discloses No. 2006/107062

[patent documentation 3] spy opens flat 9-323940 communique

[patent documentation 4] spy opens the 2004-217648 communique

[patent documentation 5] international brochure that discloses No. 2004/014308

No. 2526005 communique of [patent documentation 6] Japanese Patent

[patent documentation 7] international brochure that discloses No. 2004/017994

[patent documentation 8] international brochure that discloses No. 2004/017995

[patent documentation 9] spy opens flat 7-61983 communique

[non-patent literature 1]

[Hypertension,, the 43rd volume, 993 pages in 2004]

Summary of the invention

The problem that invention will solve

The purpose of this invention is to provide and contain the PPAR gamma agonist of tricyclic compounds as effective constituent.PPAR gamma agonist of the present invention is preferred and then have an angiotensin-ii receptor antagonistic action, for example type ii diabetes is provided, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.), arteriosclerosis, heart trouble, cerebral apoplexy, circulation system diseases such as kidney disease etc. treat and/or prevent agent.

Other in addition purpose provides new tricyclic compounds or its pharmaceutically useful salt with PPAR γ agonist activity.

Be used to solve the means of problem

The present invention relates to following (1)～(47).

(1) PPAR gamma agonist, it contains the tricyclic compounds of general formula (I) expression or its pharmaceutically useful salt as effective constituent,

[chemical formula 3]

In＜the formula, R ¹Expression can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent lower alkoxy, maybe can have substituent low-grade alkyl sulphur alkyl (ス Le Off アニ Le),

R ²And R ³Identical or different; represent hydrogen atom, can have substituent low alkyl group, can have substituent low-grade alkenyl, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl, can have substituent elementary alkyl amido methanoyl, can have substituent two elementary alkyl amido formyl radical, maybe can have substituent aliphatics heterocycle carbonyl

Perhaps, the group in the formula (I)

[chemical formula 4]

Be the group that is selected from following formula (a1)～(a20),

[chemical formula 5]

[in the formula, R ¹With above-mentioned same meaning, R ⁶And R ⁷Identical or different, expression hydrogen atom, halogen, nitro, cyano group, formyl radical, oxo, hydroxyl, can have substituent lower alkoxy, can have substituent low-grade alkane acidyl oxygen base, can have substituent low alkyl group, can have substituent low-grade alkenyl, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl ,-NR ⁹R ¹⁰(in the formula, R ⁹And R ¹⁰Identical or different, the expression hydrogen atom, can have substituent low alkyl group, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl and maybe can have substituent aralkyl, or R ⁹And R ¹⁰Form with adjacent nitrogen-atoms respectively and can have substituent nitrogen heterocycle) ,-CONR ¹¹R ¹²(in the formula, R ¹¹And R ¹²Identical or different, the expression hydrogen atom, can have substituent low alkyl group, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl and maybe can have substituent aralkyl, or R ¹¹And R ¹²Form with adjacent nitrogen-atoms respectively and can have substituent nitrogen heterocycle), can have substituent aryl, can have substituent aralkyl, can have substituent aromatic heterocycle and maybe can have substituent aliphatics heterocyclic radical, R ⁸The expression hydrogen atom maybe can have substituent low alkyl group]

R ⁴And R ⁵Identical or different, expression hydrogen atom, halogen, hydroxyl, lower alkoxy or low alkyl group,

Q ¹-Q ²-Q ³Expression CH=CH-CH=CH, S-CH=CH or CH=CH-S,

Y represents singly-bound, CH ₂, CH ₂CH ₂, CH=CH, O, S, CH ₂O, OCH ₂, CH ₂S or SCH ₂,

Z ¹-Z ²Expression C=CR ¹³(in the formula, R ¹³The expression hydrogen atom maybe can have substituent low alkyl group), CH-CR ¹⁴R ¹⁵(in the formula, R ¹⁴And R ¹⁵Identical or different, the expression hydrogen atom maybe can have substituent low alkyl group) or N-CR ¹⁶R ¹⁷(in the formula, R ¹⁶And R ¹⁷Identical or different, the expression hydrogen atom maybe can have substituent low alkyl group),

A represents to be selected from the group of following formula (b1)～(b6),

[chemical formula 6]

(b1) (b2) (b3) (b4) (b5) (b6)

(in the formula, R ¹⁸Expression can have substituent low alkyl group maybe can have substituent aryl) 〉.

(2) contain (1) described tricyclic compounds or its pharmaceutically useful salt as effective constituent, with the agent of PPAR γ agonism and angiotensin-ii receptor antagonistic action.

(3) (1) or (2) described dose, it is treatment of diseases and/or the preventive relevant with PPAR γ.

(4) (3) described dose, the disease relevant with PPAR γ are the diseases that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

(5) tricyclic compounds or its pharmaceutically useful salt of general formula (IA) expression.

[chemical formula 7]

In＜the formula, R ^1AExpression can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent lower alkoxy, maybe can have substituent low-grade alkyl sulphur alkyl,

R ^2AAnd R ^3AIdentical or different; represent hydrogen atom, can have substituent low alkyl group, can have substituent low-grade alkenyl, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl, can have substituent elementary alkyl amido methanoyl, can have substituent two elementary alkyl amido formyl radical, maybe can have substituent aliphatics heterocycle carbonyl

Perhaps, the group in the formula (IA)

[chemical formula 8]

Be the group that is selected from following formula (A1)～(A20),

[chemical formula 9]

[in the formula, R ^1AWith above-mentioned same meaning, R ^6AAnd R ^7AIdentical or different, expression hydrogen atom, halogen, nitro, cyano group, formyl radical, oxo, hydroxyl, can have substituent lower alkoxy, can have substituent low-grade alkane acidyl oxygen base, can have substituent low alkyl group, can have substituent low-grade alkenyl, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl ,-NR ^9AR ^10A(in the formula, R ^9AAnd R ^10AIdentical or different, the expression hydrogen atom, can have substituent low alkyl group, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl and maybe can have substituent aralkyl, or R ^9AAnd R ^10AForm with adjacent nitrogen-atoms respectively and can have substituent nitrogen heterocycle) ,-CONR ^11AR ^12A(in the formula, R ^11AAnd R ^12AIdentical or different, the expression hydrogen atom, can have substituent low alkyl group, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl and maybe can have substituent aralkyl, or R ^11AAnd R ^12AForm with adjacent nitrogen-atoms respectively and can have substituent nitrogen heterocycle), can have substituent aryl, can have substituent aralkyl, can have substituent aromatic heterocycle and maybe can have substituent aliphatics heterocyclic radical, R ^8AThe expression hydrogen atom maybe can have substituent low alkyl group]

R ^4AAnd R ^5AIdentical or different, expression hydrogen atom, halogen, hydroxyl, lower alkoxy or low alkyl group,

Q ^1A-Q ^2A-Q ^3AExpression CH=CH-CH=CH, S-CH=CH or CH=CH-S,

Y ^AExpression singly-bound, CH ₂, CH ₂CH ₂, CH=CH, O, S, CH ₂O, OCH ₂, CH ₂S or SCH ₂,

Z ^1A-Z ^2AExpression C=CR ^13A(in the formula, R ^13AThe expression hydrogen atom maybe can have substituent low alkyl group), CH-CR ^14AR ^15A(in the formula, R ^14AAnd R ^15AIdentical or different, the expression hydrogen atom maybe can have substituent low alkyl group) or N-CR ^16AR ^17A(in the formula, R ^16AAnd R ^17AIdentical or different, the expression hydrogen atom maybe can have substituent low alkyl group),

(i) Z ^1A-Z ^2ABe C=CR ^13AA(in the formula, R ^13AAExpression can have substituent low alkyl group), CH-CR ^14AR ^15AA(in the formula, R ^14AWith above-mentioned same meaning, R ^15AAExpression can have substituent low alkyl group) or N-CR ^16AAR ^17A(in the formula, R ^16AABe to have substituent low alkyl group, R ^17AWith above-mentioned same meaning) time,

A ^AExpression is selected from the group of following formula (B1)～(B6),

[Chemical formula 1 0]

(B1) (B2) (B3) (B4) (B5) (B6)

(in the formula, R ^18AExpression can have substituent low alkyl group maybe can have substituent aryl)

(ii) Z ^1A-Z ^2ABe C=CR ^13AB(in the formula, R ^13ABThe expression hydrogen atom), CH-CR ^14ABR ^15AB(in the formula, R ^14ABAnd R ^15ABAll represent hydrogen atom) or N-CR ^16ABR ^17AB(in the formula, R ^16ABAnd R ^17ABAll represent hydrogen atom) time,

A ^AExpression is selected from the group of following formula (B3)～(B6)

[Chemical formula 1 1]

(in the formula, R ^18AWith above-mentioned same meaning) 〉.

(6) (5) described tricyclic compounds or its pharmaceutically useful salt, the group in the formula (IA)

[Chemical formula 1 2]

It is the group that is selected from above-mentioned formula (A1)～(A20).

(7) (5) described tricyclic compounds or its pharmaceutically useful salt, in the formula (IA)

[Chemical formula 1 3]

Be to be selected from following formula (A4), (A9), (A11) and group (A12).

[Chemical formula 1 4]

(in the formula, R ^1A, R ^6AAnd R ^7ARespectively with above-mentioned same meaning)

(8) (5) described tricyclic compounds or its pharmaceutically useful salt, in the formula (IA)

[Chemical formula 1 5]

Be the group of following formula (A4) expression,

[Chemical formula 1 6]

(in the formula, R ^1A, R ^6AAnd R ^7ARespectively with above-mentioned same meaning).

(9) (5) described tricyclic compounds or its pharmaceutically useful salt, in the formula (IA)

[Chemical formula 1 7]

Be the group of following formula (A12) expression,

[Chemical formula 1 8]

(10) any described tricyclic compounds in (5)～(9) or its pharmaceutically useful salt, Z ^1A-Z ^2ABe C=CR ^13AA(in the formula, R ^13AAWith above-mentioned same meaning), CH-CHR ^15AA(in the formula, R ^15AAWith above-mentioned same meaning) or N-CR ^16AAR ^17A(in the formula, R ^16AAAnd R ^17ARespectively with above-mentioned same meaning).

(11) any described tricyclic compounds in (5)～(10) or its pharmaceutically useful salt, A ^ABe following formula (B3).

[Chemical formula 1 9]

(12) any described tricyclic compounds in (5)～(11) or its pharmaceutically useful salt, Q ^1A-Q ^2A-Q ^3ABe CH=CH-CH=CH.

(13) any described tricyclic compounds in (5)～(12) or its pharmaceutically useful salt, Y ^ABe CH ₂CH ₂Or CH ₂O.

(14) medicine, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(15) PPAR gamma agonist, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(16) with the agent of PPAR γ agonism and angiotensin-ii receptor antagonistic action, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(17) treatment of diseases and/or the preventive relevant with PPAR γ, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(18) (17) described dose, the disease relevant and then be the disease relevant with angiotensin-ii receptor with PPAR γ.

(19) (17) or (18) described dose, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

(20) angiotensin II receptor antagonists, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(21) treatment of diseases and/or the preventive relevant with angiotensin-ii receptor, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(22) depressor, contain (5)～(13) any described tricyclic compounds or its pharmaceutically useful salt is as effective constituent.

(23) make PPAR γ activated method, comprise to (1) described tricyclic compounds or its pharmaceutically useful salt of significant quantity.

(24) PPAR γ is activated and makes the method for angiotensin-ii receptor antagonism, comprise to (1) described tricyclic compounds or its pharmaceutically useful salt of significant quantity.

(25) (23) or (24) described method, making PPAR γ activated method is treatment of diseases and/or the prevention method relevant with PPAR γ.

(26) (25) described method, the disease relevant and then still relevant disease with angiotensin-ii receptor with PPAR γ.

(27) (25) or (26) described method, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

(28) make PPAR γ activated method, comprise to any described tricyclic compounds in (5)～(13) of significant quantity or its pharmaceutically useful salt.

(29) PPAR γ is activated and makes the method for angiotensin-ii receptor antagonism, comprise to any described tricyclic compounds in (5)～(13) of significant quantity or its pharmaceutically useful salt.

(30) (28) or (29) described method, making PPAR γ activated method is treatment of diseases and/or the prevention method relevant with PPAR γ.

(31) (30) described method, the treatment of diseases relevant and then still relevant disease with angiotensin-ii receptor with PPAR γ.

(32) (30) or (31) described method, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

(33) make the method for angiotensin-ii receptor antagonism, comprise to any described tricyclic compounds in (5)～(13) of significant quantity or its pharmaceutically useful salt.

(34) any described method in (29)～(33), the method that makes the angiotensin-ii receptor antagonism is treatment of diseases and/or the prevention method relevant with angiotensin-ii receptor.

(35) (34) described method, treatment of diseases relevant with angiotensin-ii receptor and/or prevention method are the hypertensive methods that treats and/or prevents.

(36) (1) described tricyclic compounds or its pharmaceutically useful salt application in preparation PPAR gamma agonist.

(37) (1) described tricyclic compounds or its pharmaceutically useful salt are in the application of preparation in the agent of PPPAR γ agonism and angiotensin-ii receptor antagonistic action.

(38) (1) described tricyclic compounds or its pharmaceutically useful salt are preparing treatment of diseases relevant with PPAR γ and/or the application in the preventive.

(39) (38) described application, the disease relevant with PPAR γ are the diseases that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

(40) application in preparation PPAR gamma agonist of any described tricyclic compounds in (5)～(13) or its pharmaceutically useful salt.

(41) any described tricyclic compounds in (5)～(13) or its pharmaceutically useful salt are in the application of preparation in the agent of PPAR γ agonism and angiotensin-ii receptor antagonistic action.

(42) any described tricyclic compounds in (5)～(13) or its pharmaceutically useful salt are preparing treatment of diseases relevant with PPAR γ and/or the application in the preventive.

(43) (42) described application, the disease relevant with PPAR γ are and then the disease relevant with angiotensin-ii receptor.

(44) (42) or (43) described application, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

(45) application in the preparation angiotensin II receptor antagonists of any described tricyclic compounds in (5)～(13) or its pharmaceutically useful salt.

(46) any described tricyclic compounds in (5)～(13) or its pharmaceutically useful salt are preparing treatment of diseases relevant with angiotensin-ii receptor and/or the application in the preventive.

(47) application in preparation depressor of any described tricyclic compounds in (5)～(13) or its pharmaceutically useful salt.

The invention effect

According to the present invention, PPAR is provided gamma agonist, it contains tricyclic compounds as effective constituent, its conduct for example, type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.) etc. to treat and/or prevent agent useful.PPAR gamma agonist provided by the invention and then preferably with the angiotensin-ii receptor antagonistic action, except above-mentioned disease, as for example, the circulation system disease of arteriosclerosis, heart trouble, cerebral apoplexy, kidney disease etc. etc. to treat and/or prevent agent also useful.

In addition, provide and have PPAR γ agonist activity, as for example type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.) etc. treat and/or prevent the useful novel tricyclic based compound of agent or its pharmaceutically useful salt.Tricyclic compounds provided by the invention or its pharmaceutically useful salt and then preferably with the angiotensin-ii receptor antagonistic action, except above-mentioned disease, as for example, the circulation system disease of arteriosclerosis, heart trouble, cerebral apoplexy, kidney disease etc. etc. to treat and/or prevent agent also useful.

The best mode that is used to carry out an invention

Below, the compound that general formula (I) is represented is called compound (I).The compound of formula sequence number for other also is same.

In the definition of general formula (I) and each group (IA),

Low alkyl group part as low alkyl group and lower alkoxy, low-grade alkyl sulphur alkyl, low-grade alkane acidyl oxygen base, low-grade alkane acidyl, elementary alkoxy carbonyl, elementary alkyl amido methanoyl and two elementary alkyl amido formyl radical; for example can enumerate the alkyl of the carbonatoms 1～10 of straight or branched; more specifically, can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl etc.2 low alkyl group parts of two elementary alkyl amido formyl radical can be identical or different.

For example can enumerate the thiazolinyl of the carbonatoms 2～10 of straight or branched as low-grade alkenyl, can enumerate vinyl, allyl group, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base, decene base etc. more specifically.

For example can enumerate the cycloalkyl of carbonatoms 3～8 as cycloalkyl, more specifically can enumerate cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.

For example can enumerate the aralkyl of carbonatoms 7～16 as aralkyl, more specifically can enumerate benzyl, styroyl, phenyl propyl, phenyl butyl, phenylpentyl, phenyl hexyl, phenyl heptyl, phenyl octyl group, phenyl nonyl, phenyl decyl, naphthyl methyl, naphthyl ethyl, naphthyl propyl group, naphthyl butyl, naphthyl amyl group, naphthyl hexyl, anthryl methyl, anthryl ethyl etc.

For example can enumerate the aryl of carbonatoms 6～14 as aryl, more specifically can enumerate phenyl, naphthyl, Azulene base, anthryl etc.

Aliphatics heterocyclic radical part as aliphatics heterocyclic radical and aliphatics heterocycle carbonyl, for example can enumerate to contain and be selected from nitrogen-atoms, 5 yuan or 6 yuan monocycle aliphatics heterocyclic radical of at least 1 atom of Sauerstoffatom and sulphur atom, 3～8 yuan ring condenses two rings that obtain or three ring property and contains and is selected from nitrogen-atoms, the condensed ring aliphatics heterocyclic radical of at least 1 atom of Sauerstoffatom and sulphur atom etc., more specifically can enumerate aziridinyl, azetidinyl, pyrrolidyl, piperidino-(1-position only), piperidyl, アゼパニ Le, 1,2,5, the 6-tetrahydro pyridyl, imidazolinyl, pyrazolidyl, piperazinyl, high piperazinyl (ホモピペラジニ Le), pyrazolinyl, Oxyranyle, tetrahydrofuran base, tetrahydrochysene-2H-pyranyl, 5,6-dihydro-2H-pyranyl oxazolidinyl, morpholino, morpholinyl Sai oxazolidinyl, thio-morpholinyl, the 2H-oxazolyl, 2H-Sai oxazolyl, indolinyl, dihydro-iso indolyl, dihydro benzo furyl, the benzimidazoline base, Er hydrogen benzoxazolyl, Er hydrogen Ben Bing Sai oxazolyl, ベ Application ゾジオキソリニ Le, tetrahydric quinoline group, tetrahydro isoquinolyl, dihydro-2H-benzopyranyl, dihydro-1H-benzopyranyl, dihydro-2H-benzo thiapyran base, dihydro-1H-benzo thiapyran base, the tetrahydroquinoxaline base, the tetrahydro quinazoline base, dihydrobenzo alkyl dioxin etc.

As aromatic heterocycle, can enumerate for example to contain and be selected from nitrogen-atoms, 5 yuan of at least 1 atom of Sauerstoffatom and sulphur atom or 3～8 yuan of rings of 6 yuan of monocycle aromatic heterocycles condense two rings that obtain or three ring property and contain and are selected from nitrogen-atoms, the condensed ring aromatic heterocycle of at least 1 atom of Sauerstoffatom and sulphur atom etc., more specifically can enumerate furyl, thienyl, pyrryl, imidazolyl, pyrazolyl oxazolyl isoxazolyl oxadiazole base, thiazolyl, isothiazolyl, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, benzofuryl, benzo thiophenyl benzoxazolyl, benzothiazolyl, pseudoindoyl, indyl, indazolyl, benzimidazolyl-, the benzotriazole base, オキサゾロピリミジニ Le, チアゾロピリミジニ Le, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, the Mi Dingbing pyridyl, purine radicals, quinolyl, isoquinolyl, give the quinoline base, 2, how basic the 3-diaza is, quinazolyl, quinoxalinyl, 1, the 5-diaza is base etc. how.

Contain the Chisso heterocyclic radical as what form with adjacent nitrogen-atoms, (this monocycle heterocyclic radical also can contain other nitrogen-atoms for example can to enumerate 5 yuan of containing at least 1 nitrogen-atoms or 6 yuan monocycle heterocyclic radical, Sauerstoffatom or sulphur atom), 3～8 yuan ring condenses two rings that obtain or three ring property and contains the condensed ring heterocyclic radical of at least 1 nitrogen-atoms that (this condensed ring heterocyclic radical can also contain other nitrogen-atoms, Sauerstoffatom or sulphur atom) etc., more specifically, can enumerate aziridinyl, azetidinyl, pyrrolidyl, piperidino-(1-position only), アゼパニ Le, pyrryl, imidazolinyl, imidazolyl, pyrazolidyl, pyrazolinyl, pyrazolyl, piperazinyl, high piperazinyl oxazolidinyl, 2H-oxazolyl Sai oxazolidinyl, 2H-Sai oxazolyl, morpholino, thio-morpholinyl, indolinyl, dihydro-iso indolyl, indyl, pseudoindoyl, tetrahydric quinoline group, tetrahydro isoquinolyl, Er hydrogen benzoxazolyl, Er hydrogen Ben Bing Sai oxazolyl, the benzimidazoline base, benzimidazolyl-, the dihydro-indazol base, indazolyl, the benzotriazole base, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, the Mi Dingbing pyridyl, purine radicals etc.

Halogen is represented each atom of fluorine, chlorine, bromine, iodine.

As can have substituent low alkyl group, can have substituent low-grade alkenyl, can have substituent lower alkoxy, can have substituent low-grade alkyl sulphur alkyl, can have substituent low-grade alkane acidyl oxygen base, can have substituent low-grade alkane acidyl, can have substituent elementary alkoxy carbonyl, can have substituent elementary alkyl amido methanoyl and the substituting group that can have in the substituent two elementary alkyl amido formyl radical identical or different, can enumerate for example replace several 1～3, be selected from

Halogen, hydroxyl, sulfane base, nitro, cyano group, formamyl, C _3-8Cycloalkyl, aliphatics heterocyclic radical, aromatic heterocycle,

C _1-10Alkoxyl group, C _3-8Cycloalkyloxy, C _6-14Aryloxy, C _7-16Aralkyl oxy, C _2-11Alkyloyl oxygen base, C _7-15Aroyl oxygen base,

C _1-10Alkyl alkylthio base,

-NR ^XR ^Y(in the formula, R ^XAnd R ^YIdentical or different, expression hydrogen atom, C _1-10Alkyl, C _3-8Cycloalkyl, C _6-14Aryl, aromatic heterocycle, C _7-16Aralkyl, C _2-11Alkyloyl, C _7-15Aroyl, C _1-10Alkoxy carbonyl or C _7-16The aralkyl oxy carbonyl),

C _2-11Alkyloyl, C _7-15Aroyl, C _1-10Alkoxy carbonyl, C _6-14Aryloxy carbonyl, C _1-10Alkyl-carbamoyl, two C _1-10The substituting group of alkyl-carbamoyl etc.

As having substituent aryl, can have substituent aralkyl and can having substituting group in the substituent aromatic heterocycle, identical or different, can enumerate for example replace several 1～3, be selected from

Halogen, hydroxyl, sulfane base, nitro, cyano group, formamyl, C _1-10Alkyl, trifluoromethyl, C _3-8Cycloalkyl, C _6-14Aryl, aliphatics heterocyclic radical, aromatic heterocycle,

C _1-10Alkyl alkylthio base,

As having substituent cycloalkyl, can have substituent aliphatics heterocyclic radical, can having substituent aliphatics heterocycle carbonyl and can have and substituently contain substituting group in the Chisso heterocyclic radical with what adjacent nitrogen-atoms formed, identical or different, can enumerate for example replace several 1～3, be selected from

Oxo, halogen, hydroxyl, sulfane base, nitro, cyano group, formamyl, C _1-10Alkyl, trifluoromethyl, C _3-8Cycloalkyl, C _6-14Aryl, aliphatics heterocyclic radical, aromatic heterocycle,

C _1-10Alkyl alkylthio base,

As at the C shown in this _1-10Alkyl and C _1-10Alkoxyl group, C _2-11Alkyloyl oxygen base, C _1-10Alkyl alkylthio base, C _2-11Alkyloyl, C _1-10Alkoxy carbonyl, C _1-10Alkyl-carbamoyl and two C _1-10The C of alkyl-carbamoyl _1-10Moieties, the group that for example routine illustration that above-mentioned low alkyl group is shown is enumerated.Two C _1-102 C in the alkyl-carbamoyl _1-10Alkyl can be identical or different.

As C _3-8Cycloalkyl and C _3-8The cycloalkyl moiety of cycloalkyloxy, for example example illustrates the group of enumerating in the illustration of above-mentioned cycloalkyl.

As C _6-14Aryl and C _6-14Aryloxy, C _7-15Aroyl, C _7-15Aroyl oxygen base and C _6-14The aryl moiety of aryloxy carbonyl, for example example illustrates the group of enumerating in the illustration of above-mentioned aryl.

As C _7-16Aralkyl and C _7-16Aralkyl oxy and C _7-16The C of aralkyl oxy carbonyl _7-16Aralkyl moiety, for example example illustrates the group of enumerating in the illustration of above-mentioned aralkyl.

The for example routine respectively group of enumerating in the illustration of above-mentioned aliphatics heterocyclic radical, above-mentioned aromatic heterocycle and above-mentioned halogen that illustrates of aliphatics heterocyclic radical, aromatic heterocycle and halogen.

As compound (I) and (IA), more preferably above-mentioned (6)～(13) described compound, more specifically, the preferred formula (IA-A) or (IA-B) compound of expression,

[Chemical formula 2 0]

(in the formula, D represents CH or N, R ^1XExpression C _1-6Alkyl, C _3-8Cycloalkyl or C _1-6Alkoxyl group, R ^6XExpression hydrogen atom, halogen, trifluoromethyl or C _1-6Alkyl, R ^7XExpression hydrogen atom, halogen or C _1-6Alkyl, Y ^XExpression CH ₂CH ₂, CH ₂O or OCH ₂, R ^13XExpression hydrogen atom or C _1-6Alkyl, A ^XRepresent following formula (b2) or (b3).

[Chemical formula 2 1]

More preferably general formula (IA-C) or (IA-D) compound of expression,

[Chemical formula 2 2]

(in the formula, D, R ^1X, R ^6X, R ^7X, Y ^X, R ^13XAnd A ^XRespectively with above-mentioned same meaning).

And then more preferably, in compound (IA-A), (IA-B), (IA-C) and each group (IA-D),

D is CH or N,

R ^1XFor example preferable methyl, ethyl, propyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyl group, oxyethyl group, propoxy-etc., more preferably ethyl, propyl group, cyclopropyl, oxyethyl group etc.

R ^6XFor example preferred hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, propyl group, sec.-propyl etc., more preferably hydrogen atom, chlorine atom, methyl etc., and then more preferably chlorine atom, methyl etc.

R ^7XFor example preferred hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, propyl group, sec.-propyl etc., more preferably hydrogen atom, methyl etc.

Y ^XMore preferred CH ₂CH ₂Or CH ₂O etc.

As R ^13X, for example preferred C _1-6Alkyl etc., more preferably methyl, ethyl, propyl group etc., and then preferable methyl etc.

A ^XFor example preferred above-mentioned formula (b3).

Compound (I) and pharmaceutically useful salt (IA) comprise for example pharmaceutically useful acid salt, metal-salt, ammonium salt, organic amine additive salt, amino acid addition salt etc.As compound (I) and pharmaceutically useful acid salt (IA), for example can enumerate hydrochloride, hydrobromate, nitrate, vitriol, inorganic acid salts such as phosphoric acid salt, acetate, oxalate, maleate, fumarate, Citrate trianion, benzoate, organic acid salts such as mesylate etc., as pharmaceutically useful metal-salt, can enumerate for example sodium salt, an alkali metal salts such as sylvite, magnesium salts, alkali earth metal salts such as calcium salt, aluminium salt, zinc salt etc., as pharmaceutically useful ammonium salt, can enumerate for example ammonium, the salt of tetramethyl-ammonium etc., as pharmaceutically useful organic amine additive salt, can enumerate for example morpholine, the additive salt of piperidines etc., as pharmaceutically useful amino acid addition salt, can enumerate for example Methionin, glycine, phenylalanine, aspartic acid, additive salt such as L-glutamic acid.

Then the preparation method to compound (I) describes.

Among the preparation method shown below, the group of definition changes under this preparation method's condition or when implementing this preparation method under the unaccommodated situation, importing by using protecting group commonly used in the Synthetic Organic Chemistry and [for example remove method, the Protective Groups in OrganicSynthesis third edition, the T.W.Greene work, John Wiley﹠amp; Sons Inc., described methods such as (1999)] etc., can prepare the purpose compound.In addition, as required, also can change the order of the reactions steps of substituting group importing etc.

The preparation method 1

In the compound (I), A is a following formula (b1) or (b2)

[Chemical formula 2 3]

(b1) (b2)

Compound can pass through known method (for example, No. the 2526005th, Japanese Patent, spy open flat 7-61983 etc.) or with the preparation of its similar methods.

The preparation method 2

In the compound (I), Z ¹-Z ²Be N-CR ¹⁶R ¹⁷(in the formula, R ¹⁶And R ¹⁷Respectively with above-mentioned same meaning), A is following formula (b2), (b3), (b4) or (b5)

[Chemical formula 2 4]

Compound (Ia)～(Id) can be according to the preparation of following step.

[Chemical formula 2 5]

[in the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ¹⁶, R ¹⁷, Q ¹-Q ²-Q ³And Y respectively with above-mentioned same meaning, X ^aThe leaving group or the following formula of expression chlorine atom, bromine atoms, iodine atom, trifyl oxygen base, methylsulfonyl oxygen base, benzenesulfonyl oxygen base, p-toluenesulfonyl oxygen base etc.

[Chemical formula 2 6]

(in the formula, X represents chlorine atom, bromine atoms, iodine atom, trifyl oxygen base, methylsulfonyl oxygen base, benzenesulfonyl oxygen base, p-toluenesulfonyl oxygen base etc., R ^aExpression C _1-10Alkyl, C _2-10Thiazolinyl, phenyl or benzyl, R ^bAnd R ^cIdentical or different, expression C _1-10Alkyl or C _3-8Cycloalkyl or R ^bAnd R ^cForm with adjacent nitrogen-atoms and to contain the Chisso heterocyclic radical) group of expression].

Step 1

Compound (III) can followingly obtain, make compound (IIa) and the normal compounds in 1 equivalent～5 (IIb) as required in the presence of the excessive alkali of 1 equivalent～a large amount of, in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～120 hours.

As alkali, for example can enumerate yellow soda ash, salt of wormwood, Quilonum Retard, cesium carbonate, sodium bicarbonate, saleratus, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium ethylate, potassium tert.-butoxide, sodium hydride, potassium hydride KH, butyllithium, the two trimethyl silyl acid amides of lithium, the two trimethyl silyl acid amides of sodium, triethylamine, diisopropyl ethyl amine, tributylamine, dicyclohexyl methylamine etc.As solvent, for example can enumerate dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), acetonitrile, isopropyl alcohol etc., they can use separately maybe can mix use.

At this, compound (IIa) can be opened described methods such as flat 7-61983 by No. the 2526005th, Japanese Patent, spy and obtain, compound (IIb) can pass through known method (for example, No. the 5332744th, United States Patent (USP), No. the 400835th, Europe patent, spy open flat 5-783228 etc.) or obtain with its similar methods.

Step 2

Compound (IV) can followingly obtain, make the excessive cyanide salt of excessive compound (IIIa) of compound (III) that step 1 obtains and 1 equivalent～a large amount of and 1 equivalent～a large amount of in the presence of the excessive acid of 1 equivalent～a large amount of, in solvent or solvent-free, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As cyanide salt, for example can enumerate sodium cyanide, potassium cyanide etc.As acid, for example can enumerate acetate, trifluoroacetic acid etc.As solvent, for example can enumerate ethylene dichloride, diox, THF, ethanol etc., they can use separately maybe can mix use.

At this, compound (IIIa) can be used as commercially available product and obtains.

Step 3

Compound (Ia) can followingly obtain, the normal sodiumazide of compound (IV) and 1 equivalent～10 that step 2 is obtained is in the presence of 1 equivalent～a large amount of excessive faintly acid, in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～120 hours.

As weak acid, for example can enumerate ammonium chloride, triethylamine hydrochloride etc.As solvent, for example can enumerate DMF, DMA, NMP, DMSO etc., they can use separately maybe can mix use.

In addition, as other method, compound (Ia) can also following obtaining, make the normal sodiumazide of compound (IV) and 1 equivalent～10, in the presence of 0.01～10 normal additive, in solvent, under the temperature between-10 ℃ and the solvent boiling point that uses, reacted 1 hour～120 hours.

As additive, for example can enumerate tributyltin chloride, trimethyltin chloride, Dibutyltin oxide etc.As solvent, for example can enumerate toluene, dimethylbenzene etc., they can use separately maybe can mix use.

Step 4

The compound (IV) that compound (Ib) can use step 2 to obtain prepares according to following step.

[Chemical formula 2 7]

(in the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ¹⁶, R ¹⁷, Q ¹-Q ²-Q ³And Y respectively with above-mentioned same meaning, R ^dExpression methyl, ethyl, propyl group, phenyl etc.)

Step 4-1

Compound (Ib-1) can followingly obtain, and makes compound (IV) and 1 equivalent～a large amount of excessive oxyamines, in solvent, under the temperature between-20 ℃ of solvent boiling points with use, reacts 5 minutes～120 hours.

Oxyamine for example can use the inorganic acid salt of hydrochloric acid oxyamine etc., can make alkali such as the sodium methylate coexistence about equivalent this moment.As solvent, for example can enumerate methyl alcohol, ethanol, DMF, DMA, DMSO etc., they can use separately maybe can mix use.

Step 4-2

Compound (Ib-2) can followingly obtain, compound (Ib-1) and 1 equivalent～a large amount of excessive chlorine carbonic ethers that above-mentioned steps 4-1 is obtained are in the presence of 1 equivalent～a large amount of excessive alkali, in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As the chlorine carbonic ether, for example can enumerate chlorine carbonic acid methyl ester, chlorine carbonic acid ethyl ester, chlorine carbonic acid propyl diester, chlorine carbonic acid phenylester etc.As alkali, for example can enumerate triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), sodium hydroxide, sodium hydride, potassium tert.-butoxide, sodium methylate etc.As solvent, for example can enumerate THF, DMF, DMA, toluene, dimethylbenzene etc., they can use separately maybe can mix use.

Step 4-3

Compound (Ib) can followingly obtain, make compound (Ib-2) that above-mentioned steps 4-2 obtains in solvent, as required, in the presence of catalytic amount～10 normal alkali, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As alkali, for example can enumerate sodium hydroxide, sodium hydride, potassium tert.-butoxide, sodium methylate etc.As solvent, for example can enumerate THF, DMF, DMA, benzene, dimethylbenzene etc., they can use separately maybe can mix use.

Above-mentioned steps 4-1～4-3 can not separate resultant, then adds reagent and carry out continuously in reaction solution.

Step 5

Compound (Ic) can followingly obtain, make the compound (Ib-1) and the 1 equivalent～a large amount of excessive N that similarly obtain by compound (IV) and above-mentioned steps 4-1, N '-thiocarbonyldiimidazole, in the presence of 1 equivalent～a large amount of excessive alkali, in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As alkali, for example can enumerate triethylamine, pyridine, DMAP, diazabicyclo undecylene (DBU) etc.As solvent, for example can enumerate THF, 1,4-diox, methylene dichloride, chloroform, acetonitrile, acetone etc., they can use separately maybe can mix use.

Step 6

Compound (Id) can followingly obtain, make the compound (Ib-1) and the 1 equivalent～a large amount of excessive N that similarly obtain by compound (IV) and above-mentioned steps 4-1, N '-thiocarbonyldiimidazole, in the presence of 1 equivalent～a large amount of excessive Lewis acids, in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As Lewis acid, for example can enumerate boron trifluoride Anaesthetie Ether complex compound, tin protochloride, zinc chloride, silica gel etc.As solvent, for example can enumerate THF, 1,4-diox, methylene dichloride, chloroform, methyl alcohol, ethanol etc., they can use separately maybe can mix use.

