CN1882590B - Fused heterocyclic compounds as serotonin receptor modulators - Google Patents

Fused heterocyclic compounds as serotonin receptor modulators Download PDF

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Publication number
CN1882590B
CN1882590B CN200480033737.8A CN200480033737A CN1882590B CN 1882590 B CN1882590 B CN 1882590B CN 200480033737 A CN200480033737 A CN 200480033737A CN 1882590 B CN1882590 B CN 1882590B
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phenyl
tri
azulene
azepines
chloro
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CN1882590A (en
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N·I·卡鲁特尔斯
W·柴
X·邓
C·A·德沃拉克
A·K·郭
J·T·梁
N·马尼
D·A·鲁多尔夫
V·D·王
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Abstract

Certain fused pyrrole- and pyrazole-containing heterocyclic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

Description

Condensed heterocyclic compouds as serotonin receptor modulator
Invention field
The invention provides the compound for serotonin receptor modulator.More particularly, the invention provides condensed heterocyclic compouds, described condensed heterocyclic compouds is to can be used for treatment by the serotonin receptor modulator of the disease of the active mediation of serotonin receptor.
Background of invention
(serotonin 5-HT) is the main neurotransmitter playing a role by multiple acceptor to thrombotonin.So far, had been found that at least ten five kinds of different 5-HT acceptors, most of result as clone cDNA, and these acceptors have been divided into seven class (5-HT 1to 5-HT 7) (Hoyer, the people .Pharmacol.Biochem.Behav. such as D. (2002) 71,533-554). in the middle of 15 kinds of clones' 5-HT acceptor, there are 14 kinds in brain, to express.5-HT and a lot of particularly disease implications of central nervous system of disease, the disease of described central nervous system comprises: depression, anxiety, schizophrenia, eating disorder, obsession, learning and memory dysfunction, migraine, chronic pain, sensation perceptual disturbance, the active obstacle of motor, temperature insufficiency of accommodation, nociception, sexual dysfunction, hormone secretion and cognitive disorder.Being accredited as of multiple 5-HT acceptor characterizes the existing therapeutical agent be considered to work by serotonergic systems provides chance.Therefore, this just causes recognizing that a lot of medicines have non-selective characteristic (Roth, B.L. wait people .Neuroscientist (2000) 6 (4) 252-262). for example, except the acceptor of other kind, antipsychotics leoponex, chlorpromazine, clofluperol and olanzapine also show avidity to multiple serotonin receptor.For the thymoleptic that comprise imipramine, nortriptyline (nortriptaline), fluoxetine and Sertraline, also notice similar characteristics.Similarly, anti-migraine agent sumatriptan demonstrates high-affinity to several serotonin receptors.Although optionally lack the normally reason of favourable treatment result, it also causes bad and side effect dose limitation (Stahl, S.M.Essential Psychopharmacology, 2 nded., CambridgeUniversity Press, Cambridge, U.K., 2000). therefore, the inhibition of thrombotonin and norepinephrine uptake and 5-HT 2receptor blocking brings the result for the treatment of of tricyclics.On the contrary, they are to histamine H 1, muscarine and alpha-adrenergic receptor blocking-up can cause respectively calmness, blurred vision and orthostatic hypotension.Equally, comprise the atypical antipsychotic of olanzapine and leoponex, based on them to 5-HT 2, D 2and 5-HT 7the effect of acceptor, is considered to have positive result for the treatment of.On the contrary, the proneness of their side effect owing to it avidity to dopaminergic, serotonergic and adrenergic receptor.
Therefore, have more optionally part and there is the potential that improves unsuitable pharmacology and new therapy is provided.The more important thing is, obtain and to there is the optionally ability of compound of known receptor, the multiple treatment mechanism of target is provided and has improved the prospect of the clinical response that single medicine has.
Summary of the invention
The present invention relates to formula (I), (II) and compound (III):
Figure S04833737820060524D000021
Wherein
M is 0,1 or 2;
N is 1,2 or 3;
P is 1,2 or 3, and condition is that p is not 1 in the situation that m is 1;
M+n is less than or equal to 4;
M+p is less than or equal to 4;
Q is 0 or 1;
R is 0,1,2,3,4 or 5;
R 3be-C 1-4alkyl, allyl group, propargyl or benzyl, described each group is optionally by-C 1-3alkyl ,-OH or halogen replace;
Ar is selected from following aryl or heteroaryl ring:
A) phenyl, it is optionally by R rmonosubstituted, two replace or three replace, or on adjacent carbons quilt-OC 1-4alkylidene group O-,-(CH 2) 2-3nH-,-(CH 2) 1-2nH (CH 2)-,-(CH 2) 2-3n(C 1-4alkyl)-or-(CH 2) 1-2n(C 1-4alkyl) (CH 2)-bis-replace;
R rto be selected from following group :-OH ,-C 1-6alkyl ,-OC 1-6alkyl ,-C 2-6alkenyl ,-OC 3-6alkenyl ,-C 2-6alkynyl ,-OC 3-6alkynyl ,-CN ,-NO 2,-N (R y) R z(R wherein yand R zindependently selected from H or C 1-6alkyl) ,-(C=O) N (R y) R z,-(N-R t) COR t,-(N-R t) SO 2c 1-6alkyl (R wherein th or C 1-6alkyl) ,-(C=O) C 1-6alkyl ,-(S=(O) n)-C 1-6alkyl (wherein n is selected from 0,1 or 2) ,-SO 2n(R y) R z,-SCF 3, halogen ,-CF 3,-OCF 3,-COOH and-COOC 1-6alkyl;
B) on two adjacent carbons ring elements, partly condense to form phenyl or the pyridyl of five yuan of aromatic rings that condense with ternary hydrocarbon, described part has one by > O, > S, > NH or > N (C 1-4alkyl) alternative carbon atom, and described part has at the most one optionally by-other carbon atom that N=substitutes, and described fused rings is optionally by R rmonosubstituted, two replacements or three replace;
C) on two adjacent ring unit, partly condense to form the phenyl of the hexa-atomic aromatic ring condensing with quaternary hydrocarbon, described part has the alternative carbon atom of one or two quilt-N=, and described fused rings is optionally by R rmonosubstituted, two replacements or three replace;
D) optionally by R rmonosubstituted, two replacement or trisubstituted naphthyls;
E) mononuclear aromatics base, described mononuclear aromatics base has five annular atomses, having is the carbon atom of connection site, has one by > O, > S, > NH or > N (C 1-4alkyl) alternative carbon atom, has at the most one optionally by-other carbon atom that N=substitutes, optionally by R rmonosubstituted or two replace, and be optionally benzo-fused on two adjacent carbon atoms or pyrido condenses, wherein said benzo-fused or part that pyrido condenses is optionally by R rmonosubstituted, two replacements or three replace; With
F) mononuclear aromatics base, described mononuclear aromatics base has six annular atomses, and having is the carbon atom of connection site, has the alternative carbon atom of one or two quilt-N=, optionally by R rmonosubstituted or two replace, and be optionally benzo-fused on two adjacent carbon atoms or pyrido condenses, wherein said benzo-fused or part that pyrido condenses is optionally by R rmonosubstituted or two replace;
G) be selected from phenyl or the pyridyl that following substituting group replaces: phenyl, pyridyl, thienyl, oxazolyl and tetrazyl, the substituted part of wherein said generation is optionally further by R rmonosubstituted, two replacements or three replace;
ALK is side chain or non-side chain C 1-8alkylidene group, C 2-8alkylene group, C 2-8alkynylene or C 3-8sub-cycloalkenyl group, described group be optionally independently selected from following substituting group monosubstituted, two replace or three replacements :-OH ,-OC 1-6alkyl ,-OC 3-6cycloalkyl ,-CN ,-NO 2,-N (R a) R b(R wherein aand R bindependently selected from H, C 1-6alkyl or C 2-6alkenyl) ,-(C=O) N (R a) R b,-(N-R c) COR c,-(N-R c) SO 2c 1-6alkyl (R wherein ch or C 1-6alkyl) ,-(C=O) C 1-6alkyl ,-(S=(O) d)-C 1-6alkyl (wherein d is selected from 0,1 or 2) ,-SO 2n(R a) R b,-SCF 3, halogen ,-CF 3,-OCF 3,-COOH and-COOC 1-6alkyl;
CYC is hydrogen or the carbocyclic ring that is selected from following groups, heterocycle, aryl or heteroaryl ring:
I) phenyl, described phenyl is optionally by R qmonosubstituted, two replace or three replace, or on adjacent carbon atom quilt-OC 1-4alkylidene group O-,-(CH 2) 2-3nH-,-(CH 2) 1-2nH (CH 2)-,-(CH 2) 2-3n(C 1-4alkyl)-or-(CH 2) 1-2n(C 1-4alkyl) (CH 2)-bis-replace;
R qto be selected from following group :-OH ,-C 1-6alkyl ,-OC 1-6alkyl ,-C 3-6cycloalkyl ,-OC 3-6cycloalkyl, phenyl ,-O phenyl, benzyl ,-O benzyl ,-CN ,-NO 2,-N (R a) R b(R wherein aand R bindependently selected from H, C 1-6alkyl or C 2-6alkenyl, or R aand R bcan form other aliphatic hydrocrbon ring with together with connected nitrogen, described ring is 5-7 ring, optionally has one by > O ,=N-, > NH or > N (C 1-4alkyl) alternative carbon atom, optionally has the carbon atom that a quilt-OH replaces, and optionally has one or two unsaturated link(age) on ring) ,-(C=O) N (R a) R b,-(N-R c) COR c,-(N-R c) SO 2c 1-6alkyl (R wherein ch or C 1-6alkyl, or two R in same substituting group ccan form together other aliphatic hydrocrbon ring by connected acid amides, described ring is 4-6 ring) ,-N-(SO 2c 1-6alkyl) 2the C of ,-(C=O) 1-6alkyl ,-(S=(O) d)-C 1-6alkyl (wherein d is selected from 0,1 or 2) ,-SO 2n(R a) R b,-SCF 3, halogen ,-CF 3,-OCF 3,-COOH and-COOC 1-6alkyl;
Ii) on two adjacent carbocyclic ring unit, partly condense to form phenyl or the pyridyl of five yuan of aromatic rings that condense with ternary hydrocarbon, described part has one by > O, > S, > NH or > N (C 1-4alkyl) alternative carbon atom, and described part has at the most one optionally by-other carbon atom that N=substitutes, and described fused rings is optionally by R qmonosubstituted, two replacements or three replace;
Iii) on two adjacent carbocyclic ring unit, partly condense to form the phenyl of the hexa-atomic aromatic ring condensing with quaternary hydrocarbon, described part has the alternative carbon atom of one or two quilt-N=, and described fused rings is optionally by R qmonosubstituted, two replacements or three replace;
Iv) optionally by R qmonosubstituted, two replacement or trisubstituted naphthyls;
V) mononuclear aromatics base, described mononuclear aromatics base has five annular atomses, having is the carbon atom of connection site, has one by > O, > S, > NH or > N (C 1-4alkyl) alternative carbon atom, has at the most one optionally by-other carbon atom that N=substitutes, optionally by R qmonosubstituted or two replace, and be optionally benzo-fused on two adjacent carbon atoms or pyrido condenses, wherein said benzo-fused or pyrido condenses part optionally by R qmonosubstituted, two replacements or three replace;
Vi) mononuclear aromatics base, described mononuclear aromatics base has six annular atomses, and having is the carbon atom of connection site, has the alternative carbon atom of one or two quilt-N=, optionally by R qmonosubstituted or two replace, and be optionally benzo-fused on two adjacent carbon atoms or pyrido condenses, wherein said benzo-fused or pyrido condenses part optionally by R qmonosubstituted or two replace;
Vii) the non-aromatic carbocyclic ring of 3-8 unit or heterocycle, described ring has 0,1 or 2 non-adjacent O, S ,-N=, > NH or > NR of being selected from qheteroatoms, there is 0,1 or 2 unsaturated link(age), having 0,1 or 2 is the carbon unit of carbonyl, optionally has the carbon unit of a formation bridge, has 0-5 substituent R q, and be optionally benzo-fused on two adjacent carbon atoms or pyrido condenses, wherein said benzo-fused or pyrido condenses part and has 0,1,2 or 3 substituent R q; With
Viii) the non-aromatic carbocyclic ring of 4-7 unit or heterocycle, described heterocycle has 0,1 or 2 non-adjacent O, S ,-N=, > NH or > NR of being selected from qheteroatoms, there is 0,1 or 2 unsaturated link(age), having 0,1 or 2 is the carbon unit of carbonyl, and the carbon unit optionally with a formation bridge, on the adjacent carbons that forms on two adjacent carbonss of saturated bond or forming saturated bond and nitrogen-atoms, with 4-7 unit's carbocyclic ring or heterocyclic fused heterocycle, it does not have 0 or 1 on junction and is selected from O, S ,-N=, > NH or > NR encircling qpossible other heteroatoms unit, there is 0,1 or 2 unsaturated link(age), having 0,1 or 2 is the carbon unit of carbonyl, and fused rings has 0-5 substituent R q;
R 1be selected from following groups: H, C 1-7alkyl, C 2-7alkenyl, C 2-7alkynyl, C 3-7cycloalkyl, C 3-7cycloalkyl C 1-7alkyl, C 3-7cycloalkenyl group, C 3-7cycloalkenyl group C 1-7alkyl and benzo-fused C 4-7cycloalkyl, described each group is optionally by R pmonosubstituted, two replacements or three replace;
R pbe selected from following groups :-OH ,-OC 1-6alkyl ,-C 3-6cycloalkyl ,-OC 3-6cycloalkyl ,-CN ,-NO 2, phenyl, pyridyl, thienyl, furyl, pyrryl ,-N (R s) R u(R wherein sand R uindependently selected from H or C 1-6alkyl, or can form other aliphatic hydrocrbon ring together with the nitrogen connecting, described ring is 5-7 ring, optionally has one by > O ,=N-, > NH or > N (C 1-4alkyl) alternative carbon, and optionally there is one or two unsaturated link(age) in ring) ,-(C=O) N (R s) R u,-(N-R v) COR v,-(N-R v) SO 2c 1-6alkyl (R wherein vh or C 1-6alkyl, or two R in same substituting group vcan form other aliphatic hydrocrbon ring together with the acid amides connecting, described ring is 4-6 ring) ,-(C=O) C 1-6alkyl ,-(S=(O) n)-C 1-6alkyl (wherein n is selected from 0,1 or 2) ,-SO 2n(R s) R u,-SCF 3, halogen ,-CF 3,-OCF 3,-COOH and-COOC 1-6alkyl, wherein aforementioned phenyl, pyridyl, thienyl, furyl and pyrryl substituting group be optionally independently selected from following substituting group monosubstituted, two replace or three replacements :-OH ,-C 1-6alkyl ,-OC 1-6alkyl ,-CN ,-NO 2,-N (R a) R b(R wherein aand R bindependently selected from H, C 1-6alkyl or C 2-6alkenyl) ,-(C=O) N (R a) R b,-(N-R c) COR c,-(N-R c) SO 2c 1-6alkyl (R wherein ch or C 1-6alkyl) ,-(C=O) C 1-6alkyl ,-S (=(O) d)-C 1-6alkyl (wherein d is selected from 0,1 or 2) ,-SO 2n(R a) R b,-SCF 3, halogen ,-CF 3,-OCF 3,-COOH and-COOC 1-6alkyl;
R 2be selected from following groups: H, C 1-7alkyl, C 2-7alkenyl, C 2-7alkynyl and C 3-7cycloalkyl; With its enantiomorph, diastereomer, hydrate, solvate and pharmacologically acceptable salt, ester and acid amides.
Similarly, within the isomeric form of formula (I), (II) and (III) compound and their pharmacologically acceptable salt, ester and acid amides are also included within the present invention, and mention a kind of such isomeric form herein and mean at least one such isomeric form.It will be recognized by those skilled in the art, the present invention can for example exist with single isomerism form, and other compound can regional isomer intermixture form exist.
The invention still further relates to the pharmaceutical composition that contains such compound, and in treatment or prevention by serotonin receptor 5-HT particularly 7and/or 5-HT 2in the disease of receptor subtype mediation, use the method for such composition.