The preparation method 3

Compound (III) can be according to following step preparation.

[Chemical formula 2 8]

(in the formula, R ¹, R ², R ³, R ⁴, R ⁵, Q ¹-Q ²-Q ³And Y respectively with above-mentioned same meaning)

Step 7

Compound (III) can followingly obtain, make compound (IIc) and 1 equivalent～5 equivalent compounds (IIb), in the presence of the excessive phosphine compound of the excessive condensing agent of 1 equivalent～a large amount of and 1 equivalent as required～a large amount of, in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As condensing agent, for example can enumerate azo-2-carboxylic acid's diethyl ester, azo-2-carboxylic acid's diisopropyl ester, azo-2-carboxylic acid two (tertiary butyl) ester, (cyano group methylene radical) trimethylammonium phosphorane, (cyano group methylene radical) tributyl phosphorane etc.As phosphine compound, for example can enumerate triphenylphosphine, tributylphosphine, support the triphenylphosphine of polymkeric substance etc.As solvent, for example can enumerate THF, DMF, methylene dichloride, acetonitrile etc., they can use separately maybe can mix use.

In addition, as other method, compound (III) can followingly obtain, make compound (IIc) in the presence of the excessive halogen agent of 1 equivalent～a large amount of, in solvent or under solvent-free, under the temperature between-20 ℃ and the solvent boiling point that uses, react after 5 minutes～72 hours, the step of following with preparation method 21 similarly obtains.

As the halogen agent, for example can enumerate thionyl (two) chlorine; Phosphorus tribromide; Triphenylphosphine, 2, the combination of 6-lutidine and tetrachloro charcoal element; Triphenylphosphine, 2, the combination of 6-lutidine and tetrabormated charcoal element; The combination of methylsulfonyl chlorine and lithium chloride; The combination of methylsulfonyl chlorine and lithiumbromide etc.As solvent, for example can enumerate THF, DMF, DMA, methylene dichloride, ethylene dichloride, acetonitrile etc., they can use separately maybe can mix use.

At this, compound (IIc) can obtain for No. 2526005 by Japanese Patent.

The preparation method 4

In the compound (I), A is following formula (b1), (b2), (b3), (b4) or (b5),

[Chemical formula 2 9]

(b1) (b2) (b3) (b4) (b5)

Z ¹-Z ²Be C=CR ¹³(in the formula, R ¹³With above-mentioned same meaning) compound (Ie) can be according to the preparation of following step.

[chemical formula 30]

(in the formula, X ^cWith above-mentioned X ^aSame meaning or expression hydroxyl, R ¹, R ², R ³, R ⁴, R ⁵, R ¹³, Q ¹-Q ²-Q ³And Y respectively with above-mentioned same meaning, A ¹The group of representing any expression of above-mentioned formula (b1)～(b5))

Step 8

Compound (VI) can followingly obtain, and uses compound (V) and compound (IIb), similarly obtains with the known method of preparation method's 1 record, preparation method 2 step 1 or preparation method 3.

At this, compound (V) can obtain by described methods such as No. the 2526005th, Japanese Patents.

Step 9

Compound (Ie) can followingly obtain, and the compound (VI) that uses step 8 to obtain similarly obtains with the known method of preparation method's 1 record or preparation method 2 step 3～6.

The preparation method 5

In the compound (I), Z ¹-Z ²Be CH-CR ¹⁴R ¹⁵(in the formula, R ¹⁴And R ¹⁵Respectively with above-mentioned same meaning) compound (If) can be according to the preparation of following step.

[chemical formula 31]

(in the formula, X ^c, R ¹, R ², R ³, R ⁴, R ⁵, R ¹⁴, R ¹⁵, Q ¹-Q ²-Q ³, Y and A ¹Respectively with above-mentioned same meaning)

Step 10

Compound (VIII) can followingly obtain, and uses compound (VII) and compound (IIb), similarly obtains with the known method of preparation method's 1 record, preparation method 2 step 1 or preparation method 3.

At this, compound (VII) can obtain by described methods such as No. 2526005, Japanese Patents.

Step 11

Compound (If) can followingly obtain, and the compound (VIII) that uses step 10 to obtain similarly obtains with the known method of preparation method's 1 record or preparation method 2 step 3～6.

The preparation method 6

In the compound (I), A is

[chemical formula 32]

(in the formula, R ¹⁸With above-mentioned same meaning)

Compound (Ih) can be according to the preparation of following step.

[chemical formula 33]

(in the formula, R ¹, R ², R ³, R ⁴, R ⁵, R ¹⁸, Q ¹-Q ²-Q ³, Z ¹-Z ²And Y respectively with above-mentioned same meaning)

Step 12

Compound (Ih) can followingly obtain, the compound that preparation method 1 is obtained is (after Ig handles with 1～50 normal carboxylic acid activator, in the presence of 1～30 equivalent alkali, with 1～50 equivalent compound (VII), in solvent, under the temperature between-20 ℃ and the solvent boiling point that uses, reacted 5 minutes～72 hours.

As the carboxylic acid activator, for example can enumerate N, N '-carbonyl dimidazoles (CDI), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) or its hydrochloride, dicyclohexylcarbodiimide (DCC) etc.As solvent, for example can enumerate methylene dichloride, acetonitrile, toluene, ethyl acetate, THF, 1,4-diox, DMF, NMP etc., they can use separately maybe can mix use.As alkali, for example can enumerate DBU, triethylamine, DMAP, N, accelerine, pyridine, N-methylmorpholine etc.In addition, compound (VII) can be used as commercially available product and obtains.

R in the compound (I) ¹, R ², R ³, R ⁴, R ⁵, Z ¹, Z ², the contained functional group of A and Y conversion can be [for example by known method, Comprehensive OrganicTransformations second edition, R.C.Larock, work, Vch Verlagsgesellschaft Mbh, described methods such as 1999] or carry out with its similar methods.

Intermediate among above-mentioned each preparation method and purpose compound can for example filter by separation and purification method commonly used in the Synthetic Organic Chemistry, extract, wash, dry, concentrate, recrystallization, various chromatograms etc. carry out separation and purification.In addition, in the intermediate, also can be refining especially and directly confession in ensuing reaction.

Compound (I) and (IA) in, can have the stereoisomerism, tautomerism of rotamerism, optical siomerism etc. etc., the present invention includes these, comprise all possible isomeries and their mixture.

When wishing to obtain compound (I) or salt (IA), compound (I) or (IA) when obtaining with the form of salt, can keep intact and refining, in addition, when obtaining with the free form, with compound (I) or (IA) dissolve or be suspended in the appropriate solvent, form salt and separate refining getting final product by adding acid or alkali.

In addition, compound (I) and (IA) and pharmaceutically useful salt also has situation about existing with the form with the affixture of water or all kinds of SOLVENTS, and these affixtures also are included among the present invention.

The particular instantiation of the compound (I) that obtains by the present invention is in table 1～table 34.But compound of the present invention is not limited to these.

[table 1]

Table 1

[table 2]

Table 2

[table 3]

Table 3

[table 4]

Table 4

[table 5]

Table 5

[table 6]

Table 6

[table 7]

Table 7

[table 8]

Table 8

[table 9]

Table 9

[table 10]

Table 10

[table 11]

Table 11

[table 12]

Table 12

[table 13]

Table 13

[table 14]

Table 14

[table 15]

Table 15

[table 16]

Table 16

[table 17]

Table 17

[table 18]

Table 18

[table 19]

Table 19

[table 20]

Table 20

[table 21]

Table 21

[table 22]

Table 22

[table 23]

Table 23

[table 24]

Table 24

[table 25]

Table 25

[table 26]

Table 26

[table 27]

Table 27

[table 28]

Table 28

[table 29]

Table 29

[table 30]

Table 30

[table 31]

Table 31

[table 32]

Table 32

[table 33]

Table 33

[table 34]

Table 34

Then, the pharmacological action at the compound of representing (I) specifically describes by testing example.

Test example 1: measure (transactivation based on the PPAR γ deactivation that utilizes the property a crossed gene to import Assay) PPAR gamma activity turns the research of usefulness into

Compound (I) at the agonist activity of PPAR γ by using deactivation assay method mensuration as DNA calmodulin binding domain CaM with the chimeric intranuclear receptor of PPAR γ ligand binding region of the GAL4 of zymic transcription factor.Particularly, by the following method according to the method [J Biol Chem., nineteen ninety-five, the 270th volume, 12953 pages] of Lehmann etc., the PPAR gamma excitomotor activity of assessing compound (I).

Use is cultivated the HEK293EBNA cell that obtains by the DMEM (イ Application PVC トロジエ Application society) that has added 10 volume/volume % foetal calf serums (イ Application PVC トロジエ Application societies).At 10cm ²Thickness of sowing is 1 * 10 in the culture plate (rock city nitre) ⁵The above-mentioned cell 30mL of individual/mL cultivates an evening.Use SuperFect Transfection reagent (キアグ Application society), the pointer plasmid of expressing the plasmid of the chimeric intranuclear receptor of GAL4-PPAR γ and expressing GAL4 responsiveness luciferase is imported one with 4: 1 ratio cross in the sexual cell, the chimeric intranuclear receptor of wherein said GAL4-PPAR γ is to make to merge as the 174-475 amino acid of the ligand binding region of people PPAR γ and 1-147 amino acid as the DNA calmodulin binding domain CaM of GAL4 to obtain.Gene imported after 5 hours, peeled off cell from culture plate, and thickness of sowing is 2 * 10 in each hole of 96 holes white plates (Sumitomo ベ one Network ライト society) ⁴The cell of the peeling off 100 μ L of individual/mL cultivate an evening.Remove substratum, the DMEM that adds with serum-free dilutes various concentration compounds (I) the 100 μ L that obtain, and 5% carbon dioxide gas flows down (5%CO ₂), 37 ℃ were reacted 24 hours down.On the other hand, as positive control, add the pioglitazone 100 μ L of 10 μ mol/L, 5% carbon dioxide gas flows down (5%CO ₂), 37 ℃ were reacted 24 hours down.As the matrix of luciferase, in each hole, add 100 μ LSteady-Glo (プロメガ society), fully stir.Use TopCount NTX (パ Star カ one De society) to measure the chemoluminescence of luciferase immediately.

At the agonist activity (activity rate (%)) of the compound (I) of PPAR γ is to be 100% o'clock relative reactivity as the agonist activity when adding pioglitazone 10 μ mol/L, calculates by following formula.

[mathematical expression 1]

The activity rate that compound (I) is shown maximum activity is as effectiveness, and the concentration that shows 50% the activity rate of rendeing a service is as EC ₅₀Value and calculating.The results are shown in table 35.

[table 35]

Table 35

From The above results can confirm compound of the present invention (I) and (IA) and pharmaceutically useful salt have PPAR γ agonist activity.Thereby, compound of the present invention (I) and (IA) and pharmaceutically useful salt expected as the various diseases relevant with PPAR γ, type ii diabetes for example, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), the neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.) etc. treat and/or prevent agent, particularly, as type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia etc. treat and/or prevent agent.

Test example 2: human angiotensin II Class1 receptor binding assays

The film fraction of the Chinese hamster ovary celI of forced expression human angiotensin II Class1 acceptor (パ one キ Application エ Le マ one society) is with measuring damping fluid (50mmol/L three (methylol) aminomethane, 5mmol/L MgCl ₂, 1mmol/L quadrol-N, N, N ', N '-tetraacethyl and 0.1 weight/volume % bovine serum albumin (biochemical industrial society; PH 7.4)) dilute 128 times, be used for following experiment.With the preparation cytolemma 150 μ L (2.1 μ g albumen), 200pmol/L [ ¹²⁵I]-Angiotensin II (アマシヤ system バイオサイエ Application ス society) 10 μ L and various concentration compound (I) solution 10 μ L join in the polypropylene tube (アシスト society).37 ℃ were reacted down after 60 minutes, on the GF/C glass filter (ワ Star トマ Application society) with the processing of 0.3 volume/volume % polymine, by using cell harvester M-48 (Block ラ Application デ Le society) suction filtration reaction were stopped.Afterwards, washing filter is with damping fluid (50mmol/L three (methylol) aminomethane; PH 7.4) 500 μ L washing 9 times.Then, strainer is moved in the polypropylene tube, use automatic gamma counter コ Block ラ (パ Star カ one De society) to measure radioactivity.

[ ¹²⁵I]-Angiotensin II and human angiotensin Class1 acceptor combine with respect to compound (I) in conjunction with inhibiting rate (%), calculate by following formula.

[mathematical expression 2]

Total binding is meant, when not having compound (I) [ ¹²⁵I]-Angiotensin II is in conjunction with exit dose, and the binding capacity when adding compound (I) is meant, in the presence of compound (I) [ ¹²⁵I]-Angiotensin II is in conjunction with exit dose, the non-specific binding amount is meant, replace compound (I) and when adding Angiotensin II (ペプチ De institute) the 10 μ mol/L of sign not [ ¹²⁵I]-Angiotensin II is in conjunction with exit dose.

As IC ₅₀Value, be from each in conjunction with inhibiting rate suppress 50% in conjunction with the time concentration calculate, (Biochem Pharmacol., 1973,22 rolled up, and p.3099) obtain by the Cheng-Prusoff formula in conjunction with suppressing constant (Ki).Compound 6,22,25,29,45,42,47,44,62,64, S13,83,95,137,138,139,146,147 etc. show the Ki value that 10nmol/L is following.

By last affirmation, compound (I) and (IA) the powerful combination that suppresses Angiotensin II with respect to human angiotensin II Class1 acceptor.Promptly, compound of the present invention (I) and (IA) and pharmaceutically useful salt have Angiotensin II Class1 receptor antagonism, expectation is as the treatment of diseases and/or the preventive of the circulation system disease of arteriosclerosis, hypertension, heart trouble, cerebral apoplexy, kidney disease etc. etc.

Test example 3: the lowering blood glucose of diabetic mice and the effect of lipid

To the db/db mouse (7 ages in week, female) of natural occurrence type ii diabetes model, with the consumption of compound (I) with 30mg/kg/ day, orally give 1 time on the 1st, 6 days.In the control group, give solvent (0.5% methocel solution).Give with 7 days after, measure glucose and tri-glyceride in the blood plasma.Have a mind to the poor Student of passing through ' s t Inspection Research on the statistics, risk (P)＜0.05 thinks that there were significant differences.

Its result, compound (I) significantly suppresses the increase of serum glucose and tri-glyceride, can confirm that compound (I) has the effect of lowering blood glucose and the effect that reduces lipid to the diabetes model of this test.

Testing the impaired glucose tolerance and the insulin resistant property improvement of routine 4II type diabetes rat does With

For the Zucker obese rat of the type ii diabetes consumption with 3mg/kg, 1 time on the 1st, 4 weeks are the orally give test compound repeatedly.In the control group, similarly give solvent (0.5% methocel solution).Give with 4 weeks after, implements per os glucose load shown below and tests.In addition, be satiated with food down and measure Regular Insulin value in the blood plasma.

Per os glucose load test: after making one evening of rat fasting, the consumption of orally give glucose solution 2g/kg.Glucose solution give with 30 minutes, 60 minutes and 120 minutes after, from the rat tail vein blood sampling, measure blood glucose value.

When several compounds of the present invention (I) are estimated as above-mentioned test compound, these compound exhibits impaired glucose tolerance and the effect of insulin resistant property improvement.In addition, can confirm to have the improvement effect of obesity.

Test example 5 is utilized the hypotensive effect of tail cover method (Tail Cuff Method) research compound (I)

Use the natural occurrence Hypertensive Rats (SHR) in 18～22 ages in week.

Medicine is given body weight, blood pressure and the heart rate with preceding each rat of mensuration, and these values are divided into groups in the mode of equal extent between each group.1 time on the 1st, orally give solvent (0.5% methocel solution) and test compound repeatedly on the 7th.Final give with about 4～9 hours after, according to following, non-nocuity ground mensuration systolic blood pressure and heart rate.

Blood pressure and heart rate measurement method

Rat is put into the round tube type slicer, be heated to 37C, use tail cover method to measure blood pressure and heart rate under the rest state.Measure to use non-nocuity formula blood pressure measurement apparatus (PS-600 type, reason is ground exploitation, Tokyo), each body measurement blood pressure and heart rate 5 times, with its mean value as each individual value.

The result of above-mentioned test can confirm that compound 26,29,42,44,47, S 13,95,137,139 etc. has hypotensive activity.

Test example 6 is utilized the hypotensive effect of telemetry research compound (I)

Abdominal aorta in natural occurrence Hypertensive Rats (SHR) is kept somewhere remote measurement sender, monitoring blood pressure and heart rate.Domestication was raised more than 4 weeks, only used to be considered to the hypertension individuality and to test.Medicine is given with preceding, divides into groups in blood pressure and the heart rate of each rat is equal extent between each group mode.1 time on the 1st, orally give solvent (0.5% methocel solution) and test compound repeatedly on the 4th.Calculate 24 hourly average systolic blood pressures, 24 hourly average blood pressures expansionary phase and the 24 hourly average hearts rate respectively given with Japan and China.

The result of above-mentioned test can confirm, compound 22,25,29,42,44,45,47, S13, S15, S16,71,86,95,100,118,124,129,137,138,146,147 etc. have hypotensive activity.

Can confirm by above test-results, compound of the present invention (I) and (IA) and pharmaceutically useful salt have PPAR γ agonist activity.Can confirm in addition, and then they also have the angiotensin-ii receptor antagonistic action.Thereby, compound of the present invention (I) and (IA) and pharmaceutically useful salt not only to the disease relevant with PPAR γ, and to the treatment of diseases relevant and/or prevent useful, particularly useful in showing the treatment of diseases that PPAR γ is relevant with the both sides of angiotensin-ii receptor and/or preventing with angiotensin-ii receptor.Promptly, compound of the present invention (I) and (IA) and pharmaceutically useful salt, expectation is as for example type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, hypertriglyceridemia, inflammatory skin diseases (for example, psoriasis, atopic dermatitis, fat leaks dermatitis, sunburn etc.), diseases associated with inflammation (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, endometritis etc.), proliferative disease (for example, atherosclerosis, angiostenosis, restenosis etc.), struvite neuropsychiatric disease (for example, multiple sclerosis etc.), the neurodegenerative neuropsychiatric disease (for example, alzheimer's disease, Parkinson's disease etc.), arteriosclerosis, heart trouble, cerebral apoplexy, the treatment of diseases and/or the preventives such as circulation system disease of kidney disease etc., particularly, as type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, the internal organ obesity, obesity, treatment of diseases and/or preventives such as hypertriglyceridemia.

About 60% concurrent impaired glucose tolerance or type ii diabetes (insulin resistance) among the known hyperpietic; thereby; compound of the present invention (I) or (IA) or its pharmaceutically useful salt particularly; expectation treats and/or prevents agent as concurrent impaired glucose tolerance or type ii diabetes (insulin resistance) hypertensive; in addition, expectation is as hypertension therapeutic and/or preventive with impaired glucose tolerance or type ii diabetes (insulin resistance) preventive effect.

Compound (I) or (IA) or its pharmaceutically useful salt can be directly give separately with, but expectation provides as common various pharmaceutical preparations.In addition, these pharmaceutical preparations can be used for the animal or human.

Pharmaceutical preparation of the present invention can contain the compound (I) or (IA) or its pharmaceutically useful salt as activeconstituents separately, perhaps can contain and other mixing active ingredients things that are used for the treatment of arbitrarily.In addition, these pharmaceutical preparations can be mixed together activeconstituents and pharmaceutically useful one or more carriers (for example, thinner, solvent, excipient etc.), by the known any means preparation of technology of pharmaceutics technical field.

As route of administration, the most effective when treatment is used in expectation, can enumerate oral or for example intravenously etc. is non-oral.

As giving and mode, for example can enumerate tablet, injection etc.

Be suitable for oral administration, for example tablet etc. can use the preparations such as tackiness agent such as lubricants such as disintegrating agent, Magnesium Stearate, hydroxy propyl cellulose such as excipient, starch of lactose etc.

Be suitable for non-oral administration, for example injection etc. can use preparations such as the thinner such as mixed solution of salts solution, glucose solution or salt solution and glucose solution or solvent.

Compound (I) or (IA) or the giving and amount and giving and number of times of its pharmaceutically useful salt, different because of giving with the character of mode, patient age, body weight, the symptom that should treat or severity etc., common oral situation, be grown up everyone, with 0.01～1000mg, the scope of preferred 0.05～100mg 1 day give with 1 time to for several times.Intravenously give with etc. the situation of non-orally give, be grown up everyone, with 0.001～1000mg, preferred 0.01～100mg gave in 1st with 1 time to for several times.But, give and measure and give and number of times about these, according to aforesaid various conditions change is arranged.

PPAR gamma agonist of the present invention (for example shows the excellent disease relevant with PPAR γ, type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity, hyperglyceridemia etc.) treat and/or prevent effect, and then compound as described above (I) or its pharmaceutically useful salt can be used in combination with other drug composition more than a kind or a kind beyond it.

As the other drug composition that is used in combination, for example can enumerate verapamil, diltiazem

Nifedipine, amlodipine, benidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, nimodipine, the beautiful Horizon of horse, Bepridil, barnidipine, flunarizine, cilnidipineb, Lacidipine (62, efonidipine, felodipine, Aranidipine calcium channel blockers such as (アラニジピ Application); ACE Depressants such as captopril, enalapril, alacepril, delapril, Yipingshu, lisinopril, benazepril, Imidapril, temocapril, quinapril, Trolapril, perindopril, fosinopril; Guanamprazine, chlorothiazide, benzthiazide, ticrynafen, acetazolamide, aminophylline, cyclothiazide, trichlormethiazide, navidrex, hydrochlorothiazide, Methyclothiazide, behyd (ベ Application チ Le ヒ De ロ Network ロロチアジ De), Pentylhydroflumethiazide (ペ Application Off Le チアジ De), P-2105, Hydroflumethiazide, polythiazide, aquedux, chlorthalidone, cyclothiazide, Hydrex, meticrane (メチ Network ラ Application), tripamide, methaqualone, indapamide, quinethazone, Furosemide, bumetanide, mefruside, Ple-1053, Ethacrynic Acid, Sodium Ethacrynate, piretanide, spironolactone, eplerenone (エプレレノ Application), canrenoate potassium, Triameme Hydrochloride, hydragog(ue) such as Carperitide; Proprasylyte, pindolol, carteolol, atenolol USP 23, Bopindolol, bisoprolol, Celiprolol, for β blocking agents such as Ni Suoluoer; αZu Duan medicines such as Prazosin, bunazosin, Doxazosin, terazosin, urapidil; α β blocking agents such as Amosulal YM-09538, carvedilol, Arottnolol; Sympathetic nerve Depressants such as guanabenz, clonidine, methyldopa; Sulphur ureas such as Glyburide, gliclazide, tolbutamide, glimepiride are medicine; Fast-acting types such as nateglinide, mitiglinide (ミチグリニ De), repaglinide are hypoglycemic agents after the meal; Biguanide-based medicine such as N1,N1-Dimethylbiguanide, W-37; Insulin resistant such as pioglitazone, rosiglitazone property improvement medicine; α glucoside enzyme inhibitors such as acarbose, voglibose, miglitol; Sitagliptin (シタグリプチ Application), Vildagliptin DPP-4 Depressants such as (PVC Le ダグリプチ Application); Glucagon-like peptide-1 or its analogue; Regular Insulin; It is medicine that his spit of fland, fluvastatin, simvastatin, pitavastatin statins such as (ピタバスタチ Application) are cut down in Pravastatin, Simvastatin, holder; Absorb Depressant according to Ezetimibe cholesterol such as (エゼチミ Block); Colestyramine, Colestilan anionite-exchange resin classes such as (コレスチミ De); Bei Te (Off イ Block ラ one ト) such as bezafibrate, fenofibrate, S-8527, clofibrate are medicine; Nicotinic acid such as tocopheryl nicotinate, pentaerythritol tetranicotinate, nicomol are medicine; Probucol; Timnodonic acid; Polyene Phosphatidylcholine (Port リエ Application ホス Off アチジ Le コリ Application); Dextran sodium sulfate; Medicines such as Proteinase, bone marrow serine.

When compound (I) or its pharmaceutically useful salt and other drug composition are used in combination, compound (I) or its pharmaceutically useful salt and other drug composition can be simultaneously give with, also can give respectively pitch time with.Their give and amount can be based on giving and amount of using clinically, according to giving with object, giving with the combination of approach, disease, pharmaceutical cpd etc. and change.

Below, by embodiment and reference example and then specify the present invention, but scope of the present invention is not limited to these embodiment.

The proton NMR spectrum that uses in embodiment and the reference example ( ¹H NMR) measure under 270MHz or 300MHz, according to compound and condition determination, the exchangeability proton has situation about can not clearly observe.The mark of signal multiple degree uses normally usedly, and br represents to refer to the apparent wide signal of.

Reference example 1: 2-ethyl-4,6-dimethylbenzimidazole

2, the 4-xylidine (0.918mL, 7.42mmol) and in the mixed solution of propionic anhydride (6.0mL), ice-cold down, with 20 minutes dropping nitrosonitric acids (1.25mL, 29.7mmol).Under ice-cold, stir after 1 hour, in mixture, add entry and ethyl acetate, extract.Organic layer is with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, and behind anhydrous magnesium sulfate drying, decompression concentrates down.Add in the residue ethyl acetate-hexane (1/1,24mL), filter the solid separate out.The solid that obtains is dissolved in the methyl alcohol (17mL), and 10% palladium charcoal (448mg) exists down, under the nitrogen atmosphere, stirs 1 hour under the room temperature.Filtering mixt, filtrate under reduced pressure concentrate.Residue is dissolved in the acetate (14mL), and 110 ℃ were stirred 30 minutes down.After mixture under reduced pressure concentrated, with the chloroform dilution, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The organic layer anhydrous magnesium sulfate drying, decompression concentrates down.Add in the residue ethyl acetate-hexane (1/5,30mL),, obtain title compound (585mg, 45%) by the solid that filtration is separated out.

¹H-NMR(CDCl ₃，δ)：1.42(t，J＝7.7Hz，3H)，2.42(s，3H)，2.56(br?s，3H)，2.95(q，J＝7.7Hz，2H)，6.86(s，1H)，7.04(br?s，1H)，8.91(s，1H).

Reference example 2: 2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridine

Mix 2,3-diamino-4,6-lutidine (US5332744; 2.70g, 19.7mmol) and tetra ethoxy methane (16.5mL 78.7mmol), stirred 2 hours at 155 ℃.After mixture cooled off room temperature, add Di Iso Propyl Ether (30mL),, obtain title compound (2.42g, 64%) by the solid that filtration is separated out.

ESI-MS?m/z：192(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.1Hz，3H)，2.54(s，3H)，2.63(s，3H)，4.61(q，J＝7.1Hz，2H)，6.78(br?s，1H)，13.42(s，1H).

Reference example 3: 2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridine

With the third imido acid ethyl ester (エチ Le プロピオ Application イミデ one ト) hydrochloride (1.37g, 10.0mmol), aminoacetonitriles hydrochloride (0.93g, 10.0mmol), 1,1,1-three fluoro-2,4-diacetylmethane (3.64mL, 30.0mmol) and diisopropyl ethyl amine (5.23mL is 30.0mmol) 1, in the 2-ethylene dichloride (50mL), reflux down, stirred 4 hours.Add ethyl acetate, water in the mixture and with after the saturated common salt water washing, use anhydrous sodium sulfate drying, decompression concentrates down.Residue is refining with silica gel column chromatography (hexane/ethyl acetate=30/70), obtains title compound (1.07g, 47%).

ESI-MS?m/z：230(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.6Hz，3H)，2.77(s，3H)，3.09(q，J＝7.6Hz，2H)，7.31(s，1H)，12.18(br?s，1H).

Reference example 4: 4-fluoro-7-methyl-2-propyl group benzoglyoxaline

Replace 2, the 4-xylidine, (3.75g 30.0mmol), replaces propionic anhydride, uses butyryl oxide (19mL), and is same with reference example 1, obtains title compound (0.70g, 12%) to use 2-fluoro-5-monomethylaniline.

ESI-MS?m/z：193(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.03(t，J＝7.3Hz，3H)，1.83-1.95(m，2H)，2.48(br?s，3H)，2.92(t，J＝7.7Hz，2H)，6.83(dd，J＝10.2，8.0Hz，1H)，6.91(dd，J＝8.0，5.0Hz，1H)，9.42(br?s，1H).

Reference example 5: 5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4,5-b] pyridine

Replace the third imido acid ethyl ester hydrochloride, and use butyl imido acid ethyl ester (エチ Le Block チ Le イミデ one ト) hydrochloride (758mg, 5.0mmol) same with reference example 3, obtain title compound (503mg, 41%).

¹H-NMR(CDCl ₃，δ)：1.05(t，J＝7.4Hz，3H)，1.85-1.96(m，2H)，2.75(s，3H)，3.02(t，J＝7.8Hz，2H)，7.32(br?s，1H)，11.52(s，1H).

Reference example 6: (E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile and (Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile

[step 1] is with 5-oxo-10,11-dihydro-5H-dibenzo [a, d] suberene-2-carboxylic acid (No. the 2526005th, Japanese Patent, 19.9g, 79mmol) and orthoformic acid triethyl ester (17.0mL 102mmol) is dissolved in ethanol (130mL), adds the vitriol oil (1.68mL, 32mmol), backflow was stirred 12 hours down.Mixture dilutes with ethyl acetate, and organic layer is used anhydrous magnesium sulfate drying after washing with saturated sodium bicarbonate aqueous solution, and decompression concentrates down.Residue is refining with silica gel column chromatography (hexane/ethyl acetate=90/10), obtains 5-oxo-10,11-dihydro-5H-dibenzo [a, d] suberene-2-carboxylic acid ethyl ester (20.8g, 94%).

ESI-MS?m/z：281(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.42(t，J＝7.2Hz，3H)，3.21-3.30(m，4H)，4.40(q，J＝7.2Hz，2H)，7.24(d，J＝7.5Hz，1H)，7.34(td，J＝7.5，1.3Hz，1H)，7.46(td，J＝7.5，1.5Hz，1H)，7.92-8.04(m，4H).

[step 2] sodium hydride (60%, 0.856g, 21.4mmol) and 1-cyano ethyl sulfonic acid diethyl ester (4.09g, 21.4mmol) DMF (35mL) solution in, ice-cold down, add that step 1 obtains 10,11-dihydro-5-oxo-5H-dibenzo [a, d] (80 ℃ were stirred 3 hours down suberene-2-carboxylic acid ethyl ester for 3.0g, DMF 10.7mmol) (10mL) solution.Add entry in the mixture, use ethyl acetate extraction.Organic layer with anhydrous magnesium sulfate drying after, decompression concentrates down and obtains residue.The residue that obtains is dissolved in THF (50mL), add lithium borohydride (1.11g, 50.9mmol) after, 50 ℃ were stirred 5 hours down.Mixture is used ethyl acetate extraction with the neutralization of 2mol/L hydrochloric acid.Organic layer with anhydrous magnesium sulfate drying after, decompression concentrates down.Residue is refining with silica gel column chromatography (chloroform/ethyl acetate=98/2), obtain (E)-2-(2-hydroxymethyl-10 respectively, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (0.730g, 27%) and (Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (0.728g, 27%).

The E body; ¹H-NMR (CDCl ₃, δ): 2.04 (s, 3H), 2.82-2.95 (m, 2H), 3.27-3.40 (m, 2H), 4.67 (d, J=5.8Hz, 2H), 7.08 (d, J=7.8Hz, 1H), 7.13-7.29 (m, 5H), 7.41 (dd, J=7.1,1.8Hz, 1H).

The Z body; ¹H-NMR (CDCl ₃, δ): 2.03 (s, 3H), 2.81-2.97 (m, 2H), 3.26-3.40 (m, 2H), 4.64 (d, J=5.6Hz, 2H), 7.07 (d, J=7.1Hz, 1H), 7.16-7.28 (m, 5H), 7.43 (d, J=7.8Hz, 1H).

Reference example 7: 2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound S 7)

5-cyano methyl-2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl that the step 2 of embodiment 10 is obtained] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(2.21g 4.5mmol) is dissolved in DMF (23mL), add sodiumazide (1.18g, 18.2mmol) and the triethylamine hydrochloride (1.87g, 13.6mmol), 90 ℃ were stirred 20 hours down.Add 5% aqueous citric acid solution in the mixture, use chloroform extraction, organic layer saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.Residue is refining with silica gel column chromatography (chloroform/methanol=25/1), obtains title compound (compound S 7) (1.97g, 81.9%).

ESI-MS?m/z：530(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.85(t，J＝7.3Hz，3H)，1.02(t，J＝7.1Hz，3H)，1.45(s，6H)，1.55(m，2H)，2.57(t，J＝7.5Hz，2H)，3.11(br?s，4H)，4.11(q，J＝7.2Hz，2H)，5.25(s，2H)，5.30(s，2H)，5.35(s，1H)，6.59-7.20(m，7H).

Reference example 8: 2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl] methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (compound S 8)

5-cyano methyl-2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl that the step 2 of use embodiment 11 obtains] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.42g, 3.00mmol) same with reference example 7, obtain title compound (compound S 8) (1.22g, 79%).

ESI-MS?m/z：516(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.09(t，J＝6.4Hz，3H)，1.15(t，J＝6.8Hz，3H)，1.60(s，6H)，2.60(q，J＝7.5Hz，2H)，3.04-3.14(m，4H)，4.17(q，J＝7.1Hz，2H)，5.26(s，2H)，5.30(s，2H)，6.57-6.63(m，2H)，6.94-7.15(m，5H).

Reference example 9: 2-[5-ethoxy carbonyl-4-(1-hydroxyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound S 9)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, and ethyl-(spy opens flat 5-783228 to the 2-propyl imidazole to use 5-ethoxy carbonyl-4-(1-hydroxyl); 1.40g, 6.19mmol), replace lithium hydroxide, the use potassium tert.-butoxide (763mg, 6.81mmol), same with the step 1 of embodiment 1, obtain 2-[5-ethoxy carbonyl-4-(1-hydroxyl) ethyl-2-propyl imidazole-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.20g, 44.9%).

ESI-MS?m/z：434(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.29(t，J＝7.1Hz，3H)，1.52(d，J＝6.4Hz，3H)，1.66-1.78(m，2H)，2.63(t，J＝7.8Hz，2H)，2.99-3.07(m，4H)，3.79(d，J＝7.9Hz，1H)，4.27(q，J＝7.2Hz，1H)，5.17-5.26(m，1H)，5.35(d，J＝16.0Hz，1H)，5.46(d，J＝16.0Hz，1H)，5.99(s，1H)，6.64-6.81(m，5H)，7.01-7.11(m，2H).

2-[5-ethoxy carbonyl-4-(1-hydroxyl) ethyl-2-propyl imidazole-1-yl that [step 2] uses step 1 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (938mg, 2.16mmol) same with the step 2 of embodiment 1, obtain 5-cyano methyl-2-[5-ethoxy carbonyl-4-(1-hydroxyl) ethyl-2-propyl imidazole-1-yl] and methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (742mg, 72.6%).

ESI-MS?m/z：473(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.28(t，J＝7.2Hz，3H)，1.52(d，J＝6.6Hz，3H)，1.66-1.79(m，2H)，2.60(t，J＝7.7Hz，2H)，3.03-3.15(m，4H)，3.74(d，J＝7.9Hz，1H)，4.25(q，J＝7.3Hz，2H)，4.53(s，2H)，5.17-5.26(m，1H)，5.39(d，J＝16.3Hz，1H)，5.47(d，J＝16.3Hz，1H)，6.73-6.79(m，2H)，7.00-7.27(m，5H).

5-cyano methyl-2-[5-ethoxy carbonyl-4-(1-hydroxyl) ethyl-2-propyl imidazole-1-yl that [step 3] uses step 2 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(732mg, 1.55mmol) same with reference example 7, obtain title compound (compound S 9) (557mg, 69.7%).

ESI-MS?m/z：516(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.81(t，J＝7.3Hz，3H)，1.22(t，J＝7.1Hz，3H)，1.47(d，J＝6.4Hz，3H)，1.58(m，2H)，2.56(t，J＝7.8Hz，2H)，3.02-3.11(m，4H)，4.15-4.27(m，2H)，5.24(s，2H)，5.25(m，1H)，5.29(d，J＝16.1Hz，1H)，5.44(d，J＝16.1Hz，1H)，6.62-6.66(m，2H)，6.92-7.11(m，5H).

Reference example 10: 2-[4-(1-hydroxyl-1-methyl) ethyl-5-propoxycarbonyl-2-propyl imidazole-1-yl] methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound S 10)

The compound S 7 that [step 1] obtains reference example 7 (793mg 1.50mmol) is dissolved in DMF (15mL), add the chlorine triphenyl methane (543mg, 1.94mmol) and triethylamine (313 μ L 2.25mmol), stirred 3.5 hours under the room temperature.Add ethyl acetate in the mixture, organic layer is with 5% aqueous citric acid solution, saturated sodium bicarbonate water and saturated common salt water washing.Organic layer with anhydrous magnesium sulfate drying after, decompression concentrates down.Residue is refining with silica gel column chromatography (chloroform/methanol=99/1), obtain 2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(981mg, 85%).

ESI-MS?m/z：772(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.91(t，J＝7.3Hz，3H)，1.12(t，J＝7.1Hz，3H)，1.61-1.73(m，2H)，1.63(s，6H)，2.56(t，J＝7.8Hz，2H)，3.03(brs，4H)，4.15(q，J＝7.1Hz，2H)，5.21(s，2H)，5.32(s，2H)，5.76(s，1H)，6.60-6.65(m，2H)，6.86-7.35(m，20H).

2-[5-ethoxy carbonyl-4-that [step 2] obtains step 1 (1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(979mg 1.27mmol) is dissolved in THF-methanol-water (12mL-3mL-3mL) mixed solvent, and (266mg 6.34mmol), stirred 15 minutes under the room temperature to add lithium hydroxide 1 hydrate.Mixture is under reduced pressure concentrated.Add chloroform and saturated aqueous common salt in the residue,, use chloroform extraction with the neutralization of 1mol/L hydrochloric acid.Organic layer with anhydrous magnesium sulfate drying after, concentrate by reducing pressure down, obtain 2-[5-carboxyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl quantitatively] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.15g).

ESI-MS?m/z：744(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.67(t，J＝6.9Hz，3H)，1.32-1.40(m，2H)，1.62(s，6H)，2.60-2.69(m，2H)，2.98(br?s，4H)，5.14(s，2H)，5.62(s，2H)，6.70-6.74(m，2H)，6.85-7.32(m，20H).

2-[5-carboxyl-4-that [step 3] obtains step 2 (1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (200mg 0.269mmol) is dissolved in DMF (1.3mL), add salt of wormwood (93.0mg, 0.673mmol) and the 1-N-PROPYLE BROMIDE (48.8 μ L, 0.537mmol), 50 ℃ were stirred 2 hours down.Add ethyl acetate in the mixture.Organic layer water and saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.Residue is refining with silica gel column chromatography (hexane/ethyl acetate=70/30), obtain 2-[4-(1-hydroxyl-1-methyl) ethyl-5-propoxycarbonyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(130mg, 62%).

ESI-MS?m/z：786(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.76(t，J＝7.4Hz，3H)，0.90(t，J＝7.4Hz，3H)，1.45-1.72(m，4H)，1.63(s，6H)，2.55(t，J＝7.8Hz，2H)，3.03(brs，4H)，4.06(t，J＝6.8Hz，2H)，5.21(s，2H)，5.32(s，2H)，5.78(s，1H)，6.61-6.64(m，2H)，6.87-7.35(m，20H).

The 2-[4-that [step 4] obtains step 3 (1-hydroxyl-1-methyl) ethyl-5-propoxycarbonyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(128mg 0.163mmol) is suspended in acetate-acetone-water (1.6mL-1.6mL-1.6mL) mixed solvent, and 50 ℃ were stirred 2 hours down.Mixture is under reduced pressure concentrated, and residue is refining with silica gel column chromatography (chloroform/methanol=99/1), obtains title compound (compound S 10) (64.5mg, 73%).

ESI-MS?m/z：544(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.75(t，J＝7.4Hz，3H)，0.84(t，J＝7.3Hz，3H)，1.43-1.64(m，4H)，1.60(s，6H)，2.54(t，J＝7.8Hz，2H)，3.00-3.13(m，4H)，4.07(t，J＝6.8Hz，2H)，5.24(s，2H)，5.31(s，2H)，6.56-6.61(m，2H)，6.92-7.13(m，5H).

Reference example 11: 2-[4-(1-hydroxyl-1-methyl) ethyl-5-isopropoxy carbonyl-2-propyl imidazole-1-yl] methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound S 11)

2-[5-carboxyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl that [step 1] uses the step 2 of reference example 10 to obtain] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(200mg, 0.269mmol), replace the 1-N-PROPYLE BROMIDE, use 2-N-PROPYLE BROMIDE (101 μ L, 1.08mmol), same with reference example 10 steps 3, obtain 2-[4-(1-hydroxyl-1-methyl) ethyl-5-isopropoxy carbonyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(140mg, 66%).

ESI-MS?m/z：786(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.90(t，J＝7.3Hz，3H)，1.08(d，J＝6.3Hz，6H)，1.58-1.71(m，2H)，1.63(s，6H)，2.54(t，J＝7.8Hz，2H)，3.04(brs，4H)，5.01-5.11(m，1H)，5.21(s，2H)，5.32(s，2H)，5.84(s，1H)，6.61-6.64(m，2H)，6.87-7.34(m，20H).

2-[4-(1-hydroxyl-1-methyl) ethyl-5-isopropoxy carbonyl-2-propyl imidazole-1-yl that [step 2] uses step 1 to obtain] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (137mg, 0.174mmol) same with the step 4 of reference example 10, obtain title compound (compound S 11) (75.8mg, 80%).

ESI-MS?m/z：544(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.83(t，J＝7.3Hz，3H)，1.02(d，J＝6.2Hz，6H)，1.51-1.61(m，2H)，1.60(s，6H)，2.55(t，J＝7.8Hz，2H)，3.02-3.13(m，4H)，5.06(q，J＝6.2Hz，1H)，5.24(s，2H)，5.30(s，2H)，6.55-6.60(m，2H)，6.92-7.14(m，5H).

Reference example 12: 2-[5-cyclohexyl methoxycarbonyl-4-(1-hydroxyl-1-methyl) ethyl 2-propyl imidazole-1-yl] methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound S 12)

2-[5-carboxyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl that [step 1] uses the step 2 of embodiment 10 to obtain] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(228mg, 0.306mmol), replace the 1-N-PROPYLE BROMIDE, use brooethyl hexanaphthene (257 μ L, 1.84mmol), same with the step 3 of reference example 10, obtain 2-[5-cyclohexyl methoxycarbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(159mg, 62%).

ESI-MS?m/z：840(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.68-1.08(m，5H)，0.90(t，J＝7.3Hz，3H)，1.35-1.65(m，8H)，1.60(s，6H)，2.54(t，J＝7.8Hz，2H)，3.03(br?s，4H)，3.92(d，J＝6.1Hz，2H)，5.20(s，2H)，5.32(s，2H)，5.89(br?s，1H)，6.57-6.61(m，2H)，6.87-7.11(m，10H)，7.20-7.34(m，10H).

2-[5-cyclohexyl methoxycarbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl that [step 2] uses step 1 to obtain] methyl-5-(2-trityl-2H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (156mg, 0.186mmol) same with reference example 10 steps 4, obtain title compound (compound S 12) (75.4mg, 68%).

ESI-MS?m/z：598(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.68-1.06(m，5H)，0.82(t，J＝7.3Hz，3H)，1.35-1.64(m，8H)，1.60(s，6H)，2.53(t，J＝7.8Hz，2H)，3.01-3.13(m，4H)，3.93(d，J＝6.1Hz，2H)，5.23(s，2H)，5.31(s，2H)，6.53-6.57(m，2H)，6.90-7.10(m，5H).

Same with No. the 2526005th, Japanese Patent, obtain compound (S13～S19) below with reference to example 13～19.

Reference example 13: 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (compound S 13)

Reference example 14: 2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(1H-tetrazolium-5-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound S 14)

Reference example 15: [2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (compound S 15)

Reference example 16: (E)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(1H-tetrazolium-5-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound S 16)

Reference example 17: (Z)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(1H-tetrazolium-5-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound S 17)

Reference example 18: (E)-and 3-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(1H-tetrazolium-5-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound S 18)

Reference example 19: (Z)-and 8-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(1H-tetrazolium-5-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound S 19)

Reference example 20: 2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridine

Mix 2,3-diamino-4-picoline (US5332744; 2.00g, 16.2mmol) and tetra ethoxy methane (15.0mL, 71.7mmol), 150 ℃ were stirred 2 hours down.After mixture is cooled to room temperature, add Di Iso Propyl Ether (15mL),, obtain title compound (1.96g, 68%) by the solid that filtration is separated out.

ESI-MS?m/z：178(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.49(t，J＝7.2Hz，3H)，2.57(s，3H)，4.63(q，J＝7.2Hz，2H)，6.93(d，J＝5.1Hz，1H)，8.03(d，J＝5.1Hz，1H).

Reference example 21: 2-oxyethyl group-3H-imidazo [4,5-b] pyridine

Mix 2,3 diamino pyridine (7.84g, 71.9mmol) and tetra ethoxy methane (35mL, 167mmol), 130 ℃ were stirred 2 hours down.After mixture is cooled to room temperature, add ethyl acetate (100mL),, obtain title compound (4.17g, 36%) by the solid that filtration is separated out.

ESI-MS?m/z：164(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.52(t，J＝7.2Hz，3H)，4.65(q，J＝7.2Hz，2H)，7.13(dd，J＝7.9，5.0Hz，1H)，7.80(dd，J＝7.9，1.3Hz，1H)，8.18(dd，J＝5.0，1.3Hz，1H).

Reference example 22: 7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridine

With 2-ethyl-3H-imidazo [4,5-b] pyridine (US5332744; 4.00g, 27.2mmol) be dissolved in chloroform (45mL), (5.18g 29.9mmol), stirred 5 hours under the room temperature to add metachloroperbenzoic acid.Concentration of reaction solution adds ethyl acetate and water and carries out separatory.Concentrate water layer, residue is dissolved in chloroform (8mL), and (24mL 257mmol) stirred 2 hours under the adding room temperature phosphoryl chloride.After adding reaction solution in the ice,, use ethyl acetate extraction with the ammoniacal liquor neutralization.Organic layer is used anhydrous magnesium sulfate drying after using the saturated common salt water washing, and decompression concentrates down.Add ethyl acetate (30mL) in the residue,, obtain title compound (3.32g, 67%) by the solid that filtration is separated out.

ESI-MS?m/z：182(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.55(t，J＝7.6Hz，3H)，3.13(q，J＝7.6Hz，2H)，7.29(d，J＝5.4Hz，1H)，8.21(d，J＝5.4Hz，1H).

Reference example 23: 7-chloro-2-oxyethyl group-3H-imidazo [4,5-b] pyridine

Replace 2,3 diamino pyridine, use 4-chloro-2,3 diamino pyridine (EP420237; 0.79g, 5.5mmol) same with reference example 21, obtain title compound (0.34g, 31%).

ESI-MS?m/z：198(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.51(t，J＝7.1Hz，3H)，4.70(q，J＝7.1Hz，2H)，7.16(d，J＝5.3Hz，1H)，8.06(d，J＝5.3Hz，1H).

Reference example 24: 7-chloro-2-cyclopropyl-3H-imidazo [4,5-b] pyridine

Replace 2-ethyl-3H-imidazo [4,5-b] pyridine, use 2-cyclopropyl-3H-imidazo [4,5-b] pyridine (EP420237; 4.79g, 30.1mmol) same with reference example 22, obtain title compound (3.22g, 55%).

ESI-MS?m/z：194(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.09-1.18(m，4H)，2.10-2.20(m，1H)，7.26(d，J＝5.4Hz，1H)，8.14(d，J＝5.4Hz，1H).

Reference example 25: 4-chloro-2-oxyethyl group benzo imidazoles

With 2-chloro-6-N-methyl-p-nitroaniline (3.45g, 20.0mmol) and stannous chloride dihydrate (18.05g 80.0mmol) refluxes in ethanol (80mL) and heated 3 hours down.Reaction solution neutralizes with aqueous sodium hydroxide solution, and precipitate is by removing by filter.Filtrate is used ethyl acetate extraction, after the saturated common salt water washing, uses anhydrous magnesium sulfate drying, and decompression concentrates down.(10mL, 47.7mmol), 130 ℃ were stirred 12 hours down to mix tetra ethoxy methane in the residue.Reaction mixture is refining with silica gel column chromatography (hexane/ethyl acetate=50/50), obtains title compound (1.38g, 35%).

ESI-MS?m/z：197(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.42-1.50(m，3H)，4.52-4.74(m，2H)，6.99-7.46(m，3H).

Reference example 26: 4-chloro-2-cyclopropyl benzo imidazoles

With 2-chloro-6-N-methyl-p-nitroaniline (3.00g, 17.4mmol) and pyridine (7.0mL 86.9mmol) is dissolved among the DMA (17mL), adds cyclopropane carboxylic acid isoxazolecarboxylic acid (4.0mL, 43.5), and 50 ℃ were stirred 3 hours down.Add methyl alcohol (10mL) and ammoniacal liquor (9mL) in the reaction solution, stirred 30 minutes under the room temperature.Add water (10mL), filter the solid of separating out.Solid is suspended in ethanol (38mL) and the water (38mL), and (13.86g, 49.9mmol) and ammoniacal liquor (19mL), 50 ℃ were stirred 4 hours down to add the ferrous sulfate heptahydrate.Filtering reacting liquid, filtrate is used ethyl acetate extraction, after the saturated common salt water washing, uses anhydrous magnesium sulfate drying, and decompression concentrates down.Add acetate (8mL) in the residue, 90 ℃ were stirred 1 hour down.The reaction solution decompression with the aqueous sodium hydroxide solution neutralization, is used ethyl acetate extraction after concentrating down.Organic layer is used anhydrous magnesium sulfate drying after using the saturated common salt water washing, and decompression concentrates down.Add ethyl acetate (5mL) and Di Iso Propyl Ether (5mL) in the residue,, obtain title compound (1.20g, 36%) by the solid that filtration is separated out.

ESI-MS?m/z：193(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.11-1.25(m，4H)，2.01-2.14(m，1H)，7.05-7.55(m，3H).

Reference example 27: 2-oxyethyl group-4-tolimidazole

Mix 2, the 3-diaminotoluene (6.09g, 49.8mmol) and tetra ethoxy methane (25mL, 119mmol), 130 ℃ were stirred 16 hours down.After mixture is cooled to room temperature, with the ethyl acetate dilution, after the saturated common salt water washing, use anhydrous magnesium sulfate drying, decompression concentrates down.Residue is refining with silica gel column chromatography (hexane/ethyl acetate=70/30), obtains title compound (6.89g, 78%).

ESI-MS?m/z：177(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.1Hz，1.2H)，1.46(t，J＝7.1Hz，1.8H)，2.41(s，1.8H)，2.56(s，1.2H)，4.59(q，J＝7.1Hz，1.2H)，4.60(q，J＝7.1Hz，0.8H)，6.91-7.10(m，2.4H)，7.38(d，J＝7.9Hz，0.6H).

Reference example 28: 2-cyclopropyl-4-tolimidazole

Use 2-methyl-6-N-methyl-p-nitroaniline (7.61g, 50.0mmol) same with reference example 26, obtain title compound (6.91g, 80%).

ESI-MS?m/z：173(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.08-1.23(m，4H)，2.11(br?s，1H)，2.51-2.62(br?m，3H)，7.00(d，J＝7.5Hz，1H)，7.11(t，J＝7.5Hz，1H)，7.18-7.52(br?m，2H).

Reference example 29: 4-chloro-2-ethyl benzo imidazole

[step 1] is cooled to 0 ℃ with propionic anhydride (40mL), and (5.0mL 47.5mmol) stirred 15 minutes to add the 2-chloroaniline.Interior temperature is remained on below 10 ℃, and (8.0mL 190mmol), ice-coldly stirred 15 fens down to drip nitrosonitric acid simultaneously.Add entry (100mL) in the reaction solution, filter the solid of separating out.Behind solid drying,, obtain N-(2-chloro-6-nitrophenyl) propionic acid amide (3.73g, 34%) by ethyl acetate (50mL) recrystallization.

¹H-NMR(CDCl ₃，δ)：1.27(t，J＝7.6Hz，3H)，2.49(q，J＝7.6Hz，2H)，7.31(t，J＝8.3Hz，1H)，7.70(dd，J＝8.3，1.3Hz，1H)，7.88(dd，J＝8.3，1.3Hz，1H).

N-(the 2-chloro-6-nitrophenyl) propionic acid amide that [step 2] use step 1 obtains (3.72g, 16.3mmol) same with reference example 26, obtain title compound (1.53g, 52%).

¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.7Hz，3H)，2.99(q，J＝7.7Hz，2H)，7.12-7.59(m，3H).

Reference example 30: (E)-2-(3-hydroxymethyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) propionitrile

[step 1] (200mmol) with THF (40mL) dilution, 0 ℃ when stirring down, with 15 minutes dropping propionitrile (7.13mL, THF 100mmol) (40mL) solution for 2.0mol/L heptane/THF/ ethylbenzene solution, 100mL with LDA.0 ℃ was stirred 30 minutes down, with 45 minutes dropping chlorine di(2-ethylhexyl)phosphate ethyl ester (14.4mL, THF 100mmol) (40mL) solution.Stir under the room temperature after 2 hours, add 11-oxo-6, (No. the 2526005th, Japanese Patent, 10.7g 40mmol), stirred 1.5 hours under the room temperature 11-dihydro-dibenzo [b, e] oxa-seven ring-3-carboxylic acid methyl ester.Add ethyl acetate and water in the reaction solution, use ethyl acetate extraction 3 times.Organic layer saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.Residue silica gel column chromatography (ethyl acetate: hexane=15: 85) refining, obtain (E)-11-(1-cyano group ethylidene)-6,11-dihydro-dibenzo [b, e] oxa-seven ring-3-carboxylic acid methyl ester (6.40g, 21.0mmol, 52.6%) and (Z)-11-(1-cyano group ethylidene)-6,11-dihydro-dibenzo [b, e] oxa-seven ring-3-carboxylic acid methyl ester (4.47g, 14.6mmol, 36.7%).

The E body; ¹H-NMR (DNSO-d ₆, δ): 2.20 (s, 3H), 3.83 (s, 3H), 5.04 (d, J=12.7Hz, 1H), 5.57 (d, J=12.7Hz, 1H), 7.34-7.62 (m, 7H).

The Z body; ¹H-NMR (DMSO-d ₆, δ): 1.98 (s, 3H), 3.83 (s, 3H), 5.03 (d, J=12.7Hz, 1H), 5.55 (d, J=12.7Hz, 1H), 7.33-7.65 (m, 7H).

[step 2] with (E)-11-(1-cyano group ethylidene)-6, (6.40g 21.0mmol) is suspended among the THF (105mL) 11-dihydro-dibenzo [b, e] oxa-seven ring-3-carboxylic acid methyl ester, and (2.29g, 105mmol), 50 ℃ were stirred 6 hours down to add lithium borohydride.Reaction solution adds ice, adds 1mol/L hydrochloric acid, is neutralized to pH 2, uses ethyl acetate extraction 2 times.Organic layer saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.The residue silica gel column chromatography (ethyl acetate: hexane=30: 70) refining, obtain title compound (4.89g, 17.6mmol, 84.1%).

¹H-NMR(CDCl ₃，δ)：1.63(t，J＝5.9Hz，1H)，2.26(s，3H)，4.61(d，J＝5.9Hz，2H)，4.87(d，J＝12.5Hz，1H)，5.48(d，J＝12.5Hz，1H)，6.84-6.96(m，2H)，7.07(d，J＝7.9Hz，1H)，7.36-7.50(m，4H).

Reference example 31: (Z)-2-(8-hydroxymethyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) propionitrile

Use 11-oxo-6,11-dihydro-dibenzo [b, e] oxa-seven ring-8-carboxylic acid methyl (No. the 2526005th, Japanese Patent, 1.00g, 3.73mmol), same with the step 2 of reference example 6, obtain title compound (0.178g, 17%) with and E isomery (0.260g, 25%).

The Z body; ¹H-NMR (CDCl ₃, δ): 2.03 (s, 3H), 4.72 (br s, 2H), 4.85 (d, J=12.6Hz, 1H), 5.48 (d, J=12.6Hz, 1H), 6.82 (dd, J=8.2,1.1Hz, 1H), 6.93-6.98 (m, 1H), 7.16 (d, J=7.9Hz, 1H), 7.22-7.27 (m, 1H), 7.37 (dd, J=7.8,1.7Hz, 1H), 7.42 (br s, 1H), 7.51 (dd, J=7.9,1.6Hz, 1H).

The E body; ¹H-NMR (CDCl ₃, δ): 2.23 (s, 3H), 4.61 (s, 2H), 4.82 (d, J=12.6Hz, 1H), 5.45 (d, J=12.6Hz, 1H), 6.83-6.92 (m, 2H), 7.05 (dd, J=7.8,1.7Hz, 1H), 7.18-7.24 (m, 1H), 7.30-7.34 (m, 2H), 7.42 (d, J=8.3Hz, 1H).

[embodiment 1]

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 1)

[step 1] with 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (US5332744; 36.55g, 209mmol) be dissolved in DMF (365.5mL), (5.62g 235mmol), stirred 15 minutes under the room temperature to add lithium hydroxide.In this mixture, add 1-(10,11-dihydro-5H-dibenzo [b, f] azepine

-2-ylmethyl)-(spy opens flat 7-61983 to 1-methyl piperidine iodide; 95.0g 219mmol) and DMF (73.1mL), 40 ℃ were stirred 8 hours down.After being cooled to room temperature, drip water (175.4mL), ice-cold stirring down 2 hours.Filter precipitate, overheatedly be dissolved in chloroform (520mL) down, add gac (5.2g), heated and stirred is after 30 minutes, filtration when hot.Add ethyl acetate (1041mL) in the filtrate,, obtain 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine by filtering precipitate (36.7g, 46%).

ESI-MS?m/z：384(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.30(t，J＝7.5Hz，3H)，2.60(s，3H)，2.63(s，3H)，2.78(q，J＝7.5Hz，2H)，2.90-3.10(m，4H)，5.34(s，2H)，6.15(s，1H)，6.26(d，J＝8.0Hz，1H)，6.65-6.85(m，4H)，6.89(s，1H)，6.95-7.10(s，2H).

The 2-that [step 2] obtains step 1 (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(55.4g 145mmol) is dissolved in acetate (500mL), 10 ℃ add down potassium cyanide (11g, 169mmol) and paraformaldehyde (4.6g 152mmol), stirred 24 hours under the room temperature.Mixture is joined in the mixing solutions of 10mol/L aqueous sodium hydroxide solution (900mL), ice (1L) and methylene dichloride (1L).Organic layer is with 0.1mol/L aqueous sodium hydroxide solution and saturated common salt water washing, and behind anhydrous magnesium sulfate drying, decompression concentrates down.Residue is refining with silica gel column chromatography (hexane/ethyl acetate/triethylamine=10/10/1), obtains 5-cyano methyl-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(39.0g, 64%).

ESI-MS?m/z：422(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.32(t，J＝7.6Hz，3H)，2.58(s，3H)，2.63(s，3H)，2.77(q，J＝7.6Hz，2H)，3.06(br?s，4H)，4.51(s，2H)，5.37(s，2H)，6.89-7.04(m，6H)，7.10-7.26(s，4H).

5-cyano methyl-2-that [step 3] obtains step 2 (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(200mg 0.47mmol) is dissolved in ethanol (4mL), and (2.37mmol), heating down 1 hour refluxes for 50% aqueous solution, 0.15mL to add oxyamine.With the mixture concentrating under reduced pressure.The residue that obtains is dissolved in DMF (1mL), 0 ℃ add down pyridine (46 μ L, 0.57mmol) and chlorine carbonic acid ethyl ester (54 μ L 0.57mmol), stirred 2 hours under the room temperature.Add ethyl acetate and saturated sodium bicarbonate aqueous solution in the mixture.Organic layer saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.The residue that obtains is dissolved in toluene (10mL), and (51mg 0.45mmol), stirred 15 minutes under the room temperature to add potassium tert.-butoxide.Add ethyl acetate in the mixture, organic layer washs with 5% aqueous citric acid solution, and behind anhydrous magnesium sulfate drying, decompression concentrates down, obtains title compound (compound 1) (190mg, 83%).

ESI-MS?m/z：481[M+H] ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.19(t，J＝7.5Hz，3H)，2.65(d，J＝15.4Hz，3H)，2.75(d，J＝15.4Hz，3H)，3.05-3.12(m，4H)，3.37(q，J＝7.0Hz，2H)，4.84(s，2H)，5.34(s，2H)，6.93(dd，J＝8.4，2.2Hz，1H)，6.93(s，1H)，6.95-6.97(m，2H)，7.10-7.18(m，4H)，12.32(br?s，1H).

[embodiment 2]

2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 2)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline (EP502314; 1.0g, 3.29mmol) same with embodiment 1 step 1, obtain 2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (1.67g, 98%).

ESI-MS?m/z：512(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.04(t，J＝6.9Hz，3H)，1.78-1.92(m，2H)，2.76(s，3H)，2.88-3.03(m，6H)，3.79(s，3H)，5.28(s，2H)，6.02(s，1H)，6.62-6.79(m，5H)，7.00-7.08(m，2H)，7.26-7.37(m，3H)，7.41(s，1H)，7.47(s，1H)，7.78-7.81(m，1H).

2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl that [step 2] uses step 1 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.67g, 3.26mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] and methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.43g, 80%).

ESI-MS?m/z：551(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.04(t，J＝7.1Hz，3H)，1.80-1.92(m，2H)，2.76(s，3H)，2.89(t，J＝7.9Hz，2H)，3.01-3.10(m，4H)，3.72(s，3H)，4.51(s，2H)，5.32(s，2H)，6.82-6.89(m，2H)，7.00-7.35(m，8H)，7.39(s，1H)，7.42(s，1H)，7.77-7.80(m，1H).

5-cyano methyl-2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl that [step 3] uses step 2 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(0.20g, 0.36mmol) same with embodiment 1 step 3, obtain title compound (compound 2) (69mg, 32%).

ESI-MS?m/z：610(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.98(t，J＝7.8Hz，3H)，1.79(q，J＝7.1Hz，2H)，2.61(s，3H)，2.89(t，J＝7.9Hz，2H)，3.07(br?s，4H)，3.74(s，3H)，4.44(s，2H)，5.44(s，2H)，6.83-6.93(m，2H)，6.99-7.11(m，5H)，7.19-7.29(m，2H)，7.45(s，1H)，7.54(t，J＝7.1Hz，1H)，7.64(d，J＝7.5Hz，1H)，7.67(s，1H)，12.54(br?s，1H).

[embodiment 3]

2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 3)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridine (US5332744; 1.89g, 10.0mmol) same with embodiment 1 step 1, obtain 2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(2.74g, 69%).

ESI-MS?m/z：397(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.96(t，J＝7.3Hz，3H)，1.66-1.79(m，2H)，2.60(s，3H)，2.62(s，3H)，2.75(t，J＝7.8Hz，2H)，2.97-3.03(m，4H)，5.35(s，2H)，5.99(s，1H)，6.60-6.84(m，5H)，6.88(s，1H)，7.00-7.09(m，2H).

2-(5,7-dimethyl-2-propyl group-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(2.54g, 6.41mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (2.01g, 72%).

ESI-MS?m/z：436(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.97(t，J＝7.3Hz，3H)，1.68-1.82(m，2H)，2.58(s，3H)，2.62(s，3H)，2.73(t，J＝7.8Hz，2H)，3.01-3.12(m，4H)，4.51(s，2H)，5.37(s，2H)，6.88-7.24(m，8H).

5-cyano methyl-2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(218mg, 0.501mmol) same with embodiment 1 step 3, obtain title compound (compound 3) (173mg, 70%).

ESI-MS?m/z：495(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.86(t，J＝7.3Hz，3H)，1.57-1.71(m，2H)，2.49(s，6H)，2.70(t，J＝7.5Hz，2H)，3.09(br?s，4H)，4.84(s，2H)，5.34(s，2H)，6.80-7.18(m，8H)，12.33(br?s，1H).

[embodiment 4]

2-(2,5-diethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 4)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2,5-diethyl-7-methyl-3H-imidazo [4,5-b] pyridine (US5332744; 226mg, 0.520mmol) same with embodiment 1 step 1, obtain 2-(2,5-diethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(139mg, 74%).

ESI-MS?m/z：367(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.6Hz，3H)，1.34(t，J＝7.5Hz，3H)，2.64(s，3H)，2.78-2.90(m，4H)，2.96-3.04(m，4H)，5.35(s，2H)，5.99(s，1H)，6.61-7.08(m，8H).

2-(2,5-diethyl-7-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (136mg, 0.343mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(2,5-diethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(102mg, 68%).

ESI-MS?m/z：436(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.32(t，J＝7.6Hz，3H)，1.33(t，J＝7.6Hz，3H)，2.63(s，3H)，2.79(q，J＝7.6Hz，2H)，2.85(q，J＝7.6Hz，2H)，3.03-3.11(m，4H)，4.51(s，2H)，5.37(s，2H)，6.89-7.26(m，8H).

5-cyano methyl-2-(2,5-diethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(54.0mg, 0.124mmol) same with embodiment 1 step 3, obtain title compound (compound 4) (28.2mg, 46%).

ESI-MS?m/z：495(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.20(t，J＝7.5Hz，3H)，1.25(t，J＝7.5Hz，3H)，2.50(s，3H)，2.77(q，J＝7.5Hz，2H)，2.77(q，J＝7.5Hz，2H)，3.08(br?s，4H)，4.84(s，2H)，5.33(s，2H)，6.89-6.97(m，3H)，7.02-7.18(m，5H)，12.31(s，1H).

[embodiment 5]

2-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 5)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 2-ethyl-4 that uses reference example 1 to obtain, 6-dimethylbenzimidazole (256mg, 1.47mmol), same with embodiment 1 step 1, obtain 2-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(422mg, 75%).

ESI-MS?m/z：382(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.25(t，J＝7.4Hz，3H)，2.33(s，3H)，2.46(s，3H)，2.81(q，J＝7.4Hz，2H)，2.85-2.91(m，4H)，5.22(s，2H)，6.62-7.05(m，10H).

2-(2-ethyl-4, the 6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(422mg, 1.11mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(241mg, 52%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.6Hz，3H)，2.38(s，3H)，2.64(s，3H)，2.85(q，J＝7.6Hz，2H)，3.02-3.12(m，4H)，4.52(s，2H)，5.21(s，2H)，6.78-6.87(m，4H)，7.00-7.24(m，5H).

5-cyano methyl-2-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(122mg, 0.290mmol) same with embodiment 1 step 3, obtain title compound (compound 5) (71.5mg, 51%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.22(t，J＝7.5Hz，3H)，2.31(s，3H)，2.46(s，3H)，2.77(q，J＝7.4Hz，2H)，3.09(br?s，4H)，4.83(s，2H)，5.28(s，2H)，6.74-7.18(m，9H)，12.34(s，1H).

[embodiment 6]

2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 6)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 4-methyl-2-propyl group benzoglyoxaline (EP400835; 3.00g, 17.2mmol) same with embodiment 1 step 1, obtain 2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (4.46g, 71%).

ESI-MS?m/z：382(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.3Hz，3H)，1.73-1.86(m，2H)，2.69(s，3H)，2.86(t，J＝8.1Hz，2H)，2.97-3.04(s，4H)，5.22(s，2H)，6.02(s，1H)，6.61-6.64(m，1H)，6.70-6.80(m，4H)，7.01-7.12(m，5H).

2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(4.46g, 11.7mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(3.73g, 76%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.1Hz，3H)，1.74-1.87(m，2H)，2.69(s，3H)，2.84(t，J＝8.1Hz，2H)，3.00-3.11(s，4H)，4.51(s，2H)，5.24(s，2H)，6.79-6.80(m，1H)，6.87(dd，J＝8.4，2.2Hz，1H)，6.98-7.24(m，8H).

5-cyano methyl-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(0.50g, 1.19mmol) same with embodiment 1 step 3, obtain title compound (compound 6) (0.20g, 35%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.90(t，J＝7.4Hz，3H)，1.69(q，J＝7.3Hz，2H)，2.48(s，3H)，2.75(t，J＝7.6Hz，2H)，3.07(br?s，4H)，4.82(s，2H)，5.32(s，2H)，6.75-6.79(m，1H)，6.90-7.02(m，4H)，7.07-7.20(m，5H)，12.35(br?s，1H).

[embodiment 7]

2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 7)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 2-oxyethyl group-5 that uses reference example 2 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridine (478mg, 2.50mmol), same with embodiment 1 step 1, obtain 2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(324mg, 33%).

ESI-MS?m/z：399(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.44(t，J＝7.1Hz，3H)，2.49(s，3H)，2.56(s，3H)，3.02(br?s，4H)，4.58(q，J＝7.0Hz，2H)，5.12(s，2H)，5.98(s，1H)，6.60-6.78(m，4H)，7.00-7.08(m，4H).

2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(320mg, 0.803mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (336mg, 96%).

ESI-MS?m/z：438(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.36(t，J＝7.1Hz，3H)，2.40(s，3H)，2.44(s，3H)，3.04(br?s，4H)，4.53(q，J＝7.1Hz，2H)，4.89(s，2H)，5.09(s，2H)，6.84(s，1H)，6.98-7.19(m，7H).

5-cyano methyl-2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (159mg, 0.363mmol) same with embodiment 1 step 3, obtain title compound (compound 7) (119mg, 66%).

ESI-MS?m/z：497(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.34(t，J＝7.0Hz，3H)，2.39(s，3H)，2.43(s，3H)，3.10(br?s，4H)，4.51(q，J＝7.1Hz，2H)，4.84(s，2H)，5.06(s，2H)，6.83(s，1H)，6.92-6.97(m，2H)，7.03-7.18(m，5H)，12.33(s，1H).

[embodiment 8]

2-(2-methoxyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 8)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-methoxyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (WO2005/82905; 443mg, 2.50mmol) same with embodiment 1 step 1, obtain 2-(2-methoxyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (285mg, 30%).

ESI-MS?m/z：385(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：2.51(s，3H)，2.56(s，3H)，3.01(br?s，4H)，4.17(s，3H)，5.12(s，2H)，5.99(s，1H)，6.60-6.79(m，4H)，6.99-7.08(m，4H).

2-(2-methoxyl group-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(281mg, 0.731mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(2-methoxyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(210mg, 68%).

ESI-MS?m/z：424(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：2.41(s，3H)，2.44(s，3H)，3.04(br?s，4H)，4.10(s，3H)，4.89(s，2H)，5.10(s，2H)，6.86(s，1H)，6.97-7.06(m，3H)，7.12-7.20(m，4H).

5-cyano methyl-2-(2-methoxyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(101mg, 0.238mmol) same with embodiment 1 step 3, obtain title compound (compound 8) (69.0mg, 60%).

ESI-MS?m/z：483(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：2.49(s，3H)，2.52(s，3H)，3.06(br?s，4H)，4.13(s，3H)，4.72(s，2H)，5.11(s，2H)，6.77(s，1H)，6.87-7.11(m，7H).

[embodiment 9]

2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 9)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (US5332744; 322mg, 2.00mmol) same with embodiment 1 step 1, obtain 2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(153mg, 21%).