Describe in detail
Preferably, m is 1 or 2, and most preferably, m is 1.
Preferably, n is 1 or 2.
Preferably, p is 1 or 2.
Preferably, m+n is 2 or 3.
Preferably, m+p is 2 or 3.
Preferably, q is 1.
Preferably, r is 0,1 or 2.
Preferably, r is 4.
Preferably, the optional R replacing 3be selected from following groups: methyl, ethyl, propyl group, sec.-propyl, butyl, allyl group, propargyl and benzyl.
Preferably, R 3it is methyl.
Preferably, the optional Ar replacing is selected from following groups:
A) phenyl, 5-, 6-, 7-, 8-phendioxin, 4-alkyl dioxin, 4-, 5-, 6-, 7-phendioxin, 3-dioxa cyclopentenyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-iso-dihydro-indole-group, 1,2,3,4-tetrahydrochysene-quinoline-4,5,6 or 7-base, 1,2,3,4-tetrahydro-isoquinoline-4,5,6 or 7-base
B) 4-, 5-, 6-or 7-benzoxazolyl, 4-, 5-, 6-or 7-benzothienyl, 4-, 5-, 6-or 7-benzofuryl, 4-, 5-, 6-or 7-indyl, 4-, 5-, 6-or 7-benzothiazolyl, 4-, 5-, 6-or 7-benzimidazolyl-, 4-, 5-, 6-or 7-indazolyl, imidazo [1, 2-a] pyridine-5, 6, 7 or 8-base, pyrazolo [1, 5-a] pyridine-4, 5, 6 or 7-base, 1H-pyrrolo-[2, 3-b] pyridine-4, 5 or 6-base, 1H-pyrrolo-[3, 2-c] pyridine-4, 6 or 7-base, 1H-pyrrolo-[2, 3-c] pyridine-4, 5 or 7-base, 1H-pyrrolo-[3, 2-b] pyridine-5, 6 or 7-base,
C) 5-, 6-, 7-or 8-isoquinolyl, 5-, 6-, 7-or 8-quinolyl, 5-, 6-, 7-or 8-quinoxalinyl, 5-, 6-, 7-or 8-quinazolyl,
D) naphthyl,
E) furyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyrryl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-Yin oxazinyl (indoxazinyl), 2-benzoxazolyl, 2-or 3-benzothienyl, 2-or 3-benzofuryl, 2-or 3-indyl, 2-[4-morpholinodithio base, 2-benzimidazolyl-, 3-indazolyl
F) pyridyl, pyridyl-N-oxide compound, pyrazinyl, pyrimidyl, pyridazinyl, 1-, 3-or 4-isoquinolyl, 2-, 3-or 4-quinolyl, 2-or 3-quinoxalinyl, 2-or 4-quinazolyl, [1,5], [1,6], [1,7] or [1,8] naphthyridine-2-, 3-or 4-base, [2,5], [2,6], [2,7], [2,8] naphthyridine-1-, 3-or 4-base, and
G) xenyl, 4-tetrazolyl phenyl.
More preferably, the optional Ar replacing is selected from following groups: phenyl, pyridyl, thiophene-2-base and thiene-3-yl-.
Concrete Ar can be selected from following groups: phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 3-cyano-phenyl, 4-cyano-phenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4 difluorobenzene base, 2,4 dichloro benzene base, 3-nitrophenyl, 4-nitrophenyl, the chloro-4-fluorophenyl of 3-, the fluoro-4-chloro-phenyl-of 3-, benzo [1,3] dioxole-4 or 5-base, 3-hydroxy phenyl, 4-hydroxy phenyl, 4-hydroxy-2-methyl phenyl, 4-hydroxyl-3-fluorophenyl, 3,4-dihydroxy phenyl, 4-dimethylaminophenyl, 4-formamyl phenyl, the fluoro-3-aminomethyl phenyl of 4-, furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-, 5-chlorothiophene-2-base, 5-thiotolene-2-base, 5-chlorothiophene-3-base, 5-thiotolene-3-base, 4 '-chlorodiphenyl and 4-tetrazolyl phenyl.
Preferably, the optional ALK replacing is selected from following groups: methylene radical, ethylidene, propylidene, butylidene, the sub-tertiary butyl, pentylidene, 1-ethyl propylidene, 2-ethyl propylidene, 2-ethyl butylidene, isopropylidene, Aden-3-thiazolinyl, isobutylidene, 3-methyl butylidene, acrol and sub-Propargyl.
Concrete ALK can be selected from following groups: methylene radical, trifluoromethyl methylene radical, methoxycarbonyl methyl, methylamino formyl radical methyl, ethylidene, propylidene, 3-methoxycarbonyl propylidene, 3-carboxyl propylidene, butylidene, the sub-tertiary butyl, 4-hydroxy butylidene, 4-methoxycarbonyl butylidene, 4-carboxyl butylidene, pentylidene, 5-hydroxyl pentylidene, 1-ethyl propylidene, 2-ethyl propylidene, 2-ethyl butylidene, isopropylidene, Aden-3-thiazolinyl, isobutylidene, 3-methyl butylidene, sub-Propargyl, 2-dimethylamino ethylidene and 2-cyano group ethylidene.
Preferably, the optional CYC replacing is hydrogen or is selected from following groups:
I) phenyl, 5-, 6-, 7-, 8-phendioxin, 4-alkyl dioxin, 4-, 5-, 6-, 7-phendioxin, 3-dioxa cyclopentenyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-iso-dihydro-indole-group, 1,2,3,4-tetrahydrochysene-quinoline-4,5,6 or 7-base, 1,2,3,4-tetrahydro-isoquinoline-4,5,6 or 7-base
Ii) 4-, 5-, 6-or 7-benzoxazolyl, 4-, 5-, 6-or 7-benzothienyl, 4-, 5-, 6-or 7-benzofuryl, 4-, 5-, 6-or 7-indyl, 4-, 5-, 6-or 7-benzothiazolyl, 4-, 5-, 6-or 7-benzimidazolyl-, 4-, 5-, 6-or 7-indazolyl, imidazo [1, 2-a] pyridine-5, 6, 7 or 8-base, pyrazolo [1, 5-a] pyridine-4, 5, 6 or 7-base, 1H-pyrrolo-[2, 3-b] pyridine-4, 5 or 6-base, 1H-pyrrolo-[3, 2-c] pyridine-4, 6 or 7-base, 1H-pyrrolo-[2, 3-c] pyridine-4, 5 or 7-base, 1H-pyrrolo-[3, 2-b] pyridine-5, 6 or 7-base,
Iii) 5-, 6-, 7-or 8-isoquinolyl, 5-, 6-, 7-or 8-quinolyl, 5-, 6-, 7-or 8-quinoxalinyl, 5-, 6-, 7-or 8-quinazolyl,
Iv) naphthyl,
V) furyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thienyl, thiazolyl, isothiazolyl, pyrryl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-Yin oxazinyl (indoxazinyl), 2-benzoxazolyl, 2-or 3-benzothienyl, 2-or 3-benzofuryl, 2-or 3-indyl, 2-[4-morpholinodithio base, 2-benzimidazolyl-, 3-indazolyl
Vi) pyridyl, pyridyl-N-oxide compound, pyrazinyl, pyrimidyl, pyridazinyl, 1-, 3-or 4-isoquinolyl, 2-, 3-or 4-quinolyl, 2-or 3-quinoxalinyl, 2-or 4-quinazolyl, [1,5], [1,6], [1,7] or [1,8] naphthyridine-2-, 3-or 4-base, [2,5], [2,6], [2,7], [2,8] naphthyridine-1-, 3-or 4-base
Vii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, ring octyl group, adamantyl, pyrrolinyl, pyrrolidyl, pyrazolinyl, piperidyl, homopiperidinyl, azepan base, tetrahydrofuran base, THP trtrahydropyranyl, piperazinyl, morpholinyl, thio-morpholinyl, piperidone base, 2,3-indanyl, indolinyl, oxindole base, pyrrolin pyridyl, and
Viii) dicyclo [4.1.0] heptane, octahydro indyl, octahydro isoindoline base, decahydroquinolyl, Decahydroisoquinolinpreparation base, octahydro pyrrolopyridinyl and octahydro pyrrolopyrrole alkyl.
More preferably, the optional CYC replacing is selected from following groups: hydrogen, phenyl, indyl, benzothiazolyl, isoquinolyl, quinazolyl, naphthalene-1 or 2-base, thiophene-2-base, thiene-3-yl-, furans-2-base, furans-3-base, pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, piperidines-2, 3 or 4-base, 2-pyrroline-2, 3, 4 or 5-base, 3-pyrroline-2 or 3-base, 2-pyrazoline-3, 4 or 5-base, morpholine-2, 3, 5 or 6-base, thiomorpholine-2, 3, 5 or 6-base, piperazine-2, 3, 5 or 6-base, tetramethyleneimine-2 or 3-base, homopiperidinyl, adamantyl and octahydro indyl.
Most preferably, the optional CYC replacing is selected from following groups: hydrogen, phenyl, pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, thiophene-2-base, thiene-3-yl-, THP trtrahydropyranyl, furans-2-base, furans-3-base and naphthalene-1 or 2-base.
Concrete CYC can be selected from following groups: hydrogen, phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4 difluorobenzene base, 2,4 dichloro benzene base, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-3,5-dimethylphenyl, 2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl, cyclobutyl, cyclohexyl, cyclopentyl, the fluoro-3-aminomethyl phenyl of 4-, 3-nitrophenyl, 4-nitrophenyl, 4-methyl-3-fluorophenyl, 3,4-3,5-dimethylphenyl, 4-methoxyl group-3-fluorophenyl, 4-methoxyl group-2-aminomethyl phenyl, 3-aminophenyl, 4-aminophenyl, 4-methoxycarbonyl (carbomethoxy) phenyl, 3-methylsulfonyl amino-phenyl, 4-methylsulfonyl amino-phenyl, 3-diformazan sulfuryl amino-phenyl, 4-diformazan sulfuryl amino-phenyl, thiophene-2-base, thiene-3-yl-, 5-chlorothiophene-2-base, benzo [1,3] dioxole-4 or 5-base, tetrahydropyrans-2, 3 or 4-base, furans-2-base, furans-3-base, 5-carboxy ethyl-furans-2-base, naphthalene-1 or 2-base, 3,4-benzyloxy phenenyl, 2-hydroxy phenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 4-hydroxy-2-methyl phenyl, 4-hydroxyl-3-fluorophenyl and 3,4-dihydroxy phenyl.
Preferably, R 1be selected from following groups: hydrogen, C 1-3alkyl, C 2-4alkenyl, C 2-4alkynyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-3alkyl, C 5-6cycloalkenyl group, benzo-fused C 5-6cycloalkyl, each group is optionally by R pmonosubstituted, two replacements or three replace.
More preferably, optionally by R pthe R replacing 1be selected from following groups: hydrogen, methyl, ethyl, propyl group and sec.-propyl.
Concrete R 1can be selected from following groups: hydrogen, methyl, ethyl, propyl group, sec.-propyl, 3-hydroxypropyl, benzyl, 3,4-dimethoxy-benzyl, methoxycarbonyl methyl, carbamyl ylmethyl, styroyl, hydrocinnamyl and hydroxyethyl.
Preferably, R 2hydrogen, C 1-3alkyl, C 2-4alkenyl, C 2-4alkynyl or C 3-6cycloalkyl.
More preferably, R 2hydrogen or methyl.
Should be appreciated that some compound as referred to herein be chirality and/or there is rotamerism center, for example E and Z isomer.The present invention includes all such optically active isomers, comprise steric isomer and racemic mixture, diastereomer and the geometrical isomer with the compounds of this invention feature activity.Some compound as referred to herein can exist with solvation and non-solvated form in addition.Should be appreciated that all solvations and the non-solvated form with the compounds of this invention feature activity that the present invention includes.
Through modification so as the compounds of this invention that can survey by some analytical technology also within the scope of the invention.Can be with radioelement for example 125i, 18f, 11c, 64cu etc. are the radiotherapy for video picture or patient by the compounds of this invention mark.The example of such compound is isotope-labeled compound, for example 18the compound of F mark, described compound can be used as surveying and/or the shadowgraph technique probe of positron emission computerized tomography (PET) and single photon emission computerized tomography(SPECT) (SPECT) for example.Preferably, 18f or 11positron emission computerized tomography (PET) molecular probe of the disease that the compounds of this invention of C mark can be mediated by thrombotonin as research.Another example of such compound is isotope-labeled compound, for example can be for the deuterium of reaction kinetics research/or tritium-labeled compound.Can adopt conventional chemical technology by compound described herein and suitable functionalized radioactivity reagent react, so that radiolabeled compound to be provided.
Pharmacologically acceptable salt, ester and acid amides are included in rational benefit/risk ratio, and pharmacology effectively and be suitable for contacting with patient's tissue and do not generate excessive toxicity, stimulation or anaphylactoid carboxylate salt (C for example 1-8alkyl, C 3-8cycloalkyl, aryl, C 2-10heteroaryl or C 2-10non-aromatic heterocyclic), amino additive salt, acid salt, ester and acid amides.The representative additive salt that shows formula (I) compound of alkaline functionality comprises hydrobromate, hydrochloride, vitriol, hydrosulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate (naphthylate), mesylate, gluceptate, Lactobionate and lauryl sulfonate.The representative additive salt that shows acid functionality's formula (I) compound is those additive salt with the non-toxicity subsalt of such compound formation.These salt can comprise alkali and alkaline earth metal ions positively charged ion for example sodium, potassium, calcium and magnesium, and non-toxicity ammonium, quaternary ammonium and amine positively charged ion for example tetramethylammonium, methylamine, Trimethylamine 99 and ethamine.Referring to such as people such as S.M.Berge, " Pharmaceutical Salts, " J.Pharm.Sci., 1977,66:1-19, is quoted as a reference herein.
The representative pharmaceutically acceptable acid amides of the present invention comprises derived from ammonia, uncle C 1-6alkylamine and secondary two (C 1-6alkyl) those acid amides of amine.Secondary amine comprises and contains at least one nitrogen-atoms and optional 1 to 2 other heteroatomic 5 or 6 yuan of heterocycles or hetero-aromatic ring part.Preferred acid amides is derived from ammonia, C 1-3kiber alkyl amine and two (C 1-2alkyl) amine.The representative pharmaceutically acceptable ester of the present invention comprises C 1-7alkyl, C 5-7cycloalkyl, phenyl and phenyl (C 1-6) alkyl ester.Preferred ester comprises methyl ester.