ESI-MS?m/z：369(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.25(t，J＝7.4Hz，3H)，2.55(s，3H)，2.85(q，J＝7.4Hz，2H)，2.89(br?s，4H)，5.33(s，2H)，6.61-6.66(m，1H)，6.82-7.08(m，7H)，8.16(d，J＝4.8Hz，1H)，8.30(s，1H).

2-(2-ethyl-7-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(150mg, 0.407mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(156mg, 94%).

ESI-MS?m/z：408(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.5Hz，3H)，2.69(s，3H)，2.84(q，J＝7.5Hz，2H)，3.02-3.10(m，4H)，4.50(s，2H)，5.40(s，2H)，6.90-7.26(m，8H)，8.19(d，J＝5.0Hz，1H).

5-cyano methyl-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(79.0mg, 0.194mmol) same with embodiment 1 step 3, obtain title compound (compound 9) (20.6mg, 23%).

ESI-MS?m/z：467(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.23(t，J＝7.6Hz，3H)，2.58(s，3H)，2.79(q，J＝7.6Hz，2H)，2.87-2.99(m，4H)，4.74(s，2H)，5.35(s，2H)，6.50(s，1H)，6.77(s，1H)，6.84-7.16(m，7H)，8.13(d，J＝5.0Hz，1H).

[embodiment 10]

2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 10)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, and (spy opens flat 5-783228 to ethyl-2-propyl imidazole to use 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl); 5.87g, 13.5mmol), replace lithium hydroxide, the use potassium tert.-butoxide (1.67g, 14.9mmol), same with embodiment 1 step 1, obtain 2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(2.73g, 45%).

ESI-MS?m/z：448(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.21(t，J＝7.1Hz，3H)，1.63-1.76(m，2H)，1.63(s，6H)，2.63(t，J＝7.8Hz，2H)，2.99-3.07(m，4H)，4.25(q，J＝7.1Hz，2H)，5.34(s，2H)，5.80(s，1H)，5.99(s，1H)，6.58-6.81(m，5H)，7.02-7.10(m，2H).

2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl that [step 2] uses step 1 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (2.73g, 6.1mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] and methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(2.21g, 74%).

ESI-MS?m/z：487(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94(t，J＝7.3Hz，3H)，1.19(t，J＝7.1Hz，3H)，1.62-1.77(m，2H)，1.63(s，6H)，2.60(t，J＝7.8Hz，2H)，3.06-3.14(m，4H)，4.23(q，J＝7.1Hz，2H)，4.54(s，2H)，5.37(s，2H)，5.73(s，1H)，6.68-6.76(m，2H)，7.01-7.28(m，5H).

5-cyano methyl-2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl that [step 3] uses step 2 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (131mg, 0.269mmol) same with embodiment 1 step 3, obtain title compound (compound 10) (106mg, 72%).

ESI-MS?m/z：546(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.92(t，J＝7.3Hz，3H)，1.13(t，J＝7.1Hz，3H)，1.61(s，6H)，1.68(m，2H)，2.58(t，J＝7.8Hz，2H)，3.13(br?s，4H)，4.18(q，J＝7.2Hz，2H)，4.81(s，2H)，5.33(s，2H)，5.79(br?s，1H)，6.66-6.70(m，2H)，7.20-6.97(m，5H).

[embodiment 11]

2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl] methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 11)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, and ethoxy carbonyl-(spy opens flat 5-783228 to ethyl imidazol(e) to 2-ethyl-4-(1-hydroxyl-1-methyl) to use 5-; 650mg 1.50mmol), replaces lithium hydroxide, the use potassium tert.-butoxide (1.67g, 14.9mmol), same with embodiment 1 step 1, obtain 2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(302mg, 47%).

ESI-MS?m/z：434(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.22(t，J＝7.1Hz，3H)，1.25(t，J＝7.5Hz，3H)，1.64(s，6H)，2.69(q，J＝7.5Hz，2H)，2.99-3.07(m，4H)，4.26(q，J＝7.1Hz，2H)，5.34(s，2H)，5.79(s，1H)，5.98(s，1H)，6.57-6.81(m，5H)，7.02-7.10(m，2H).

2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl that [step 2] uses step 1 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(299mg, 0.690mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl] and methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(253mg, 78%).

ESI-MS?m/z：473(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.20(t，J＝7.2Hz，3H)，1.25(t，J＝7.6Hz，3H)，1.63(s，6H)，2.65(q，J＝7.6Hz，2H)，3.06-3.14(m，4H)，4.24(q，J＝7.2Hz，2H)，4.54(s，2H)，5.37(s，2H)，5.71(s，1H)，6.69-6.77(m，2H)，7.01-7.28(m，5H).

5-cyano methyl-2-[5-ethoxy carbonyl-2-ethyl-4-(1-hydroxyl-1-methyl) ethyl imidazol(e)-1-yl that [step 3] uses step 2 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(126mg, 0.267mmol) same with embodiment 1 step 3, obtain title compound (compound 11) (97.5mg, 69%).

ESI-MS?m/z：532(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.14(t，J＝7.1Hz，3H)，1.23(t，J＝7.6Hz，3H)，1.61(s，6H)，2.63(q，J＝7.5Hz，2H)，3.14(br?s，4H)，4.20(q，J＝7.1Hz，2H)，4.82(s，2H)，5.34(s，2H)，5.77(s，1H)，6.68-6.71(m，2H)，6.98-7.19(m，5H).

[embodiment 12]

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 12)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (US5332744; 166mg, 0.850mmol) same with embodiment 1 step 1, obtain 2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(246mg, 72%).

ESI-MS?m/z：403(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.25(t，J＝7.5Hz，3H)，2.57(s，3H)，2.83(q，J＝7.4Hz，2H)，2.89(br?s，4H)，5.32(s，2H)，6.61-7.03(m，7H)，7.28(s，1H).

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(242mg, 0.601mmol) same with embodiment 1 step 2, obtain 2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-cyano methyl-10,11-dihydro-5H-dibenzo [b, f] azepine

(208mg, 78%).

ESI-MS?m/z：442(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.5Hz，3H)，2.60(s，3H)，2.80(q，J＝7.5Hz，2H)，3.01-3.12(m，4H)，4.52(s，2H)，5.37(s，2H)，6.86-7.25(m，8H).

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl-5-cyano methyl-10 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(101mg, 0229mmol) same with embodiment 1 step 3, obtain title compound (compound 12) (92.4mg, 81%).

ESI-MS?m/z：501(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.21(t，J＝7.4Hz，3H)，2.54(s，3H)，2.78(q，J＝7.5Hz，2H)，3.09(br?s，4H)，4.84(s，2H)，5.37(s，2H)，6.84-6.98(m，3H)，7.09-7.18(m，4H)，7.27(s，1H)，12.33(s，1H).

[embodiment 13]

2-(2-butyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 13)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-butyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (US5332744; 2.03g, 10.0mmol) same with embodiment 1 step 1, obtain 2-(2-butyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(2.35g, 57%).

ESI-MS?m/z：411(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.88(t，J＝7.3Hz，3H)，1.32-1.43(m，2H)，1.62-1.72(m，2H)，2.60(s，3H)，2.62(s，3H)，2.77(t，J＝8.0Hz，2H)，2.96-3.04(m，4H)，5.35(s，2H)，5.99(s，1H)，6.61-6.88(m，6H)，7.00-7.09(m，2H).

2-(2-butyl-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(2.15g, 5.24mmol) same with embodiment 1 step 2, obtain 2-(2-butyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-cyano methyl-10,11-dihydro-5H-dibenzo [b, f] azepine

(1.48g, 63%).

ESI-MS?m/z：450(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.87(t，J＝7.3Hz，3H)，1.30-1.43(m，2H)，1.62-1.74(m，2H)，2.58(s，3H)，2.62(s，3H)，2.74(t，J＝8.0Hz，2H)，3.01-3.12(m，4H)，4.51(s，2H)，5.37(s，2H)，6.88-7.24(m，8H).

2-(2-butyl-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl-5-cyano methyl-10 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(225mg, 0.500mmol) same with embodiment 1 step 3, obtain title compound (compound 13) (195mg, 77%).

ESI-MS?m/z：509(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.77(t，J＝7.3Hz，3H)，1.20-1.34(m，2H)，1.51-1.62(m，2H)，2.49(s，6H)，2.71(t，J＝7.7Hz，2H)，3.09(br?s，4H)，4.84(s，2H)，5.34(s，2H)，6.80-7.19(m，8H)，12.34(br?s，1H).

[embodiment 14]

2-(5-ethoxy carbonyl-4-ethyl-2-propyl imidazole-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 14)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, and [(Bioorg.Med.Chem.Lett.) 1994 the 4th volumes are p.63 to use 5-ethoxy carbonyl-4-ethyl-2-propyl imidazole; 1.50g, 3.45mmol], replace lithium hydroxide, the use potassium tert.-butoxide (1.67g, 14.9mmol) same with embodiment 1 step 1, obtain 2-(5-ethoxy carbonyl-4-ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(372mg, 26%).

ESI-MS?m/z：418(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94(t，J＝7.3Hz，3H)，1.25(t，J＝7.8Hz，3H)，1.30(t，J＝7.5Hz，3H)，1.63-1.76(m，2H)，2.62(t，J＝7.8Hz，2H)，2.90(q，J＝7.5Hz，2H)，2.98-3.06(m，4H)，4.25(q，J＝7.3Hz，2H)，5.41(s，2H)，5.97(s，1H)，6.65-6.79(m，5H)，7.01-7.10(m，2H).

2-(5-ethoxy carbonyl-4-ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(369mg, 0.884mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(5-ethoxy carbonyl-4-ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(356mg, 88%).

ESI-MS?m/z：457(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94(t，J＝7.1Hz，3H)，1.22-1.32(m，6H)，1.65-1.75(m，2H)，2.59(t，J＝7.6Hz，2H)，2.90(q，J＝7.4Hz，2H)，3.05-3.13(m，4H)，4.23(q，J＝7.1Hz，2H)，4.52(s，2H)，5.43(s，2H)，6.74-6.78(m，2H)，6.99-7.28(m，5H).

5-cyano methyl-2-(5-ethoxy carbonyl-4-ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(242mg, 0.530mmol) same with embodiment 1 step 3, obtain title compound (compound 14) (163mg, 60%).

ESI-MS?m/z：516(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.90(t，J＝7.3Hz，3H)，1.28(t，J＝7.4Hz，3H)，1.29(t，J＝7.1Hz，3H)，1.68(m，2H)，2.76(t，J＝7.8Hz，2H)，2.97(q，J＝7.5Hz，2H)，3.14(br?s，4H)，4.26(q，J＝7.2Hz，2H)，4.83(s，2H)，5.47(s，2H)，6.75(m，2H)，6.98-7.18(m，5H).

[embodiment 15]

2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 15)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, 2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4, the 5-b] pyridine (160mg that uses reference example 3 to obtain, 0.700mmol), same with embodiment 1 step 1, obtain 2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(153mg, 50%).

ESI-MS?m/z：437(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.4Hz，3H)，2.67(s，3H)，2.89(q，J＝7.4Hz，2H)，2.90(br?s，4H)，5.38(s，2H)，6.61-7.04(m，7H)，7.46(s，1H).

2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(150mg, 0.344mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(134mg, 82%).

ESI-MS?m/z：476(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.6Hz，3H)，2.69(s，3H)，2.85(q，J＝7.5Hz，2H)，3.03-3.13(m，4H)，4.52(s，2H)，5.41(s，2H)，6.89-7.29(m，8H).

5-cyano methyl-2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (66.6mg, 0.140mmol) same with embodiment 1 step 3, obtain title compound (compound 15) (65.3mg, 87%).

ESI-MS?m/z：535(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.30(t，J＝7.5Hz，3H)，2.67(s，3H)，2.82(q，J＝7.5Hz，2H)，3.11(br?s，4H)，4.80(s，2H)，5.38(s，2H)，6.89-7.18(m，7H)，7.27(s，1H).

[embodiment 16]

2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (compound 16)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (US5332744; 355mg, 0.817mmol) same with embodiment 1 step 1, obtain 2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(222mg, 67%).

ESI-MS?m/z：403(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.5Hz，3H)，2.56(s，3H)，2.83(q，J＝7.5Hz，2H)，2.90(br?s，4H)，5.29(s，2H)，6.62-7.03(m，7H)，7.18(s，1H).

2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(199mg, 0.494mmol) same with embodiment 1 step 2, obtain 2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-cyano methyl-10,11-dihydro-5H-dibenzo [b, f] azepine

(164mg, 75%).

ESI-MS?m/z：442(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.5Hz，3H)，2.65(s，3H)，2.78(q，J＝7.5Hz，2H)，3.03-3.12(m，4H)，4.51(s，2H)，5.34(s，2H)，6.88-7.28(m，8H).

2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl-5-cyano methyl-10 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (50.7mg, 0.115mmol) same with embodiment 1 step 3, obtain title compound (compound 16) (48.1mg, 84%).

ESI-MS?m/z：501(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.27(t，J＝7.6Hz，3H)，2.61(s，3H)，2.76(q，J＝7.5Hz，2H)，3.08(br?s，4H)，4.80(s，2H)，5.31(s，2H)，6.84-7.18(m，8H).

[embodiment 17]

2-(7-fluoro-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 17)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 4-fluoro-7-methyl-2-propyl group benzoglyoxaline (478mg that uses reference example 4 to obtain, 1.10mmol), same with embodiment 1 step 1, obtain 2-(7-fluoro-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(370mg, 92%).

ESI-MS?m/z：400(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.96(t，J＝7.3Hz，3H)，1.72-1.75(m，2H)，2.47(s，3H)，2.84(q，J＝7.3Hz，2H)，2.89(br?s，4H)，5.37(s，2H)，6.61-7.03(m，9H).

2-(the 7-fluoro-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (367mg, 0.919mmol) same with embodiment 1 step 2, obtain 5-cyano methyl-2-(7-fluoro-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (323mg, 80%).

ESI-MS?m/z：439(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.01(t，J＝7.3Hz，3H)，1.76-1.85(m，2H)，2.61(s，3H)，2.80(t，J＝7.8Hz，2H)，3.02-3.12(m，4H)，4.51(s，2H)，5.41(s，2H)，6.73-7.27(m，9H).

5-cyano methyl-2-(7-fluoro-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(162mg, 0.369mmol) same with embodiment 1 step 3, obtain title compound (compound 17) (118mg, 64%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.92(t，J＝7.3Hz，3H)，1.72(m，2H)，2.55(s，3H)，2.88(t，J＝7.9Hz，2H)，3.05(br?s，4H)，4.78(s，2H)，5.39(s，2H)，6.77-7.15(m，9H).

[embodiment 18]

2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 18)

2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 1] uses embodiment 6 steps 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(531mg 1.39mmol), replaces paraformaldehyde, use acetaldehyde (117 μ L, 2.09mmol), same with embodiment 1 step 2, obtain 5-(1-cyano ethyl)-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(527mg, 87%).

ESI-MS?m/z：435(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.3Hz，3H)，1.48(d，J＝7.3Hz，3H)，1.75-1.85(m，2H)，2.68(s，3H)，2.84(t，J＝7.9Hz，2H)，2.89-3.10(m，4H)，4.65(q，J＝7.3Hz，1H)，5.24(s，2H)，6.75-7.58(m，10H).

5-(1-cyano ethyl)-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(251mg, 0.578mmol) same with embodiment 1 step 3, obtain title compound (compound 18) (55.5mg, 19%).

ESI-MS?m/z：494(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.48(d，J＝6.4Hz，3H)，1.75(m，2H)，2.64(s，3H)，2.79(t，J＝7.9Hz，2H)，2.88-3.16(m，4H)，5.20(s，2H)，5.21(q，J＝6.5Hz，1H)，6.74-6.79(m，2H)，6.96-7.12(m，8H).

[embodiment 19]

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 19)

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 1] uses embodiment 1 step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(532mg 1.39mmol), replaces paraformaldehyde, uses acetaldehyde (156 μ L, 2.78mmol), same with embodiment 1 step 2, obtain 5-(1-cyano ethyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(595mg, 99%).

ESI-MS?m/z：436(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.22(t，J＝7.5Hz，3H)，1.37(d，J＝6.9Hz，3H)，2.50(s，6H)，2.77(q，J＝7.5Hz，2H)，2.99(br?s，4H)，5.08(q，J＝6.9Hz，1H)，5.36(s，2H)，6.92-7.42(m，8H).

5-(1-cyano ethyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(337mg, 0.774mmol) same with embodiment 1 step 3, obtain title compound (compound 19) (114mg, 30%).

ESI-MS?m/z：495(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.17(t，J＝7.4Hz，3H)，1.37(d，J＝6.4Hz，3H)，2.49(s，6H)，2.72(q，J＝7.4Hz，2H)，3.07(br?s，4H)，5.29(q，J＝6.4Hz，1H)，5.32(s，2H)，6.77-7.22(m，8H)，12.38(s，1H).

[embodiment 20]

2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 20)

2-(2-ethyl-7-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 1] uses embodiment 9 steps 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(586mg 1.6mmol), replaces paraformaldehyde, uses acetaldehyde (134 μ L, 2.4mmol), same with embodiment 1 step 2, obtain 5-(1-cyano ethyl)-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(593mg, 88%).

ESI-MS?m/z：422(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.6Hz，3H)，1.47(d，J＝7.1Hz，3H)，2.68(s，3H)，2.83(q，J＝7.6Hz，2H)，2.85-3.14(m，4H)，4.64(q，J＝7.1Hz，1H)，5.40(s，2H)，6.87(d，J＝1.5Hz，1H)，6.96-7.12(m，4H)，7.16-7.22(m，1H)，7.48-7.56(m，2H)，8.20(d，J＝5.0Hz，1H).

5-(1-cyano ethyl)-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(186mg, 0.44mmol) same with embodiment 1 step 3, obtain title compound (compound 20) (98mg, 46%).

ESI-MS?m/z：481(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.29(t，J＝7.5Hz，3H)，1.45(d，J＝6.4Hz，3H)，2.66(s，3H)，2.79(q，J＝7.5Hz，2H)，2.87-3.11(m，4H)，5.19(q，J＝6.4Hz，1H)，5.35(s，2H)，6.82-6.85(m，2H)，6.95-7.11(m，6H)，8.15(d，J＝4.9Hz，1H).

[embodiment 21]

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 21)

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 1] uses embodiment 12 steps 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (1.71g 4.3mmol), replaces paraformaldehyde, uses acetaldehyde (358 μ L, 6.4mmol), same with embodiment 1 step 2, obtain 2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(1-cyano ethyl)-10,11-dihydro-5H-dibenzo [b, f] azepine

(1.59g, 82%).

ESI-MS?m/z：456(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，1.48(d，J＝7.3Hz，3H)，2.61(s，3H)，2.80(q，J＝7.5Hz，2H)，2.90-3.11(m，4H)，4.65(q，J＝7.3Hz，1H)，5.37(s，2H)，6.84(d，J＝2.0Hz，1H)，6.99-7.13(m，4H)，7.17-7.23(m，1H)，7.50-7.58(m，2H).

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(1-cyano ethyl)-10 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (550mg, 1.2mmol) same with embodiment 1 step 3, obtain title compound (compound 21) (255mg, 41%).

ESI-MS?m/z：515(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.27(t，J＝7.5Hz，3H)，1.47(d，J＝6.4Hz，3H)，2.59(s，3H)，2.74(q，J＝7.5Hz，2H)，2.95-3.17(m，4H)，5.21(q，J＝6.4Hz，1H)，5.26-5.38(m，2H)，6.83-6.87(m，2H)，6.95-7.09(m，6H).

[embodiment 22]

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 22)

With 5-(1-cyano ethyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that embodiment 19 steps 1 obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(520mg 1.19mmol) is dissolved in toluene (12mL), add the nitrogenize trimethyl silane (2.54mL, 19.1mmol) and Dibutyltin oxide (177mg, 0.71mmol), 70 ℃ were stirred 2 down.Mixture is under reduced pressure concentrated, and residue is refining with silica gel column chromatography (chloroform/methanol=25/1), obtains title compound (compound 22) (354mg, 62%).

ESI-MS?m/z：479(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.17(t，J＝7.5Hz，3H)，1.57(d，J＝6.6Hz，3H)，2.60(s，3H)，2.61(s，3H)，2.82(q，J＝7.5Hz，2H)，2.80-3.26(m，4H)，5.36(s，2H)，5.71(q，J＝6.6Hz，1H)，6.71-7.19(m，8H).

[embodiment 23]

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) propyl group]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 23)

(600mg 1.57mmol), replaces paraformaldehyde, uses propionic aldehyde (227 μ L, 3.14mmol), same with embodiment 1 step 2, obtain 5-(1-cyano group propyl group)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(669mg, 95%).

ESI-MS?m/z：450(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.01(t，J＝7.4Hz，3H)，1.31(t，J＝7.6Hz，3H)，1.79-1.89(m，2H)，2.59(s，3H)，2.63(s，3H)，2.77(q，J＝7.5Hz，2H)，2.92-3.10(m，4H)，4.36(t，J＝7.9Hz，1H)，5.37(s，2H)，6.61-7.26(m，6H)，7.49-7.58(m，2H).

5-(1-cyano group propyl group)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(671mg 1.49mmol), similarly to Example 22, obtains title compound (compound 23) (265mg, 36%).

ESI-MS?m/z：493(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.75(t，J＝7.3Hz，3H)，1.12(t，J＝7.5Hz，3H)，1.91-2.17(m，2H)，2.46(s，3H)，2.56(s，3H)，2.66(q，J＝7.5Hz，2H)，2.77-3.05(m，4H)，5.29(s，2H)，5.49(dd，J＝8.5，4.7Hz，1H)，6.67-6.73(m，2H)，6.87-7.03(m，5H)，7.14(d，J＝7.5Hz，1H).

[embodiment 24]

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) butyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 24)

(600mg 1.57mmol), replaces paraformaldehyde, uses butyraldehyde (283 μ L, 3.14mmol), same with embodiment 1 step 2, obtain 5-(1-cyano group butyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(697mg, 96%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.87(t，J＝7.4Hz，3H)，1.31(t，J＝7.6Hz，3H)，1.40-1.51(m，2H)，1.74-1.83(m，2H)，2.59(s，3H)，2.63(s，3H)，2.77(q，J＝7.5Hz，2H)，2.95-3.08(m，4H)，4.44(t，J＝7.8Hz，1H)，5.37(s，2H)，6.61-7.26(m，6H)，7.51-7.60(m，2H).

5-(1-cyano group butyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (695mg 1.50mmol), similarly to Example 22, obtains title compound (compound 24) (101mg, 13%).

ESI-MS?m/z：507(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.76(t，J＝7.2Hz，3H)，0.97-1.29(m，2H)，1.15(t，J＝7.6Hz，3H)，1.91-2.12(m，2H)，2.62(s，3H)，2.65(s，3H)，2.82-2.94(m，2H)，2.90(q，J＝7.6Hz，2H)，3.09-3.38(m，2H)，5.38(s，2H)，5.62(dd，J＝9.2，4.4Hz，1H)，6.73(dd，J＝8.2，1.8Hz，1H)，6.84(d，J＝1.8Hz，1H)，6.92-7.08(m，5H)，7.19(d，J＝7.7Hz，1H).

[embodiment 25]

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 25)

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl-5-(1-cyano ethyl)-10 that uses embodiment 21 steps 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(1.00g 2.2mmol), similarly to Example 22, obtains title compound (compound 25) (738mg, 67%).

ESI-MS?m/z：499(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.13(t，J＝7.5Hz，3H)，1.58(d，J＝6.6Hz，3H)，2.59(s，3H)，2.60(q，J＝7.5Hz，2H)，2.80-3.07(m，4H)，5.22-5.35(m，2H)，5.71(q，J＝6.6Hz，1H)，6.70-6.75(m，2H)，6.89-7.04(m，4H)，7.10-7.13(m，2H).

[embodiment 26]

2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 26)

5-(1-cyano ethyl)-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that the step 1 of use embodiment 20 obtains, 11-dihydro-5H-dibenzo [b, f] azepine

(1.24g 3.0mmol), similarly to Example 22, obtains title compound (compound 26) (1.00g, 73%).

ESI-MS?m/z：465(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.22(t，J＝7.5Hz，3H)，1.49(d，J＝6.8Hz，3H)，2.57(s，3H)，2.74(q，J＝7.5Hz，2H)，2.75-2.96(m，4H)，5.32(s，2H)，5.66(q，J＝6.8Hz，1H)，6.69-6.72(m，2H)，6.90-7.03(m，5H)，7.10(d，J＝7.9Hz，1H)，8.12(d，J＝4.9Hz，1H).

[embodiment 27]

2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 27)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridine (US5332744; 2.0g, 11.4mmol) same with embodiment 1 step 1, obtain 2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.10g, 25%).

ESI-MS?m/z：383(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99(t，J＝7.3Hz，3H)，1.70-1.83(m，2H)，2.68(s，3H)，2.78-2.83(m，2H)，2.96-3.03(m，4H)，5.37(s，2H)，6.01(s，1H)，6.61-6.84(m，5H)，7.01-7.08(m，3H)，8.21(d，J＝4.9Hz，1H).

2-(7-methyl-2-propyl group-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(1.09g 2.9mmol), replaces paraformaldehyde, (0.48mL 8.6mmol), similarly obtains 5-(1-cyano ethyl)-2-(7-methyl-2-propyl group-3H-imidazo [4 quantitatively with embodiment 1 step 2 to use acetaldehyde, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(1.31g).

ESI-MS?m/z：436(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.98(t，J＝7.3Hz，3H)，1.47(d，J＝7.1Hz，3H)，1.71-1.84(m，2H)，2.68(s，3H)，2.76-2.81(m，2H)，2.85-3.12(m，4H)，4.65(q，J＝7.1Hz，1H)，5.40(s，2H)，6.87(d，J＝1.8Hz，1H)，6.96-7.22(m，5H)，7.49-7.57(m，2H)，8.19(d，J＝4.9Hz，1H).

5-(1-cyano ethyl)-2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(1.31g 2.9mmol), similarly to Example 22, obtains title compound (compound 27) (956mg, 70%).

ESIMS?m/z：479(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.87(t，J＝7.3Hz，3H)，1.50(d，J＝6.6Hz，3H)，1.61-1.73(m，2H)，2.58(s，3H)，2.70(t，J＝7.8Hz，2H)，2.76-2.93(m，4H)，5.33(s，2H)，5.66(q，J＝6.6Hz，1H)，6.69-6.72(m，2H)，6.90-7.03(m，5H)，7.10(d，J＝7.3Hz，1H)，8.12(d，J＝4.9Hz，1H).

[embodiment 28]

2-(5-ethoxy carbonyl-4-ethyl-2-propyl group-1H-imidazoles-1-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 28)

2-(5-ethoxy carbonyl-4-ethyl-2-propyl group-1H-imidazoles-1-yl) methyl isophthalic acid 0 that [step 1] uses embodiment 14 steps 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (452mg 1.1mmol), replaces paraformaldehyde, use acetaldehyde (183 μ L, 3.3mmol), same with embodiment 1 step 2, obtain 5-(1-cyano ethyl)-2-(5-ethoxy carbonyl-4-ethyl-2-propyl group-1H-imidazoles-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(481mg, 94%).

ESI-MS?m/z：471(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93(t，J＝7.3Hz，3H)，1.22-1.32(m，6H)，1.49(d，J＝7.2Hz，3H)，1.63-1.76(m，2H)，2.58(t，J＝7.8Hz，2H)，2.86-3.10(m，4H)，2.90(q，J＝7.5Hz，2H)，4.23(q，J＝7.3Hz，2H)，4.66(q，J＝7.2Hz，1H)，5.43(s，2H)，6.72-6.80(m，2H)，7.01-7.23(m，3H)，7.48-7.58(m，2H).

5-(1-cyano ethyl)-2-(5-ethoxy carbonyl-4-ethyl-2-propyl group-1H-imidazoles-1-yl) methyl isophthalic acid 0 that [step 2] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine (480mg 1.0mmol), similarly to Example 22, obtains title compound (compound S 7)) (200mg, 38%).

ESI-MS?m/z：514(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.81(t，J＝7.1Hz，3H)，1.26(t，J＝7.3Hz，3H)，1.30(t，J＝7.1Hz，3H)，1.53-1.62(m，2H)，1.61(d，J＝6.9Hz，3H)，2.68(t，J＝7.8Hz，2H)，2.94-3.33(m，4H)，2.97(q，J＝7.3Hz，2H)，4.28(q，J＝7.1Hz，2H)，5.45(s，2H)，5.72(q，J＝6.9Hz，1H)，6.54(dd，J＝8.3，1.8Hz，1H)，6.73(d，J＝1.8Hz，1H)，6.95-7.00(m，1H)，7.05-7.10(m，3H)，7.24(d，J＝7.9Hz，1H).

[embodiment 29]

(E)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 29)

[step 1] is with (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (No. the 2526005th, Japanese Patent; 1.26g, 4.8mmol) be dissolved in THF (50mL), add 2, the 6-lutidine (3.4mL, 29.2mmol), lithiumbromide (2.54g, 29.2mmol) and the methylsulfonic acid acid anhydride (2.02g 11.6mmol), stirred 24 hours under the room temperature.Add ethyl acetate in the mixture, organic layer saturated common salt water washing.Organic layer with anhydrous magnesium sulfate drying after, decompression concentrates down and obtains residue.

With 2-ethyl-5, (0.85g 4.8mmol) is dissolved in DMF (15mL) to 7-dimethyl-3H-imidazo [4,5-b] pyridine, and (0.60g 5.3mmol) stirred 10 minutes 0 ℃ of following adding potassium tert.-butoxide.In this mixture, add DMF (8mL) solution of the above-mentioned residue that obtains, stirred 2 hours under the room temperature.Add ethyl acetate in the mixture, organic layer saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.(hexane/ethyl acetate=3/1-1/3) refining obtains (E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo [4 residue with silica gel column chromatography, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.28g, 63%).

ESI-MS?m/z：419(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.32(t，J＝7.5Hz，3H)，2.57(s，3H)，2.63(s，3H)，2.75(q，J＝7.5Hz，2H)，3.06(br?s，4H)，5.41(s，2H)，5.66(s，1H)，6.88-6.92(m，3H)，7.19-7.32(m，4H)，7.41-7.42(m，1H).

(E)-[2-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (250mg, 0.60mmol), same with embodiment 1 step 3, obtain title compound (compound 29) (215mg, 75%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.22(t，J＝7.6Hz，3H)，2.46(s，3H)，2.53(s，3H)，2.70-2.78(m，2H)，2.80-3.39(m，4H)，5.39(s，2H)，6.32(s，1H)，6.85(dd，J＝7.8，1.4Hz，1H)，6.92(s，1H)，6.99-7.12(m，3H)，7.22-7.30(m，3H).

[embodiment 30]

(E)-and 2-(6-methoxycarbonyl-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 30)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 5-methoxycarbonyl-7-methyl-2-propyl group benzoglyoxaline (EP502314; 1.19g, 5.13mmol) same with embodiment 29 steps 1, obtain (E)-[2-(6-methoxycarbonyl-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.78g, 73%).

ESI-MS?m/z；476(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.3Hz，3H)，1.75-1.89(m，2H)，2.70(s，3H)，2.82(t，J＝7.8Hz，2H)，3.06(br?s，4H)，3.88(s，3H)，5.33(s，2H)，5.67(s，1H)，6.68(s，1H)，6.81(dd，J＝8.1，1.4Hz，1H)，7.20-7.34(m，4H)，7.43(dd，J＝7.4，1.8Hz，1H)，7.74(d，J＝1.0Hz，1H)，7.77(d，J＝1.0Hz，1H).

(E)-[2-(6-methoxycarbonyl-4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.68g, 1.43mmol), same with embodiment 1 step 3, obtain title compound (compound 30) (0.27g, 35%).

ESI-MS?m/z；535(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.93(t，J＝7.3Hz，3H)，1.68-1.81(m，2H)，2.55(s，3H)，2.81(t，J＝7.5Hz，2H)，2.83-3.25(m，4H)，3.79(s，3H)，5.53(s，2H)，6.33(s，1H)，6.77(d，J＝7.9Hz，1H)，6.94(s，1H)，7.05(d，J＝7.3Hz，1H)，7.09-7.14(m，1H)，7.23-7.25(m，2H)，7.30(d，J＝7.9Hz，1H)，7.62(d，J＝1.0Hz，1H)，7.84(d，J＝1.2Hz，1H).

[embodiment 31]

(E)-and 2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 31)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridine (0.80g, 3.07mmol), same with embodiment 29 steps 1, obtain (E)-2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.86g, 65%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.96(t，J＝7.4Hz，3H)，1.69-1.83(m，2H)，2.56(s，3H)，2.63(s，3H)，2.70(t，J＝8.1Hz，2H)，3.06(br?s，4H)，5.41(s，2H)，5.66(s，1H)，6.87-6.94(m，3H)，7.19-7.35(m，4H)，7.43(dd，J＝7.4，1.8Hz，1H).

(E)-2-(5 that [step 2] uses step 1 to obtain, 7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.42g, 0.96mmol), same with embodiment 1 step 3, obtain title compound (compound 31) (0.31g, 66%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.90(t，J＝7.3Hz，3H)，1.61-1.76(m，2H)，2.47(s，3H)，2.51(s，3H)，2.72(t，J＝8.4Hz，2H)，2.90-3.19(m，4H)，5.42(s，2H)，6.35(s，1H)，6.85-6.88(m，1H)，6.93(s，1H)，7.00-7.01(m，1H)，7.06-7.08(m，1H)，7.11-7.17(m，1H)，7.26-7.32(m，3H).

[embodiment 32]

(E)-and 2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 32)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline (0.99g, 3.25mmol), same with embodiment 29 steps 1, obtain (E)-2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.13g, 64%).

ESI-MS?m/z：548(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.03(t，J＝7.3Hz，3H)，1.78-1.92(m，2H)，2.76(s，3H)，2.84-2.91(m，2H)，3.05(br?s，4H)，3.73(s，3H)，5.35(s，2H)，5.66(s，1H)，6.81-6.89(m，2H)，7.17-7.44(m，10H)，7.76-7.79(m，1H).

(E)-2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl that [step 2] uses step 1 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.20g, 0.37mmol), same with embodiment 1 step 3, obtain title compound (compound 32) (0.20g, 88%).

ESI-MS?m/z：607(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.96(t，J＝7.5Hz，3H)，1.73-1.84(m，2H)，2.61(s，3H)，2.86(t，J＝7.5Hz，2H)，2.88-3.27(m，4H)，3.71(s，3H)，5.53(s，2H)，6.32(s，1H)，6.88(d，J＝8.1Hz，1H)，7.05(d，J＝7.9Hz，2H)，7.10-7.32(m，6H)，7.45(s，1H)，7.53(d，J＝7.1Hz，1H)，7.61(d，J＝7.5Hz，2H).

[embodiment 33]

(E)-and 2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 33)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 4-methyl-2-propyl group benzoglyoxaline (1.04g, 4.00mmol), same with embodiment 29 steps 1, obtain (E)-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.94g, 57%).

ESI-MS?m/z：418(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.5Hz，3H)，1.73-1.86(m，2H)，2.69(s，3H)，2.82(t，J＝8.2Hz，2H)，3.06(br?s，4H)，5.28(s，2H)，5.67(s，1H)，6.80(s，1H)，6.85(dd，J＝7.9，1.7Hz，1H)，6.95(dd，J＝6.6，2.0Hz，1H)，7.03-7.10(m，2H)，7.18-7.35(m，4H)，7.43(dd，J＝7.3，1.7Hz，1H).

(E)-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.40g, 0.96mmol), same with embodiment 1 step 3, obtain title compound (compound 33) (0.20g, 45%).

ESI-MS?m/z：477(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.94(t，J＝7.3Hz，3H)，1.69-1.80(m，2H)，2.52(s，3H)，2.79(t，J＝7.6Hz，2H)，2.82-3.30(m，4H)，5.42(s，2H)，6.33(s，1H)，6.82(d，J＝7.9Hz，1H)，6.94-7.19(m，6H)，7.25-7.32(m，3H).

[embodiment 34]

(E)-and 2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 34)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (684mg, 4.3mmol), same with embodiment 29 steps 1, obtain (E)-[2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (470mg, 27%).

ESI-MS?m/z：405(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.6Hz，3H)，2.69(s，3H)，2.82(q，J＝7.6Hz，2H)，3.06(br?s，4H)，5.43(s，2H)，5.66(s，1H)，6.89(s，1H)，6.93(d，J＝8.1Hz，1H)，7.03(d，J＝4.9Hz，1H)，7.20(d，J＝7.7Hz，2H)，7.28-7.35(m，2H)，7.42(dd，J＝7.4，1.6Hz，1H)，8.18(d，J＝4.9Hz，1H).

(E)-[2-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (200mg, 0.49mmol), same with embodiment 1 step 3, obtain title compound (compound 34) (102mg, 44%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.4Hz，3H)，2.54(s，3H)，2.80(q，J＝7.4Hz，2H)，2.85-3.28(m，4H)，5.43(s，2H)，6.32(s，1H)，6.91(d，J＝8.4Hz，1H)，7.02-7.14(m，4H)，7.23-7.30(m，3H)，8.11(d，J＝5.0Hz，1H).

[embodiment 35]

(E)-and 2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 35)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole (253mg, 1.05mmol), same with embodiment 29 steps 1, obtain (E)-2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit } acetonitrile (379mg, 82%).

ESI-MS?m/z：484(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94(t，J＝7.3Hz，3H)，1.18(t，J＝7.2Hz，3H)，1.63(s，6H)，1.77-1.66(m，2H)，2.57(t，J＝7.8Hz，2H)，3.24-3.00(m，4H)，4.21(q，J＝7.2Hz，2H)，5.41(s，2H)，5.67(s，1H)，5.69(s，1H)，6.68(s，1H)，6.73(d，J＝7.9Hz，1H)，7.37-7.19(m，4H)，7.44(dd，J＝7.3，1.7Hz，1H).

(E) that [step 2] use step 1 obtains-and 2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit } acetonitrile (144mg, 0.3mmol), same with embodiment 1 step 3, obtain title compound (compound 35) (80mg, 49%).

ESI-MS?m/z：543(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94(t，J＝7.3Hz，3H)，1.18(t，J＝7.1Hz，3H)，1.63(s，6H)，1.77-1.66(m，2H)，2.58(t，J＝7.8Hz，2H)，3.00-2.81(m，2H)，3.43-3.19(m，2H)，4.22(q，J＝7.1Hz，2H)，5.40(s，2H)，5.66(s，1H)，6.50(s，1H)，6.62(s，1H)，6.79(d，J＝8.2Hz，1H)，7.46-7.17(m，5H).

[embodiment 36]

(E)-and 2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 36)

[step 1] is with (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (120mg, 0.46mmol) and 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (117mg 0.60mmol) is dissolved in THF (6.6mL), 0 ℃ adds the triphenylphosphine (469mg that supports polymkeric substance down, 0.92mmol) and azo-2-carboxylic acid's di-t-butyl (211mg 0.92mmol), stirred under the room temperature 2 hours.Filtering mixt, filtrate under reduced pressure concentrate.Residue is refining with silica gel column chromatography (hexane/ethyl acetate=3/1), obtain (E)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (90mg, 45%).

ESI-MS?m/z：439(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.6Hz，3H)，2.65(s，3H)，2.76(q，J＝7.5Hz，2H)，3.02-3.12(m，4H)，5.38(s，2H)，5.67(s，1H)，6.88(s，1H)，6.93(dd，J＝8.0，1.7Hz，1H)，7.06(d，J＝0.7Hz，1H)，7.18-7.35(m，4H)，7.43(dd，J＝7.3，1.5Hz，1H).

(E)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (90mg, 0.21mmol), same with embodiment 1 step 3, obtain title compound (compound 36) (54mg, 52%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.65(d，J＝0.7Hz，3H)，2.73-2.96(m，2H)，2.77(q，J＝7.5Hz，2H)，3.22-3.39(m，2H)，5.37(s，2H)，6.48(s，1H)，6.84(s，1H)，6.96(d，J＝8.1Hz，1H)，7.06(d，J＝0.7Hz，1H)，7.16(dd，J＝7.5，0.9Hz，1H)，7.26-7.44(m，4H).

[embodiment 37]

(E)-and 2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 37)

[step 1] replaces 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, use 2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridine (160mg, 0.7mmol), same with embodiment 36 steps 1, obtain (E)-[2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (221mg, 87%).

ESI-MS?m/z：473(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.67(s，3H)，2.83(q，J＝7.5Hz，2H)，3.00-3.13(m，4H)，5.45(s，2H)，5.67(s，1H)，6.89(s，1H)，6.95(dd，J＝7.9，1.6Hz，1H)，7.19-7.36(m，5H)，7.43(dd，J＝7.2，1.6Hz，1H).

(E)-[2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (221mg, 0.47mmol), same with embodiment 1 step 3, obtain title compound (compound 37) (184mg, 76%).

ESI-MS?m/z：532(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.67(s，3H)，2.80-2.98(m，2H)，2.83(q，J＝7.6Hz，2H)，3.22-3.39(m，2H)，5.45(s，2H)，6.49(s，1H)，6.85(s，1H)，6.99(d，J＝7.9Hz，1H)，7.17(dd，J＝7.4，1.0Hz，1H)，7.26-7.44(m，5H).

[embodiment 38]

(E)-and 2-(5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 38)

[step 1] replaces 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, 5-methyl-2-propyl group-7-trifluoromethyl-3H-the imidazo [4 that uses reference example 5 to obtain, 5-b] and pyridine (169mg, 0.7mmol), same with embodiment 36 steps 1, obtain (E)-[2-(5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] the thick resultant of acetonitrile conduct.

(E)-[2-(5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile, same with embodiment 1 step 3, obtain title compound (compound 38) (170mg, 58%).

ESI-MS?m/z：546(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.97(t，J＝7.3Hz，3H)，1.73-1.85(m，2H)，2.67(s，3H)，2.78(t，J＝7.9Hz，2H)，2.78-2.96(m，2H)，3.23-3.40(m，2H)，5.45(s，2H)，6.50(s，1H)，6.84(s，1H)，6.99(d，J＝7.9Hz，1H)，7.17(dd，J＝7.4，1.2Hz，1H)，7.26-7.44(m，5H).

[embodiment 39]

(E)-and 2-(8-oxo-2-propyl group-8H-ring imidazoles in heptan-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 39)

[step 1] uses (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (140mg, 0.54mmol), replace 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, [BioMed.Chem.Lett.1993 the 3rd volume is p.1559 to use 8-oxo-2-propyl group ring imidazoles in heptan; 150mg, 0.8mmol], same with embodiment 36 steps 1, obtain (E)-[2-(8-oxo-2-propyl group-8H-ring imidazoles in heptan-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (146mg, 63%).

ESI-MS?m/z：432(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.3Hz，3H)，1.76-1.90(m，2H)，2.73(t，J＝7.7Hz，2H)，2.98-3.10(m，4H)，5.66(s，1H)，5.95(s，2H)，6.79(s，1H)，6.80(d，J＝7.7Hz，1H)，6.95(ddd，J＝11.0，8.3，1.0Hz，1H)，7.07(dt，J＝12.5，0.9Hz，1H)，7.14-7.34(m，5H)，7.41(dd，J＝7.3，1.5Hz，1H)，7.72(dt，J＝10.9，1.0Hz，1H).

(E)-[2-(8-oxo-2-propyl group-8H-ring imidazoles in heptan-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (146mg, 0.34mmol), same with embodiment 1 step 3, obtain title compound (compound 39) (115mg, 70%).

ESI-MS?m/z：491(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.3Hz，3H)，1.77-1.90(m，2H)，2.74(t，J＝7.7Hz，2H)，2.79-2.97(m，2H)，3.22-3.38(m，2H)，5.94(s，2H)，6.48(s，1H)，6.75(s，1H)，6.82(d，J＝8.1Hz，1H)，6.94(ddd，J＝11.0，8.2，0.9Hz，1H)，7.05-7.43(m，7H)，7.72(dt，J＝10.9，1.0Hz，1H).

[embodiment 40]

(E)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 40)

(E)-2-(2-hydroxymethyl-10 that [step 1] uses reference example 6 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (367mg, 1.3mmol), replace 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, use 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] and pyridine (366mg, 2.1mmol), same with embodiment 36 steps 1, obtain (E)-2-[2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (399mg, 69%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.6Hz，3H)，1.99(s，3H)，2.58(s，3H)，2.63(s，3H)，2.73-2.88(m，2H)，2.76(q，J＝7.6Hz，2H)，3.18-3.34(m，2H)，5.41(s，2H)，6.90-7.01(m，4H)，7.13(dd，J＝7.1，1.6Hz，1H)，7.18-7.28(m，2H)，7.39(dd，J＝7.1，1.6Hz，1H).

(E)-2-[2-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (192mg, 0.44mmol), same with embodiment 1 step 3, obtain title compound (compound 40) (166mg, 76%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.5Hz，3H)，2.09(s，3H)，2.57(s，3H)，2.62(s，3H)，2.72-2.87(m，4H)，3.21-3.37(m，2H)，5.40(s，2H)，6.91-6.94(m，3H)，7.06-7.11(m，2H)，7.19-7.35(m，3H).

[embodiment 41]

(E)-and 2-(8-oxo-2-propyl group-4,5,6,7-tetrahydrochysene-8H-ring imidazoles in heptan-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 41)

The compound 39 that embodiment 39 is obtained (50mg 0.1mmol) is dissolved in THF (1mL), under the nitrogen atmosphere, add platinum oxide (IV) (23mg, 0.1mmol).Then under the nitrogen atmosphere, stirred 7 hours under the room temperature.Filtering mixt, decompression is concentrated filtrate down, and it is refining that the residue that obtains is got thin-layer chromatography (hexane/ethyl acetate=1/4) with branch, obtains title compound (compound 41) (12mg, 24%).

ESI-MS?m/z：495(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.66-1.79(m，2H)，1.83-1.97(m，4H)，2.54-2.65(m，4H)，2.81-3.03(m，2H)，3.01(t，J＝6.1Hz，2H)，3.24-3.39(m，2H)，5.48(s，2H)，6.49(s，1H)，6.71(s，1H)，6.78(d，J＝8.1Hz，1H)，7.16(dd，J＝7.3，0.9Hz，1H)，7.26-7.43(m，4H).

[embodiment 42]

(E)-and 2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 42)

[step 1] uses (E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (200mg, 0.73mmol), replace 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (152mg, 0.94mmol), same with embodiment 29 steps 1, obtain (E)-2-[2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (153mg, 50%).

ESI-MS?m/z：419(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，1.98(s，3H)，2.69(s，3H)，2.71-2.88(m，2H)，2.82(q，J＝7.6Hz，2H)，3.18-3.34(m，2H)，5.44(s，2H)，6.91-7.04(m，4H)，7.12(dd，J＝7.1，1.4Hz，1H)，7.18-7.28(m，2H)，7.38(dd，J＝7.3，1.6Hz，1H)，8.19(d，J＝4.9Hz，1H).

((E)-2-[2-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (153mg, 0.37mmol), same with embodiment 1 step 3, obtain title compound (compound 42) (111mg, 64%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.5Hz，3H)，2.09(s，3H)，2.69(s，3H)，2.73-2.87(m，2H)，2.83(q，J＝7.5Hz，2H)，3.22-3.36(m，2H)，5.43(s，2H)，6.92(s，1H)，6.94(d，J＝7.5Hz，1H)，7.02-7.11(m，4H)，7.19-7.35(m，2H)，8.19(d，J＝4.9Hz，1H).

[embodiment 43]

(E)-and 2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 43)

[step 1] uses (E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (200mg, 0.73mmol), replace 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole (192mg, 0.8mmol), same with embodiment 29 steps 1, obtain (E)-2-{2-[5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit } propionitrile (311mg, 86%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93(t，J＝7.3Hz，3H)，1.14(t，J＝7.1Hz，3H)，1.63(s，6H)，1.65-1.75(m，2H)，2.01(s，3H)，2.59(t，J＝7.8Hz，2H)，2.75-2.92(m，2H)，3.22-3.38(m，2H)，4.21(q，J＝7.1Hz，2H)，5.41(s，2H)，5.71(s，1H)，6.73(d，J＝8.1Hz，1H)，6.77(s，1H)，7.03(d，J＝7.9Hz，1H)，7.15(dd，J＝7.1，1.5Hz，1H)，7.20-7.30(m，2H)，7.41(dd，J＝7.1，1.6Hz，1H).

(E)-2-[2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (311mg, 0.63mmol), same with embodiment 1 step 3, obtain title compound (compound 43) (195mg, 56%).

ESI-MS?m/z：557(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93(t，J＝7.3Hz，3H)，1.11(t，J＝7.2Hz，3H)，1.63(s，6H)，1.66-1.76(m，2H)，2.11(s，3H)，2.59(t，J＝7.7Hz，2H)，2.76-2.90(m，2H)，3.26-3.42(m，2H)，4.21(q，J＝7.1Hz，2H)，5.39(s，2H)，5.70(s，1H)，6.70-6.84(m，2H)，7.09-7.13(m，2H)，7.17-7.37(m，3H).

[embodiment 44]

(E)-and 2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 44)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (586mg, 3.0mmol), same with embodiment 40 steps 1, obtain (E)-2-[2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (674mg, 74%).

ESI-MS?m/z：453(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，1.99(s，3H)，2.60(s，3H)，2.72-2.89(m，2H)，2.78(q，J＝7.6Hz，2H)，3.19-3.35(m，2H)，5.41(s，2H)，6.92(d，J＝7.5Hz，1H)，6.94(s，1H)，7.01(d，J＝8.6Hz，1H)，7.12-7.28(m，4H)，7.39(dd，J＝7.0，1.8Hz，1H).

(E)-2-[2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (337mg, 0.74mmol), same with embodiment 1 step 3, obtain title compound (compound 44) (324mg, 85%).

ESI-MS?m/z：512(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.10(s，3H)，2.60(s，3H)，2.74-2.88(m，2H)，2.79(q，J＝7.6Hz，2H)，3.22-3.39(m，2H)，5.40(s，2H)，6.90(s，1H)，6.95(d，J＝7.9Hz，1H)，7.08-7.12(m，3H)，7.20-7.36(m，3H).

[embodiment 45]

(E)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 45)

(E)-2-[2-(the 2-ethyl-5 that uses embodiment 40 steps 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (193mg, 0.45mmol), similarly to Example 22, obtain title compound (compound 45) (190mg, 90%).

ESI-MS?m/z：476(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.28(t，J＝7.5Hz，3H)，2.31(s，3H)，2.53(s，3H)，2.58(s，3H)，2.66-2.78(m，4H)，3.09-3.25(m，2H)，5.41(s，2H)，6.88-6.91(m，2H)，6.99-7.02(m，2H)，7.13-7.32(m，4H).

[embodiment 46]

(E)-and 2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 46)

(E)-2-[2-(the 7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that uses embodiment 44 steps 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (337mg, 0.74mmol), similarly to Example 22, obtain title compound (compound 46) (313mg, 85%).

ESI-MS?m/z：496(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.32(t，J＝7.5Hz，3H)，2.34(s，3H)，2.60(s，3H)，2.74-2.83(m，2H)，2.78(q，J＝7.6Hz，2H)，3.23-3.32(m，2H)，5.41(s，2H)，6.89(s，1H)，6.97-7.03(m，2H)，7.12(s，1H)，7.16-7.22(m，2H)，7.29-7.36(m，2H).

[embodiment 47]

(E)-and 2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 47)

(E)-2-[2-(the 2-ethyl-7-methyl-3H-imidazo [4 that uses embodiment 42 steps 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (288mg, 0.69mmol), similarly to Example 22, obtain title compound (compound 47) (261mg, 82%).

ESI-MS?m/z：462(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.32(s，3H)，2.65(s，3H)，2.68-2.87(m，2H)，2.83(q，J＝7.5Hz，2H)，3.21-3.29(m，2H)，5.44(s，2H)，6.91(s，1H)，6.96-7.04(m，3H)，7.16-7.22(m，2H)，7.29-7.36(m，2H)，8.19(d，J＝4.9Hz，1H).

[embodiment 48]

(Z)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 48)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile uses (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (No. the 2526005th, Japanese Patent; 1.54g, 5.91mmol) same with embodiment 29 steps 1, obtain (Z)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.66g, 67%).

ESI-MS?m/z：419(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.6Hz，3H)，2.58(s，3H)，2.64(s，3H)，2.77(q，J＝7.3Hz，2H)，2.99-3.13(m，4H)，5.45(s，2H)，5.68(s，1H)，6.90-6.92(m，2H)，7.05(dd，J＝7.6，1.6Hz，1H)，7.12(d，J＝7.1Hz，1H)，7.20-7.31(m，3H)，7.40(d，J＝7.8Hz，1H).

(Z)-[2-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.30g, 0.72mmol), same with embodiment 1 step 3, obtain title compound (compound 48) (0.16g, 47%).

ESI-MS?m/z：478(M+H) ⁺；H-NMR(DMSO-d ₆，δ)：1.20(t，J＝7.4Hz，3H)，2.49(s，3H)，2.50(s，3H)，2.70-2.77(m，2H)，2.78-3.38(m，4H)，5.43(s，2H)，6.34(s，1H)，6.83(dd，J＝8.0，1.4Hz，1H)，6.94(s，1H)，7.06(d，J＝8.0Hz，2H)，7.17-7.32(m，4H).

[embodiment 49]

(Z)-and 2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 49)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (0.85g, 3.25mmol), same with embodiment 32 steps 1, obtain (Z)-2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.30g, 73%).

ESI-MS?m/z；548(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.05(t，J＝7.4Hz，3H)，1.80-1.93(m，2H)，2.77(s，3H)，2.87-2.95(m，2H)，2.98-3.13(m，4H)，3.68(s，3H)，5.39(s，2H)，5.69(s，1H)，6.88(s，1H)，7.00(d，J＝8.4Hz，1H)，7.11(d，J＝7.6Hz，1H)，7.17-7.33(m，6H)，7.36-7.45(m，3H)，7.75-7.79(m，1H).

(Z)-2-[4-methyl-6-(1-tolimidazole-2-yl)-2-propyl group benzoglyoxaline-1-yl that [step 2] uses step 1 to obtain] methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.40g, 0.73mmol), same with embodiment 1 step 3, obtain title compound (compound 49) (0.26g, 58%).

ESI-MS?m/z：607(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.95(t，J＝7.3Hz，3H)，1.70-1.82(m，2H)，2.61(s，3H)，2.78-3.25(m，4H)，2.86(t，J＝7.5Hz，2H)，3.71(s，3H)，5.55(s，2H)，6.33(s，1H)，6.90(d，J＝7.8Hz，1H)，7.07-7.34(m，8H)，7.46(s，1H)，7.52(d，J＝6.6Hz，1H)，7.63(dd，J＝7.0，1.6Hz，1H)，7.71(s，1H).

[embodiment 50]

(Z)-and 2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 50)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (0.80g, 3.07mmol), same with embodiment 31 steps 1, obtain (Z)-2-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.64g, 49%).

ESI-MS?m/z；433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.96(t，J＝7.5Hz，3H)，1.69-1.82(m，2H)，2.58(s，3H)，2.64(s，3H)，2.72(t，J＝7.9Hz，2H)，3.00-3.11(m，4H)，5.45(s，2H)，5.69(s，1H)，6.89-6.91(m，2H)，7.04(dd，J＝7.7，1.5Hz，1H)，7.12(d，J＝7.3Hz，1H)，7.18-7.31(m，3H)，7.40(d，J＝7.9Hz，1H).

(Z)-2-(5 that [step 2] uses step 1 to obtain, 7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.30g, 0.69mmol), same with embodiment 1 step 3, obtain title compound (compound 50) (0.20g, 60%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.86(t，J＝7.3Hz，3H)，1.58-1.71(m，2H)，2.48(s，3H)，2.49(s，3H)，2.68(t，J＝7.3Hz，2H)，2.80-3.20(m，4H)，5.42(s，2H)，6.33(s，1H)，6.81(d，J＝7.9Hz，1H)，6.92(s，1H)，7.03-7.34(m，6H).

[embodiment 51]

(Z)-and 2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 51)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile uses (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (1.04g, 4.00mmol), same with embodiment 33 steps 1, obtain (Z)-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.20g, 72%).

ESI-MS?m/z：418(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.6Hz，3H)，1.73-1.87(m，2H)，2.69(s，3H)，2.84(t，J＝8.2Hz，2H)，2.96-3.11(m，4H)，5.32(s，2H)，5.69(s，1H)，6.81(s，1H)，6.98-7.13(m，5H)，7.20-7.32(m，3H)，7.42(d，J＝7.9Hz，1H).

(Z)-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.45g, 1.08mmol), same with embodiment 1 step 3, obtain title compound (compound 51) (0.36g, 70%).

ESI-MS?m/z：477(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.92(t，J＝7.3Hz，3H)，1.65-1.77(m，2H)，2.52(s，3H)，2.78(t，J＝7.6Hz，2H)，2.79-3.25(m，4H)，5.43(s，2H)，6.34(s，1H)，6.83(dd，J＝7.9，1.6Hz，1H)，6.95(d，J＝7.1Hz，1H)，7.00-7.08(m，3H)，7.16-7.34(m，5H).

[embodiment 52]

(Z)-and 2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 52)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (0.97g, 3.71mmol), same with embodiment 34 steps 1, obtain (Z)-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.67g, 44%).

ESI-MS?m/z：405(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.4Hz，3H)，2.70(s，3H)，2.84(q，J＝7.4Hz，2H)，2.98-3.12(m，4H)，5.47(s，2H)，5.68(s，1H)，6.94-6.95(m，1H)，7.02-7.07(m，2H)，7.11(d，J＝8.1Hz，1H)，7.16-7.31(m，3H)，7.39(d，J＝8.1Hz，1H)，8.19(d，J＝5.0Hz，1H).

(Z)-2-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.15g, 0.37mmol), same with embodiment 1 step 3, obtain title compound (compound 52) (0.11g, 64%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.21(t，J＝7.5Hz，3H)，2.54(s，3H)，2.79(q，J＝7.5Hz，2H)，2.81-3.26(m，4H)，5.45(s，2H)，6.32(s，1H)，6.87(dd，J＝7.8，1.7Hz，1H)，7.02-7.07(m，3H)，7.12-7.33(m，4H)，8.13(d，J＝4.8Hz，1H).

[embodiment 53]

(Z)-and 2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 53)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (1.50g, 5.74mmol), replace 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] and pyridine (1.10g, 5.74mmol), same with embodiment 29 steps 1, obtain (Z)-2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (1.11g, 44%).

ESI-MS?m/z：435(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.42(t，J＝7.0Hz，3H)，2.50(s，3H)，2.54(s，3H)，3.02-3.13(m，4H)，4.58(q，J＝7.1Hz，2H)，5.22(s，2H)，5.68(s，1H)，6.79(s，1H)，7.11-7.30(m，6H)，7.39(d，J＝7.9Hz，1H).

(Z)-2-(2-oxyethyl group-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (0.30g, 0.69mmol), same with embodiment 1 step 3, obtain title compound (compound 53) (0.19g, 56%).

ESI-MS?m/z：494(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.32(t，J＝7.1Hz，3H)，2.39(s，3H)，2.42(s，3H)，2.86-3.24(m，4H)，4.51(q，J＝7.1Hz，2H)，5.14(s，2H)，6.32(s，1H)，6.83(s，1H)，6.92(dd，J＝8.0，1.6Hz，1H)，7.05(d，J＝7.7Hz，1H)，7.13-7.32(m，5H).

[embodiment 54]

(Z)-and 2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 54)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-[2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (250mg, 0.96mmol), same with embodiment 35 steps 1, obtain (Z)-[2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (362mg, 78%).

ESI-MS?m/z：484(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.14(t，J＝7.1Hz，3H)，1.64(s，6H)，1.65-1.78(m，2H)，2.61(t，J＝7.8Hz，2H)，3.00-3.19(m，4H)，4.20(q，J＝7.2Hz，2H)，5.44(s，2H)，5.70(s，1H)，5.79(s，1H)，6.72(s，1H)，6.88(dd，J＝7.8，1.4Hz，1H)，7.13-7.33(m，4H)，7.43(d，J＝7.9Hz，1H).

(Z) that [step 2] step 1 obtains-[2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (146mg, 0.3mmol) use, same with embodiment 1 step 3, obtain title compound (compound 54) (88mg, 53%).

ESI-MS?m/z：543(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.97(t，J＝7.4Hz，3H)，1.19(t，J＝7.1Hz，3H)，1.64(s，6H)，1.68-1.78(m，2H)，2.65(t，J＝7.7Hz，2H)，2.75-3.01(m，2H)，3.27-3.43(m，2H)，4.23(q，J＝7.0Hz，2H)，5.47(d，J＝4.4Hz，2H)，5.60(s，1H)，6.53(s，1H)，6.87(s，1H)，6.90(d，J＝7.7Hz，1H)，7.10-7.31(m，4H)，7.37(dd，J＝7.4，1.7Hz，1H).

[embodiment 55]

(Z)-and 2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 55)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (120mg, 0.46mmol), same with embodiment 36 steps 1, obtain (Z)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (147mg, 73%).

ESI-MS?m/z：439(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.5Hz，3H)，2.66(s，3H)，2.79(q，J＝7.5Hz，2H)，2.98-3.14(m，4H)，5.42(s，2H)，5.69(s，1H)，6.94(s，1H)，7.02-7.07(m，2H)，7.13(d，J＝7.5Hz，1H)，7.20-7.32(m，3H)，7.41(d，J＝7.7Hz，1H).

(Z)-[2-(5-chloro-2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (147mg, 0.33mmol), same with embodiment 1 step 3, obtain title compound (compound 55) (99mg, 59%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.37(t，J＝7.5Hz，3H)，2.66(d，J＝0.5Hz，3H)，2.75-3.00(m，2H)，2.84(q，J＝7.5Hz，2H)，3.25-3.40(m，2H)，5.45(s，2H)，6.51(s，1H)，7.05-7.17(m，5H)，7.20-7.30(m，2H)，7.36(dd，J＝7.3，1.6Hz，1H).

[embodiment 56]

(Z)-and 2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 56)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (140mg, 0.54mmol), same with embodiment 37 steps 1, obtain (Z)-[2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (214mg, 85%).

ESI-MS?m/z：473(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.6Hz，3H)，2.69(s，3H)，2.85(q，J＝7.5Hz，2H)，2.98-3.15(m，4H)，5.50(s，2H)，5.70(s，1H)，6.93(s，1H)，7.05-7.14(m，2H)，7.18-7.32(m，4H)，7.42(d，J＝7.9Hz，1H).

(Z)-[2-(2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (214mg, 0.45mmol), same with embodiment 1 step 3, obtain title compound (compound 56) (192mg, 77%).

ESI-MS?m/z：532(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.37(t，J＝7.6Hz，3H)，2.68(s，3H)，2.73-2.98(m，2H)，2.89(q，J＝7.6Hz，2H)，3.25-3.40(m，2H)，5.53(s，2H)，6.52(s，1H)，7.05-7.17(m，4H)，7.20-7.31(m，3H)，7.36(dd，J＝7.3，1.6Hz，1H).

[embodiment 57]

(Z)-and 2-(5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 57)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile, use (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (140mg, 0.54mmol), same with embodiment 38 steps 1, obtain (Z)-[2-(5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] the thick resultant of acetonitrile conduct.

(Z)-[2-(5-methyl-2-propyl group-7-trifluoromethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile, same with embodiment 1 step 3, obtain title compound (compound 57) (165mg, 57%).

ESI-MS?m/z：546(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99(t，J＝7.3Hz，3H)，1.76-1.86(m，2H)，2.68(s，3H)，2.76-2.99(m，2H)，2.84(t，J＝7.8Hz，2H)，3.28-3.40(m，2H)，5.53(s，2H)，6.52(s，1H)，7.04-7.17(m，4H)，7.21-7.30(m，3H)，7.37(dd，J＝7.2，1.7Hz，1H).

[embodiment 58]

(Z)-and 2-(8-oxo-2-propyl group-8H-ring imidazoles in heptan-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 58)

[step 1] replaces (E)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile uses (Z)-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) acetonitrile (140mg, 0.54mmol), embodiment 39 steps 1 are same, obtain (Z)-[2-(8-oxo-2-propyl group-8H-ring imidazoles in heptan-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (206mg, 89%).

ESI-MS?m/z：432(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.4Hz，3H)，1.77-1.89(m，2H)，2.76(t，J＝7.7Hz，2H)，2.99-3.15(m，4H)，5.67(s，1H)，6.01(s，2H)，6.89-6.99(m，3H)，7.07-7.31(m，6H)，7.40(d，J＝8.4Hz，1H)，7.73(d，J＝11.0Hz，1H).

(Z)-[2-(8-oxo-2-propyl group-8H-ring imidazoles in heptan-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] acetonitrile (206mg, 0.48mmol), same with embodiment 1 step 3, obtain title compound (compound 58) (108mg, 46%).

ESI-MS?m/z：491(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.02(t，J＝7.3Hz，3H)，1.80-1.93(m，2H)，2.80(t，J＝7.7Hz，2H)，2.84-2.99(m，2H)，3.28-3.40(m，2H)，5.93(s，2H)，6.50(s，1H)，6.86(d，J＝7.9Hz，1H)，6.95-7.13(m，5H)，7.20-7.29(m，3H)，7.36(dd，J＝7.3，1.8Hz，1H)，7.76(d，J＝11.0Hz，1H).

[embodiment 59]

(Z)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 59)

(Z)-2-(2-hydroxymethyl-10 that [step 1] uses reference example 6 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (350mg, 1.3mmol), replace 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, use 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] and pyridine (349mg, 2.0mmol), same with embodiment 36 steps 1, obtain (Z)-2-[2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (376mg, 68%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.4Hz，3H)，2.00(s，3H)，2.56(s，3H)，2.63(s，3H)，2.73-2.84(m，2H)，2.75(q，J＝7.4Hz，2H)，3.20-3.30(m，2H)，5.40(s，2H)，6.83(s，1H)，6.88(s，1H)，6.97(dd，J＝8.0，1.6Hz，1H)，7.04(dd，J＝8.0，1.6Hz，1H)，7.15-7.25(m，3H)，7.36(d，J＝7.9Hz，1H).

(Z)-2-[2-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (197mg, 0.46mmol), same with embodiment 1 step 3, obtain title compound (compound 59) (126mg, 56%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.5Hz，3H)，2.11(s，3H)，2.55(s，3H)，2.63(s，3H)，2.75-2.83(m，4H)，3.26-3.33(m，2H)，5.42(s，2H)，6.89(s，1H)，6.91-6.94(m，2H)，7.05-7.24(m，5H).

[embodiment 60]

(Z)-and 2-(8-oxo-2-propyl group-4,5,6,7-tetrahydrochysene-8H-ring imidazoles in heptan-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 60)

The compound 58 that use embodiment 58 obtains (131mg, 0.27mmol) same with embodiment 41, obtain title compound (compound 60) (5mg, 4%).

ESI-MS?m/z：495(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.98(t，J＝7.4Hz，3H)，1.68-1.79(m，2H)，1.82-1.98(m，4H)，2.54-2.67(m，4H)，2.80-3.04(m，2H)，3.02(t，J＝6.2Hz，2H)，3.22-3.40(m，2H)，5.50(s，2H)，6.50(s，1H)，6.71-6.85(m，2H)，6.96(s，1H)，7.06-7.45(m，4H).

[embodiment 61]

(Z)-and 2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 61)

[step 1] replaces (E)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile, use (Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit) propionitrile (200mg, 0.73mmol), same with embodiment 43 steps 1, obtain (Z)-2-[2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (282mg, 78%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93(t，J＝7.3Hz，3H)，1.12(t，J＝7.1Hz，3H)，1.63(s，6H)，1.65-1.75(m，2H)，2.02(s，3H)，2.59(t，J＝7.8Hz，2H)，2.75-2.89(m，2H)，3.21-3.33(m，2H)，4.19(q，J＝7.1Hz，2H)，5.39(s，2H)，5.79(s，1H)，6.62(s，1H)，6.82(dd，J＝7.9，1.6Hz，1H)，7.06(dd，J＝8.0，1.4Hz，1H)，7.17-7.31(m，3H)，7.39(d，J＝7.9Hz，1H).

(Z)-2-[2-(5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl group-1H-imidazoles-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (282mg, 0.57mmol), same with embodiment 1 step 3, obtain title compound (compound 61) (67mg, 21%).

ESI-MS?m/z：557(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.12(t，J＝7.2Hz，3H)，1.62(s，6H)，1.78-1.65(m，2H)，2.12(s，3H)，2.61(t，J＝7.8Hz，2H)，2.90-2.76(m，2H)，3.39-3.27(m，2H)，4.20(q，J＝7.2Hz，2H)，5.41(s，2H)，5.66(s，1H)，6.74(s，1H)，6.81(dd，J＝7.8，1.8Hz，1H)，7.27-7.05(m，5H).

[embodiment 62]

(Z)-and 2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 62)

(Z)-2-[2-(the 2-ethyl-5 that uses embodiment 59 steps 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (212mg, 0.49mmol), similarly to Example 22, obtain title compound (compound 62) (171mg, 74%).

ESI-MS?m/z：476(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.6Hz，3H)，2.33(s，3H)，2.54(s，3H)，2.61(s，3H)，2.68-2.82(m，4H)，3.15-3.35(m，2H)，5.38(s，2H)，6.83-6.94(m，4H)，7.13-7.24(m，4H).

[embodiment 63]

2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (compound 63)

[step 1] uses 5-cyano methyl-2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene (No. the 2526005th, Japanese Patent; 335mg 1.3mmol), replaces 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, use 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] and pyridine (403mg, 3.8mmol), same with embodiment 36 steps 1, obtain 5-cyano methyl-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (252mg, 47%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.30(t，J＝7.6Hz，3H)，2.58(s，3H)，2.63(s，3H)，2.75(q，J＝7.6Hz，2H)，2.90-3.05(m，4H)，3.14-3.26(m，2H)，4.38(t，J＝8.1Hz，1H)，5.40(s，2H)，6.87-6.94(m，3H)，7.10-7.23(m，5H).

5-cyano methyl-2-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] and suberene (252mg, 0.60mmol), same with embodiment 1 step 3, obtain title compound (compound 63) (224mg, 78%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.27(t，J＝7.5Hz，3H)，2.55(s，3H)，2.58(s，3H)，2.73(q，J＝7.5Hz，2H)，2.79-2.91(m，2H)，3.02-3.24(m，4H)，4.28(br?s，1H)，5.35(s，2H)，6.75(d，J＝7.8Hz，1H)，6.79(s，1H)，6.88(d，J＝7.8Hz，1H)，6.90(s，1H)，7.00-7.17(m，4H).

[embodiment 64]

2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (compound 64)

[step 1] uses 5-cyano methyl-2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene (408mg, 1.55mmol), replace 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 4-methyl-2-propyl group benzoglyoxaline (297mg, 1.70mmol), same with embodiment 29 steps 1, obtain 5-cyano methyl-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (508mg, 78%).

ESI-MS?m/z：420(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99(t，J＝7.3Hz，3H)，1.73-1.85(m，2H)，2.69(s，3H)，2.80-2.86(m，2H)，2.88-3.29(m，4H)，3.04(d，J＝8.2Hz，2H)，4.39(t，J＝8.2Hz，1H)，5.27(s，2H)，6.78(s，1H)，6.88(d，J＝7.7Hz，1H)，6.98-7.24(m，8H).

5-cyano methyl-2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene (508mg, 1.2mmol), same with embodiment 1 step 3, obtain title compound (compound 64) (363mg, 63%).