For the preferred compound of fused pyrrole is selected from:
Example Chemical name
1 1-benzyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
2 1-benzyl-3-(the fluoro-phenyl of the chloro-4-of 3-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
3 4-(1-benzyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridin-3-yl also)-phenol;
4 1-benzyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
5 1-benzyl-3-(the chloro-thiophene-2-of 5-yl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
6 1-benzyl-3-thiophene-2-base-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
7 1-(the chloro-benzyl of 3-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
8 1-benzyl-3-(the fluoro-phenyl of 3-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
9 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
10 1-(the chloro-benzyl of 3-)-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
11 1-(the chloro-benzyl of 2-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
12 1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
13 1-benzyl-3-(the chloro-phenyl of 2,4-bis-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
14 1-(4-methoxyl group-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
15 1-(the chloro-benzyl of 2-)-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
16 1-(the chloro-benzyl of 2,4-bis-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
17 1-benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
18 1-benzyl-3-p-methylphenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
19 1-benzyl-3-(the chloro-phenyl of 3,4-bis-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also;
Figure S04833737820060524D000131
It is that the preferred compound of the 1-position substituted pyrazolecarboxylic that condenses is selected from:
Example Chemical name
43 1-benzyl-3-(4-trifluoromethyl-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (azulene);
44 1-benzyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
45 1-benzyl-3-(the fluoro-phenyl of 2-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
46 1-benzyl-3-(the fluoro-phenyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
47 1-benzyl-3-(the fluoro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
48 1-benzyl-3-(the fluoro-phenyl of 2,3-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
49 1-benzyl-3-(the chloro-phenyl of 3,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
50 1-[4-(1-benzyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-phenyl]-ethyl ketone;
51 1-benzyl-3-(4-trifluoromethoxy-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
52 1-benzyl-3-(the chloro-phenyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
53 3-(1-benzyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
54 4-(1-benzyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
55 1-(the chloro-benzyl of 4-)-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
56 1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
57 1-benzyl-3-phenyl-6-propyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
58 1-benzyl-6-sec.-propyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
59 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
60 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene;
61 3-(the chloro-phenyl of 4-)-1-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
63 3-(the chloro-phenyl of 4-)-1-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
65 3-(the chloro-phenyl of 4-)-1-propyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
67 1-butyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
69 3-(the chloro-phenyl of 4-)-1-(2-cyclohexyl-ethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
71 3-(the chloro-phenyl of 4-)-1-styroyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
73 3-(the chloro-phenyl of 4-)-1-(the fluoro-3-methyl-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
74 3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
75 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
76 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
77 3-(the chloro-phenyl of 4-)-1-(4-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
78 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
79 3-(the chloro-phenyl of 4-)-1-(3-nitro-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
80 3-(the chloro-phenyl of 4-)-1-(the fluoro-4-methyl-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
81 3-(the chloro-phenyl of 4-)-1-(3,4-dimethyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
85 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-methyl valerate;
86 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-valeric acid;
87 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-penta-1-alcohol;
88 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-methyl-butyrate;
91 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-butyric acid;
93 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-Ding-1-alcohol;
96 3-(the chloro-phenyl of 4-)-1-(the fluoro-4-methoxyl group-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-tri-
Azepine-Azulene;
98 3-(the chloro-phenyl of 4-)-1-(4-nitro-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
99 4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-aniline;
100 N-[4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-phenyl]-Toluidrin;
101 N, N-[4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-phenyl]-bis-Toluidrins;
102 1-benzyl-3-p-methylphenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
103 3-(the chloro-phenyl of 4-)-1-thiophene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
104 1-benzyl-3-thiophene-2-base-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
105 3-(the chloro-phenyl of 4-)-1-(3-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
106 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
107 3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
108 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
109 3-(the chloro-phenyl of 4-)-1-(2-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
110 1-(the chloro-benzyl of 2-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
111 1-fourth-3-thiazolinyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
112 1-(the bromo-benzyl of 2-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
113 1-(the bromo-benzyl of 4-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
114 3-(the chloro-phenyl of 4-)-1-(2-ethyl-butyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
115 3-(the chloro-phenyl of 4-)-1-(the chloro-thiophene-2-of 5-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
116 1-(the bromo-benzyl of 3-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
117 3-(the chloro-phenyl of 4-)-1-cyclohexyl methyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
118 3-(the chloro-phenyl of 4-)-1-isobutyl--Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
119 1-benzo [1,3] dioxole-5-ylmethyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
120 3-(the chloro-phenyl of 4-)-1-(tetrahydrochysene-pyrans-4-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
121 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,6-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
123 3-(the chloro-phenyl of 4-)-1-(4-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
124 3-(the chloro-phenyl of 4-)-1-(3-methyl-butyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
125 3-(the chloro-phenyl of 4-)-1-(2-trifluoromethyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
128 3-(the chloro-phenyl of 4-)-1-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
134 3-(the chloro-phenyl of 4-)-1-Propargyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
135 3-(the chloro-phenyl of 4-)-1-pentafluorophenyl group methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
137 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4,6-tri-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
138 2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-benzonitrile;
142 3-(4-nitrogen-phenyl)-1-naphthalene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
144 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-furans-2-ethyl formate;
145 3-(the chloro-phenyl of 4-)-1-naphthalene-1-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
147 [3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-methyl acetate;
148 2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-N-methyl-ethanamide;
150 3-(the chloro-phenyl of 4-)-1-(3,4,5-trimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
152 3-(the chloro-phenyl of 4-)-1-(2,6-dimethyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
154 1-(3,4-, bis--benzyloxy-benzyl)-3-(4-ammonia-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
156 3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-phenol;
157 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-phenol;
158 4-[3-(4-oxygen-phenyl)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-3-methyl-phenol;
159 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-benzene-1,2-bis--phenol;
160 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] the fluoro-phenol of-2-;
162 2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-phenol;
165 1-benzyl-3-(the chloro-phenyl of 4-)-6-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
166 1-benzyl-3-(4-ammonia-phenyl)-6-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
167 3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
168 1-butyl-3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
169 1-benzyl-3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
170 [1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-methyl acetate;
171 2-[1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-ethanol;
172 3-(the chloro-phenyl of 4-)-1-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
173 3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7,8,9-six hydrogen-1H-1,2,6-, tri-azepines-cyclopenta cyclooctene;
174 3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7,8,9-six hydrogen-1H-1,2,7-, tri-azepines-cyclopenta cyclooctene;
175 3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
230 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] and-phenyl }-methyl-amine;
237 3-(the chloro-phenyl of 4-)-1-cyclobutyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
239 3-(the chloro-phenyl of 4-)-1-cyclohexyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
254 3-(the chloro-phenyl of 4-)-1-suberyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
255 3-(the chloro-phenyl of 4-)-1-encircles octyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
273 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion;
316 3-(the chloro-phenyl of 4-)-1-pyridin-4-yl methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
317 3-(the chloro-phenyl of 4-)-1-pyridine-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
319 3-(the chloro-phenyl of 4-)-1-pyridin-3-yl methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
320 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-methyl benzoate;
321 3-(the chloro-phenyl of 4-)-1-(tetrahydrochysene-pyrans-4-yl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
322 3-(the chloro-phenyl of 4-)-1-(4-methyl-cyclohexyl base)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
323 2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl] and-ethyl)-dimethyl-amine.
324 3-(the chloro-phenyl of 4-)-1-(1-oxygen base-pyridine-2-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
325 2-[1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-ethanamide;
326 3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-propionitrile;
332 1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene;
333 3-(the chloro-phenyl of 4-)-1-(4-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene;
334 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene;
335 3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene;
336 3-(the chloro-phenyl of 4-)-1-(the fluoro-4-methyl-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene; With
337 3-(the chloro-phenyl of 4-)-1-(the fluoro-3-methyl-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene.
It is that the preferred compound of the pyrazoles of 2 replacements condensing is selected from:
Example Chemical name
62 3-(the chloro-phenyl of 4-)-2-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
64 3-(the chloro-phenyl of 4-)-2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
66 3-(the chloro-phenyl of 4-)-2-propyl group-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
68 2-butyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
70 3-(the chloro-phenyl of 4-)-2-(2-cyclohexyl-ethyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
72 3-(the chloro-phenyl of 4-)-2-styroyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
82 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-methyl valerate;
83 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-valeric acid;
84 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-penta-1-alcohol;
89 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene 2-yl]-methyl-butyrate;
90 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-butyric acid;
92 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-Ding-1-alcohol;
94 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
95 3-(the chloro-phenyl of 4-)-2-(4-methyl-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
97 3-(the chloro-phenyl of 4-)-2-(the fluoro-4-methoxyl group-benzyl of 3-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
122 3-(the chloro-phenyl of 4-)-2-cyclohexyl methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
126 3-(the chloro-phenyl of 4-)-2-(2-methyl-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
127 2-benzyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
129 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
130 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl]-furans-2-ethyl formate;
131 3-(the chloro-phenyl of 4-)-2-isobutyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
132 3-(the chloro-phenyl of 4-))-2-(2-methoxyl group-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
133 2-benzyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
136 3-(the chloro-phenyl of 4-)-2-thiophene-2-ylmethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
139 3-(the chloro-phenyl of 4-)-2-(the chloro-thiophene-2-of 5-ylmethyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
140 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,6-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
141 3-(the chloro-phenyl of 4-)-2-(2-trifluoromethyl-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
143 3-(the chloro-phenyl of 4-)-2-(2-ethyl-butyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
146 2-benzo [1,3] dioxole-5-ylmethyl 3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
149 3-(the chloro-phenyl of 4-)-2-pentafluorophenyl group methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
151 3-(the chloro-phenyl of 4-)-2-naphthalene-1-ylmethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
153 3-(the chloro-phenyl of 4-)-2-(3,4,5-trimethoxy-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
155 2-(3,4-, bis--benzyloxy-benzyl)-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
161 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl] the fluoro-phenol of-2-;
163 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene 2-ylmethyl]-3-methyl-phenol;
164 2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl]-phenol;
176 2,3-phenylbenzene-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
177 2-cyclohexyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
178 3-(the chloro-phenyl of 4-)-2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
179 2-cyclohexyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
180 2-cyclopentyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
181 3-(the chloro-phenyl of 4-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
182 2-cyclopentyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
183 2-(1-ethyl-propyl group)-3-(the fluoro-phenyl of 3-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
184 2-(1-ethyl-propyl group)-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
185 2-(1-ethyl-propyl group)-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
186 2-(1-ethyl-propyl group) 3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
187 3-(the chloro-phenyl of 4-)-2-(the fluoro-ethyl of 2,2,2-tri-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
188 2-(the fluoro-ethyl of 2,2,2-tri-)-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
189 2-sec.-propyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
190 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
191 2-(1-ethyl-propyl group)-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
192 2-cyclopentyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
193 2-ethyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
194 2-ethyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
195 2-ethyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
196 2-(the chloro-phenyl of 3-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
197 2-(the fluoro-phenyl of 3-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
198 2-(the chloro-phenyl of 2-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
199 2-phenyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
200 3-(the fluoro-phenyl of 4-)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
201 3-(the chloro-phenyl of 4-)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
202 3-(the chloro-phenyl of 3-)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
203 2-phenyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
204 2,3-phenylbenzene-4,5,6,7-tetrahydrochysene-2H-pyrazolo [4,3-c] pyridine;
205 3-phenyl-2-(3-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
206 3-(4-methoxyl group-phenyl)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
207 2-(the chloro-phenyl of 4-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
208 6-methyl-2,3-phenylbenzene-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
209 2-sec.-propyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
210 3-(4-ethyl-phenyl)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
211 3-(the chloro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
212 4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
213 2-sec.-propyl 3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
214 2-ethyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
215 The 2-tertiary butyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
216 The 2-tertiary butyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
217 2-cyclopentyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
218 2-cyclopentyl 3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
219 3-(the chloro-phenyl of 3-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
220 2-cyclopentyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8--six hydrogen-1,2,6-, tri-azepines-Azulene;
221 2-(3,3-dimethyl-cyclopentyl)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
222 2-(3,3-dimethyl-cyclopentyl)-3-(fluoro-phenyl-2 of 4-, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
223 3-(the chloro-phenyl of 4-)-2-(3,3-dimethyl-cyclopentyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
224 2-cyclohexyl 3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
225 2-cyclohexyl-3-(the fluoro-phenyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
226 2-cyclohexyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
227 2-cyclohexyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
228 4-(2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
229 3-(the chloro-phenyl of 3-)-2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
231 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [4,3-c] pyridine;
232 2-cyclopentyl-3-furans-3-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
233 2-cyclopentyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
234 The 2-tertiary butyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
235 The 2-tertiary butyl-3-furans-3-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
236 2-cyclopentyl-3-(the fluoro-phenyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
238 3-(the chloro-phenyl of 4-)-2-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
240 2-tertiary butyl 3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
241 3-(the fluoro-phenyl of the chloro-4-of 3-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
242 2-sec.-propyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
243 2-sec.-propyl-3-(4-trifluoromethoxy-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
244 2-sec.-propyl-3-(4-sec.-propyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
245 3-(the 4-tertiary butyl-phenyl)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
246 Tolyl-2 between 2-sec.-propyl-3-, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
247 2-sec.-propyl-3-o-tolyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
248 3-(the chloro-phenyl of 3,4-bis-) 2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
249 2-benzyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
250 2-sec.-propyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
251 3-(the chloro-phenyl of 2-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
252 1-[4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene 3-yl)-phenyl]-ethyl ketone;
253 2-sec.-propyl-3-(4-nitro-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
256 2-benzyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,5-, tri-azepines-Azulene;
257 2-ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
258 4-(2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
259 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-6-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
260 3-(the fluoro-phenyl of 4-)-2,6-di-isopropyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
261 2-ethyl-3-(4-sec.-propyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
262 2-ethyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
263 2-ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
264 2-ethyl-3-o-tolyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
265 3-(the chloro-phenyl of 2-)-2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
266 2-ethyl-3-(the fluoro-phenyl of 2-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
267 3-(the chloro-phenyl of 2,4-bis-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
268 [4-(2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene 3-yl)-phenyl]-dimethyl-amine;
269 6-benzyl-3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
270 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-6-(3-phenyl-propyl group)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
271 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-6-styroyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene; With
272 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate;
274 3-(4 '-chloro-biphenyl-4-yl) 2-(the fluoro-ethyl of 2,2,2-tri-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
275 3-(4 '-chloro-biphenyl-4-yl) 2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
276 2-cyclobutyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
277 2-cyclobutyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
278 2-cyclobutyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
279 2-cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
280 4-(2-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
281 2-cyclopropyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
282 2-cyclopropyl 3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
283 2-(1-ethyl-propyl group) 3-(the fluoro-3-methyl-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
284 2-cyclopropyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
285 2-cyclopropyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
286 4-(2-cyclopropyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
287 6-benzyl-2-sec.-propyl-3-phenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
288 2-sec.-propyl-3-phenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
289 6-benzyl-2-sec.-propyl-3-thiene-3-yl--4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
290 6-benzyl-2-sec.-propyl 3-p-methylphenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
291 6-benzyl-3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
292 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
293 2-sec.-propyl-3-p-methylphenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine;
294 2-cyclopentyl 3-(the fluoro-phenyl of 4-)-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
295 2-cyclopentyl-5,5,7,7-tetramethyl--3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
296 2-sec.-propyl-5,5,7,7-tetramethyl--3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
297 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
298 2-sec-butyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
299 2-sec-butyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
300 2-sec-butyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
301 2-sec-butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
302 2-cyclopentyl-3-(the fluoro-phenyl of 4-)-6-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
303 4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene 3-yl)-benzamide;
304 2-sec.-propyl-3-[4-(1H-TETRAZOLE-5-yl)-phenyl]-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
305 6-benzyl-3-(the fluoro-phenyl of 4-) 2-sec.-propyl-8-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
306 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-8-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
307 3-(the fluoro-phenyl of 4-)-2-isopropyl-4-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
308 2-cyclopentyl-3-(the fluoro-phenyl of 4-)-7-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
309 2-cyclopentyl 3-(the fluoro-phenyl of 4-)-5-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
310 2-cyclopentyl-7-methyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
311 2-sec.-propyl-7-methyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
312 2-sec.-propyl-5-methyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
313 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-7-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
314 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
315 2-sec.-propyl-7-methyl 3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
318 3-(the chloro-phenyl of 4-)-2-pyridine-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
327 3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene 2-yl]-propionitrile;
328 3-(the chloro-phenyl of 4-)-2-suberyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
329 3-(the chloro-phenyl of 4-)-2-encircles octyl group-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
330 3-(the chloro-phenyl of 4-)-2-(4-methyl-cyclohexyl base)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
331 2-benzyl-3-(the chloro-phenyl of 4-)-2,4,5,6-tetrahydrochysene-pyrrolo-[3,4-c] pyrazoles; With
338 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5,7-dimethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
In another embodiment of the present invention, preferred compound is selected from:
example chemical name
59 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
74 3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
75 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-azepine-Azulene;
76 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
103 3-(the chloro-phenyl of 4-)-1-thiophene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
104 1-benzyl-3-thiophene-2-base-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
108 3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
160 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] the fluoro-phenol of-2-;
165 1-benzyl-3-(the chloro-phenyl of 4-)-6-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
166 1-benzyl-3-(the chloro-phenyl of 4-)-6-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
214 2-ethyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
257 2-ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene; With
273 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion.