ESI-MS?m/z：479(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95(t，J＝7.3Hz，3H)，1.67-1.78(m，2H)，2.59(s，3H)，2.67-2.86(m，2H)，2.77(t，J＝7.8Hz，2H)，2.94-3.17(m，2H)，3.19-3.34(m，2H)，4.40(br?s，1H)，5.24(s，2H)，6.70(s，1H)，6.76(d，J＝7.9Hz，1H)，6.97(d，J＝7.9Hz，1H)，7.03-7.17(m，7H).

[embodiment 65]

2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (compound 65)

[step 1] uses 5-cyano methyl-2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene (310mg, 1.2mmol), replace 5-chloro-2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine, use 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (345mg, 1.8mmol), same with embodiment 36 steps 1, obtain 5-cyano methyl-2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (362mg, 70%).

ESI-MS?m/z：441(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.5Hz，3H)，2.60(s，3H)，2.78(q，J＝7.5Hz，2H)，2.90-3.05(m，2H)，3.04(d，J＝8.2Hz，2H)，3.14-3.28(m，2H)，4.39(t，J＝8.2Hz，1H)，5.40(s，2H)，6.85(s，1H)，6.94(dd，J＝7.9，1.6Hz，1H)，7.11-7.15(m，2H)，7.17-7.23(m，4H).

5-cyano methyl-2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (362mg, 0.82mmol), same with embodiment 1 step 3, obtain title compound (compound 65) (338mg, 82%).

ESI-MS?m/z：500(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.27(t，J＝7.5Hz，3H)，2.60(s，3H)，2.74(q，J＝7.5Hz，2H)，2.82-2.95(m，2H)，3.06-3.33(m，4H)，4.39(br?s，1H)，5.37(s，2H)，6.80-6.83(m，2H)，6.98(d，J＝8.3Hz，1H)，7.04-7.16(m，5H).

[embodiment 66]

2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (compound 66)

[step 1] uses 5-cyano methyl-2-hydroxymethyl-10,11-dihydro-5H-dibenzo [a, d] suberene (362mg, 1.4mmol), replace 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (214mg, 1.3mmol), same with embodiment 29 steps 1, obtain 5-cyano methyl-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (171mg, 35%).

ESI-MS?m/z：407(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.6Hz，3H)，2.69(s，3H)，2.82(q，J＝7.6Hz，2H)，2.90-3.04(m，2H)，3.03(d，J＝8.1Hz，2H)，3.13-3.26(m，2H)，4.38(t，J＝8.1Hz，1H)，5.43(s，2H)，6.89(s，1H)，6.94(dd，J＝7.8，1.7Hz，1H)，7.03(dd，J＝4.9，0.7Hz，1H)，7.11-7.24(m，5H)，8.19(d，J＝4.9Hz，1H).

5-cyano methyl-2-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene (171mg, 0.42mmol), same with embodiment 1 step 3, obtain title compound (compound 66) (178mg, 91%).

ESI-MS?m/z：466(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.5Hz，3H)，2.67(s，3H)，2.74-3.17(m，6H)，2.82(q，J＝7.5Hz，2H)，4.23(br?s，1H)，5.38(s，2H)，6.72(d，J＝8.1Hz，1H)，6.81-6.85(m，2H)，6.97(d，J＝7.3Hz，1H)，7.03-7.18(m，4H)，8.10(d，J＝4.9Hz，1H).

[embodiment 67]

2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 67)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (EP420237; 2.0g, 10.7mmol) same with the step 1 of embodiment 1, obtain 2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(2.19g, 52%).

ESI-MS?m/z：395(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94-1.01(m，2H)，1.12-1.18(m，2H)，1.90(tt，J＝8.3，5.0Hz，1H)，2.58(s，3H)，2.59(s，3H)，2.96-3.06(m，4H)，5.44(s，2H)，6.00(s，1H)，6.60-6.65(m，1H)，6.68-6.78(m，2H)，6.85-6.91(m，3H)，7.00-7.09(m，2H).

2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(540mg, 1.37mmol) same with the step 2 of embodiment 1, obtain 5-cyano methyl-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(580mg, 98%).

ESI-MS?m/z：434(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95-1.01(m，2H)，1.13-1.18(m，2H)，1.81-1.89(m，1H)，2.57(s，6H)，3.04-3.10(m，4H)，4.52(s，2H)，5.47(s，2H)，6.85(s，1H)，6.96-7.04(m，3H)，7.11(dd，J＝7.5，1.5Hz，1H)，7.16-7.24(m，3H).

5-cyano methyl-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(146mg, 0.34mmol) same with the step 3 of embodiment 1, obtain title compound (compound 67) (137mg, 82%).

ESI-MS?m/z：493(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.92-0.98(m，2H)，1.09-1.14(m，2H)，1.77-1.86(m，1H)，2.52(s，6H)，2.97-3.07(m，4H)，4.71(s，2H)，5.44(s，2H)，6.84(s，1H)，6.87-7.01(m，5H)，7.07-7.16(m，2H).

[embodiment 68]

2-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(compound 68)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, 2-oxyethyl group-7-methyl-3H-imidazo [4, the 5-b] pyridine (4.90g that uses reference example 20 to obtain, 11.3mmol), same with the step 1 of embodiment 1, obtain 2-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (300mg, 6.9%).

ESI-MS?m/z：385(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.41(t，J＝7.0Hz，3H)，2.45(s，3H)，2.90(m，4H)，4.58(q，J＝7.0Hz，2H)，5.05(s，2H)，6.64(td，J＝7.2，1.3Hz，1H)，6.86-7.04(m，7H)，7.99(d，J＝5.0Hz，1H)，8.29(s，1H).

2-(2-oxyethyl group-7-methyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(297mg, 0.772mmol) same with the step 2 of embodiment 1, obtain 5-cyano methyl-2-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine

(261mg, 80%).

ESI-MS?m/z：424(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.46(t，J＝7.1Hz，3H)，2.54(s，3H)，3.05-3.11(m，4H)，4.50(s，2H)，4.62(q，J＝7.1Hz，2H)，5.16(s，2H)，6.89-7.23(m，8H)，8.03(d，J＝5.1Hz，1H).

5-cyano methyl-2-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 3] uses step 2 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(133mg, 0.314mmol) same with the step 3 of embodiment 1, obtain title compound (compound 68) (135mg, 89%).

ESI-MS?m/z：483(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.43(t，J＝7.1Hz，3H)，2.51(s，3H)，3.02(br?s，4H)，4.59(q，J＝7.1Hz，2H)，4.71(s，2H)，5.11(s，2H)，6.85-7.13(m，8H)，7.95(d，J＝5.1Hz，1H).

[embodiment 69]

2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 69)

5-(1-cyano ethyl)-2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that the step 2 of use embodiment 27 obtains, 11-dihydro-5H-dibenzo [b, f] azepine

(204mg, 0.47mmol) same with the step 3 of embodiment 1, obtain title compound (compound 69) (109mg, 47%).

ESIMS?m/z：495(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.97(t，J＝7.3Hz，3H)，1.49(d，J＝6.5Hz，3H)，1.70-1.84(m，2H)，2.69(s，3H)，2.79(t，J＝7.8Hz，2H)，2.94-3.18(m，4H)，5.23(q，J＝6.5Hz，1H)，5.39(s，2H)，6.86-6.89(m，2H)，6.99-7.15(m，6H)，8.19(d，J＝5.0Hz，1H).

[embodiment 70]

2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 70)

2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4, the 5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 1] uses the step 1 of embodiment 67 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(1.66g, 4.20mmol), replace paraformaldehyde, (707 μ L 12.6mmol), similarly obtain 5-(1-cyano ethyl)-2-(2-cyclopropyl-5 quantitatively with the step 2 of embodiment 1 to use acetaldehyde, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [b, f] azepine (1.95g).

ESI-MS?m/z：448(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94-1.02(m，2H)，1.12-1.18(m，2H)，1.47(d，J＝7.1Hz，3H)，1.80-1.89(m，1H)，2.57(s，6H)，2.98-3.02(br?m，4H)，4.65(q，J＝7.1Hz，1H)，5.47(s，2H)，6.85-7.22(m，6H)，7.51-7.54(m，2H).

5-(1-cyano ethyl)-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [b, f] azepine

(453mg, 1.01mmol) same with the step 3 of embodiment 1, obtain title compound (compound 70) (242mg, 47%).

ESI-MS?m/z：507(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.90-0.96(m，2H)，1.08-1.13(m，2H)，1.48(d，J＝6.6Hz，3H)，1.75-1.85(m，1H)，2.52(s，3H)，2.55(s，3H)，2.90-3.13(m，4H)，5.21(q，J＝6.6Hz，1H)，5.42(s，2H)，6.83(s，1H)，6.91-7.10(m，7H).

[embodiment 71]

2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 71)

5-(1-cyano ethyl)-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0 that the step 1 of use embodiment 70 obtains, 11-dihydro-5H-dibenzo [b, f] azepine

(1.50g 3.23mmol), similarly to Example 22, obtains title compound (compound 71) (736mg, 45%).

ESI-MS?m/z：491(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.82-0.87(m，2H)，1.00-1.04(m，2H)，1.52(d，J＝6.6Hz，3H)，1.70-1.79(m，1H)，2.28(s，3H)，2.47-2.87(m，4H)，2.55(s，3H)，5.42(s，2H)，5.71(q，J＝6.6Hz，1H)，6.77(s，1H)，6.84(s，1H)，6.86-6.89(m，3H)，6.93-7.10(m，3H).

[embodiment 72]

(-)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 72)

Compound 22 usefulness ダイセ Le chemistry system CHIRALPAK AD (ethanol/hexane/trifluoroacetic acid=20/80/0.1) are separated, obtain title compound (compound 72) ([α] _D, CHCl ₃:-37 °).

[embodiment 73]

(+)-2-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 73)

Compound 22 is similarly separated with embodiment 72, obtain title compound (compound 73) ([α] _D, CHCl ₃:+42 °).

[embodiment 74]

(-)-2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 74)

Compound 25 is similarly separated with embodiment 72, obtain title compound (compound 74) ([α] _D, CHCl ₃:-34 °).

[embodiment 75]

(+)-2-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 75)

Compound 25 is similarly separated with embodiment 72, obtain title compound (compound 75) ([α] _D, CHCl ₃:+35 °).

[embodiment 76]

(-)-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 76)

Compound 26 is similarly separated with embodiment 72, obtain title compound (compound 76) ([α] _D, CHCl ₃:-30 °).

[embodiment 77]

(+)-2-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 77)

Compound 26 is similarly separated with embodiment 72, obtain title compound (compound 77) ([α] _D, CHCl ₃:+30 °).

[embodiment 78]

(-)-2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine (compound 78)

Compound 27 is similarly separated with embodiment 72, obtain title compound (compound 78) ([α] _D, CHCl ₃:-25 °).

[embodiment 79]

(+)-2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 79)

Compound 27 is similarly separated with embodiment 72, obtain title compound (compound 79) ([α] _D, CHCl ₃:+26 °).

[embodiment 80]

(-)-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 80)

Compound 71 is similarly separated with embodiment 72, obtain title compound (compound 80) ([α] _D, CHCl ₃:-46 °).

[embodiment 81]

(+)-2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethyl]-10,11-dihydro-5H-dibenzo [b, f] azepine

(compound 81)

Compound 71 is similarly separated with embodiment 72, obtain title compound (compound 81) ([α] _D, CHCl ₃:+40 °).

[embodiment 82]

(E)-and 2-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 82)

[step 1] replaces 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole, use 2-ethyl-4,6-dimethylbenzimidazole (123mg, 0.71mmol), same with the step 1 of embodiment 43, obtain (E)-2-[2-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (208mg, 68%).

ESI-MS?m/z：432(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.6Hz，3H)，2.00(s，3H)，2.38(s，3H)，2.65(s，3H)，2.71-2.88(m，2H)，2.84(q，J＝7.6Hz，2H)，3.19-3.35(m，2H)，5.24(s，2H)，6.79(s，1H)，6.81-6.88(m，3H)，7.01(d，J＝7.9Hz，1H)，7.14(dd，J＝7.0，2.0Hz，1H)，7.21-7.27(m，2H)，7.40(dd，J＝7.1，1.8Hz，1H).

(E)-2-[2-(2-ethyl-4 that [step 2] uses step 1 to obtain, 6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (206mg, 0.48mmol), same with the step 3 of embodiment 1, obtain title compound (compound 82) (94mg, 40%).

ESI-MS?m/z：491(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.23(t，J＝7.5Hz，3H)，1.92(s，3H)，2.30(s，3H)，2.46(s，3H)，2.75(m，2H)，2.76(q，J＝7.5Hz，2H)，3.30(m，2H)，5.37(s，2H)，6.70-7.19(m，9H).

[embodiment 83]

(E)-and 2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 83)

[step 1] replaces 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole, use 4-methyl-2-propyl group benzoglyoxaline (123mg, 0.71mmol), same with the step 1 of embodiment 43, obtain (E)-2-[2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (179mg, 58%).

ESI-MS?m/z：432(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99(t，J＝7.4Hz，3H)，1.73-1.86(m，2H)，1.99(s，3H)，2.69(s，3H)，2.71-2.88(m，4H)，3.18-3.35(m，2H)，5.28(s，2H)，6.84(d，J＝7.8Hz，1H)，6.88(s，1H)，6.97-7.29(m，7H)，7.40(dd，J＝7.3，1.8Hz，1H).

(E)-2-[2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (139mg, 0.32mmol), same with the step 3 of embodiment 1, obtain title compound (compound 83) (65mg, 41%).

ESI-MS?m/z：491(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.90(t，J＝7.4Hz，3H)，1.70(m，2H)，1.92(s，3H)，2.50(s，3H)，2.70(m，2H)，2.78(t，J＝7.6Hz，2H)，3.28(m，2H)，5.42(s，2H)，6.76-7.25(m，10H).

[embodiment 84]

(E)-and 2-(2-propyl group benzoglyoxaline-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 84)

[step 1] replaces 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole, use 2-propyl group benzoglyoxaline (114mg, 0.71mmol), same with the step 1 of embodiment 43, obtain (E)-2-[2-(2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (260mg, 88%).

ESI-MS?m/z：418(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00(t，J＝7.2Hz，3H)，1.80-1.94(m，2H)，2.00(s，3H)，2.67-2.89(m，4H)，3.19-3.36(m，2H)，5.30(s，2H)，6.82-6.88(m，2H)，7.02(d，J＝7.6Hz，1H)，7.12-7.29(m，6H)，7.40(dd，J＝7.1，1.8Hz，1H)，7.77(d，J＝7.6Hz，1H).

(E)-2-[2-(2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (257mg, 0.62mmol), same with the step 3 of embodiment 1, obtain title compound (compound 84) (93mg, 32%).

ESI-MS?m/z：477(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.90(t，J＝7.4Hz，3H)，1.72(m，2H)，1.92(s，3H)，2.74(m，2H)，2.78(t，J＝7.4Hz，2H)，3.30(m，2H)，5.44(s，2H)，6.75-7.65(m，11H).

[embodiment 85]

(E)-and 2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 85)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridine (223mg, 1.27mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(7-methyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (198mg, 36%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.97(t，J＝7.3Hz，3H)，1.73-1.78(m，2H)，1.98(s，3H)，2.68(s，3H)，2.71-2.88(m，4H)，3.18-3.34(m，2H)，5.44(s，2H)，6.91-7.04(m，4H)，7.12(dd，J＝7.1，1.5Hz，1H)，7.18-7.25(m，2H)，7.39(dd，J＝7.2，1.7Hz，1H)，8.19(d，J＝4.9Hz，1H).

(E)-2-[2-(7-methyl-2-propyl group-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (196mg, 0.45mmol), same with the step 3 of embodiment 1, obtain title compound (compound 85) (147mg, 66%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.96(t，J＝7.5Hz，3H)，1.73-1.79(m，2H)，2.08(s，3H)，2.67(s，3H)，2.73-2.86(m，2H)，2.77(t，J＝7.5Hz，2H)，3.20-3.37(m，2H)，5.43(s，2H)，6.92-6.95(m，2H)，7.01-7.10(m，3H)，7.15-7.35(m，3H)，8.18(d，J＝5.0Hz，1H).

[embodiment 86]

(E)-and 2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 86)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (243mg, 1.27mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (268mg, 47%).

ESI-MS?m/z：449(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.41(t，J＝7.1Hz，3H)，2.00(s，3H)，2.49(s，3H)，2.53(s，3H)，2.79-2.89(m，2H)，3.21-3.34(m，2H)，4.57(q，J＝7.1Hz，2H)，5.17(s，2H)，6.78(s，1H)，6.99(d，J＝7.9Hz，1H)，7.11-7.39(m，6H)

(E)-2-[2-(2-oxyethyl group-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (262mg, 0.58mmol), same with the step 3 of embodiment 1, obtain title compound (compound 86) (53mg, 18%).

ESI-MS?m/z：508(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.41(t，J＝7.1Hz，3H)，2.10(s，3H)，2.49(s，3H)，2.53(s，3H)，2.76-2.88(m，2H)，3.23-3.38(m，2H)，4.57(q，J＝7.1Hz，2H)，5.17(s，2H)，6.78(s，1H)，7.05-7.33(m，7H).

[embodiment 87]

(E)-and 2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 87)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (354mg, 1.89mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (401mg, 48%).

ESI-MS?m/z：445(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93-0.99(m，2H)，1.12-1.17(m，2H)，1.77-1.86(m，1H)，1.99(s，3H)，2.56(s，3H)，2.58(d，J＝0.5Hz，3H)，2.72-2.86(m，2H)，3.19-3.35(m，2H)，5.51(d，J＝1.8Hz，2H)，6.86(s，1H)，7.00-7.02(m，3H)，7.13(dd，J＝7.0，1.5Hz，1H)，7.19-7.28(m，2H)，7.39(dd，J＝7.2，1.7Hz，1H).

(E)-2-[2-(2-cyclopropyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (190mg, 0.43mmol), same with the step 3 of embodiment 1, obtain title compound (compound 87) (152mg, 70%).

ESI-MS?m/z：504(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93-1.00(m，2H)，1.12-1.17(m，2H)，1.77-1.87(m，1H)，2.10(s，3H)，2.56(s，3H)，2.57(s，3H)，2.73-2.88(m，2H)，3.22-3.39(m，2H)，5.50(s，2H)，6.86(s，1H)，6.98-7.11(m，4H)，7.19-7.36(m，3H).

[embodiment 88]

(E)-and 2-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 88)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (EP420237; 164mg, 0.94mmol) same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (148mg, 36%).

ESI-MS?m/z：431(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.98-1.05(m，2H)，1.18-1.23(m，2H)，1.84-1.92(m，1H)，1.99(s，3H)，2.63(s，3H)，2.72-2.88(m，2H)，3.19-3.34(m，2H)，5.54(s，2H)，6.98-7.03(m，4H)，7.12(dd，J＝7.0，1.5Hz，1H)，7.17-7.28(m，2H)，7.39(dd，J＝7.2，1.9Hz，1H)，8.16(d，J＝4.9Hz，1H).

(E)-2-[2-(2-cyclopropyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (148mg, 0.34mmol), same with the step 3 of embodiment 1, obtain title compound (compound 88) (120mg, 71%).

ESI-MS?m/z：490(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.98-1.05(m，2H)，1.18-1.23(m，2H)，1.84-1.94(m，1H)，2.09(s，3H)，2.62(d，J＝0.5Hz，3H)，2.72-2.87(m，2H)，3.21-3.37(m，2H)，5.53(s，2H)，6.97-7.10(m，5H)，7.18-7.35(m，3H)，8.15(d，J＝4.8Hz，1H).

[embodiment 89]

(E)-and 2-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 89)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridine (420mg, 2.37mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (109mg, 11%).

ESI-MS?m/z：435(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.44(t，J＝7.2Hz，3H)，1.99(s，3H)，2.55(s，3H)，2.75-2.88(m，2H)，3.20-3.35(m，2H)，4.62(q，J＝7.2Hz，2H)，5.20(s，2H)，6.92(d，J＝5.6Hz，1H)，6.99(d，J＝7.9Hz，1H)，7.11-7.24(m，5H)，7.37(dd，J＝7.3，1.7Hz，1H)，8.03(d，J＝5.0Hz，1H).

(E)-2-[2-(2-oxyethyl group-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (104mg, 0.24mmol), same with the step 3 of embodiment 1, obtain title compound (compound 89) (85mg, 72%).

ESI-MS?m/z：494(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.1Hz，3H)，2.09(s，3H)，2.55(s，3H)，2.75-2.88(m，2H)，3.22-3.39(m，2H)，4.62(q，J＝7.1Hz，2H)，5.20(s，2H)，6.88-6.93(m，2H)，7.06-7.33(m，6H)，8.02(d，J＝5.1Hz，1H).

[embodiment 90]

(E)-and 2-(2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 90)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-3H-imidazo [4,5-b] pyridine (US5332744; 470mg, 3.20mmol) same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (655mg, 51%).

ESI-MS?m/z：405(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.40(t，J＝7.3Hz，3H)，1.99(s，3H)，2.72-2.88(m，4H)，3.19-3.33(m，2H)，5.45(s，2H)，6.92-7.02(m，3H)，7.13(dd，J＝7.3，1.5Hz，1H)，7.20-7.27(m，3H)，7.39(dd，J＝7.3，1.8Hz，1H)，8.03(dd，J＝8.1，1.5Hz，1H)，8.34(dd，J＝5.1，1.5Hz，1H).

(E)-2-[2-(2-ethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (446mg, 1.10mmol), same with the step 3 of embodiment 1, obtain title compound (compound 90) (433mg, 85%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.40(t，J＝7.4Hz，3H)，2.09(s，3H)，2.72-2.87(m，2H)，2.82(q，J＝7.4Hz，2H)，3.21-3.38(m，2H)，5.44(s，2H)，6.94-6.98(m，2H)，7.09(d，J＝8.6Hz，2H)，7.17-7.34(m，4H)，8.02(dd，J＝7.9，1.3Hz，1H)，8.33(dd，J＝4.8，1.3Hz，1H).

[embodiment 91]

(E)-and 2-(2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 91)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 2-oxyethyl group-3H-imidazo [4 that uses reference example 21 to obtain, 5-b] pyridine (652mg, 4.00mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (471mg, 28%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.1Hz，3H)，2.00(s，3H)，2.76-2.89(m，2H)，3.22-3.35(m，2H)，4.62(q，J＝7.1Hz，2H)，5.22(s，2H)，7.01(d，J＝7.7Hz，1H)，7.09-7.26(m，6H)，7.38(dd，J＝7.3，1.8Hz，1H)，7.75(dd，J＝7.9，1.5Hz，1H)，8.17(dd，J＝5.1，1.5Hz，1H).

(E)-2-[2-(2-oxyethyl group-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (370mg, 0.88mmol), same with the step 3 of embodiment 1, obtain title compound (compound 91) (330mg, 78%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.1Hz，3H)，2.10(s，3H)，2.77-2.89(m，2H)，3.25-3.39(m，2H)，4.62(q，J＝7.1Hz，2H)，5.22(s，2H)，7.07-7.34(m，8H)，7.74(dd，J＝7.9，1.3Hz，1H)，8.16(dd，J＝5.0，1.3Hz，1H).

[embodiment 92]

(E)-and 2-(2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 92)

[step 1] replaces 2-ethyl-5, and 7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-3H-imidazo [4,5-b] pyridine (EP420237; 509mg, 3.20mmol) same with the step 1 of embodiment 40, obtain (E)-2-[2-(2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (517mg, 39%).

ESI-MS?m/z：417(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.02-1.09(m，2H)，1.22-1.27(m，2H)，1.88-1.94(m，1H)，2.00(s，3H)，2.74-2.90(m，2H)，3.20-3.33(m，2H)，5.57(s，2H)，7.02-7.06(m，3H)，7.12-7.29(m，4H)，7.39(dd，J＝7.3，1.7Hz，1H)，7.93(dd，J＝7.9，1.5Hz，1H)，8.30(dd，J＝5.0，1.5Hz，1H).

(E)-2-[2-(2-cyclopropyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (345mg, 0.83mmol), same with the step 3 of embodiment 1, obtain title compound (compound 92) (237mg, 60%).

ESI-MS?m/z：476(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.03-1.10(m，2H)，1.21-1.29(m，2H)，1.88-1.98(m，1H)，2.10(s，3H)，2.75-2.88(m，2H)，3.23-3.39(m，2H)，5.56(s，2H)，7.02-7.12(m，4H)，7.16-7.35(m，4H)，7.92(dd，J＝8.1，1.5Hz，1H)，8.29(dd，J＝4.8，1.5Hz，1H).

[embodiment 93]

(E)-and 2-(7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 93)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 7-chloro-2-ethyl-3H-imidazo [4 that uses reference example 22 to obtain, 5-b] pyridine (257mg, 1.42mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (280mg, 45%).

ESI-MS?m/z：439(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.37(t，J＝7.5Hz，3H)，1.98(s，3H)，2.71-2.88(m，2H)，2.85(q，J＝7.5Hz，2H)，3.19-3.35(m，2H)，5.44(s，2H)，6.92-7.03(m，3H)，7.13(dd，J＝6.8，2.1Hz，1H)，7.17-7.29(m，3H)，7.39(dd，J＝7.3，1.7Hz，1H)，8.21(d，J＝5.3Hz，1H).

(E)-2-[2-(7-chloro-2-ethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (280mg, 0.64mmol), same with the step 3 of embodiment 1, obtain title compound (compound 93) (229mg, 72%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.37(t，J＝7.5Hz，3H)，2.09(s，3H)，2.72-2.89(m，2H)，2.85(q，J＝7.5Hz，2H)，3.22-3.38(m，2H)，5.44(s，2H)，6.92(s，1H)，6.95(dd，J＝7.9，1.6Hz，1H)，7.07-7.11(m，2H)，7.17-7.34(m，4H)，8.21(d，J＝5.3Hz，1H).

[embodiment 94]

(E)-and 2-(7-chloro-2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 94)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 7-chloro-2-oxyethyl group-3H-imidazo [4 that uses reference example 23 to obtain, 5-b] pyridine (200mg, 1.01mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(7-chloro-2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (187mg, 41%).

ESI-MS?m/z：455(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.46(t，J＝7.0Hz，3H)，2.00(s，3H)，2.79-2.86(m，2H)，3.24-3.32(m，2H)，4.69(q，J＝7.0Hz，2H)，5.21(s，2H)，7.01(d，J＝7.6Hz，1H)，7.11-7.28(m，6H)，7.38(dd，J＝7.1，1.8Hz，1H)，8.04(d，J＝5.6Hz，1H).

(E)-2-[2-(7-chloro-2-oxyethyl group-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (186mg, 0.41mmol), same with the step 3 of embodiment 1, obtain title compound (compound 94) (154mg, 73%).

ESI-MS?m/z：514(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.1Hz，3H)，2.08(s，3H)，2.77-2.90(m，2H)，3.26-3.43(m，2H)，4.68(q，J＝7.1Hz，2H)，5.21(s，2H)，7.06-7.30(m，8H)，8.05(d，J＝5.5Hz，1H).

[embodiment 95]

(E)-and 2-(7-chloro-2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 95)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, the 7-chloro-2-cyclopropyl-3H-imidazo [4 that uses reference example 24 to obtain, 5-b] pyridine (422mg, 2.18mmol), same with the step 1 of embodiment 40, obtain (E)-2-[2-(7-chloro-2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (352mg, 36%).

ESI-MS?m/z：451(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.03-1.10(m，2H)，1.26-1.34(m，2H)，1.86-1.95(m，1H)，1.99(s，3H)，2.72-2.90(m，2H)，3.20-3.36(m，2H)，5.55(s，2H)，7.02-7.05(m，3H)，7.13(dd，J＝7.0，1.7Hz，1H)，7.18-7.28(m，3H)，7.39(dd，J＝7.2，1.8Hz，1H)，8.17(d，J＝5.3Hz，1H).

(E)-2-[2-(7-chloro-2-cyclopropyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (300mg, 0.67mmol), same with the step 3 of embodiment 1, obtain title compound (compound 95) (283mg, 83%).

ESI-MS?m/z：510(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.03-1.10(m，2H)，1.28-1.34(m，2H)，1.87-1.97(m，1H)，2.10(s，3H)，2.74-2.89(m，2H)，3.22-3.40(m，2H)，5.54(s，2H)，6.87-7.13(m，4H)，7.18-7.35(m，4H)，8.17(d，J＝5.3Hz，1H).

[embodiment 96]

(E)-and 2-(4-chloro-2-oxyethyl group benzo imidazoles-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 96)

[step 1] replaces 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole, the 4-chloro-2-oxyethyl group benzo imidazoles (393mg that uses reference example 25 to obtain, 2.00mmol), same with the step 1 of embodiment 43, obtain (E)-2-[2-(4-chloro-2-oxyethyl group benzo imidazoles 1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (370mg, 41%).

ESI-MS?m/z：454(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.46(t，J＝7.1Hz，3H)，2.00(s，3H)，2.74-2.89(m，2H)，3.20-3.33(m，2H)，4.71(q，J＝7.1Hz，2H)，5.11(s，2H)，6.92-7.02(m，5H)，7.11-7.26(m，4H)，7.39(dd，J＝7.1，1.8Hz，1H).

(E)-2-[2-(4-chloro-2-oxyethyl group benzo imidazoles 1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (368mg, 0.82mmol), same with the step 3 of embodiment 1, obtain title compound (compound 96) (228mg, 54%).

ESI-MS?m/z：513(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.38(t，J＝7.1Hz，3H)，1.92(s，3H)，2.74(m，2H)，3.30(m，2H)，4.59(q，J＝7.1Hz，2H)，5.20(s，2H)，6.89-7.39(m，10H).

[embodiment 97]

(E)-and 2-(4-chloro-2-cyclopropyl benzo imidazoles-1-yl) methyl-5-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 97)

[step 1] replaces 5-ethoxy carbonyl-4-(1-hydroxyl-1-methyl) ethyl-2-propyl imidazole, the 4-chloro-2-cyclopropyl benzo imidazoles (385mg that uses reference example 26 to obtain, 2.00mmol), same with the step 1 of embodiment 43, obtain (E)-2-[2-(4-chloro-2-cyclopropyl benzo imidazoles 1-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (687mg, 76%).

ESI-MS?m/z：450(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.96-1.36(m，4H)，1.82-1.94(m，1H)，2.00(s，3H)，2.70-2.92(m，2H)，3.18-3.39(m，2H)，5.41(s，2H)，6.91-7.42(m，10H).

(E)-2-[2-(4-chloro-2-cyclopropyl benzo imidazoles-1-yl) methyl isophthalic acid 0 that [step 2] uses step 1 to obtain, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (584mg, 1.30mmol), same with the step 3 of embodiment 1, obtain title compound (compound 97) (125mg, 19%).

ESI-MS?m/z：509(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.98-1.12(m，4H)，1.92(s，3H)，2.25(m，1H)，2.77(m，2H)，3.30(m，2H)，5.59(s，2H)，6.90-7.20(m，9H)，7.44(d，J＝8.1Hz，1H).

[embodiment 98]

(E)-and 2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 98)

(E)-2-[2-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 0 that the step 1 of use embodiment 83 obtains, 11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (110mg, 0.26mmol), similarly to Example 22, obtain title compound (compound 98) (63mg, 52%).

ESI-MS?m/z：475(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.91(t，J＝7.4Hz，3H)，1.71(m，2H)，2.01(s，3H)，2.50(s，3H)，2.75(m，2H)，2.79(t，J＝7.6Hz，2H)，3.38(m，2H)，5.43(s，2H)，6.57(d，J＝7.2Hz，1H)，6.77-7.28(m，9H).

[embodiment 99]

(E)-and 2-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 99)

(E)-2-[2-(2-cyclopropyl-5 that the step 1 of use embodiment 87 obtains, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (211mg, 0.47mmol), similarly to Example 22, obtain title compound (compound 99) (156mg, 67%).

ESI-MS?m/z：488(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.90-0.98(m，2H)，1.04-1.11(m，2H)，1.76-1.86(m，1H)，2.27(s，3H)，2.39(s，3H)，2.51-2.67(m，2H)，2.58(s，3H)，2.89-2.99(m，1H)，3.08-3.18(m，1H)，5.47(d，J＝16.3Hz，1H)，5.56(d，J＝16.2Hz，1H)，6.86(s，1H)，6.90-6.98(m，2H)，7.07-7.13(m，3H)，7.18-7.23(m，2H).

[embodiment 100]

(E)-and 2-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 100)

(E)-2-[2-(2-cyclopropyl-7-methyl-3H-imidazo [4 that the step 1 of use embodiment 88 obtains, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (131mg, 0.30mmol), similarly to Example 22, obtain title compound (compound 100) (38mg, 26%).

ESI-MS?m/z：474(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99-1.06(m，2H)，1.16-1.21(m，2H)，1.86-1.95(m，1H)，2.32(s，3H)，2.58(s，3H)，2.71-2.80(m，2H)，3.16-3.28(m，2H)，5.54(s，2H)，6.91-7.08(m，4H)，7.16-7.34(m，4H)，8.15(d，J＝4.9Hz，1H).

[embodiment 101]

(E)-and 2-(2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 101)

(E)-2-[2-(2-ethyl-3H-imidazo [4 that the step 1 of use embodiment 90 obtains, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (202mg, 0.50mmol), similarly to Example 22, obtain title compound (compound 101) (183mg, 82%).

ESI-MS?m/z：448(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.38(t，J＝7.5Hz，3H)，2.32(s，3H)，2.68-2.82(m，2H)，2.82(q，J＝7.5Hz，2H)，3.16-3.29(m，2H)，5.45(s，2H)，6.92(s，1H)，6.98-7.02(m，2H)，7.14-7.34(m，5H)，7.96(dd，J＝7.9，1.5Hz，1H)，8.33(dd，J＝4.8，1.5Hz，1H).

[embodiment 102]

(E)-and 2-(2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 102)

(E)-2-[2-(2-oxyethyl group-3H-imidazo [4 that the step 1 of use embodiment 91 obtains, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (100mg, 0.24mmol), similarly to Example 22, obtain title compound (compound 102) (66mg, 60%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.0Hz，3H)，2.36(s，3H)，2.76-2.91(m，2H)，3.25-3.38(m，2H)，4.62(q，J＝7.0Hz，2H)，5.23(s，2H)，7.02(d，J＝7.6Hz，1H)，7.09-7.34(m，7H)，7.74(dd，J＝7.4，1.0Hz，1H)，8.16(dd，J＝5.0，1.0Hz，1H).

[embodiment 103]

(E)-and 2-(2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-5-[1-(1H-tetrazolium-5-yl) ethylidene]-10,11-dihydro-5H-dibenzo [a, d] suberene (compound 103)

(E)-2-[2-(2-cyclopropyl-3H-imidazo [4 that the step 1 of use embodiment 92 obtains, 5-b] pyridin-3-yl) methyl isophthalic acid 0,11-dihydro-5H-dibenzo [a, d] suberene-5-subunit] propionitrile (161mg, 0.39mmol), similarly to Example 22, obtain title compound (compound 103) (148mg, 83%).

ESI-MS?m/z：460(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.02-1.09(m，2H)，1.19-1.24(m，2H)，1.88-1.97(m，1H)，2.31(s，3H)，2.68-2.79(m，2H)，3.13-3.29(m，2H)，5.57(s，2H)，6.98-7.01(m，2H)，7.07-7.32(m，6H)，7.86(dd，J＝8.1，1.5Hz，1H)，8.29(dd，J＝4.8，1.5Hz，1H).

[embodiment 104]

(E)-and 3-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 104)

[step 1] is with (E)-(3-hydroxymethyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) acetonitrile (No. the 2526005th, Japanese Patent; 250mg, 0.950mmol) and 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (250mg, 1.42mmol) be dissolved in THF (9.5mL), 0 ℃ add down the triphenylphosphine that supports polymkeric substance (633mg, 1.90mmol) and azo-2-carboxylic acid's di-t-butyl (437mg, 1.90mmol), stirred 3 hours under the room temperature.Filtering mixt, filtrate under reduced pressure concentrate.Residue is refining with silica gel column chromatography (hexane/ethyl acetate=1/1), obtains (E)-[3-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (158mg, 26%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.22(t，J＝7.4Hz，3H)，2.47(s，3H)，2.50(s，3H)，2.74(q，J＝7.4Hz，2H)，5.14(s，2H)，5.39(s，2H)，6.33(s，1H)，6.52(d，J＝1.8Hz，1H)，6.72(dd，J＝8.2，1.8Hz，1H)，6.94(s，1H)，7.42(d，J＝8.2Hz，1H)，7.47-7.54(m，4H).

(E)-[3-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (156mg, 0.371mmol), same with the step 3 of embodiment 1, obtain title compound (compound 104) (94.3mg, 53%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.32(t，J＝7.6Hz，3H)，2.56(s，3H)，2.61(s，3H)，2.75(q，J＝7.6Hz，2H)，4.86(br?s，1H)，5.37(s，2H)，5.44(br?s，1H)，6.54(d，J＝1.7Hz，1H)，6.58(s，1H)，6.74(dd，J＝8.1，1.7Hz，1H)，6.88(s，1H)，7.24-7.31(m，2H)，7.44-7.52(m，3H).

[embodiment 105]

(E)-and 3-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 105)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (276mg, 1.71mmol), same with the step 1 of embodiment 104, obtain (E)-[3-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (151mg, 22%).

ESI-MS?m/z：407(M+H) ⁺； ¹H-NMR(DMSO-d ₃，δ)：1.25(t，J＝7.5Hz，3H)，2.56(s，3H)，2.80(q，J＝7.5Hz，2H)，5.14(s，2H)，5.43(s，2H)，6.32(s，1H)，6.57(d，J＝1.6Hz，1H)，6.75(dd，J＝8.2，1.6Hz，1H)，7.07(d，J＝4.9Hz，1H)，7.41(d，J＝8.2Hz，1H)，7.47-7.54(m，4H)，8.12(d，J＝4.9Hz，1H).

(E)-[3-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (149mg, 0.367mmol), same with the step 3 of embodiment 1, obtain title compound (compound 105) (64.9mg, 38%).

ESI-MS?m/z：466(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.25(t，J＝7.5Hz，3H)，2.56(s，3H)，2.80(q，J＝7.5Hz，2H)，5.16(br?s，2H)，5.42(s，2H)，6.54(d，J＝1.8Hz，1H)，6.55(s，1H)，6.75(dd，J＝8.1，1.8Hz，1H)，7.07(dd，J＝4.9，0.7Hz，1H)，7.21(dd，J＝7.3，1.2Hz，1H)，7.31-7.50(m，4H)，8.12(d，J＝4.8Hz，1H)，11.99(s，1H).

[embodiment 106]

(E)-and 3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 106)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (201mg, 1.03mmol), same with the step 1 of embodiment 104, obtain (E)-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (199mg, 44%).

ESI-MS?m/z：441(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.5Hz，3H)，2.53(s，3H)，2.78(q，J＝7.5Hz，2H)，5.15(s，2H)，5.43(s，2H)，6.33(s，1H)，6.57(d，J＝1.7Hz，1H)，6.74(dd，J＝8.1，1.7Hz，1H)，7.29(s，1H)，7.42(d，J＝8.1Hz，1H)，7.48-7.55(m，4H).

(E)-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (196mg, 0.445mmol), same with the step 3 of embodiment 1, obtain title compound (compound 106) (130mg, 58%).

ESI-MS?m/z：500(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.4Hz，3H)，2.53(s，3H)，2.79(q，J＝7.5Hz，2H)，5.17(br?s，2H)，5.42(s，2H)，6.53(d，J＝1.7Hz，1H)，6.56(s，1H)，6.73(dd，J＝8.1，1.7Hz，1H)，7.20-7.51(m，6H).

[embodiment 107]

(E)-and 3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 107)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (235mg, 1.25mmol), same with the step 1 of embodiment 104, obtain (E)-[3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (147mg, 27%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.96-1.01(m，4H)，2.07-2.15(m，1H)，2.44(s，3H)，2.46(s，3H)，5.15(s，2H)，5.50(s，2H)，6.33(s，1H)，6.61(d，J＝1.7Hz，1H)，6.79(dd，J＝8.2，1.7Hz，1H)，6.90(s，1H)，7.42(d，J＝8.2Hz，1H)，7.47-7.55(m，4H).

(E)-[3-(2-cyclopropyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (145mg, 0.335mmol), same with the step 3 of embodiment 1, obtain title compound (compound 107) (97.7mg, 59%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.96-1.02(m，4H)，2.07-2.15(m，1H)，2.44(s，3H)，2.46(s，3H)，5.17(br?s，2H)，5.49(s，2H)，6.56(s，1H)，6.57(d，J＝1.8Hz，1H)，6.79(dd，J＝8.1，1.8Hz，1H)，6.90(s，1H)，7.19-7.51(m，5H)

[embodiment 108]

(E)-and 3-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 108)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (177mg, 1.02mmol), same with the step 1 of embodiment 104, obtain (E)-[3-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (62.5mg, 15%).

ESI-MS?m/z：419(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.01-1.11(m，4H)，2.18-2.24(m，1H)，2.49(s，3H)，5.15(s，2H)，5.54(s，2H)，6.33(s，1H)，6.67(d，J＝1.7Hz，1H)，6.83(dd，J＝8.2，1.7Hz，1H)，7.04(d，J＝4.8Hz，1H)，7.42(d，J＝8.2Hz，1H)，7.47-7.54(m，4H)，8.08(d，J＝4.8Hz，1H).

(E)-[3-(2-cyclopropyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (60.3mg, 0.144mmol), same with the step 3 of embodiment 1, obtain title compound (compound 108) (26.8mg, 39%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.01-1.06(m，4H)，2.18-2.24(m，1H)，2.49(s，3H)，5.16(br?s，2H)，5.53(s，2H)，6.56(s，1H)，6.63(d，J＝1.8Hz，1H)，6.83(dd，J＝8.1，1.8Hz，1H)，7.03(dd，J＝4.9，0.7Hz，1H)，7.21(dd，J＝7.4，1.3Hz，1H)，7.31-7.50(m，4H)，8.09(d，J＝4.9Hz，1H).

[embodiment 109]

(E)-and 3-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 109)

(E)-2-(3-hydroxymethyl-6 that [step 1] uses reference example 30 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) propionitrile (264mg, 0.952mmol) and 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (250mg, 1.43mmol), same with the step 1 of embodiment 104, obtain (E)-2-[3-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (168mg, 27%).

ESI-MS?m/z：435(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.31(t，J＝7.5Hz，3H)，2.22(s，3H)，2.56(s，3H)，2.62(s，3H)，2.74(q，J＝7.5Hz，2H)，4.81(d，J＝12.6Hz，1H)，5.35(s，2H)，5.44(d，J＝12.6Hz，1H)，6.58(d，J＝1.6Hz，1H)，6.64(dd，J＝8.1，1.6Hz，1H)，6.88(s，1H)，6.98(d，J＝8.1Hz，1H)，7.32-7.45(m，4H).

(E)-2-[3-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (165mg, 0.380mmol), same with the step 3 of embodiment 1, obtain title compound (compound 109) (90.5mg, 48%).

ESI-MS?m/z：494(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.22(t，J＝7.5Hz，3H)，2.15(s，3H)，2.48(s，3H)，2.50(s，3H)，2.73(q，J＝7.5Hz，2H)，4.90(d，J＝12.5Hz，1H)，5.37(s，2H)，5.49(d，J＝12.5Hz，1H)，6.49(d，J＝1.7Hz，1H)，6.65(dd，J＝7.9，1.7Hz，1H)，6.94(s，1H)，7.03-7.06(m，1H)，7.16(d，J＝7.9Hz，1H)，7.24-7.35(m，2H)，7.42-7.45(m，1H).

[embodiment 110]

(E)-and 3-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 110)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (279mg, 1.73mmol), same with the step 1 of embodiment 109, obtain (E)-2-[3-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (173mg, 24%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.5Hz，3H)，2.14(s，3H)，2.55(s，3H)，2.80(q，J＝7.5Hz，2H)，4.92(d，J＝12.7Hz，1H)，5.41(s，2H)，5.43(d，J＝12.7Hz，1H)，6.55(d，J＝1.7Hz，1H)，6.70(dd，J＝8.0，1.7Hz，1H)，7.07(d，J＝4.9Hz，1H)，7.18(d，J＝8.0Hz，1H)，7.40-7.52(m，4H)，8.12(d，J＝4.9Hz，1H).

(E)-2-[3-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (172mg, 0.409mmol), same with the step 3 of embodiment 1, obtain title compound (compound 110) (126mg, 64%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.5Hz，3H)，2.14(s，3H)，2.55(s，3H)，2.80(q，J＝7.5Hz，2H)，4.90(d，J＝12.4Hz，1H)，5.40(s，2H)，5.49(d，J＝12.4Hz，1H)，6.55(d，J＝1.6Hz，1H)，6.68(dd，J＝8.1，1.6Hz，1H)，7.02-7.45(m，6H)，8.12(d，J＝4.9Hz，1H).

[embodiment 111]

(E)-and 3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 111)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (350mg, 1.79mmol), same with the step 1 of embodiment 109, obtain (E)-2-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (519mg, 64%).

ESI-MS?m/z：455(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.23(t，J＝7.4Hz，3H)，2.15(s，3H)，2.52(s，3H)，2.78(q，J＝7.4Hz，2H)，4.93(d，J＝12.7Hz，1H)，5.41(s，2H)，5.44(d，J＝12.7Hz，1H)，6.55(d，J＝1.6Hz，1H)，6.68(dd，J＝8.1，1.6Hz，1H)，7.19(d，J＝8.1Hz，1H)，7.28(s，1H)，7.41-7.52(m，4H).

(E)-2-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (397mg, 0.873mmol), same with the step 3 of embodiment 1, obtain title compound (compound 111) (296mg, 66%).

ESI-MS?m/z：514(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.23(t，J＝7.4Hz，3H)，2.15(s，3H)，2.53(s，3H)，2.78(q，J＝7.4Hz，2H)，4.91(d，J＝12.6Hz，1H)，5.41(s，2H)，5.50(d，J＝12.6Hz，1H)，6.55(d，J＝1.7Hz，1H)，6.67(dd，J＝8.1，1.7Hz，1H)，7.03-7.07(m，1H)，7.17(d，J＝8.1Hz，1H)，7.25-7.35(m，3H)，7.43-7.46(m，1H).

[embodiment 112]

(E)-and 3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 112)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (446mg, 2.38mmol), same with the step 1 of embodiment 109, obtain (E)-2-[3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (353mg, 33%).

ESI-MS?m/z：447(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.94-1.01(m，4H)，2.15(s，3H)，2.16-2.24(m，1H)，2.44(s，3H)，2.46(s，3H)，4.93(d，J＝12.7Hz，1H)，5.43(d，J＝12.7Hz，1H)，5.49(s，2H)，6.59(d，J＝1.8Hz，1H)，6.74(dd，J＝8.1，1.8Hz，1H)，6.90(s，1H)，7.19(d，J＝8.1Hz，1H)，7.40-7.52(m，4H).

(E)-2-[3-(2-cyclopropyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (351mg, 0.786mmol), same with the step 3 of embodiment 1, obtain title compound (compound 112) (197mg, 50%).

ESI-MS?m/z：506(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.01-1.05(m，4H)，2.15(s，3H)，2.16-2.24(m，1H)，2.44(s，3H)，2.46(s，3H)，4.91(d，J＝12.5Hz，1H)，5.49(d，J＝12.5Hz，1H)，5.51(s，2H)，6.63(d，J＝1.8Hz，1H)，6.76(dd，J＝8.1，1.8Hz，1H)，7.02-7.06(m，2H)，7.17(d，J＝8.1Hz，1H)，7.24-7.35(m，2H)，7.42-7.45(m，1H)，8.08(d，J＝4.9Hz，1H).

[embodiment 113]

(E)-and 3-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 113)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (300mg, 1.73mmol), same with the step 1 of embodiment 109, obtain (E)-2-[3-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (109mg, 15%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.99-1.05(m，4H)，2.15(s，3H)，2.15-2.19(m，1H)，2.49(s，3H)，4.92(d，J＝12.8Hz，1H)，5.43(d，J＝12.8Hz，1H)，5.52(s，2H)，6.64(d，J＝1.7Hz，1H)，6.77(dd，J＝8.1，1.7Hz，1H)，7.03(d，J＝4.9Hz，1H)，7.18(d，J＝8.1Hz，1H)，7.40-7.50(m，4H)，8.08(d，J＝4.9Hz，1H).

(E)-2-[3-(2-cyclopropyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (107mg, 0.247mmol), same with the step 3 of embodiment 1, obtain title compound (compound 113) (78.2mg, 64%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.01-1.05(m，4H)，2.15(s，3H)，2.17-2.22(m，1H)，2.49(s，3H)，4.91(d，J＝12.5Hz，1H)，5.49(d，J＝12.5Hz，2H)，5.51(s，1H)，6.63(d，J＝1.8Hz，1H)，6.76(dd，J＝8.1，1.8Hz，1H)，7.02-7.06(m，2H)，7.17(d，J＝8.1Hz，1H)，7.24-7.45(m，3H)，8.08(d，J＝4.9Hz，1H).

[embodiment 114]

(E)-and 3-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 114)

(E)-2-[3-(2-ethyl-5 that the step 1 of use embodiment 109 obtains, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (82.2mg, 0.189mmol), similarly to Example 22, obtain title compound (compound 114) (40.2mg, 44%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.22(t，J＝7.5Hz，3H)，2.23(s，3H)，2.50(s，3H)，2.51(s，3H)，2.75(q，J＝7.5Hz，2H)，4.93(d，J＝12.3Hz，1H)，5.38(s，2H)，5.59(d，J＝12.3Hz，1H)，6.50(d，J＝1.6Hz，1H)，6.63-6.70(m，2H)，6.94(s，1H)，7.08(td，J＝7.5，1.2Hz，1H)，7.20-7.27(m，2H)，7.41(d，J＝6.7Hz，1H).

[embodiment 115]

(E)-and 3-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 115)

(E)-2-[3-(2-ethyl-7-methyl-3H-imidazo [4 that the step 1 of use embodiment 110 obtains, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (330mg, 0.785mmol), similarly to Example 22, obtain title compound (compound 115) (152mg, 42%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.25(t，J＝7.5Hz，3H)，2.23(s，3H)，2.56(s，3H)，2.81(q，J＝7.5Hz，2H)，4.93(d，J＝12.5Hz，1H)，5.41(s，2H)，5.59(d，J＝12.5Hz，1H)，6.56(d，J＝1.5Hz，1H)，6.67-6.71(m，2H)，7.07-7.10(m，2H)，7.19-7.27(m，2H)，7.41(d，J＝6.6Hz，1H)，8.13(d，J＝4.9Hz，1H).

[embodiment 116]

(E)-and 3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 116)

(E)-2-[3-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that the step 1 of use embodiment 111 obtains, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (120mg, 0.264mmol), similarly to Example 22, obtain title compound (compound 116) (33.4mg, 25%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.5Hz，3H)，2.24(s，3H)，2.54(s，3H)，2.79(q，J＝7.5Hz，2H)，4.94(d，J＝12.5Hz，1H)，5.41(s，2H)，5.60(d，J＝12.5Hz，1H)，6.55(d，J＝1.6Hz，1H)，6.66-6.70(m，2H)，7.09(td，J＝7.5，1.2Hz，1H)，7.20-7.29(m，3H)，7.42(d，J＝6.6Hz，1H).

[embodiment 117]

(E)-and 3-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 117)

(E)-2-[3-(2-cyclopropyl-5 that the step 1 of use embodiment 112 obtains, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (292mg, 0.654mmol), similarly to Example 22, obtain title compound (compound 117) (163mg, 51%).

ESI-MS?m/z：490(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.97-1.01(m，4H)，2.07-2.14(m，1H)，2.24(s，3H)，2.44(s，3H)，2.47(s，3H)，4.94(d，J＝12.3Hz，1H)，5.49(s，2H)，5.60(d，J＝12.3Hz，1H)，6.58(d，J＝1.6Hz，1H)，6.68-6.75(m，2H)，6.91(s，1H)，7.05-7.28(m，3H)，7.42(d，J＝6.6Hz，1H).

[embodiment 118]

(Z)-and 8-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 118)

[step 1] uses (Z)-(8-hydroxymethyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) acetonitrile (No. the 2526005th, Japanese Patent; 270mg, 1.00mmol) and 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (270mg, 1.50mmol), same with the step 1 of embodiment 104, obtain (Z)-[8-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (70mg, 16%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.33(t，J＝7.5Hz，3H)，2.57(s，3H)，2.64(s，3H)，2.76(q，J＝7.5Hz，2H)，5.07(s，2H)，5.45(s，1H)，5.46(s，2H)，6.87-6.91(m，2H)，6.99-7.13(m，3H)，7.20-7.33(m，2H)，7.69(dd，J＝7.8，1.6Hz，1H).

(Z)-[8-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (70mg, 0.17mmol), same with the step 3 of embodiment 1, obtain title compound (compound 118) (45mg, 56%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.30(t，J＝7.5Hz，3H)，2.57(s，3H)，2.61(s，3H)，2.74(q，J＝7.5Hz，2H)，5.07(br?s，2H)，5.45(s，2H)，6.27(s，1H)，6.87-6.97(m，3H)，7.02(s，1H)，7.09-7.15(m，2H)，7.30(d，J＝7.8Hz，2H).

[embodiment 119]

(Z)-and 8-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 119)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridine (281mg, 1.49mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (270mg, 42%).

ESI-MS?m/z：435(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.97(t，J＝7.3Hz，3H)，1.70-1.84(m，2H)，2.57(s，3H)，2.63(s，3H)，2.72(t，J＝7.8Hz，2H)，5.08(s，2H)，5.46(s，1H)，5.47(s，2H)，6.88-6.92(m，2H)，6.99-7.13(m，3H)，7.22(d，J＝7.8Hz，1H)，7.28-7.34(m，1H)，7.70(dd，J＝7.9，1.7Hz，1H).

[step 2] use that step 1 obtains (Z)-[8-(5,7-dimethyl-2-propyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (200mg, 0.46mmol), same with the step 3 of embodiment 1, obtain title compound (compound 119) (163mg, 72%).

ESI-MS?m/z：494(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.96(t，J＝7.3Hz，3H)，1.69-1.83(m，2H)，2.57(s，3H)，2.62(s，3H)，2.71(t，J＝7.8Hz，2H)，5.12(br?s，2H)，5.46(s，2H)，6.31(s，1H)，6.90(s，1H)，6.94-7.03(m，3H)，7.09-7.17(m，2H)，7.30-7.37(m，2H).

[embodiment 120]

(Z)-and 8-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 120)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (189mg, 1.17mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (135mg, 28%).

ESI-MS?m/z：407(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.36(t，J＝7.5Hz，3H)，2.69(s，3H)，2.83(q，J＝7.5Hz，2H)，5.07(s，2H)，5.45(s，1H)，5.49(s，2H)，6.89(dd，J＝8.2，1.1Hz，1H)，6.99-7.14(m，4H)，7.22(d，J＝7.9Hz，1H)，7.31(ddd，J＝8.6，6.8，1.5Hz，1H)，7.69(dd，J＝7.9，1.5Hz，1H)，8.19(d，J＝4.9Hz，1H).

(Z)-[8-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (135mg, 0.33mmol), same with the step 3 of embodiment 1, obtain title compound (compound 120) (119mg, 77%).

ESI-MS?m/z：466(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.5Hz，3H)，2.68(s，3H)，2.82(q，J＝7.5Hz，2H)，5.04(br?s，2H)，5.47(s，2H)，6.24(s，1H)，6.89-7.16(m，6H)，7.26-7.33(m，2H)，8.11(d，J＝5.0Hz，1H).

[embodiment 121]

(Z)-and 8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 121)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (97mg, 0.49mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (94mg, 43%).

ESI-MS?m/z：441(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.36(t，J＝7.5Hz，3H)，2.60(s，3H)，2.79(q，J＝7.5Hz，2H)，5.09(s，2H)，5.47(br?s，3H)，6.90(dd，J＝8.2，1.1Hz，1H)，7.00-7.14(m，4H)，7.24(d，J＝7.9Hz，1H)，7.32(ddd，J＝8.4，7.0，1.6Hz，1H)，7.70(dd，J＝7.9，1.6Hz，1H).

(Z)-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (94mg, 0.21mmol), same with the step 3 of embodiment 1, obtain title compound (compound 121) (96mg, 90%).

ESI-MS?m/z：500(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.60(s，3H)，2.77(q，J＝7.5Hz，2H)，5.14(br?s，2H)，5.46(s，2H)，6.31(s，1H)，6.91-7.03(m，3H)，7.09-7.18(m，3H)，7.29-7.35(m，2H).

[embodiment 122]

(Z)-and 8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 122)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (159mg, 0.85mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (126mg, 34%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95-1.01(m，2H)，1.14-1.19(m，2H)，1.81(tt，J＝8.2，5.0Hz，1H)，2.56(s，3H)，2.58(s，3H)，5.09(s，2H)，5.46(s，1H)，5.57(s，2H)，6.87(s，1H)，6.90(dd，J＝8.3，1.0Hz，1H)，7.00-7.05(m，1H)，7.15(s，1H)，7.19(dd，J＝7.9，1.7Hz，1H)，7.23(d，J＝7.9Hz，1H)，7.28-7.34(m，1H)，7.70(dd，J＝7.9，1.5Hz，1H).

(Z)-[8-(2-cyclopropyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (126mg, 0.29mmol), same with the step 3 of embodiment 1, obtain title compound (compound 122) (117mg, 82%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.95-1.01(m，2H)，1.13-1.19(m，2H)，1.76-1.87(m，1H)，2.56(s，3H)，2.57(s，3H)，5.13(br?s，2H)，5.56(s，2H)，6.30(s，1H)，6.87(s，1H)，6.93-7.00(m，2H)，7.10-7.13(m，2H)，7.21-7.36(m，3H).

[embodiment 123]

(Z)-and 8-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 123)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (203mg, 1.17mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (104mg, 21%).

ESI-MS?m/z：419(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00-1.07(m，2H)，1.19-1.29(m，2H)，1.85-1.90(m，1H)，2.64(s，3H)，5.09(s，2H)，5.45(s，1H)，5.59(s，2H)，6.89(dd，J＝8.3，1.2Hz，1H)，7.01-7.03(m，2H)，7.17-7.34(m，4H)，7.69(dd，J＝7.8，1.7Hz，1H)，8.16(d，J＝5.0Hz，1H).

(Z)-[8-(2-cyclopropyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (103mg, 0.25mmol), same with the step 3 of embodiment 1, obtain title compound (compound 123) (89mg, 75%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00-1.07(m，2H)，1.19-1.24(m，2H)，1.83-1.92(m，1H)，2.62(s，3H)，5.04(br?s，2H)，5.57(s，2H)，6.22(s，1H)，6.89-7.00(m，3H)，7.08-7.11(m，2H)，7.22(dd，J＝7.8，1.7Hz，1H)，7.27-7.34(m，2H)，8.05(d，J＝5.1Hz，1H).

[embodiment 124]

(Z)-and 8-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 124)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (400mg, 2.09mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (450mg, 49%).

ESI-MS?m/z：437(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.42(t，J＝7.2Hz，3H)，2.50(s，3H)，2.54(s，3H)，4.58(q，J＝7.2Hz，2H)，5.10(s，2H)，5.23(s，2H)，5.45(s，1H)，6.80(s，1H)，6.89(dd，J＝8.3，1.3Hz，1H)，7.02(ddd，J＝8.3，6.9，1.0Hz，1H)，7.21(d，J＝7.6Hz，1H)，7.27-7.35(m，3H)，7.69(dd，J＝7.9，1.7Hz，1H).

(Z)-[8-(2-oxyethyl group-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (442mg, 1.01mmol), same with the step 3 of embodiment 1, obtain title compound (compound 124) (353mg, 70%).

ESI-MS?m/z：496(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.42(t，J＝7.1Hz，3H)，2.49(s，3H)，2.52(s，3H)，4.56(q，J＝7.1Hz，2H)，5.15(br?s，2H)，5.23(s，2H)，6.23(s，1H)，6.80(s，1H)，6.88-6.94(m，2H)，7.10(dd，J＝7.9，1.6Hz，1H)，7.25-7.35(m，4H).

[embodiment 125]

(Z)-and 8-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 125)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridine (592mg, 3.34mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (374mg, 26%).

ESI-MS?m/z：423(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.46(t，J＝7.1Hz，3H)，2.55(s，3H)，4.63(q，J＝7.1Hz，2H)，5.10(s，2H)，5.26(s，2H)，5.45(s，1H)，6.87-7.04(m，3H)，7.21-7.36(m，4H)，7.69(dd，J＝7.9，1.3Hz，1H)，8.03(d，J＝5.3Hz，1H).

(Z)-[8-(2-oxyethyl group-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (369mg, 0.88mmol), same with the step 3 of embodiment 1, obtain title compound (compound 125) (268mg, 64%).

ESI-MS?m/z：482(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.1Hz，3H)，2.55(s，3H)，4.62(q，J＝7.1Hz，2H)，5.08(br?s，2H)，5.25(s，2H)，6.25(s，1H)，6.91-6.99(m，3H)，7.09(dd，J＝7.7，1.8Hz，1H)，7.24(d，J＝1.1Hz，1H)，7.29-7.37(m，3H)，7.96(d，J＝5.1Hz，1H).

[embodiment 126]

(Z)-and 8-(7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) methylene radical-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 126)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridine (209mg, 1.15mmol), same with the step 1 of embodiment 118, obtain (Z)-[8-(7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (177mg, 36%).

ESI-MS?m/z：427(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.39(t，J＝7.5Hz，3H)，2.85(q，J＝7.5Hz，2H)，5.09(s，2H)，5.46(s，1H)，5.50(s，2H)，6.90(dd，J＝8.3，1.0Hz，1H)，7.03(ddd，J＝8.2，7.0，1.0Hz，1H)，7.09-7.15(m，2H)，7.23-7.34(m，3H)，7.70(dd，J＝7.9，1.5Hz，1H)，8.22(d，J＝5.3Hz，1H).

(Z)-[8-(7-chloro-2-ethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] acetonitrile (146mg, 0.34mmol), same with the step 3 of embodiment 1, obtain title compound (compound 126) (127mg, 77%).

ESI-MS?m/z：486(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.38(t，J＝7.5Hz，3H)，2.84(q，J＝7.5Hz，2H)，5.12(br?s，2H)，5.49(s，2H)，6.30(s，1H)，6.92-7.00(m，2H)，7.05(d，J＝1.5Hz，1H)，7.10(dd，J＝7.8，1.7Hz，1H)，7.17(dd，J＝7.8，1.7Hz，1H)，7.25-7.35(m，3H)，8.20(d，J＝5.3Hz，1H).

[embodiment 127]

(Z)-and 8-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 127)

(Z)-2-(8-hydroxymethyl-6 that [step 1] uses reference example 31 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) propionitrile (178mg, 0.64mmol) and 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (169mg, 0.96mmol), same with the step 1 of embodiment 104, obtain (Z)-2-[8-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (158mg, 57%).

ESI-MS?m/z：435(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.32(t，J＝7.5Hz，3H)，1.98(s，3H)，2.58(s，3H)，2.64(s，3H)，2.77(q，J＝7.5Hz，2H)，4.73(d，J＝12.6Hz，1H)，5.41(d，J＝12.6Hz，1H)，5.46(s，2H)，6.80(dd，J＝8.3，1.2Hz，1H)，6.91(s，1H)，6.95(td，J＝7.6，1.2Hz，1H)，7.07-7.14(m，2H)，7.16(s，1H)，7.21-7.27(m，1H)，7.49(dd，J＝7.9，1.6Hz，1H).

(Z)-2-[8-(2-ethyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (133mg, 0.31mmol), same with the step 3 of embodiment 1, obtain title compound (compound 127) (85mg, 56%).

ESI-MS?m/z：494(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.23(t，J＝7.5Hz，3H)，2.06(s，3H)，2.54(s，3H)，2.58(s，3H)，2.68(q，J＝7.5Hz，2H)，4.51(d，J＝12.6Hz，1H)，5.28(d，J＝12.6Hz，1H)，5.44(s，2H)，6.65(dd，J＝8.3，1.1Hz，1H)，6.80(td，J＝7.5，1.1Hz，1H)，6.90(s，1H)，7.01(dd，J＝7.8，1.7Hz，1H)，7.06(s，1H)，7.11-7.15(m，1H)，7.17(br?s，2H).

[embodiment 128]

(Z)-and 8-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 128)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridine (392mg, 2.43mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (181mg, 18%).

ESI-MS?m/z：421(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.6Hz，3H)，1.98(s，3H)，2.70(s，3H)，2.83(q，J＝7.5Hz，2H)，4.73(d，J＝12.7Hz，1H)，5.40(d，J＝12.7Hz，1H)，5.49(s，2H)，6.79(dd，J＝8.3，1.1Hz，1H)，6.92-7.27(m，6H)，7.48(dd，J＝7.8，1.7Hz，1H)，8.20(d，J＝5.0Hz，1H).

(Z)-2-[8-(2-ethyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (153mg, 0.36mmol), same with the step 3 of embodiment 1, obtain title compound (compound 128) (118mg, 67%).

ESI-MS?m/z：480(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.6Hz，3H)，2.08(s，3H)，2.68(s，3H)，2.83(q，J＝7.6Hz，2H)，4.74(d，J＝12.7Hz，1H)，5.46(d，J＝12.7Hz，1H)，5.49(s，2H)，6.81-6.91(m，2H)，6.99(dd，J＝7.6，1.6Hz，1H)，7.04(dd，J＝4.9，0.8Hz，1H)，7.15-7.29(m，4H)，8.20(d，J＝4.8Hz，1H).

[embodiment 129]

(Z)-and 8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 129)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridine (317mg, 1.62mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (374mg, 51%).

ESI-MS?m/z：455(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.35(t，J＝7.5Hz，3H)，1.99(s，3H)，2.60(s，3H)，2.80(q，J＝7.5Hz，2H)，4.74(d，J＝12.6Hz，1H)，5.42(d，J＝12.6Hz，1H)，5.47(s，2H)，6.81(dd，J＝8.3，1.2Hz，1H)，6.93-6.98(m，1H)，7.11-7.13(m，3H)，7.17(s，1H)，7.22-7.29(m，1H)，7.49(dd，J＝7.8，1.7Hz，1H).

(Z)-2-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (334mg, 0.73mmol), same with the step 3 of embodiment 1, obtain title compound (compound 129) (283mg, 75%).

ESI-MS?m/z：514(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.5Hz，3H)，2.10(s，3H)，2.61(s，3H)，2.79(q，J＝7.6Hz，2H)，4.76(d，J＝12.8Hz，1H)，5.47(s，2H)，5.48(d，J＝10.8Hz，1H)，6.82-6.92(m，2H)，7.00(dd，J＝7.7，1.6Hz，1H)，7.13-7.30(m，5H).

[embodiment 130]

(Z)-and 8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 130)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (304mg, 1.62mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (241mg, 33%).

ESI-MS?m/z：447(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.94-1.00(m，2H)，1.13-1.18(m，2H)，1.77-1.86(m，1H)，1.99(s，3H)，2.57(s，3H)，2.58(d，J＝0.5Hz，3H)，4.74(d，J＝12.8Hz，1H)，5.42(d，J＝12.8Hz，1H)，5.57(s，2H)，6.80(dd，J＝8.3，1.0Hz，1H)，6.88(s，1H)，6.92-6.98(m，1H)，7.10(d，J＝7.9Hz，1H)，7.17-7.28(m，3H)，7.49(dd，J＝7.9，1.5Hz，1H).

(Z)-2-[8-(2-cyclopropyl-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (200mg, 0.45mmol), same with the step 3 of embodiment 1, obtain title compound (compound 130) (191mg, 85%).

ESI-MS?m/z：506(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.93-0.99(m，2H)，1.12-1.17(m，2H)，1.77-1.86(m，1H)，2.10(s，3H)，2.57(d，J＝0.5Hz，3H)，2.57(s，3H)，4.74(d，J＝12.8Hz，1H)，5.45(d，J＝12.5Hz，1H)，5.57(s，2H)，6.82-6.91(m，3H)，7.01(dd，J＝7.7，1.6Hz，1H)，7.17-7.29(m，4H).

[embodiment 131]

(Z)-and 8-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 131)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (422mg, 2.43mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (205mg, 19%).

ESI-MS?m/z：433(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99-1.06(m，2H)，1.18-1.24(m，2H)，1.84-1.93(m，1H)，1.98(s，3H)，2.64(s，3H)，4.74(d，J＝12.7Hz，1H)，5.41(d，J＝12.9Hz，1H)，5.60(s，2H)，6.80(dd，J＝8.3，1.0Hz，1H)，6.92-7.02(m，2H)，7.10(d，J＝7.8Hz，1H)，7.18-7.28(m，3H)，7.48(dd，J＝7.8，1.7Hz，1H)，8.16(d，J＝4.8Hz，1H).

(Z)-2-[8-(2-cyclopropyl-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (164mg, 0.38mmol), same with the step 3 of embodiment 1, obtain title compound (compound 131) (104mg, 56%).

ESI-MS?m/z：492(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.01-1.06(m，2H)，1.19-1.23(m，2H)，1.85-1.96(m，1H)，2.09(s，3H)，2.63(s，3H)，4.76(d，J＝12.6Hz，1H)，5.47(d，J＝12.8Hz，1H)，5.60(s，2H)，6.82-6.91(m，2H)，6.98-7.01(m，2H)，7.18-7.29(m，4H)，8.16(d，J＝4.9Hz，1H).

[embodiment 132]

(Z)-and 8-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 132)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine, use 2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (414mg, 2.16mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-oxyethyl group-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (454mg, 47%).

ESI-MS?m/z：451(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.41(t，J＝7.1Hz，3H)，1.99(s，3H)，2.50(s，3H)，2.54(s，3H)，4.58(q，J＝7.1Hz，2H)，4.77(d，J＝12.5Hz，1H)，5.23(s，2H)，5.42(d，J＝12.6Hz，1H)，6.78-6.81(m，2H)，6.94(td，J＝7.6，1.1Hz，1H)，7.09(d，J＝7.7Hz，1H)，7.20-7.26(m，1H)，7.31-7.37(m，2H)，7.48(dd，J＝7.9，1.6Hz，1H).

(Z)-2-[8-(2-oxyethyl group-5 that [step 2] uses step 1 to obtain, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (454mg, 1.01mmol), same with the step 3 of embodiment 1, obtain title compound (compound 132) (311mg, 60%).

ESI-MS?m/z：510(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.41(t，J＝7.1Hz，3H)，2.10(s，3H)，2.49(s，3H)，2.54(s，3H)，4.56(q，J＝7.1Hz，2H)，4.78(d，J＝12.5Hz，1H)，5.23(s，2H)，5.48(d，J＝12.5Hz，1H)，6.80-6.91(m，3H)，6.99(dd，J＝7.7，1.8Hz，1H)，7.16-7.28(m，2H)，7.35-7.38(m，2H).

[embodiment 133]

(Z)-and 8-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 133)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridine (579mg, 3.03mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-oxyethyl group-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (329mg, 25%).

ESI-MS?m/z：437(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.1Hz，3H)，1.99(s，3H)，2.56(s，3H)，4.63(q，J＝7.1Hz，2H)，4.77(d，J＝12.8Hz，1H)，5.26(s，2H)，5.42(d，J＝12.6Hz，1H)，6.79(dd，J＝8.3，1.2Hz，1H)，6.91-6.97(m，2H)，7.09(d，J＝7.7Hz，1H)，7.16-7.53(m，4H)，8.04(d，J＝5.1Hz，1H).