In another embodiment of the present invention, preferred compound is selected from:
Example Chemical name
131 3-(the chloro-phenyl of 4-)-2-isobutyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
133 2-benzyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
177 2-cyclohexyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
178 3-(the chloro-phenyl of 4-)-2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
181 3-(the chloro-phenyl of 4-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
182 2-cyclopentyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
183 2-(1-ethyl-propyl group)-3-(the fluoro-phenyl of 3-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
184 2-(1-ethyl-propyl group)-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
186 2-(1-ethyl-propyl group)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
191 2-(1-ethyl-propyl group)-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
215 The 2-tertiary butyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
216 The 2-tertiary butyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
217 2-cyclopentyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
218 2-cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
220 2-cyclopentyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
236 2-cyclopentyl-3-(the fluoro-phenyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
238 3-(the chloro-phenyl of 4-)-2-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
241 3-(the fluoro-phenyl of the chloro-4-of 3-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
242 2-sec.-propyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
277 2-cyclobutyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
278 2-cyclobutyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
279 2-cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-
azulene;
284 2-cyclopropyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
300 2-sec-butyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
302 2-cyclopentyl-3-(the fluoro-phenyl of 4-)-6-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
306 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-8-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene; With
310 2-cyclopentyl-7-methyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
In another embodiment of the present invention, preferred compound is selected from:
example chemical name
47 1-benzyl-3-(the fluoro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
64 3-(the chloro-phenyl of 4-)-2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
118 3-(the chloro-phenyl of 4-)-1-isobutyl--Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
180 2-cyclopentyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
190 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
192 2-cyclopentyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
209 2-sec.-propyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
210 3-(4-ethyl-phenyl)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
211 3-(the chloro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
212 4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile;
213 2-sec.-propyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene;
232 2-cyclopentyl-3-furans 3-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
233 2-cyclopentyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
284 2-cyclopropyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
300 2-sec-butyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene; With
315 2-sec.-propyl-7-methyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
The features and advantages of the present invention it will be apparent to those skilled in the art that.Based on the disclosure, comprise general introduction, detailed description, background, embodiment and claim, those skilled in the art can change and revise to adapt to various conditions and purposes.Publication described herein is quoted as a reference on the whole.
Can come preparation formula (I), (II) and condensed heterocyclic compouds (III) by multiple reaction scheme.The approach of acquisition formula (I) compound is described in reaction scheme 1.The preparation of formula (II) compound is described in reaction scheme 2,3,5 and 6.Synthesizing as shown in reaction scheme 3 and 4 of formula (III) compound.It will be recognized by those skilled in the art, compare with other reaction scheme, some compound is more favourable by a kind of reaction scheme preparation.
Reaction scheme 1
Figure S04833737820060524D000321
Reference reaction scheme 1, can be by formula (IV) compound preparation formula (I) compound.As shown in it; amine moiety in formula (IV) compound can be is suitably for example " blocking group in organic synthesis " third edition (T.W.Greene and P.G.M.Wuts of alkyl or benzyl amine, acid amides, carbamate or other group by substituting group G protection; John Wiley & Sons, 1999) (G is-C the middle group of describing 1-6alkyl ,-COOC 1-6alkyl ,-(C=O) C 1-6alkyl or benzyl, described benzyl is unsubstituted or quilt-OC 1-6alkyl or-C 1-6alkyl replaces).Preferred protecting group is t-butyl carbamate (Boc) group.Can be at suitable solvent for example in THF, toluene, benzene, methyl alcohol or ethanol, at 20-110 ℃ of temperature, the carbonyl functional group of compound (IV) is processed with formula (V) primary amine, simultaneously with Dean-Rodney Stark division box or by adding for example SiO of dewatering agent 2, MgSO 4, CuSO 4, Ti (O-iPr) 4or
Figure S04833737820060524D000322
molecular sieve, except anhydrating, forms corresponding formula (VI) imines.Preferred solvent is toluene and ethanol, and simultaneously preferred dewatering agent is SiO 2with
Figure S04833737820060524D000331
molecular sieve.Those skilled in the art will recognize that, formula (VI) imines is to exist with more than one tautomeric form.Then formula (VI) formula for compound (VII) nitroolefin can be processed to the azole compounds with production (VIII).Those skilled in the art will recognize that, by processing with formula (VII) nitroolefin, formula (VI) imines existing with more than one enamine tautomers is by formation zone isomer, and this depends on according to the structure of formula (IV) compound.Can the blocking group on nitrogen be removed by common received method, or, can be converted into formula (I) compound according to the type of relevant group.More specifically, can be at solvent CH for example 2cl 2, in ethanol or methyl alcohol, with acid, remove for example t-butyl carbamate of group as trifluoroacetic acid or hydrochloric acid etc., with production (IX) compound.Generally will recognize that the subgroup of formula (IX) compounds represented formula (I) compound, wherein R 1equal H.By method known to those skilled in the art, formula (IX) compound and formula (I) compound can be converted into their corresponding salt.
With conventional synthetic method for example alkylation or reduction amination, can prepare for example formula (I) compound of compound by formula (IX) compound.Therefore,, under reductive agent and catalyzer exist, in solvent, with formula (X) compound treatment formula (IX) compound that contains carbonyl, with production (I) compound, described reductive agent is NaBH for example 4, NaBH 3cN, NaBH (OAc) 3or hydrogen, described solvent is CH for example 2cl 2, DCE, THF, ethanol, methyl alcohol or similar solvent.It will be recognized by those skilled in the art, it may be essential adding acid to the pH of reaction mixture is reduced to pH7 following.The example of acid can comprise AcOH, Ti (O-iPr) 4, trifluoroacetic acid or hydrochloric acid etc.In addition, can be by for example (IX) use formula (XI) alkylating agent processing of compound.For example, at alkali as NaHCO 3, Na 2cO 3, K 2cO 3or Cs 2cO 3under existence, at solvent, for example in DMF, DMA, THF or ethanol, with alkyl chloride, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (I) compound.
Reaction scheme 2
Reference reaction scheme 2, can be by formula (XII) compound preparation formula (II) compound.As shown in reaction scheme 1; the amine moiety of formula (XII) compound can be is aptly alkyl or benzyl amine, acid amides, carbamate or other group " blocking group in organic synthesis " third edition (T.W.Greene and P.G.M.Wuts for example by substituting group G protection; John Wiley & Sons, 1999) the middle group of describing.Preferred blocking group is t-butyl carbamate (Boc) group.At 20-80 ℃ of temperature, at solvent, for example in methyl alcohol, ethanol, Virahol or the trimethyl carbinol, by hydrazine and formula (XII) compound condensation, will form formula (XIII) compound.Those skilled in the art will recognize that, formula (XIII) compound can more than one resonance form exist.More specifically, formula (XIII) compound and corresponding 3-hydroxypyrazoles compound tautomerism.Can by compound for example formula (XIII) compound with alkylating agent for example formula (XIV) alkylating agent process production (XV) compound.For example,, at alkali NaHCO for example 3, Na 2cO 3, K 2cO 3, NaH, potassium tert.-butoxide or Cs 2cO 3under existence, in DMF, DMA, THF or ethanol, with alkyl or benzyl chloride compound, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (XV) compound.Those skilled in the art will recognize that, the alkylation of formula (XIII) compound can formation zone isomer.Formula (XV) compound can be converted into the precursor for transition metal-catalyzed cross-coupling reaction, and described cross-coupling reaction is for example Stille, Suzuki, Negishi or other such linked reaction well known by persons skilled in the art.For example, use POCl 3, PCl 3, PCl 5, PBR 3or POBr 3processing can generate corresponding 3-halo pyrazoles.Preferred method is included in alkali as under pyridine, triethylamine or diisopropylethylamine existence, at DCE, CH 2cl 2, in THF etc., with fluoroform sulfonyl agent for example trifluoromethanesulfanhydride anhydride or N-phenyl trifluoromethanesulfonate methylsulfonyl imines process, with the pyrazoles triflate of production (XVI).Under alkali exists, in solvent, under catalyzer exists, with formula (XVII) organoboron compound, process formula (XVI) triflate, by production (XVIII) compound, described alkali is Na for example 2cO 3, K 2cO 3, Cs 2cO 3, K 3pO 4, KF, CsF, KOAc etc., described solvent is for example THF, Isosorbide-5-Nitrae-dioxs, DMA, DMF, DME, toluene, toluene/ethanol or toluene/H 2o mixture, described catalyzer is Pd (PPh for example 3) 4, PdCl 2(PPh 3) 2, PdCl 2(Po-tol 3) 2, PdCl 2or PdCl (dppe) 2(dppf). preferred catalyzer is to be with or without additive for example dppf and catalytic Bu 4pd (the PPh of NBr 3) 4and PdCl 2(dppf).Preferred solvent comprises THF, Isosorbide-5-Nitrae-dioxs, toluene and toluene/H 2o mixture, preferred alkali is Na 2cO 3, K 2cO 3, Cs 2cO 3and K 3pO 4.Can be by the method for the common employing known to those skilled in the art, remove the protecting group on the nitrogen of formula (XVIII) compound.More specifically, can be at solvent CH for example 2cl 2, in ethanol or methyl alcohol, with such as trifluoroacetic acid or hydrochloric acid etc. of acid, remove for example t-butyl carbamate of group, with production (XIX) compound.Can use method known to those skilled in the art, by formula (XIX) or (II) compound be converted into their corresponding salt.For example, can solvent for example in methyl alcohol by formula (XIX) amine citric acid treatment, generate corresponding Citrate trianion.Can recognize the subgroup of formula (XIX) compounds represented formula (II) compound, wherein R 1equal H.
Can, with conventional synthetic method for example alkylation or reduction amination, by formula (XIX) compound, prepare compound for example (II).Therefore,, in solvent, under catalyzer exists, under reductive agent exists, with formula (X) compound treatment formula (XIX) compound that contains carbonyl, by production (II) compound, described solvent is CH for example 2cl 2, DCE, THF, ethanol, methyl alcohol or similar solvent, described reductive agent is NaBH for example 4, NaBH 3cN, NaBH (OAc) 3or hydrogen.Those skilled in the art will recognize that, it may be essential adding acid to the pH of reaction mixture is reduced to pH7 following.The example of acid comprises AcOH, Ti (O-iPr) 4, trifluoroacetic acid or hydrochloric acid etc.In addition, can use formula (XI) alkylating agent to process compound for example (XIX).For example,, at alkali NaHCO for example 3, Na 2cO 3, K 2cO 3or Cs 2cO 3under existence, at solvent, for example in DMF, DMA, THF or ethanol, with alkyl chloride, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (II) compound.
Reaction scheme 3
Reference reaction scheme 3, as it is described, preparation formula (II), (III), (XXVII) and (XXVIII) compound.As shown in it; amine moiety in formula (XX) compound can be is aptly alkyl or benzyl amine, acid amides, carbamate or other group " blocking group in organic synthesis " third edition (T.W.Greene and P.G.M.Wuts for example by substituting group G protection; John Wiley & Sons, 1999) the middle group of describing.Preferred protecting group is t-butyl carbamate (Boc) group.Can be at 20-110 ℃ of temperature, suitable solvent as toluene or benzene in, be with or without acid catalyst for example TsOH in the situation that, by the carbonyl functional group of compound (XX) with saturated secondary amine for example morpholine process, with Dean Rodney Stark water trap, remove and anhydrate simultaneously, can generate corresponding formula (XXI) enamine.Those skilled in the art will recognize that, formula (XXI) enamine can exist with more than one the form of enamine regional isomer, and this depends on the structure of formula (XX) compound.With Benzoyl chloride, process enamine (XXI) by production (XXIV) dione compounds.In addition, can be at Lewis acid BF for example 3under existence, with diazo-ketones, process the carbonyl functional group of compound (XX), directly generate dione compounds (XXIV).At 20-80 ℃ of temperature, solvent as methyl alcohol, ethanol, Virahol or the trimethyl carbinol in, by hydrazine and formula (XXIV) compound condensation, will form formula (XXV) pyrazole compound.Can use the alkylating agent of formula (XIV) to process compound for example (XXV).For example, at alkali as NaHCO 3, Na 2cO 3, NaH, potassium tert.-butoxide, K 2cO 3or Cs 2cO 3under existence, in DMF, DMA, THF or ethanol, with alkyl or benzyl chloride compound, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (XXVI) and (XVIII) mixture of compound.Those skilled in the art will recognize that, the mixture of formula (XXVI) and (XVIII) compound can carry out separated with chromatogram or crystallization technique.Can be by the method for the common employing known to those skilled in the art, except the protecting group on denitrification.More specifically, can be at solvent CH for example 2cl 2, in ethanol or methyl alcohol, with acid, as trifluoroacetic acid or hydrochloric acid etc., from formula (XXVI) with (XVIII), compound, removes for example t-butyl carbamate of group, to form respectively formula (XXVII) and (XIX) compound.Can with method known to those skilled in the art by formula (XXVII), (XIX), (II) or (III) compound be converted into their corresponding salt.Generally will recognize that, formula (XXVII) and (XIX) compound represent respectively formula (III) and (II) subgroup of compound, wherein R 1equal H.
Can be with conventional synthetic method for example alkylation or reduction amination, respectively by formula (XIX) and (XXVII) compound prepare compound for example (H) and (III). therefore, in solvent, under reductive agent and catalyzer existence, with the formula that contains carbonyl (X) compound treatment formula (XIX) compound, by production (II) compound, described reductive agent is NaBH for example 4, NaBH 3cN, NaBH (OAc) 3or hydrogen, described solvent is CH for example 2cl 2, DCE, THF, ethanol, methyl alcohol or similar solvent.Those skilled in the art will recognize that, it may be essential adding acid to the pH of reaction mixture is reduced to pH7 following.The example of acid comprises AcOH, Ti (O-iPr) 4, trifluoroacetic acid or hydrochloric acid etc.In addition, can use the alkylating agent of formula (XI) to process compound for example (XIX).For example, at alkali as NaHCO 3, Na 2cO 3, K 2cO 3or Cs 2cO 3under existence, at solvent, for example in DMF, DMA, THF or ethanol, with alkyl chloride, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (II) compound.
Reaction scheme 4
Figure S04833737820060524D000381
Reference reaction scheme 4, as it is described, preparation formula (III) compound.As shown in it; amine moiety in formula (XII) compound can be is aptly for example " blocking group in organic synthesis " third edition (T.W.Greene and P.G.M.Wuts of alkyl or benzyl amine, acid amides, carbamate or other group by substituting group G protection; John Wiley & Sons, 1999) the middle group of describing.Solvent as methyl alcohol, ethanol, Virahol or the trimethyl carbinol in, at 20-80 ℃ of temperature, be with or without for example NaHCO of alkali 3, Na 2cO 3, K 2cO 3, Cs 2cO 3, triethylamine or diisopropylethylamine situation under, by formula (XXVIII) alkyl or aryl hydrazine or its salt and formula (XII) compound condensation, by production XXIX) compound.Preferred solvent is ethanol and the trimethyl carbinol, and preferred alkali is triethylamine and diisopropylethylamine.Formula (XXIX) compound can be converted into the precursor for transition metal-catalyzed cross-coupling reaction, and described cross-coupling reaction is for example Stille, Suzuki, Negishi or other such linked reaction well known by persons skilled in the art.For example, use POCl 3, PCl 3, PCl 5, PBr 3or POBr 3processing can generate corresponding 3-halo pyrazoles.Preferred method is included in alkali as under pyridine, triethylamine or diisopropylethylamine existence, at DCE, CH 2cl 2, in THF etc., with fluoroform sulfonyl agent for example trifluoromethanesulfanhydride anhydride or N-phenyl trifluoromethanesulfonate methylsulfonyl imines process, with the pyrazoles triflate of production (XXX).Under alkali exists, in solvent, under catalyzer exists, with formula (XVII) organoboron compound, process formula (XXX) triflate, by production (XXVI) compound, described alkali is Na for example 2cO 3, K 2cO 3, Cs 2cO 3, K 3pO 4, KF, CsF, KOAc etc., described solvent is for example THF, Isosorbide-5-Nitrae-dioxs, DMA, DMF, DME, toluene, toluene/ethanol or toluene/H 2o mixture, described catalyzer is Pd (PPh for example 3) 4, PdCl 2(PPh 3) 2, PdCl 2(Po-tol 3) 2, PdCl 2or PdCl (dppe) 2(dppf).Preferred catalyzer is to be with or without additive for example dppf and catalytic Bu 4pd (the PPh of NBr 3) 4and PdCl 2(dppf).Preferred solvent comprises THF, Isosorbide-5-Nitrae-dioxs, toluene and toluene/H 2o mixture, preferred alkali is Na 2cO 3, K 2cO 3, Cs 2cO 3and K 3pO 4.Can be by the method for the common employing known to those skilled in the art, remove the protecting group on the nitrogen of formula (XXVI) compound.More specifically, can be at solvent CH for example 2cl 2, in ethanol or methyl alcohol, with such as trifluoroacetic acid or hydrochloric acid etc. of acid, remove for example t-butyl carbamate of group, with production (XXVII) compound.Can use method known to those skilled in the art, by formula (XXVII) or (III) compound be converted into their corresponding salt.Can recognize the subgroup of formula (XXVII) compounds represented formula (III) compound, wherein R 1equal H.
Can use conventional synthetic method for example alkylation or reduction amination, by formula (XXVII) compound, prepare compound for example (III).Therefore,, in solvent, under reductive agent and catalyzer exist, with formula (X) compound treatment formula (XXVII) compound that contains carbonyl, by production (III) compound, described reductive agent is NaBH for example 4, NaBH 3cN, NaBH (OAc) 3or hydrogen, described solvent is CH for example 2cl 2, DCE, THF, ethanol, methyl alcohol or similar solvent.Those skilled in the art will recognize that, it may be essential adding acid to the pH of reaction mixture is reduced to pH7 following.The example of acid comprises AcOH, Ti (O-iPr) 4, trifluoroacetic acid or hydrochloric acid etc.In addition, can use the alkylating agent of formula (XI) to process compound for example (XXVII).For example, at alkali as NaHCO 3, Na 2cO 3, K 2cO 3or Cs 2cO 3under existence, at solvent, for example in DMF, DMA, THF or ethanol, with alkyl chloride, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (III) compound.
Reaction scheme 5
Reference reaction scheme 5, in another embodiment, can be by formula (XXXI) ketone preparation formula (II) compound.According to shown in scheme 3 for formula (XX) compound being converted into the method for formula (XVIII) compound, formula (XXXI) ketone can be converted into formula (XXXII) pyrazoles.By processing with aqueous acid, can be by formula (XXXII) compound preparation formula (XXXIII) compound.For example, at high temperature in moisture THF, at HCl, process formula (XXXII) compound, by production (XXXIII) compound.By processing with oxyamine, preferably by processing with the oxyamine in pyridine, formula (XXXIII) ketone can be converted into formula (XXXIV) oxime.Formula (XXXIV) compound can individual isomer or the form of the mixture of steric isomer exist.With hydride reducer, process formula (XXXIV) oxime, can production (XIX) compound.In preferred embodiments, reductive agent is CH 2cl 2in diisobutylaluminium hydride.Can, by the method for describing in scheme 3, formula (XIX) compound be converted into formula (II) compound.
Reaction scheme 6
Figure S04833737820060524D000401
Reference reaction scheme 6, in another embodiment, also preparation formula (XIX) compound as described in it.As shown in it; amine moiety in formula (XIII) compound can be is aptly alkyl or benzyl amine, acid amides, carbamate or other group " blocking group in organic synthesis " third edition (T.W.Greene and P.G.M.Wuts for example by substituting group G protection; John Wiley & Sons, 1999) the middle group of describing.Preferably, can be by step shown in scheme 6 compound for wherein p=1, m=2 and G=tertiary butyl formamyl.In pyridine or other non-nucleophilicity amine alkali, with fluoroform sulfonyl agent, for example N-phenyl trifluoromethanesulfonate methylsulfonyl imines or trifluoromethanesulfanhydride anhydride are processed formula (XIII) pyrazolone, production (XXXV) pyrazoles triflate.Can use formula (XIV) alkylating agent to process compound for example (XXXV).For example, at alkali as NaHCO 3, Na 2cO 3, NaH, K 2cO 3, Cs 2cO 3or under potassium tert.-butoxide existence, in DMF, DMA, THF or ethanol, with alkyl or benzyl chloride compound, bromide, iodide, methanesulfonates or tosylate (wherein X is Cl, Br, I, OMs, OTs etc.), process, by production (XVI) compound.Preferably, at suitable alkali under for example potassium tert.-butoxide exists, with alkylating agent for example bromotoluene carry out alkylation.Can be according to processing formula described in scheme 2 (XVI) pyrazoles, with production (XIX) and (II) compound.
The compounds of this invention is serotonin receptor modulator, and therefore, the compounds of this invention is used for the treatment of the disease being mediated by thrombotonin.Particularly, the compounds of this invention can be used for the treatment of or prevent CNS disease, for example stress be with other after somnopathy, depressive and/or anxiety, generalized anxiety disorder, schizophrenia, two-phase sexual dysfunction, psychotic disease mental disorder, obsession, mood disorder, wound with obstacle that stress be relevant, migraine, pain, eating disorder, obesity, sexual dysfunction, metabolic disturbance, hormone imbalances, alcohol abuse, addictive disorders, feel sick, hypertension, sleep/Arousal disorders, jet lag (jetlag) and the diel rhythm of inflammation, nervus centralis impact be abnormal.The compounds of this invention also can be used for the treatment of with prevention ypotension, peripheral blood vessel obstacle, cardiovascular shock (cardiovascular shock), ephrosis, gastric motility disorder, diarrhoea, spastic colon, easily swash property enteropathy, ischemic, septic shock, the urinary incontinence and the Other diseases relevant with stomach and vascular system.In addition, the compounds of this invention can be used for the treatment of and prevent various illness in eye to comprise glaucoma, optic neuritis, diabetic retinopathy, retinal edema and age-related macular degeneration.
The compounds of this invention is 5-HT 7conditioning agent and be much 5-HT 7antagonist.Therefore, the compounds of this invention can be used for treatment by 5-HT 7the disease of mediation.At the compounds of this invention, there is significant 5-HT 7in the situation of antagonistic activity, they can be used in particular for treatment or prevention depressive and/or anxiety, sleep/Arousal disorders, jet lag (jetlag), migraine, the urinary incontinence, gastric motility disorder and Yi Ji enteropathy.
Chemical compound lot of the present invention is 5-HT 2conditioning agent and be much 5-HT 2antagonist.Therefore, the compounds of this invention is used for the treatment of by 5-HT 2disease and the illness of mediation.At the compounds of this invention, there is significant 5-HT 2in the situation of antagonistic activity, they can be used in particular for after treatment or prevention depressive and/or anxiety, generalized anxiety disorder, schizophrenia, bipolar disorder, psychotic disease mental disorder, obsession, mood disorder, wound stress with other and obstacle, somnopathy, sexual dysfunction, eating disorder, migraine, addictive disorders and peripheral blood vessel illness that stress be relevant.
Can expect, the administration of the compounds of this invention can be via oral or parenteral route, comprises intravenously, intramuscular, intraperitoneal, subcutaneous, rectum and topical and suction.For oral administration, the compounds of this invention is provided by tablet or capsule or provide as the form of the aqueous solution or suspension conventionally.Tablet for oral use can comprise the pharmaceutically acceptable excipient promoting agent that for example inert diluent, disintegrating agent, tackiness agent, slipping agent, sweeting agent, seasonings, tinting material and sanitas mix.Suitable inert diluent comprises sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate and lactose.W-Gum and alginic acid are suitable disintegrating agents.Bonding agent can comprise starch and gel.Slipping agent (if existence) is Magnesium Stearate, stearic acid or talcum powder normally.If needed, can be by material for example stearin or distearin dressing for tablet, to postpone the absorption in intestines and stomach.Capsule for oral use comprises hard capsule, and wherein active ingredient is mixed with solid diluent, and soft capsule, wherein for example peanut oil, whiteruss or sweet oil of active ingredient and water or oil.For intramuscular, intraperitoneal, subcutaneous and intravenously, use, the compounds of this invention is conventionally to be buffered to the aseptic aqueous solution of suitable pH and isotonicity or the form of suspension provides.Suitable water is cut out body and is comprised Ringer ' s solution and isotonic sodium chlorrde solution.Aqeous suspension of the present invention can comprise for example derivatived cellulose, sodiun alginate, polyvinylpyrrolidone and tragakanta and wetting agent Yelkin TTS for example of suspension agent.Suitable sanitas for aqeous suspension comprises ethyl p-hydroxybenzoate and n-propyl.
The effective dose of the compounds of this invention can be determined by ordinary method.The needed concrete dosage level of particular patient will depend on a number of factors, and comprise the seriousness, route of administration and the patient's that are treated disease body weight.Yet, can expect, per daily dose (with single dose or decile dosed administration) is generally 0.01-1000mg every day, is more typically 1-500mg every day, and is generally 10-200mg every day most.Be expressed as dosage/per weight, typical dosage is expected to be 0.0001mg/kg-15mg/kg, 0.01mg/kg-7mg/kg especially, and 0.15mg/kg-2.5mg/kg the most particularly.
Embodiment
The present invention for the purpose of illustration, comprises the following example.These embodiment are not restriction the present invention.They are only that method of the present invention is implemented in intention suggestion. those skilled in the art can find that other implement method of the present invention, and described method is apparent for them.Yet those methods are considered to belong to the scope of the invention with interior.
About preparing the scheme of reversed-phase HPLC
Figure S04833737820060524D000421
Post: YMC-Pack ODS-A, 5 μ m, 75 * 30mm
Flow velocity: 25mL/min
Detect: λ=220 & 254nm
Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)
1) 0.0min 15% acetonitrile/85% water
2) 20.0min 99% acetonitrile/1% water
The scheme of HPLC (anti-phase)
Method A:
Hewlett Packard Series 1100
Post: Agilent ZORBAX
Figure S04833737820060524D000431
bonus RP, 5 μ m, 4.6 * 250mm
Flow velocity: 1m/min
Detect :=220 & 254nm
Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)
1) 0.0min 1% acetonitrile/99% water
2) 20.0min 99% acetonitrile/1% water
Method B:Hewlett Packard HPLC
Post: Agilent ZORBAX eclipse XDB-C8,5 μ m, 4.6 * 150mm
Flow velocity: 1m/min
Detect: λ=220 & 254nm
Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)
1) 0.0min 1% acetonitrile/99% water
2) 8.0min 99% acetonitrile/1% water
3) 12.0min 99% acetonitrile/1% water
The scheme of preparation SFC
Thar Technologies
Figure S04833737820060524D000433
Post: Chiracel AD, 10 μ m, 250 * 20mm
Flow velocity: 37gm/min
Detect: λ=220 & 254nm
Moving phase: 30%IPA/70%CO such as degree of grade 2
Pressure: 150 bar
Temperature: 35 ℃
Analyze the scheme of SFC
Jasco
Figure S04833737820060524D000434
Post: Chiracel AD, 10 μ m, 250 * 4.6mm
Flow velocity: 1gm/min
Detect: λ=220 & 254nm
Moving phase: 30%IPA/70%CO such as degree of grade 2
Pressure: 150 bar
Temperature: 35 ℃
Mass spectrum is on Agilent series 1100 MSD, uses electro-spray ionization (ESI) to obtain in plus or minus mode (as noted).
Use Merck silica gel 60 F 2542.5cm * 7.5cm 250 μ m or 5.0cm * 10.0cm250 μ m precoating silica-gel plate, carry out thin-layer chromatography.With EMScience silica gel 60 F with 20cm * 4cm enrichment region 25420cm * 20cm 0.5mm precoating plate, is prepared thin-layer chromatography.
On Bruker model DPX400 (400MHz), DPX500 (500MHz) or DPX600 (600MHz) spectrometer, obtain NMR spectrum.Below 1the form of H NMR data is: the chemical shift representing with ppm (multiplicity, the coupling constant J, the integration that represent with Hz) that tetramethylsilane reference substance is low.
Embodiment 1
1-benzyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also.
steps A .1-benzyl-3-(4-nitro-phenyl)-Isosorbide-5-Nitrae, 6,7-tetrahydrochysene-pyrrolo-[3,2-c] pyridine-5-t-butyl formate.in solution to the 4-oxo-piperidines-1-t-butyl formate (0.69g) stirring in toluene (5mL), add 378 μ L benzylamines.Mixture is stirred 10 minutes, then add 0.70g silica gel (SiO 2).In stirring at room, after 8 hours, add the solution of 0.77g 1-nitro-4-(2-nitro-vinyl)-benzene in toluene (5mL), and by mixture stirring at room 14 hours.Then mixture is passed through to diatomite filtration, and concentrated in a vacuum.At SiO 2upper chromatogram purification (8 to 20%EtOAc/ hexane), obtains the needed compound of 0.48g.MS (ESI): C 25h 27n 3o 4accurate calculation quality, 433.20; Measured value, m/z 434.2[M+H] +, 456.2[M+Na] +.
step B.to the 0.20g above-claimed cpd stirring at CH 2cl 2in solution in 10: 1 mixtures of/MeOH (6mL), add 1.9mL 1.0M HCl at Et 2solution in O.In stirring at room, after 12 hours, form white solid, by filtration, collect, obtain this title compound of 0.11g.MS (ESI): C 20h 19n 3o 2accurate calculation quality, 333.15; Measured value, m/z 334.2[M+H] +.
1H NMR(500MHz，CD 3OD)：8.26-8.21(m，2H)，7.59-7.55(m，2H)，7.42(s，1H)，7.36(t，J＝7.4Hz，2H)，7.30(t，J＝7.4Hz，1Hz)，7.20(d，J＝7.4Hz，2H)，5.19(s，2H)，4.44(s，2H)，3.53(t，J＝6.3Hz，2H)，2.89(t，J＝6.3Hz，2H).
According to the method Preparation Example 2-25 described in embodiment 1, relevant change as described in.
Embodiment 2
Figure S04833737820060524D000451
1-benzyl-3-(the fluoro-phenyl of the chloro-4-of 3-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.54g 4-oxo-piperidines-1-t-butyl formate, 293 μ L benzylamines and the fluoro-4-of the chloro-1-of 0.62g 2-(2-nitro-vinyl)-benzene, prepare this title compound (0.18g).MS (ESI): C 20h 18clFN 2accurate calculation quality, 340.11; Measured value, m/z 341.1[M+H] +, 343.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.43(m，1H)，7.36-7.16(m，8H)，5.15(s，2H)，4.35(s，2H)，3.50(t，J＝6.3Hz，2H)，2.85(t，J＝6.3Hz，2H).
Embodiment 3
Figure S04833737820060524D000452
4-(1-benzyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridin-3-yl also)-phenol
By 1.22g 4-oxo-piperidines-1-t-butyl formate, 856 μ L benzylamines with add 1.29g 4-(2-nitro-vinyl)-phenol in EtOH (12mL), prepare this title compound.MS (ESI): C 20h 20n 2the accurate calculation quality of O, 304.16; Measured value, m/z 305.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.35-7.32(m，2H)，7.29-7.25(m，2H)，7.17-7.14(m，4H)，6.98(s，1H)，6.80-6.77(m，2H)，5.12(s，2H)，4.31(s，2H)，3.49(t，J＝6.3Hz，2H)，2.85(t，J＝6.3Hz，2H).
Embodiment 4
Figure S04833737820060524D000461
1-benzyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2c] pyridine also
Use CH 2cl 2as solvent, by 0.50g 4-oxo-piperidines-1 t-butyl formate, 274 μ L benzylamines and 0.59g 1-trifluoromethoxy-4-(2-nitro-vinyl)-benzene, prepare this title compound (0.28g) .MS (ESI): C 21h 19f 3n 2the accurate calculation quality of O: 372.14; Measured value, m/z373.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.44-7.41(m，2H)，7.37-7.26(m，5H)，7.19-7.17(m，3H)，5.15(s，2H)，4.37(s，2H)，3.51(t，J＝6.3Hz，2H)，2.87(t，J＝6.3Hz，2H).