(Z)-2-[8-(2-oxyethyl group-7-methyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (329mg, 0.75mmol), same with the step 3 of embodiment 1, obtain title compound (compound 133) (216mg, 58%).

ESI-MS?m/z：496(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.1Hz，3H)，2.09(s，3H)，2.55(s，3H)，4.62(q，J＝7.2Hz，2H)，4.78(d，J＝12.8Hz，1H)，5.26(s，2H)，5.48(d，J＝12.5Hz，1H)，6.81-7.00(m，4H)，7.17-7.28(m，2H)，7.35-7.38(m，2H)，8.03(d，J＝5.1Hz，1H).

[embodiment 134]

(Z)-and 8-(2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 134)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-ethyl-3H-imidazo [4,5-b] pyridine (584mg, 3.97mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (659mg, 41%).

ESI-MS?m/z：407(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.41(t，J＝7.5Hz，3H)，1.99(s，3H)，2.83(q，J＝7.5Hz，2H)，4.74(d，J＝12.8Hz，1H)，5.42(d，J＝12.8Hz，1H)，5.50(s，2H)，6.80(dd，J＝8.4，1.1Hz，1H)，6.92-6.98(m，1H)，7.09-7.16(m，2H)，7.20-7.26(m，3H)，7.49(dd，J＝7.9，1.6Hz，1H)，8.04(dd，J＝8.1，1.5Hz，1H)，8.34(dd，J＝4.8，1.5Hz，1H).

(Z)-2-[8-(2-ethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (448mg, 1.10mmol), same with the step 3 of embodiment 1, obtain title compound (compound 134) (385mg, 75%).

ESI-MS?m/z：466(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.39(t，J＝7.5Hz，3H)，2.09(s，3H)，2.82(q，J＝7.5Hz，2H)，4.72(d，J＝12.8Hz，1H)，5.45(d，J＝12.8Hz，1H)，5.50(s，2H)，6.80(d，J＝8.4Hz，1H)，6.87(t，J＝7.7Hz，1H)，7.00(dd，J＝7.7，1.5Hz，1H)，7.16-7.26(m，5H)，8.01(d，J＝7.7Hz，1H)，8.34(d，J＝4.8Hz，1H).

[embodiment 135]

(Z)-and 8-(2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 135)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-oxyethyl group-3H-imidazo [4,5-b] pyridine (518mg, 3.17mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (387mg, 29%).

ESI-MS?m/z：423(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.1Hz，3H)，1.99(s，3H)，4.63(q，J＝7.1Hz，2H)，4.78(d，J＝12.6Hz，1H)，5.28(s，2H)，5.43(d，J＝12.6Hz，1H)，6.80(dd，J＝8.3，1.2Hz，1H)，6.92-6.97(m，1H)，7.10-7.15(m，2H)，7.20-7.26(m，1H)，7.35-7.41(m，2H)，7.48(dd，J＝7.8，1.7Hz，1H)，7.76(dd，J＝7.8，1.4Hz，1H)，8.17(dd，J＝5.0，1.4Hz，1H).

(Z)-2-[8-(2-oxyethyl group-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (380mg, 0.92mmol), same with the step 3 of embodiment 1, obtain title compound (compound 135) (324mg, 73%).

ESI-MS?m/z：482(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.1Hz，3H)，2.10(s，3H)，4.62(q，J＝7.1Hz，2H)，4.80(d，J＝12.8Hz，1H)，5.28(s，2H)，5.50(d，J＝12.8Hz，1H)，6.81-6.89(m，2H)，6.99(dd，J＝7.9，1.6Hz，1H)，7.13(dd，J＝7.9，4.9Hz，1H)，7.18-7.27(m，2H)，7.38-7.40(m，2H)，7.75(dd，J＝7.9，1.3Hz，1H)，8.17(dd，J＝4.9，1.3Hz，1H).

[embodiment 136]

(Z)-and 8-(2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 136)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 2-cyclopropyl-3H-imidazo [4,5-b] pyridine (505mg, 3.17mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (402mg, 30%).

ESI-MS?m/z：419(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.05-1.09(m，2H)，1.23-1.28(m，2H)，1.88-1.96(m，1H)，1.99(s，3H)，4.76(d，J＝12.6Hz，1H)，5.43(d，J＝12.6Hz，1H)，5.62(s，2H)，6.80(dd，J＝8.3，1.2Hz，1H)，6.93-6.98(m，1H)，7.12(J，J＝7.9Hz，1H)，7.19-7.28(m，4H)，7.49(dd，J＝7.8，1.7Hz，1H)，7.94(dd，J＝8.0，1.4Hz，1H)，8.31(dd，J＝4.9，1.4Hz，1H).

(Z)-2-[8-(2-cyclopropyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (400mg, 0.96mmol), same with the step 3 of embodiment 1, obtain title compound (compound 136) (377mg, 82%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.04-1.10(m，2H)，1.22-1.28(m，2H)，1.88-1.97(m，1H)，2.10(s，3H)，4.77(d，J＝12.6Hz，1H)，5.49(d，J＝12.6Hz，1H)，5.62(s，2H)，6.83(dd，J＝8.4，1.1Hz，1H)，6.88(td，J＝7.4，1.1Hz，1H)，7.00(dd，J＝7.7，1.8Hz，1H)，7.18-7.28(m，5H)，7.93(dd，J＝8.1，1.5Hz，1H)，8.30(dd，J＝4.8，1.5Hz，1H).

[embodiment 137]

(Z)-and 8-(7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 137)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridine (442mg, 2.43mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(7-chloro-2-ethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (442mg, 41%).

ESI-MS?m/z：441(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.38(t，J＝7.5Hz，3H)，1.98(s，3H)，2.86(q，J＝7.5Hz，2H)，4.74(d，J＝12.7Hz，1H)，5.41(d，J＝12.6Hz，1H)，5.50(s，2H)，6.80(dd，J＝8.3，1.2Hz，1H)，6.92-6.98(m，1H)，7.12-7.30(m，5H)，7.49(dd，J＝7.8，1.7Hz，1H)，8.22(d，J＝5.4Hz，1H).

(Z)-2-[8-(7-chloro-2-ethyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (400mg, 0.91mmol), same with the step 3 of embodiment 1, obtain title compound (compound 137) (191mg, 42%).

ESI-MS?m/z：500(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.27(t，J＝7.4Hz，3H)，1.96(s，3H)，2.90(q，J＝7.5Hz，2H)，4.87(d，J＝12.6Hz，1H)，5.56(s，2H)，5.59(d，J＝13.7Hz，1H)，6.72-6.80(m，2H)，6.93(dd，J＝7.7，1.6Hz，1H)，7.13-7.22(m，2H)，7.30-7.42(m，3H)，8.25(d，J＝5.1Hz，1H).

[embodiment 138]

(Z)-and 8-(7-chloro-2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 138)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-oxyethyl group-3H-imidazo [4,5-b] pyridine (53mg, 0.27mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(7-chloro-2-oxyethyl group-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (40mg, 32%).

ESI-MS?m/z：457(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.2Hz，3H)，1.99(s，3H)，4.70(q，J＝7.2Hz，2H)，4.78(d，J＝12.6Hz，1H)，5.27(s，2H)，5.43(d，J＝12.6Hz，1H)，6.80(dd，J＝8.3，1.0Hz，1H)，6.94(td，J＝7.6，1.1Hz，1H)，7.10-7.16(m，2H)，7.21-7.23(m，1H)，7.33-7.39(m，2H)，7.48(dd，J＝7.6，1.7Hz，1H)，8.05(d，J＝5.6Hz，1H).

(Z)-2-[8-(7-chloro-2-oxyethyl group-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (39mg, 0.087mmol), same with the step 3 of embodiment 1, obtain title compound (compound 138) (15mg, 34%).

ESI-MS?m/z：516(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.46(t，J＝7.0Hz，3H)，2.09(s，3H)，4.66(q，J＝7.0Hz，2H)，4.77(d，J＝12.6Hz，1H)，5.27(s，2H)，5.48(d，J＝12.6Hz，1H)，6.78-6.89(m，2H)，6.98(dd，J＝7.7，1.8Hz，1H)，7.15(d，J＝5.5Hz，1H)，7.19-7.23(m，2H)，7.36-7.39(m，2H)，8.06(d，J＝5.5Hz，1H).

[embodiment 139]

(Z)-and 8-(7-chloro-2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 139)

[step 1] replaces 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine uses 7-chloro-2-cyclopropyl-3H-imidazo [4,5-b] pyridine (494mg, 2.55mmol), same with the step 1 of embodiment 127, obtain (Z)-2-[8-(7-chloro-2-cyclopropyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (376mg, 32%).

ESI-MS?m/z：453(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.05-1.12(m，2H)，1.29-1.34(m，2H)，1.87-1.95(m，1H)，1.99(s，3H)，4.76(d，J＝12.6Hz，1H)，5.43(d，J＝12.8Hz，1H)，5.60(s，2H)，6.80(dd，J＝8.2，1.1Hz，1H)，6.95(td，J＝7.6，1.0Hz，1H)，7.12(d，J＝7.9Hz，1H)，7.19-7.27(m，4H)，7.49(dd，J＝7.8，1.7Hz，1H)，8.18(d，J＝5.3Hz，1H).

(Z)-2-[8-(7-chloro-2-cyclopropyl-3H-imidazo [4 that [step 2] uses step 1 to obtain, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (335mg, 0.74mmol), same with the step 3 of embodiment 1, obtain title compound (compound 139) (214mg, 56%).

ESI-MS?m/z：512(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.04-1.13(m，4H)，1.97(s，3H)，2.28-2.37(m，1H)，4.88(d，J＝12.6Hz，1H)，5.61(d，J＝12.3Hz，1H)，5.69(s，2H)，6.72-6.81(m，2H)，6.93(dd，J＝7.8，1.7Hz，1H)，7.14-7.19(m，1H)，7.25-7.44(m，4H)，8.21(d，J＝5.3Hz，1H).

[embodiment 140]

(Z)-and 8-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 140)

[step 1] is with (Z)-2-(8-hydroxymethyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits) propionitrile (150mg, 0.54mmol) be dissolved in THF (5.5mL), add 2,6-lutidine (0.378mL, 3.25mmol), lithiumbromide (282mg, 3.25mmol) and the methylsulfonic acid acid anhydride (236mg 1.35mmol), stirred under the room temperature 16 hours.Add ethyl acetate in the mixture, organic layer saturated common salt water washing.Organic layer with anhydrous magnesium sulfate drying after, decompression concentrates down and obtains residue.With residue and the 2-ethyl-4 that obtains, (123mg 0.71mmol) is dissolved in DMF (3.0mL) to the 6-dimethylbenzimidazole, and (24mg 0.98mmol), stirred 2 hours under the room temperature 0 ℃ of following adding lithium hydroxide.Add ethyl acetate in the mixture, organic layer saturated common salt water washing, behind anhydrous magnesium sulfate drying, decompression concentrates down.The residue silica gel column chromatography (hexane/ethyl acetate=7/3-6/4) refining obtains (Z)-2-[8-(2-ethyl-4,6-dimethylbenzimidazole-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (219mg, 93%).

ESI-MS?m/z：434(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.34(t，J＝7.6Hz，3H)，1.99(s，3H)，2.38(s，3H)，2.65(s，3H)，2.84(q，J＝7.6Hz，2H)，4.74(d，J＝12.5Hz，1H)，5.30(s，2H)，5.42(d，J＝12.5Hz，1H)，6.78-6.83(m，2H)，6.89(s，1H)，6.93-7.01(m，2H)，7.09-7.11(m，2H)，7.22-7.28(m，1H)，7.49(dd，J＝7.6，1.6Hz，1H).

(Z)-2-[8-(2-ethyl-4 that [step 2] uses step 1 to obtain, 6-dimethylbenzimidazole-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (217mg, 0.50mmol), same with the step 3 of embodiment 1, obtain title compound (compound 140) (38mg, 15%).

ESI-MS?m/z：493(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.24(t，J＝7.4Hz，3H)，1.95(s，3H)，2.31(s，3H)，2.47(s，3H)，2.79(q，J＝7.4Hz，2H)，4.86(d，J＝12.6Hz，1H)，5.45(s，2H)，5.59(d，J＝12.6Hz，1H)，6.70-6.80(m，3H)，6.91(dd，J＝7.6，1.7Hz，1H)，7.00-7.05(m，2H)，7.12-7.18(m，1H)，7.26(d，J＝1.3Hz，1H)，7.30(d，J＝7.9Hz，1H).

[embodiment 141]

(Z)-and 8-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 141)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, use 4-methyl-2-propyl group benzoglyoxaline (163mg, 0.94mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (301mg, 74%).

ESI-MS?m/z：434(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.99(t，J＝7.4Hz，3H)，1.77-1.83(m，2H)，1.99(s，3H)，2.69(s，3H)，2.83(t，J＝7.9Hz，2H)，4.74(d，J＝12.6Hz，1H)，5.35(s，2H)，5.41(d，J＝12.6Hz，1H)，6.81(dd，J＝8.2，1.0Hz，1H)，6.93-7.12(m，7H)，7.23-7.27(m，1H)，7.49(dd，J＝7.9，1.6Hz，1H).

(Z)-2-[8-(4-methyl-2-propyl group benzoglyoxaline-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (248mg, 0.57mmol), same with the step 3 of embodiment 1, obtain title compound (compound 141) (63mg, 22%).

ESI-MS?m/z：493(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.91(t，J＝7.5Hz，3H)，1.66-1.77(m，2H)，1.94(s，3H)，2.51(s，3H)，2.81(t，J＝7.5Hz，2H)，4.85(d，J＝12.5Hz，1H)，5.50(s，2H)，5.58(d，J＝12.5Hz，1H)，6.71-6.78(m，2H)，6.91(dd，J＝7.9，1.6Hz，1H)，6.95(d，J＝7.0Hz，1H)，6.99-7.08(m，2H)，7.12-7.18(m，1H)，7.23(d，J＝7.7Hz，1H)，7.28-7.31(m，2H).

[embodiment 142]

(Z)-and 8-(2-propyl group benzoglyoxaline-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 142)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, use 2-propyl group benzoglyoxaline (114mg, 0.71mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(2-propyl group benzoglyoxaline-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (256mg, 87%).

ESI-MS?m/z：420(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.01(t，J＝7.6Hz，3H)，1.81-1.95(m，2H)，1.99(s，3H)，2.80(t，J＝7.6Hz，2H)，4.74(d，J＝12.6Hz，1H)，5.36(s，2H)，5.42(d，J＝12.6Hz，1H)，6.81(dd，J＝8.4，1.2Hz，1H)，6.95-7.01(m，2H)，7.10-7.29(m，6H)，7.49(dd，J＝7.9，1.6Hz，1H)，7.77-7.79(m，1H).

(Z)-2-[8-(2-propyl group benzoglyoxaline-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (256mg, 0.61mmol), same with the step 3 of embodiment 1, obtain title compound (compound 142) (67mg, 23%).

ESI-MS?m/z：479(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.91(t，J＝7.4Hz，3H)，1.69-1.79(m，2H)，1.94(s，3H)，2.81(t，J＝7.4Hz，2H)，4.85(d，J＝12.6Hz，1H)，5.52(s，2H)，5.59(d，J＝12.6Hz，1H)，6.70-6.79(m，2H)，6.91(dd，J＝7.6，1.7Hz，1H)，7.07-7.18(m，4H)，7.29-7.32(m，2H)，7.43-7.45(m，1H)，7.56-7.59(m，1H).

[embodiment 143]

(Z)-and 8-(2-oxyethyl group-4-tolimidazole-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 143)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, 2-oxyethyl group-4-tolimidazole (the 349mg that uses reference example 27 to obtain, 1.98mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(2-oxyethyl group-4-tolimidazole-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (653mg, 76%).

ESI-MS?m/z：436(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.45(t，J＝7.2Hz，3H)，1.99(s，3H)，2.58(s，3H)，4.65(q，J＝7.2Hz，2H)，4.76(d，J＝12.6Hz，1H)，5.15(s，2H)，5.42(d，J＝12.6Hz，1H)，6.80(dd，J＝8.3，1.3Hz，1H)，6.88-7.00(m，4H)，7.10(d，J＝7.9Hz，1H)，7.19-7.26(m，3H)，7.48(dd，J＝7.9，1.7Hz，1H).

(Z)-2-[8-(2-oxyethyl group-4-tolimidazole-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (600mg, 0.61mmol), same with the step 3 of embodiment 1, obtain title compound (compound 143) (288mg, 42%).

ESI-MS?m/z：495(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.38(t，J＝7.1Hz，3H)，1.94(s，3H)，2.42(s，3H)，4.57(q，J＝7.1Hz，2H)，4.86(d，J＝12.5Hz，1H)，5.23(s，2H)，5.59(d，J＝12.5Hz，1H)，6.68-7.44(m，10H).

[embodiment 144]

(Z)-and 8-(2-cyclopropyl-4-tolimidazole-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 144)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, 2-cyclopropyl-4-tolimidazole (the 342mg that uses reference example 28 to obtain, 1.98mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(2-cyclopropyl-4-tolimidazole-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (764mg, 89%).

ESI-MS?m/z：432(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.00-1.04(m，2H)，1.19-1.22(m，2H)，1.85-1.90(m，1H)，1.99(s，3H)，2.65(s，3H)，4.74(d，J＝12.8Hz，1H)，5.42(d，J＝12.8Hz，1H)，5.46(s，2H)，6.79-6.83(m，1H)，6.92-7.18(m，7H)，7.23-7.27(m，1H)，7.49(dd，J＝7.9，1.6Hz，1H).

(Z)-2-[8-(2-cyclopropyl-4-tolimidazole-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (662mg, 1.53mmol), same with the step 3 of embodiment 1, obtain title compound (compound 144) (290mg, 39%).

ESI-MS?m/z：491(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：0.92-1.10(m，4H)，1.94(s，3H)，2.22(m，1H)，2.45(s，3H)，4.86(d，J＝12.3Hz，1H)，5.61(s，2H)，5.60(d，J＝12.3Hz，1H)，6.68-7.40(m，10H).

[embodiment 145]

(Z)-and 8-(4-chloro-2-ethyl benzo imidazole-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 145)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, the 4-chloro-2-ethyl benzo imidazole (559mg that uses reference example 29 to obtain, 3.09mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(4-chloro-2-ethyl benzo imidazole-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (816mg, 60%).

ESI-MS?m/z：440(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.40(t，J＝7.6Hz，3H)，1.99(s，3H)，2.90(q，J＝7.6Hz，2H)，4.74(d，J＝12.6Hz，1H)，5.36(s，2H)，5.42(d，J＝12.6Hz，1H)，6.81(dd，J＝8.3，1.0Hz，1H)，6.93-7.15(m，6H)，7.23-7.29(m，2H)，7.49(dd，J＝7.9，1.7Hz，1H).

(Z)-2-[8-(4-chloro-2-ethyl benzo imidazole-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (697mg, 1.58mmol), same with the step 3 of embodiment 1, obtain title compound (compound 145) (244mg, 31%).

ESI-MS?m/z：499(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.37(t，J＝7.6Hz，3H)，2.10(s，3H)，2.86(q，J＝7.6Hz，2H)，4.69(d，J＝12.5Hz，1H)，5.36(s，2H)，5.46(d，J＝12.5Hz，1H)，6.75-7.33(m，10H).

[embodiment 146]

(Z)-and 8-(4-chloro-2-oxyethyl group benzo imidazoles-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 146)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, the 4-chloro-2-oxyethyl group benzo imidazoles (389mg that uses reference example 25 to obtain, 1.98mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(4-chloro-2-oxyethyl group benzo imidazoles-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (294mg, 33%).

ESI-MS?m/z：456(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.47(t，J＝7.2Hz，3H)，1.99(s，3H)，4.72(q，J＝7.2Hz，2H)，4.77(d，J＝12.8Hz，1H)，5.17(s，2H)，5.43(d，J＝12.8Hz，1H)，6.81(dd，J＝8.4，1.2Hz，1H)，6.92-7.28(m，8H)，7.49(dd，J＝7.9，1.6Hz，1H).

(Z)-2-[8-(4-chloro-2-oxyethyl group benzo imidazoles-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (293mg, 0.64mmol), same with the step 3 of embodiment 1, obtain title compound (compound 146) (200mg, 60%).

ESI-MS?m/z：515(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.37(t，J＝7.0Hz，3H)，1.93(s，3H)，4.58(q，J＝7.0Hz，2H)，4.86(d，J＝12.6Hz，1H)，5.26(s，2H)，5.58(d，J＝12.6Hz，1H)，6.66-7.48(m，10H).

[embodiment 147]

(Z)-and 8-(4-chloro-2-cyclopropyl benzo imidazoles-1-yl) methyl isophthalic acid 1-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 147)

[step 1] replaces 2-ethyl-4, the 6-dimethylbenzimidazole, the 4-chloro-2-cyclopropyl benzo imidazoles (382mg that uses reference example 26 to obtain, 1.98mmol), same with the step 1 of embodiment 140, obtain (Z)-2-[8-(4-chloro-2-cyclopropyl benzo imidazoles-1-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (710mg, 79%).

ESI-MS?m/z：452(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.03-1.32(m，4H)，1.85-1.92(m，1H)，2.00(s，3H)，4.75(d，J＝12.9Hz，1H)，5.43(d，J＝12.9Hz，1H)，5.48(s，2H)，6.81(dd，J＝8.0，1.3Hz，1H)，6.96(td，J＝7.6，1.1Hz，1H)，7.05-7.27(m，7H)，7.50(dd，J＝7.6，1.7Hz，1H).

(Z)-2-[8-(4-chloro-2-cyclopropyl benzo imidazoles-1-yl) methyl-6 that [step 2] uses step 1 to obtain, 11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (600mg, 1.33mmol), same with the step 3 of embodiment 1, obtain title compound (compound 147) (176mg, 26%).

ESI-MS?m/z：511(M+H) ⁺； ¹H-NMR(DMSO-d ₆，δ)：1.01-1.26(m，4H)，2.02(s，3H)，2.36(m，1H)，4.94(d，J＝12.3Hz，1H)，5.66(d，J＝12.3Hz，1H)，5.74(s，2H)，6.72-7.60(m，10H).

[embodiment 148]

(Z)-and 8-(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 148)

(Z)-2-[8-(2-ethyl-5 that the step 1 of use embodiment 127 obtains, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (20mg, 0.046mmol), similarly to Example 22, obtain title compound (compound 148) (12mg, 54%).

ESI-MS?m/z：478(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.10(t，J＝7.6Hz，3H)，2.15(s，3H)，2.34(s，3H)，2.58(q，J＝7.6Hz，2H)，2.60(s，3H)，4.20(d，J＝12.5Hz，1H)，5.05(d，J＝12.5Hz，1H)，5.42(d，J＝16.4Hz，1H)，5.49(d，J＝16.4Hz，1H)，6.45(d，J＝8.2Hz，1H)，6.61(t，J＝7.5Hz，1H)，6.72(d，J＝7.7Hz，1H)，6.91(s，1H)，6.93(s，1H)，7.00(t，J＝7.7Hz，1H)，7.30(br?s，2H).

[embodiment 149]

(Z)-and 8-(2-ethyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 149)

(Z)-2-[8-(2-ethyl-7-methyl-3H-imidazo [4 that the step 1 of use embodiment 128 obtains, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (28mg, 0.07mmol), similarly to Example 22, obtain title compound (compound 149) (8.8mg, 29%).

ESI-MS?m/z：464(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.23(t，J＝7.5Hz，3H)，2.17(s，3H)，2.53(s，3H)，2.73(q，J＝7.6Hz，2H)，4.37(d，J＝12.3Hz，1H)，5.22(d，J＝12.5Hz，1H)，5.48(s，2H)，6.59-6.75(m，3H)，7.03-7.11(m，3H)，7.24-7.30(m，2H)，8.19(d，J＝4.9Hz，1H).

[embodiment 150]

(Z)-and 8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl ,-11-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 150)

(Z)-2-[8-(7-chloro-2-ethyl-5-methyl-3H-imidazo [4 that the step 1 of use embodiment 129 obtains, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (41mg, 0.09mmol), similarly to Example 22, obtain title compound (compound 150) (27mg, 62%).

ESI-MS?m/z：498(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：1.21(t，J＝7.5Hz，3H)，2.23(s，3H)，2.62(s，3H)，2.68(q，J＝7.5Hz，2H)，4.50(d，J＝12.6Hz，1H)，5.34(d，J＝12.6Hz，1H)，5.43(d，J＝16.2Hz，1H)，5.52(d，J＝16.3Hz，1H)，6.64-6.80(m，3H)，7.03(s，1H)，7.09-7.16(m，2H)，7.22-7.31(m，2H).

[embodiment 151]

(Z)-and 8-(2-cyclopropyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 151)

(Z)-2-[8-(2-cyclopropyl-5 that the step 1 of use embodiment 130 obtains, 7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (41.5mg, 0.09mmol), similarly to Example 22, obtain title compound (compound 151) (22.3mg, 49%).

ESI-MS?m/z：490(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.79-0.85(m，2H)，0.98-1.03(m，2H)，1.66-1.72(m，1H)，2.18(s，3H)，2.32(s，3H)，2.60(s，3H)，4.26(d，J＝12.6Hz，1H)，5.03(d，J＝12.4Hz，1H)，5.56(d，J＝3.5Hz，2H)，6.56(d，J＝8.1Hz，1H)，6.69(t，J＝6.9Hz，1H)，6.80(dd，J＝7.8，1.7Hz，1H)，6.88(s，1H)，7.04-7.12(m，2H)，7.27-7.37(m，2H).

[embodiment 152]

(Z)-and 8-(2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl isophthalic acid 1-[1-(1H-tetrazolium-5-yl) ethylidene]-6,11-dihydro-dibenzo [b, e] oxa-seven rings (compound 152)

(Z)-2-[8-(2-cyclopropyl-7-methyl-3H-imidazo [4 that the step 1 of use embodiment 131 obtains, 5-b] pyridin-3-yl) methyl-6,11-dihydro-dibenzo [b, e] oxa-seven ring-11-subunits] propionitrile (41.3mg, 0.10mmol), similarly to Example 22, obtain title compound (compound 152) (4mg, 9%).

ESI-MS?m/z：476(M+H) ⁺； ¹H-NMR(CDCl ₃，δ)：0.86-0.96(m，2H)，1.07-1.12(m，2H)，1.75-1.84(m，1H)，2.16(s，3H)，2.43(s，3H)，4.31(d，J＝12.5Hz，1H)，5.12(d，J＝12.5Hz，1H)，5.57(s，2H)，6.57(d，J＝8.2Hz，1H)，6.68(t，J＝7.3Hz，1H)，6.76(dd，J＝7.8，1.6Hz，1H)，7.01(d，J＝5.1Hz，1H)，7.05-7.10(m，2H)，7.23-7.38(m，2H)，8.15(d，J＝4.9Hz，1H).

[embodiment 153]

Tablet (compound S 16)

According to conventional methods, the preparation contain following composition tablet.Mixing cpd S16 (40g), lactose 286.8g and yam starch 60g are to 10% aqueous solution 120g that wherein adds hydroxy propyl cellulose.The mixture that obtains is mediated according to conventional methods, and after the granulation drying, whole grain is made the compressing tablet particle.Carry out compressing tablet to wherein adding Magnesium Stearate 1.2g and mix, use the tablet machine (the system RT-15 of chrysanthemum water society type) that has diameter 8mm and dash, obtain tablet (every contains activeconstituents 20mg).

[table 36]

Prescription compound S 16 20mg

Lactose 143.4mg

Yam starch 30mg

Hydroxypropylcellulose 6mg

Magnesium Stearate 0.6mg

200mg

[embodiment 154]

Injection (compound S 13)

According to conventional methods, the preparation contain following composition injection.Stay interpolation compound S 13 (1g) and mixing in the water in the injection steaming, and then add hydrochloric acid and aqueous sodium hydroxide solution, after adjustment pH was 7, staying water to add to full dose with the injection steaming was 1000mL.The mixed solution that obtains is filled into the 2mL glass ampoule respectively, obtains injection (every peace bottle contains activeconstituents 2mg).

[table 37]

Prescription compound S 13 2mg

Hydrochloric acid is an amount of

Aqueous sodium hydroxide solution is an amount of

Distilled water for injection is an amount of

2.00mL

[industrial applicability]

According to the present invention, can provide and contain tricyclic compounds as the PPAR γ of active ingredient Activator etc.

In addition, can also provide novel tricyclic based compound with PPAR γ agonist activity etc. or Its pharmaceutically useful salt.

Claims

1. peroxisome proliferation matter sensitization acceptor (PPAR) gamma agonist, it contains the tricyclic compounds of general formula (I) expression or its pharmaceutically useful salt as effective constituent,

[chemical formula 34]

In＜the formula, R ¹Expression can have substituent low alkyl group, can have substituent cycloalkyl, can have substituent lower alkoxy, maybe can have substituent low-grade alkyl sulphur alkyl,

Perhaps, the group in the formula (I)

[chemical formula 35]

Be the group that is selected from following formula (a1)～(a2O),

[chemical formula 36]

Q ¹-Q ²-Q ³Expression CH=CH-CH=CH, S-CH=CH or CH=CH-S,

A represents to be selected from the group of following formula (b1)～(b6),

[chemical formula 37]

2. with the agent of PPAR γ agonism and angiotensin-ii receptor antagonistic action, it contains the described tricyclic compounds of claim 1 or its pharmaceutically useful salt as effective constituent.

3. according to claim 1 and 2 dose, it is treatment of diseases and/or the preventive relevant with PPAR γ.

4. according to claim 3 dose, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

5. tricyclic compounds or its pharmaceutically useful salt of general formula (IA) expression,

[chemical formula 38]

Perhaps, the group in the formula (IA)

[chemical formula 39]

Be the group that is selected from following formula (A1)～(A20),

[chemical formula 40]

Q ^1A-Q ^2A-Q ^3AExpression CH=CH-CH=CH, S-CH=CH or CH=CH-S,

A ^AExpression is selected from the group of following formula (B1)～(B6),

[chemical formula 41]

(ii) Z ^1A-Z ^2AExpression C=CR ^13AB(in the formula, R ^13ABThe expression hydrogen atom), CH-CR ^14ABR ^15AB(in the formula, R ^14ABAnd R ^15ABAll represent hydrogen atom) or N-CR ^16ABR ^17AB(in the formula, R ^16ABAnd R ^17ABAll represent hydrogen atom) time,

A ^ABe the group that is selected from following formula (B3)～(B6),

[chemical formula 42]

(in the formula, R ^18AWith above-mentioned same meaning) 〉.

6. tricyclic compounds according to claim 5 or its pharmaceutically useful salt, the group in the formula (IA)

[chemical formula 43]

It is the group that is selected from above-mentioned formula (A1)～(A20).

7. tricyclic compounds according to claim 5 or its pharmaceutically useful salt, in the formula (IA)

[chemical formula 44]

Be to be selected from following formula (A4), (A9), (A11) and group (A12),

[chemical formula 45]

8. tricyclic compounds according to claim 5 or its pharmaceutically useful salt, in the formula (IA)

[chemical formula 46]

Be the group of following formula (A4) expression,

[chemical formula 47]

9. tricyclic compounds according to claim 5 or its pharmaceutically useful salt, in the formula (IA)

[chemical formula 48]

Be the group of following formula (A12) expression,

[chemical formula 49]

10. according to any described tricyclic compounds of claim 5～9 or its pharmaceutically useful salt, Z ^1A-Z ^2ABe C=CR ^13AA(in the formula, R ^13AAWith above-mentioned same meaning), CH-CHR ^15AA(in the formula, R ^15AAWith above-mentioned same meaning) or N-CR ^16AAR ^17A(in the formula, R ^16AAAnd R ^17ARespectively with above-mentioned same meaning).

11. according to any described tricyclic compounds of claim 5～10 or its pharmaceutically useful salt, AA is following formula (B3)

[chemical formula 50]

12. according to any described tricyclic compounds of claim 5～11 or its pharmaceutically useful salt, Q ^1A-Q ^2A-Q ^3ABe CH=CH-CH=CH.

13. according to any described tricyclic compounds of claim 5～12 or its pharmaceutically useful salt, Y ^ABe CH ₂CH ₂Or CH ₂O.

14. medicine, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

15.PPAR gamma agonist, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

16. with the agent of PPAR γ agonism and angiotensin-ii receptor antagonistic action, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

17. treatment of diseases and/or the preventive relevant with PPAR γ, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

18. according to claim 17 dose, the disease relevant and then be the disease relevant with angiotensin-ii receptor with PPAR γ.

19. according to claim 17 or 18 described doses, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

20. angiotensin II receptor antagonists, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

21. treatment of diseases relevant with angiotensin-ii receptor and/or preventive, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

22. depressor, it contains any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt as effective constituent.

23. make PPAR γ activated method, comprise to the described tricyclic compounds of the claim 1 of significant quantity or its pharmaceutically useful salt.

24. PPAR γ activated and make the method for angiotensin-ii receptor antagonism, comprise to the described tricyclic compounds of the claim 1 of significant quantity or its pharmaceutically useful salt.

25. according to claim 23 or 24 described methods, making PPAR γ activated method is treatment of diseases and/or the prevention method relevant with PPAR γ.

26. method according to claim 25, the disease relevant and then still relevant disease with angiotensin-ii receptor with PPAR γ.

27. according to claim 25 or 26 described methods, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

28. make PPAR γ activated method, comprise to any described tricyclic compounds of the claim 5～13 of significant quantity or its pharmaceutically useful salt.

29. PPAR γ activated and make the method for angiotensin-ii receptor antagonism, comprise to any described tricyclic compounds of the claim 5～13 of significant quantity or its pharmaceutically useful salt.

30. according to claim 28 or 29 described methods, making PPAR γ activated method is treatment of diseases and/or the prevention method relevant with PPAR γ.

31. method according to claim 30, the disease relevant and then still relevant disease with angiotensin-ii receptor with PPAR γ.

32. according to claim 30 or 31 described methods, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

33. make the method for angiotensin-ii receptor antagonism, comprise to any described tricyclic compounds of the claim 5～13 of significant quantity or its pharmaceutically useful salt.

34. according to any described method of claim 29～33, the method that makes the angiotensin-ii receptor antagonism is treatment of diseases and/or the prevention method relevant with angiotensin-ii receptor.

35. method according to claim 34, treatment of diseases relevant with angiotensin-ii receptor and/or prevention method are the hypertensive methods that treats and/or prevents.

36. the described tricyclic compounds of claim 1 or its pharmaceutically useful salt application in preparation PPAR gamma agonist.

37. the described tricyclic compounds of claim 1 or its pharmaceutically useful salt are in the application of preparation in the medicine of PPPAR γ agonism and angiotensin-ii receptor antagonistic action.

38. the described tricyclic compounds of claim 1 or its pharmaceutically useful salt are preparing treatment of diseases relevant with PPAR γ and/or the application in the preventive.

39. according to the described application of claim 38, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

40. any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt application in preparation PPAR gamma agonist.

41. any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt are in the application of preparation in the agent of PPAR γ agonism and angiotensin-ii receptor antagonistic action.

42. any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt are preparing treatment of diseases relevant with PPAR γ and/or the application in the preventive.

43. according to the described application of claim 42, the disease relevant and then be the disease relevant with angiotensin-ii receptor with PPAR γ.

44. according to claim 42 or 43 described application, the disease relevant with PPAR γ is the disease that is selected from type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidaemia, metabolism syndrome, internal organ obesity, obesity and hypertriglyceridemia.

45. any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt application in the preparation angiotensin II receptor antagonists.

46. any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt are preparing treatment of diseases relevant with angiotensin-ii receptor and/or the application in the preventive.

47. any described tricyclic compounds of claim 5～13 or its pharmaceutically useful salt application in preparation depressor.