Embodiment 5
1-benzyl-3-(the chloro-thiophene-2-of 5-yl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2c] pyridine also
By 0.56g 4-oxo-piperidines-1 t-butyl formate, 300 μ L benzylamines and the chloro-5-of 0.53g 2-(2-nitro-vinyl)-thiophene, prepare this title compound (82.3mg).MS (ESI): C 18h 17clN 2the accurate calculation quality of S, 328.08; Measured value, m/z 329.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.33(m，2H)，7.30-7.27(m，1H)，7.17-7.15(m，2H)，7.12(s，1H)，6.89(d，J＝3.8Hz，1H)，6.73(d，J＝3.8Hz，1H)，5.12(s，2H)，4.31(s，2H)，3.48(t，J＝6.3Hz，2H)，2.84(t，J＝6.3Hz，2H).
Embodiment 6
Figure S04833737820060524D000471
1-benzyl-3-thiophene-2-base-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.53g 4-oxo-piperidines-1-t-butyl formate, 300 μ L benzylamines and 0.41g 2-(2-nitro-vinyl)-thiophene, prepare this title compound (136.8mg).MS (ESI): C 18h 18n 2the accurate calculation quality of S, 294.12; Measured value, m/z 295.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.32(m，2H)，7.30-7.26(m，1H)，7.22(dd，J＝5.2，1.1Hz，1H)，7.18-7.15(m，2H)，7.12(s，1H)，7.02(dd，J＝5.2，3.6Hz，1H)，6.94(dd，J＝3.6，1.1Hz，1H)，5.13(s，2H)，4.34(s，2H)，3.49(t，J＝6.3Hz，2H)，2.85(t，J＝6.3Hz，2H).
Embodiment 7
1-(the chloro-benzyl of 3-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
Do not add SiO 2, by 0.55g 4-oxo-piperidines-1 t-butyl formate, 334 μ L 3-chlorobenzylamines and 0.40g (2-nitro-vinyl)-benzene, prepare this title compound (159.0mg).MS (ESI): C 20h 19clN 2accurate calculation quality: 322.12; Measured value, m/z 323.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.32(m，5H)，7.31-7.28(m，1H)，7.23-7.19(m，1H)，7.17-7.16(m，1H)，7.13(s，1H)，7.12-7.10(m，1H)，5.16(s，2H)，4.37(s，2H)，3.52(t，J＝6.3Hz，2H)，2.86(t，J＝6.3Hz，2H).
Embodiment 8
Figure S04833737820060524D000481
1-benzyl-3-(the fluoro-phenyl of 3-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
Do not add SiO 2, with EtOH, as solvent, by 0.61g 4-oxo-piperidines-1-t-butyl formate, 330 μ L benzylamines and 0.50g (2-nitro-vinyl)-3-fluorobenzene, prepare this title compound (282.6mg): C 20h 19fN 2accurate calculation quality, 306.15; Measured value, m/z 307.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.32(m，3H)，7.30-7.26(m，1H)，7.20-7.14(m，4H)，7.10-7.06(m，1H)，6.95-6.90(m，1H)，5.15(s，2H)，4.36(s，2H)，3.50(t，J＝6.3Hz，2H)，2.86(t，J＝6.3Hz，2H).
Embodiment 9
Figure S04833737820060524D000482
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2c] pyridine also
With what pulverize molecular sieve replaces SiO 2, by 0.49g 4-oxo-piperidines-1 t-butyl formate, 286 μ L 2-flunamines and 0.46g (2-nitro-vinyl)-4-chlorobenzene, prepare this title compound (129.2mg): C 20h 18clFN 2accurate calculation quality, 340.11; Measured value, m/z 341.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.30(m，5H)，7.18-7.12(m，3H)，7.10-7.06(m，1H)，5.20(s，2H)，4.35-4.34(m，2H)，3.54(t，J＝6.3Hz，2H)，2.94(t，J＝6.3Hz，2H).
Embodiment 10
Figure S04833737820060524D000491
1-(the chloro-benzyl of 3-)-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
With what pulverize
Figure S04833737820060524D000492
molecular sieve replaces SiO 2, by 0.55g 4-oxo-piperidines-1-t-butyl formate, 340 μ L 3-chlorobenzylamines and 0.51g (2-nitro-vinyl)-4-chlorobenzene, prepare this title compound (212.8mg).MS (ESI): C 20h 18cl 2n 2accurate calculation quality, 356.08; Measured value, m/z 357.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.28(m，6H)，7.18-7.15(m，2H)，7.12-7.09(m，1H)，5.16(s，2H)，4.36(s，2H)，3.52(t，J＝6.3Hz，2H)，2.86(t，J＝6.3Hz，2H).
Embodiment 11
Figure S04833737820060524D000493
1-(the chloro-benzyl of 2-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.55g 4-oxo-piperidines-1 t-butyl formate, 334 μ L 2-chlorobenzylamines, 0.40g (2 nitros-vinyl)-benzo and there is no SiO 2, prepare this title compound (113.8mg).MS (ESI): C 20h 19clN 2accurate calculation quality, 322.12; Measured value, m/z 323.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.46(m，1H)，7.37-7.26(m，6H)，7.22-7.19(m，1H)，7.07(s，1H)，6.85-6.82(m，1H)，5.25(s，2H)，4.39(s，2H)，3.54(t，J＝6.3Hz，2H)，2.88(t，J＝6.3Hz，2H).
Embodiment 12
Figure S04833737820060524D000494
1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2c] pyridine also
By 0.55g 4-oxo-piperidines-1 t-butyl formate, 340 μ L 4-chlorobenzylamines and 0.51g (2-nitro-vinyl)-4-chlorobenzene, prepare this title compound (260.2mg).MS (ESI): C 20h 18cl 2n 2accurate calculation quality, 356.08; Measured value, m/z 357.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.31(m，6H)，7.17-7.13(m，3H)，5.15(s，2H)，4.35(s，2H)，3.51(t，J＝6.3Hz，2H)，2.85(t，J＝6.3Hz，2H).
Embodiment 13
Figure S04833737820060524D000501
1-benzyl-3-(the chloro-phenyl of 2,4-bis-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 5: 1 EtOH/ toluene mixture, as solvent, by 0.52g 4-oxo-piperidines-1-t-butyl formate, 280 μ L benzylamines and 0.57g 2, the chloro-1-of 4-bis-(2-nitro-vinyl)-benzene, prepared this title compound (454.6mg).MS (ESI): C 20h 18cl 2n 2accurate calculation quality, 356.08; Measured value, m/z 357.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.53(d，J＝2.2Hz，1H)，7.36-7.32(m，3H)，7.30-7.28(m，2H)，7.20-7.17(m，2H)，7.04(s，1H)，5.16(s，2H)，4.13(s，2H)，3.50(t，J＝6.3Hz，2H)，2.88(t，J＝6.3Hz，2H).
Embodiment 14
Figure S04833737820060524D000502
1-(4-methoxyl group-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
With EtOH as solvent and omit SiO 2, by 1.51g 4-oxo-piperidines-1 t-butyl formate, 1.0mL 4-methoxybenzylamine and 1.13g (2-nitro-vinyl)-benzene, prepare this title compound (0.19g).MS (ESI): C 21h 22n 2the accurate calculation quality of O, 318.17; Measured value, m/z319.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.30(m，4H)，7.20-7.15(m，1H)，7.14-7.11(m，2H)，7.08(s，1H)，6.90-6.87(m，2H)，5.05(s，2H)，4.34(s，2H)，3.50(t，J＝6.3Hz，2H)，2.88(t，J＝6.3Hz，2H).
Embodiment 15
Figure S04833737820060524D000511
1-(the chloro-benzyl of 2-)-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
With what pulverize
Figure S04833737820060524D000512
molecular sieve replaces SiO 2, by 0.50g 4-oxo-piperidines-1-t-butyl formate, 304 μ L 2-chlorobenzylamines and 0.46g (2-nitro-vinyl)-4-chlorobenzene, prepare this title compound (149.9mg).MS (ESI): C 20h 18cl 2n 2accurate calculation quality, 356.08; Measured value, m/z 357.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.58-7.56(m，1H)，7.47-7.45(m，1H)，7.37-7.26(m，5H)，7.10(s，1H)，6.85-6.82(m，1H)，5.25(s，2H)，4.38(s，2H)，3.53(t，J＝6.3Hz，2H)，2.88(t，J＝6.3Hz，2H).
Embodiment 16
Figure S04833737820060524D000513
1-(the chloro-benzyl of 2,4-bis-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
With EtOH, as solvent, by 0.55g 4-oxo-piperidines-1 t-butyl formate, 370 μ L 2,4-dichloro-benzylamine and 0.41g (2-nitro-vinyl)-benzene, prepares this title compound (0.43g).MS (ESI): C 20h 18cl 2n 2accurate calculation quality, 356.08; Measured value, m/z357.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.55-7.50(m，2H)，7.37-7.29(m，4H)，7.22-7.18(m，1H)，7.07(s，1H)，6.77(d，J＝8.5Hz，1H)，5.23(s，2H)，4.38(s，2H)，3.54(t，J＝6.3Hz，2H)，2.86(t，J＝6.3Hz，2H).
Embodiment 17
Figure S04833737820060524D000521
1-benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.51g 4-oxo-piperidines-1-t-butyl formate, 272 μ L benzylamines and 0.41g (2-nitro-propenyl)-benzene, prepare this title compound (89.4mg).MS (ESI): C 21h 22n 2accurate calculation quality, 302.18; Measured value, m/z 303.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.41-7.36(m，2H)，7.35-7.30(m，2H)，7.28-7.21(m，4H)，7.05-7.01(m，2H)，5.16(s，2H)，4.18(s，2H)，3.52(t，J＝6.3Hz，2H)，2.89(t，J＝6.3Hz，2H).
Embodiment 18
Figure S04833737820060524D000522
1-benzyl-3-p-methylphenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.51g 4-oxo-piperidines-1-t-butyl formate, 272 μ L benzylamines and 0.41g 1-methyl-4-(2-nitro-vinyl)-benzene, prepare this title compound (89.7mg) .MS (ESI): C 21h 22n 2accurate calculation quality, 302.18; Measured value, m/z 303.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.35-7.31(m，2H)，7.29-7.25(m，1H)，7.23-7.20(m，2H)，7.18-7.14(m，4H)，7.06(s，1H)，5.13(s，2H)，4.33(s，2H)，3.49(t，J＝6.3Hz，2H)，2.86(t，J＝6.3Hz，2H).
Embodiment 19
1-benzyl-3-(the chloro-phenyl of 3,4-bis-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.49g 4-oxo-piperidines-1 t-butyl formate, 268 μ L benzylamines and 0.55g 1, the chloro-4-of 2-bis-(2-nitro-vinyl)-benzene, prepares this title compound (228.2mg).MS (ESI): C 20h 18cl 2n 2accurate calculation quality, 356.08; Measured value, m/z 357.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.51-7.47(m，2H)，7.36-7.32(m，2H)，7.32-7.25(m，2H)，7.22(s，1H)，7.19-7.15(m，2H)，5.15(s，2H)，4.35(s，2H)，3.50(t，J＝6.3Hz，2H)，2.85(t，J＝ 6.3Hz，2H).
Embodiment 20
Figure S04833737820060524D000532
3-benzo [1,3] dioxole-5-base-1-benzyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.49g 4-oxo-piperidines-1 t-butyl formate, 268 μ L benzylamines and 0.48g 5-(2-nitro-vinyl)-benzo [1,3] dioxole, prepare this title compound (306.0mg).MS (ESI): C 21h 20n 2o 2, 332.15; Measured value, m/z333.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.36-7.30(m，2H)，7.29-7.24(m，1H)，7.18-7.14(m，2H)，7.01(s，1H)，6.85-6.75(m，3H)，5.93(s，2H)，5.12(s，2H)，4.31(s，2H)，3.49(t，J＝6.3Hz，2H)，2.85(t，J＝6.3Hz，2H).
Embodiment 21
1-benzyl-3-(the fluoro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 1.31g 4-oxo-piperidines-1 t-butyl formate, 700 μ L benzylamines and the fluoro-4-of 1.10g 1-(2-nitro-vinyl)-benzene, prepare this title compound (706.2mg).MS (ESI): C 20h 19fN 2accurate calculation quality, 306.15; Measured value, m/z 307.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.25(m，5H)，7.18-7.15(m，2H)，7.11-7.05(m，3H)，5.13(s，2H)，4.33(s，2H)，3.50(t，J＝6.3Hz，2H)，2.86(t，J＝6.3Hz，2H).
Embodiment 22
Figure S04833737820060524D000542
1-butyl-3-p-methylphenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.56g 4-oxo-piperidines-1-t-butyl formate, 260 μ L butylamines and 0.45g 1-methyl-4-(2-nitro-vinyl)-benzene, prepare this title compound (292.8mg).MS (ESI): C 18h 24n 2, 268.19; Measured value, m/z 269.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.20-7.14(m，4H)，6.93(s，1H)，4.32(s，2H)，3.88(t，J＝7.1Hz，2H)，3.56(t，J＝6.0Hz，2H)，3.00(t，J＝6.0Hz，2H)，2.32(s，3H)，1.77-1.70(m，2H)，1.41-1.33(m，2H)，0.97(t，J＝7.4Hz，3H).
Embodiment 23
1-benzyl-3-(the bromo-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
By 0.66g 4-oxo-piperidines-1-t-butyl formate, 300 μ L benzylamines and the bromo-4-of 0.63g 1-(2-nitro-vinyl)-benzene, prepare this title compound (0.38g).MS (ESI): C 20h 19brN 2accurate calculation quality, 366.07; Measured value, m/z 367.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.51-7.48(m，2H)，7.36-7.32(m，2H)，7.30-7.25(m，3H)，7.19-7.16(m，2H)，5.14(s，2H)，4.35(s，2H)，3.50(t，J＝6.3Hz，2H)，2.87(t，J＝6.3Hz，2H).
Embodiment 24
Figure S04833737820060524D000551
1-benzyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
With acetonitrile, as solvent, by 0.50g 4-oxo-piperidines-1-t-butyl formate, 274 μ L benzylamines and 0.55g 1-trifluoromethyl-4-(2-nitro-vinyl)-benzene, prepare this title compound (0.23g).MS (ESI): C 21h 19f 3n 2accurate calculation quality, 356.16; M/z measured value, 357.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.65-7.63(m，2H)，7.54-7.52(m，2H)，7.36-7.27(m，4H)，7.20-7.18(m，2H)，5.17(s，2H)，4.40(s，2H)，3.52(t，J＝6.3Hz，2H)，2.88(t，J＝6.3Hz，2H).
Embodiment 25
1-benzyl-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
With 1: 1 mixture of EtOH/ toluene, as solvent, by 1.55g 4-oxo-piperidines-1-t-butyl formate, 850 μ L benzylamines and the chloro-4-of 1.43g 1-(2-nitro-vinyl)-benzene, prepare this title compound (1.19g).MS (ESI): C 20h 20cl 2n 2accurate calculation quality, 322.12; M/z measured value, 323.2[M+H] +, 325.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.37-7.26(m，7H)，7.18-7.16(m，3H)，5.15(s，2H)，4.35(s，2H)，3.50(t，J＝6.3Hz，2H)，2.87(t，J＝6.3Hz，2H).
Embodiment 26
Figure S04833737820060524D000561
1-benzyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-pyrrolo-[2,3-d] azepine
Figure S04833737820060524D000562
Steps A .1-benzyl-3-phenyl-4,5,7,8-tetrahydro-1 H-pyrrolo is [2,3-d] azepine also
Figure S04833737820060524D000563
-6-t-butyl formate.Compound (0.53g) prepared by embodiment 59 step B and the 272 μ L benzylamines solution in benzene (10mL) is used Dean Rodney Stark instrument reflux 24 hours.Except desolventizing, roughage is dissolved in to toluene (10mL), and adds 0.38g (2-nitro-vinyl)-benzene.Mixture is stirring at room 24 hours, then concentrated in a vacuum.At SiO 2upper chromatogram purification (1 to 20%EtOAc/ hexane), obtains the needed compound of 108.0mg.MS (ESI): C 26h 30n 2o 2accurate calculation quality, 402.53; Measured value, m/z 403.2[M+H] +.
step B.the compound of preparing to the steps A stirring (108.0mg) is at CH 2cl 2(5mL) in the solution in, add TFA (1mL).Mixture is stirring at room 12 hours, then concentrated in a vacuum.By resistates at CH 2cl 2(10mL) and between 1M NaOH (10mL) distribute.Layer is separated, and by water layer CH 2cl 2(2 * 10mL) extraction.The organic phase merging is concentrated.At SiO 2upper chromatogram purification (5% 2M NH in MeOH 3/ CH 2cl 2), obtain this title compound of 66.5mg.MS (ESI): C 21h 22n 2calculating accurate mass, 302.41; Measured value, m/z 303.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.42-7.22(m，8H)，7.08(m，2H)，6.67(s，1H)，5.08(s，2H)，3.06-2.91(m，4H)，2.90-2.82(m，2H)，2.77-2.68(m，2H)，2.25(br s，1H).
Embodiment 27
Figure S04833737820060524D000564
1-benzyl-3-(5-methyl-thiophene-2-yl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
steps A .1-benzyl-3-(5-methyl-thiophene-2-yl)-Isosorbide-5-Nitrae, 6,7-tetrahydrochysene-pyrrolo-[3,2-c] pyridine-5-t-butyl formate.by 4-oxo-piperidines-1-t-butyl formate (0.54g) and 300 μ L benzylamines, the mixture in toluene (10mL) is used Dean Rodney Stark instrument reflux 6 hours.Solution is cooled to room temperature, then adds 0.47g 2-methyl-5-(2-nitro-vinyl)-thiophene.Mixture is stirring at room 16 hours, then concentrated under vacuum.By resistates at SiO 2upper chromatogram purification (1 to 30%EtOAc/ hexane), obtains this title compound of 281.9mg.TLC (SiO 2, 33%EtOAc/ hexane): R f=0.54.
step B.(1M is at Et in the solution of the compound of preparing to steps A (281.9mg) in EtOH (10mL), to add HCl 2solution in O, 5mL).Gained mixture is stirring at room 24 hours, then concentrated in a vacuum.Then by resistates at CH 2cl 2(10mL) and between 1M NaOH (10mL) distribute.Layer is separated, and by water layer CH 2cl 2(2 * 10mL) extraction.The organic layer merging is concentrated.At SiO 2upper chromatogram purification (CH 2cl 2to 5%2M NH 3solution/CH in MeOH 2cl 2), obtain this title compound of 59.0mg.MS (ESI): C 19h 20n 2the accurate calculation quality of S, 308.13; Measured value, m/z 309.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.35-7.25(m，3H)，7.09-7.06(m，2H)，6.76(s，1H)，6.65-6.62(m，2H)，4.96(s，2H)，4.03(s，2H)，3.14(t，J＝5.8Hz，2H)，2.50(t，J＝5.8Hz，2H)，2.45(s，3H).
Embodiment 28
Figure S04833737820060524D000571
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-pyrrolo-[2,3-d] azepine
Figure S04833737820060524D000572
Steps A .1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydro-1 H-pyrrolo is [2,3-d] azepine also -6-t-butyl formate.The same with embodiment 1 steps A, the compound (0.56g) of being prepared by embodiment 59 step B, 280 μ L benzylamines and the chloro-4-of 0.49g 1-(2-nitro-vinyl)-benzene are prepared needed compound (54.2mg).MS (ESI): C 26h 29clN 2o 2accurate calculation quality, 436.19; Measured value, m/z 437.2[M+H] +.
step B.the same with embodiment 27 step B, compound (54.2mg) is converted into this title compound (19.2mg) above.MS (ESI): C 21h 21clN 2accurate calculation quality, 336.14; Measured value, m/z 337.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.34-7.24(m，7H)，7.04(d，J＝7.1Hz，2H)，6.62(s，1H)，5.05(s，2H)，3.03-3.00(m，2H)，2.97-2.94(m，2H)，2.83-2.80(m，2H)，2.74-2.71(m，2H).
Embodiment 29
Figure S04833737820060524D000581
1-benzyl-3-(the chloro-thiophene-2-of 5-yl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-pyrrolo-[2,3-d] azepine
Figure S04833737820060524D000582
Steps A .1-benzyl-3-(the chloro-thiophene-2-of 5-yl)-4,5,7,8-tetrahydro-1 H-pyrrolo is [2,3-d] azepine also -6-t-butyl formate.The same with embodiment 1 steps A, the compound (0.55g) of being prepared by embodiment 59 step B, 280 μ L benzylamines and the chloro-5-of 0.49g 2-(2-nitro-vinyl)-thiophene are prepared needed compound (124.5mg).MS (ESI): C 24h 27clN 2o 2the accurate calculation quality of S, 442.15; Measured value, m/z 443.2[M+H] +.
step B.as embodiment 27 step B, compound (124.5mg) is converted into this title compound (30.7mg) above.MS (ESI): C 19h 19clN 2the accurate calculation quality of S, 342.10; Measured value, m/z 343.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.35-7.31(m，2H)，7.29-7.25(m，1H)，7.04-7.00(m，2H)，6.82(d，J＝3.8Hz，1H)，6.66(s，1H)，6.64(d，J＝3.8Hz，1H)，5.02(s，2H)，3.06-3.03(m，2H)，2.97-2.93(m，2H)，2.88-2.84(m，2H)，2.72-2.68(m，2H).
Embodiment 30
Figure S04833737820060524D000584
1-(the chloro-benzyl of 4-)-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
steps A .1-(4-hydrogen-benzyl)-3-phenyl-Isosorbide-5-Nitrae, 6,7-tetrahydrochysene-pyrrolo-[3,2-cl pyridine-5-t-butyl formate.the same with embodiment 1 steps A, by 0.53g 4-oxo-piperidines-1-t-butyl formate, 334 μ L2-chlorobenzylamines and 0.34g (2-nitro-vinyl)-benzene, prepare the needed compound of 405.6mg.MS (ESI): C 25h 27clN 2o 2accurate calculation quality, 422.18; Measured value, m/z 423.2[M+H] +.
step B.the same with embodiment 27 step B, with MeOH, as solvent, compound (405.6mg) is converted into this title compound (206.7mg) above.Then needed product is processed with the oxysuccinic acid (75.0mg) in EtOAc, obtained corresponding maleate.MS (ESI): C 20h 19clN 2accurate calculation quality, 322.12; Measured value, m/z 323.2[M+H] +.
1H NMR(500 MHz，CD 3OD)：7.37-7.32(m，6H)，7.22-7.18(m，1H)，7.16-7.13(m，2H)，7.12(s，1H)，6.24(s，2H)，5.14(s，2H)，4.35(s，2H)，3.51(t，J＝6.3Hz，2H)，2.84(t，J＝6.3 Hz，2H).
Embodiment 31
1-benzyl-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
steps A .1-benzyl-3-phenyl-Isosorbide-5-Nitrae, 6,7-hydrogen-pyrrolo-[3,2-c] pyridine-5-formic acid tertiary butyl ester.the same with embodiment 1 steps A, by 0.51g 4-oxo-piperidines-1-t-butyl formate, 280 μ L benzylamines and 0.39g (2-nitro-vinyl)-benzene, prepare needed compound (380.7mg).MS (ESI): C 25h 28n 2o 2accurate calculation quality, 388.22; Measured value, m/z 389.2[M+H] +.
step B.the same with embodiment 26 step B, compound (0.37g) is converted into this title compound (234.7mg) above.MS (ESI): C 20h 20n 2accurate calculation quality, 288.16; Measured value, m/z 289.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.27-7.23(m，6H)，7.22-7.17(m，1H)，7.12-7.07(m，1H)，7.03-6.99(m，2H)，6.77(s，1H)，4.93(s，2H)，3.98(s，2H)，3.07(t，J＝5.8Hz，2H)，2.48(t，J＝5.8Hz，2H).
Embodiment 32
1-benzyl-3-(the chloro-phenyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-pyrrolo-[2,3-d] azepine
Figure S04833737820060524D000602
In the solution of the compound (0.51g) of preparing to embodiment 59 step B in toluene (5mL), add 280 μ L benzylamines and 0.8mL Ti (OiPr) 4.By gained mixture stirring at room 3 hours.Then the disposable chloro-3-of 1-(2-nitro-vinyl)-benzene (0.46g) that adds, and continue to stir other 16 hours in room temperature.Compound is poured into water, and passes through diatomite filtration.To extract containing EtOAc for filter liquor (3 * 20mL), and it is concentrated in a vacuum to merge organic phase.At SiO 2upper chromatogram purification (1 to 35%EtOAc/ hexane), obtains 106.7mg 1-benzyl-3-(the chloro-phenyl of 3-)-4,5,7, and 8-tetrahydro-1 H-pyrrolo is [2,3-d] azepine also
Figure S04833737820060524D000603
-6-t-butyl formate.Then the same with embodiment 27 step B, with 10: 1 CH 2cl 2/ MeOH, as solvent, is converted into this title compound (19.1mg) by this compound.MS (ESI): C 21h 21clN 2accurate calculation quality, 336.14; Measured value, m/z 337.2[M+H] +. 1HNMR(500MHz，CDCl 3)：7.36-7.30(m，3H)，7.29-7.25(m，2H)，7.23-7.17(m，2H)，7.05.-7.02(m，2H)，6.64(s，1H)，5.05(s，2H)，3.01-2.98(m，2H)，2.94-2.91(m，2H)，2.82-2.97(m，2H)，2.71-2.68(m，2H).
Embodiment 33
Figure S04833737820060524D000604
1-benzyl-3-(the chloro-phenyl of 3-)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also.
The same with embodiment 9, by 0.50g 4-oxo-piperidines-1-t-butyl formate, 260 μ L benzylamines and the chloro-3-of 0.45g 1-(2-nitro-vinyl)-benzene, prepare this title compound (193.3mg).MS (ESI): C 20h 19clN 2accurate calculation quality, 322.12; Measured value, m/z 323.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.36-7.20(m，6H)，7.14-7.07(m，3H)，6.81(s，1H)，5.01(s，2H)，4.04(s，2H)，3.14(t，J＝5.8Hz，2H)，2.51(t，J＝5.8Hz，2H).
Embodiment 34
1-benzyl-3-(4-methoxyl group-phenyl)-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
steps A .1-benzyl-3-(4-methoxyl group-phenyl)-Isosorbide-5-Nitrae, 6,7-tetrahydrochysene-pyrrolo-[3,2-c] pyridine-5-t-butyl formate.to 0.50g 4-oxo-piperidines-1-t-butyl formate and 260 μ L benzylamines, in the solution in toluene (5mL), add 0.48g MgSO 4with 16.7mg Bu 2snCl 2.After 1 hour, add 0.45g 1-methoxyl group-4-(2-nitro-vinyl)-benzene, and by mixture stirring at room 16 hours.Then by mixture water (80mL) dilution, with EtOAc (3 * 15mL) extraction, will merge organic phase concentrated in a vacuum.At SiO 2upper chromatogram purification (1 to 20%EtOAc/ hexane), obtains the needed compound of 0.38g.MS (ESI): C 26h 30n 2o 3accurate calculation quality, 418.23; Measured value, m/z 419.2[M+H] +.
step B.the same with embodiment 26 step B, compound (0.47g) is converted into this title compound (275.2mg) above.MS (ESI): C 21h 22n 2the accurate calculation quality of O, 318.17; Measured value, m/z 319.2[M+H] +.
1H NMR(400MHz，CDCl 3)：7.35-7.24(m，5H)，7.12-7.08(m，2H)，6.90-6.86(m，2H)，6.74(s，1H)，4.99(s，2H)，4.04(s，2H)，3.81(s，3H)，3.16(t，J＝5.8Hz，2H)，2.53(t，J＝5.8Hz，2H).
Embodiment 35
Figure S04833737820060524D000612
1-benzyl-3-(the chloro-phenyl of 4-)-5-ethyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
To 1-benzyl-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo also [3,2-c] pyridine (embodiment 25; 0.11g) in the solution in 1,2-ethylene dichloride (5mL), add 18 μ L acetic acid, 26 μ L acetaldehyde and 0.10g NaBH (OAc) 3.By mixture stirring at room 15 hours.By mixture CH 2cl 2dilution, and use NaHCO 3saturated aqueous solution washing (2x).To merge organic phase at Na 2sO 4upper dry, filter, and concentrated under vacuum.At SiO 2upper chromatogram purification (1%2M NH 3solution/CH at MeOH 2cl 2), obtain this title compound of 0.02g.This product is dissolved in to Et 2in O, and use Et 2excessive HCl in O processes, and obtains the corresponding HCl salt of 0.02g.MS (ESI): C 22h 23clN 2accurate calculation quality, 350.15; Measured value, m/z 315.2[M+H] +, 353.2[M+H] +. 1HNMR(500MHz，CD 3OD)：7.37-7.27(m，7H)，7.19-7.17(m，3H)，5.17-5.13(m，2H)，4.48-4.37(m，2H)，3.85-3.76(m，2H)，3.45-3.23(m，2H)，3.00-2.84(m，2H)，1.38(t，J＝7.1Hz，3H).
Embodiment 36
Figure S04833737820060524D000621
1-benzyl-3-(the chloro-phenyl of 4-)-5-sec.-propyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
The same with embodiment 35, by 1-benzyl-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo also [3,2-c] pyridine (embodiment 25; 0.10g) He 32 μ L acetone are prepared this title compound (0.1g).MS (ESI): C 23h 25clN 2accurate calculation quality, 364.17; Measured value, m/z365.2[M+H] +, 367.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.27(m，7H)，7.21-7.17(m，3H)，5.15(d，J＝5.2Hz，2H)，4.58-4.54(m，1H)，4.28-4.25(m，1H)，3.78-3.65(m，2H)，3.45-3.35(m，1H)，3.03-2.85(m，2H)，1.42(t，J＝6.6Hz，6H).
Embodiment 37
Figure S04833737820060524D000631
3-[1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 6,7-tetrahydrochysene-pyrrolo-[3,2-c] pyridine-5-yl]-propyl-1-alcohol
To 1-benzyl-3-(the chloro-phenyl of 4-)-4,5,6,7-tetrahydro-1 H-pyrrolo also [3,2-c] pyridine (embodiment 25; 0.51g) in the solution in DMF (14mL), add 1.39g Cs 2cO 3with the bromo-1-propyl alcohol of 142 μ L3-.By mixture at stirring at room 12 hours, then dilute with water.By water layer Et 2o extraction, and will merge organic layer at Na 2sO 4upper dry, filter, and concentrated under vacuum.At SiO 2chromatogram purification (2%2 MNH 3solution/CH in MeOH 2cl 2), obtain this title compound of 0.15g.This product is dissolved in to Et 2o, and use Et 2excessive 1.0M HCl in O processes, and obtains the corresponding HCl salt of 0.16g.MS (ESI): C 23h 25clN 2the accurate calculation quality of O, 380.17; Measured value, m/z 381.2[M+H] +, 383.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.27(m，7H)，7.19-7.17(m，3H)，5.15(s，2H)，4.47(br s，2H)，3.93-3.25(m，6H)，2.94-2.93(m，2H)，2.01-1.96(m，2H).
Embodiment 38
Figure S04833737820060524D000632
1-benzyl-3-(the chloro-phenyl of 4-)-5-methyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
steps A .1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 6,7-tetrahydrochysene-pyrrolo-[3,2-c] pyridine-5-ethyl formate.in solution to the 3.0g 4-oxo-piperidines-1-ethyl formate stirring in benzene (355mL), add 1.91mL benzylamine.Mixture is used to Dean Rodney Stark instrument reflux 24 hours.Except desolventizing, obtain light yellow oil.Part crude product (0.50g) is dissolved in toluene (4mL), adds the chloro-4-of 0.35g 1-(2-nitro-vinyl)-benzene, then add 0.7g molecular sieve.By gained mixture stirring at room 12 hours.Then mixture is passed through to diatomite filtration, and by filtrate NH 4c saturated aqueous solution washing (3x).Merging organic extract at Na 2sO 4upper dry, filter, and vacuum concentration.At SiO 2upper chromatogram purification (8%EtOAc/ hexane), obtains this title compound of 0.25g.TLC (SiO 2, 25%EtOAc/ hexane): R f=0.34.MS (ESI): C 23h 23clN 2o 2accurate calculation quality, 394.14; Measured value, m/z395.2[M+H] +, 397.2[M+H] +, 417.1[M+Na] +.
step B.in the solution of compound above stirring (0.25g) in toluene (20mL), add two (2-methoxy ethoxy) the aluminium sodium (Red-Al, the solution in 1.5M toluene) of 571 μ L hydrogenations.By mixture stirring at room 48 hours, then by adding sodium-potassium tartrate saturated aqueous solution stopped reaction.Organic layer is separated, at Na 2sO 4upper dry, and concentrated in a vacuum, obtain this title compound of 0.16g.TLC(SiO 2，10％MeOH/EtOAc)：R f＝0.14。MS (ESI): C 21h 21clN 2accurate calculation quality, 336.14; Measured value, m/z 337.2[M+H] +, 339.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.31-7.24(m，7H)，7.07-7.06(m，2H)，6.76(s，1H)，4.98(s，2H)，3.56(s，2H)，2.72(t，J＝6.3Hz，2H)，2.60(t，J＝6.3Hz，2H).
Embodiment 39
1-benzyl-3-(the chloro-phenyl of 3-)-5-methyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
The same with embodiment 38, by 3.0g 4-oxo-piperidines-1-ethyl formate, 1.91mL benzylamine and the chloro-3-of 1.2g 1-(2-nitro-vinyl)-benzene, prepare this title compound (0.34g).TLC (SiO 2, 2%NH 3solution/EtOAc in MeOH): R f=0.25.MS (ESI): C 21h 21clN 2accurate calculation quality, 336.14; Measured value, m/z 337.2 [M+H] +, 339.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.32(m，4H)，7.30-7.25(m，2H)，7.21-7.16(m，4H)，5.15(s，2H)，4.41(s，2H)，3.53(t，J＝6.3Hz，2H)，2.98(s，3H)，2.91(t，J＝6.3Hz，2H)，2.82-2.70(m，4H).
Embodiment 40
Figure S04833737820060524D000651
1-benzyl-3-(the fluoro-phenyl of the chloro-4-of 3-)-5-methyl-4,5,6,7-tetrahydrochysene-1H pyrrolo-[3,2-c] pyridine
The same with embodiment 35, by 1-benzyl-3-(the fluoro-phenyl of the chloro-4-of 3-)-4,5,6,7-tetrahydro-1 H-pyrrolo also [3,2-c] pyridine (embodiment 2) and paraformaldehyde is prepared this title compound (0.03g).Then this product is dissolved in to 1/1 EtOAc/CH 2cl 2in, and by 0.03g (0.15mmol) citric acid treatment, obtain the corresponding Citrate trianion of 0.05g.MS (ESI): C 21h 20clFN 2accurate calculation quality, 354.13; Measured value, m/z 355.1[M+H] +, 357.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.22(m，1H)，7.34(t，J＝7.7Hz，2H)，7.30-7.26(m，2H)，7.22(t，J＝9.1Hz，1H)，7.19-7.13(m，3H)，5.14(s，2H)，4.36(s，2H)，3.50(t，J＝5.8Hz，2H)，2.96(s，3H)，2.89(t，J＝5.8，2H)，2.82-2.71(m，4H).
Embodiment 41
Figure S04833737820060524D000652
1,5-dibenzyl-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
In solution to the 0.46mL 1-benzyl-piperidin-4-one-stirring in anhydrous EtOH (5mL), add 0.27mL benzylamine.After 3 hours, in vacuum, remove desolventizing.By anhydrous EtOH (5mL) dilution for resistates, and once add 0.37g (2-nitro-vinyl)-benzene.By mixture stirring at room 16 hours, by diatomite filtration, and concentrated.At SiO 2upper chromatogram purification (1 to 20%EtOAc/ hexane), obtains this title compound of 0.48g.MS (ESI): C 27h 26n 2accurate calculation quality, 378.21; Measured value, m/z 379.2 [M+H] +.
1H NMR(500MHz，CDCl 3)：7.40-7.22(m，12H)，7.18-7.10(m，3H)，6.80(s，1H)，4.99(s，2H)，3.78(br m，2H)，3.75(s，2H)，2.79-2.74(m，2H)，2.59-2.55(m，2H).
Embodiment 42
1-benzyl-5-sec.-propyl-3-phenyl-4,5,6,7-tetrahydro-1 H-pyrrolo is [3,2-c] pyridine also
The same with embodiment 41, by 372 μ L 1-sec.-propyl-piperidin-4-one-s, 270 μ L benzylamines and 0.38g (2-nitro-vinyl)-benzene, prepare this title compound (111.0mg).This product is processed with EtOAc, and added oxysuccinic acid (39.0mg).By filtration, collect the solid forming, obtain this title compound as maleate.MS (ESI): C 23h 26n 2accurate calculation quality, 330.21; Measured value, m/z331.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.33(m，6H)，7.30-7.27(m，1H)，7.23-7.19(m，3H)，7.14(s，1H)，6.25(s，2H)，5.15(s，2H)，3.74-3.66(m，1H)，2.96-2.91(br m，2H)，1.41(d，J＝6.6Hz，6H).
Embodiment 43
Figure S04833737820060524D000662
1-benzyl-3-(4-trifluoromethyl-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .3-oxo-2,3,4,5,7,8-, six hydrogen-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.to 5-oxo-azepan-Isosorbide-5-Nitrae-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, (embodiment 59, steps A; 8.29g) in the solution in 80mL EtOH, add 1.5mL hydrazine hydrate.By solution reflux 2 days, be then cooled to room temperature.Solvent is reduced to about 20mL, then gained solution is stored 16 hours at-15 ℃.Add water, then solid by filtration is collected, wash with water and be dried, obtain the needed compound of 4.99g, it is white crystalline solid.MS (ESI): C 12h 19n 3o 3accurate calculation quality, 253.14; Measured value, m/z 254.1[M+H] +.
step is benzyl-3-oxo-2 B.1-, 3,4,5,7,8-, six hydrogen-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in the solution of the compound of preparing to the 1.16g steps A stirring in 15mL DMF, add 1.80g Cs 2cO 3.By suspension stirring at room 20 minutes.Add bromotoluene (0.6mL), and by mixture in stirring at room other 12 hours.By mixture dilute with water, and use Et 2o extraction.To merge organic layer water, salt water washing, at Na 2sO 4above be dried and concentrate, obtain the colourless semisolid of 1.77g.At SiO 2upper chromatogram purification (15 to 50%EtOAc/ hexane) 1 hour, obtains the needed compound of 1.21g, and it is the mixture of single henzylate isomer.TLC (SiO 2, 50%EtOAc/ hexane): R f=0.34.MS (ESI): C 19h 25n 3o 3accurate calculation quality, 343.19; Measured value, m/z 344.2[M+H] +, 366.2[M+Na] +.
step is benzyl-3-trifluoro-methanesulfonyl oxy-4 C.1-, 5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.the mixture of the regional isomer of preparing above stirring (1.21g) is at 35mL CH 2cl 2in solution in add 1.93mL i-Pr 2nEt and 1.58g N-phenyl trifluoromethanesulfonate methylsulfonyl imines.By mixture reflux 12 hours, cooling and vacuum concentration then.At SiO 2upper chromatogram purification (5 to 20%EtOAc/ hexane), obtains the needed compound of 0.63g.TLC (SiO 2, 25%EtOAc/ hexane): R f=0.37.MS (ESI): C 20h 24f 3n 3o 5the accurate calculation quality of S, 475.14; Measured value, m/z 476.2 [M+H] +.In addition, also obtain the non-desired single henzylate 3-of 0.68g benzyloxy-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.
step is benzyl-3-(4-trifluoromethyl-phenyl)-4,5,7 D.1-, 8-tetrahydrochysene-1H-1.2,6-tri-azepines-Azulene-6-formic acid tertiary butyl ester.in the solution of the compound of preparing to step C (0.17g) in 5mL THF, add 0.12g K 3pO 4, 0.08g 4-trifluoromethyl phenyl boronic acid and 0.03gPdCl 2dppf.By mixture reflux 12 hours.Mixture is cooling, by diatomite filtration vacuum concentration.At SiO 2upper chromatogram purification (5 to 40%EtOAc/ hexane), obtains the needed compound of 0.05g.TLC (SiO 2, 25%EtOAc/ hexane): R f=0.49.
step e .1-benzyl-3-(4-trichloromethyl-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.the compound of preparing to the step D stirring (0.05g) is at 2mL CH 2cl 2in solution in add 2.0mL TFA.By mixture at stirring at room 2 hours vacuum concentration.Crude product is dissolved in to CH again 2cl 2in and use
Figure S04833737820060524D000671
550A plastic resin treatment.Stir after 2 hours, mixture is filtered and vacuum concentration, obtain this title compound of 0.04g.This product is dissolved in to Et 2in O and be used in Et 2excessive 1.0M HCl in O processes 30 minutes.In vacuum, except desolventizing, obtain the corresponding HCl salt of 0.05g.MS (ESI): C 21h 20f 3n 3accurate calculation quality, 371.16; Measured value, m/z372.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.78-7.74(m，4H)，7.37-7.28(m，3H)，7.20(t，J＝6.9Hz，2H)，5.46(br s，2H)，4.65(br s，1H)，3.40-3.37(m，3H)，3.17-3.10(m，4H).
Unless otherwise instructed, according to the title compound of the general method Preparation Example 44-53 described in embodiment 43 step D and E.
Embodiment 44
Figure S04833737820060524D000681
1-benzyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
By compound (0.16g) and the 0.05g phenyl-boron dihydroxide of embodiment 43 step C, prepare this title compound (0.07g).MS (ESI): C 20h 21n 3accurate calculation quality, 303.17; Measured value, m/z 304.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.56-7.54(m，2H)，7.51-7.43(m，3H)，7.39-7.36(m，2H)，7.33-7.29(m，1H)，7.21(d，J＝6.9Hz，2H)，5.50(s，2H)，3.43-3.38(m，4H)，3.22-3.20(m，2H)，3.12-3.10(m，2H).
Embodiment 45
1-benzyl-3-(the fluoro-phenyl of 2-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With Isosorbide-5-Nitrae-dioxs, as solvent, by compound (0.31g) and the 0.10g 2-fluorophenyl boric acid of embodiment 43 step C, prepare this title compound (0.06g).MS (ESI): C 20h 20fN 3accurate calculation quality, 321.16; Measured value, m/z 322.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.52-7.46(m，2H)，7.38-7.18(m，7H)，5.46(s，2H)，3.38-3.33(m，4H)，3.17-3.15(m，2H)，2.91-2.89(m，2H).
Embodiment 46
Figure S04833737820060524D000683
1-benzyl-3-(the fluoro-phenyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With Isosorbide-5-Nitrae-dioxs, as solvent, by compound (0.30g) and the 0.10g 3-fluorophenyl boric acid of embodiment 43 step C, prepare this title compound (0.07g).MS (ESI): C 20h 20fN 3accurate calculation quality, 321.16; Measured value, m/z 322.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.52-7.47(m，1H)，7.38-7.27(m，5H)，7.20-7.13(m，3H)，5.47(s，2H)，3.43-3.34(m，4H)，3.23-3.06(m，4H).
Embodiment 47
Figure S04833737820060524D000691
1-benzyl-3-(the fluoro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
Add 9.1mg dppf, and with Isosorbide-5-Nitrae-dioxs as solvent, by compound (0.22g) and the 0.20g 4-fluorophenyl boric acid of embodiment 43 step C, prepare this title compound (0.07g).MS (ESI): C 20h 20fN 3accurate calculation quality, 321.16; Measured value, m/z322.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.54-7.51(m，2H)，7.33-7.30(m，2H)，7.28-7.24(m，1H)，7.12-7.07(m，4H)，5.35(s，2H)，2.98-2.95(m，2H)，2.94-2.92(m，2H)，2.80-2.77(m，2H)，2.76-2.74(m，2H).
Embodiment 48
Figure S04833737820060524D000692
1-benzyl-3-(the fluoro-phenyl of 2,3-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 1,4 diox, as solvent, by compound (0.30g) and the 0.11g 3 of embodiment 43 step C, 4-difluorophenyl boric acid is prepared this title compound (0.05g).MS (ESI): C 20h 19f 2n 3accurate calculation quality 339.15; Measured value, m/z 340.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.26(m，6H)，7.21-7.18(m，2H)，5.46(s，2H)，3.38-3.34(m，4H)，3.18-3.16(m，2H)，2.92-2.90(m，2H).
Embodiment 49
1-benzyl-3-(the chloro-phenyl of 3,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
By compound (0.17g) and the 0.08g 3 of embodiment 43 step C, 4-dichlorophenyl boric acid is prepared this title compound (0.02g).MS (ESI): C 20h 19cl 2n 3accurate calculation quality, 371.10; Measured value, m/z 372.1[M+H] +, 374.1[M+H] +, 376.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.78-7.74(m，4H)，7.37-7.28(m，3H)，7.21-7.18(m，2H)，5.46-5.45(m，2H)，3.40-3.30(m，4H)，3.17-3.10(m，4H).
Embodiment 50
Figure S04833737820060524D000702
1-[4-(1-benzyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-phenyl]-ethyl ketone
With Isosorbide-5-Nitrae-diox, as solvent, by compound (0.20g) and the 0.08g 4-acetylbenzene ylboronic acid of embodiment 43 step C, prepare this title compound (0.02g).MS (ESI): C 22h 23n 3the accurate calculation quality of O, 345.18; Measured value, m/z 346.2[M+H] +.
1H NMR(500MHz，CD 3OD)：8.10-8.09(m，2H)，7.71-7.70(m，2H)，7.38-7.19(m，5H)，5.48(s，2H)，3.40(br s，4H)，3.28-3.10(m，4H)，2.64(s，3H).
Embodiment 51
Figure S04833737820060524D000711
1-benzyl-3-(4-trifluoromethoxy-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With Isosorbide-5-Nitrae-dioxs, as solvent, by compound (0.26g) and the 0.13g 4-Trifluoromethoxyphen-l boric acid of embodiment 43 step C, prepare this title compound (0.03g).MS (ESI): C 21h 20f 3n 3the accurate calculation quality of O, 387.16; Measured value, m/z 388.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.67-7.63(m，2H)，7.39-7.28(m，5H)，7.20-7.17(m，2H)，5.44(s，2H)，3.39-3.36(m，2H)，3.32-3.30(m，2H)，3.15-3.06(m，4H).
Embodiment 52
Figure S04833737820060524D000712
1-benzyl-3-(the chloro-phenyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With Isosorbide-5-Nitrae-dioxs, as solvent, by compound (0.20g) and the 0.07g 3-chlorophenylboronic acid of embodiment 43 step C, prepare this title compound (0.04g).MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.1[M+H] +, 340.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.56(brs，1H)，7.47-7.29(m，6H)，7.29-7.19(m，2H)，5.44(s，2H)，3.38-3.36(m，2H)，3.32-3.30(m，2H)，3.19-3.06(m，4H).
Embodiment 53
3-(1-benzyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
With Isosorbide-5-Nitrae-dioxs, as solvent, by compound (0.30g) and the 0.10g 3-cyano-phenyl boric acid of embodiment 43 step C, prepare this title compound (0.04g).MS (ESI): C 21h 20n 4accurate calculation quality, 328.17; Measured value, m/z329.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.91-7.86(m，2H)，7.76-7.75(m，1H)，7.65(t，J＝7.7Hz，1H)，7.37-7.20(m，3H)，7.19-7.18(m，2H)，5.45(s，2H)，3.39-3.37(m，4H)，3.17-3.08(m，4H).
Embodiment 54
Figure S04833737820060524D000721
4-(1-benzyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
To 1-benzyl-3-trifluoro-methanesulfonyl oxy-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 43 step C; 0.30g) in the solution in 9mL Isosorbide-5-Nitrae-dioxs, add 0.20g K 3pO 4, 0.10g 4-cyano-phenyl boric acid and 0.05g PdCl 2dppf.By mixture reflux 72 hours.Mixture, by diatomite filtration vacuum concentration, is obtained to 0.33g orange solids.At SiO 2upper chromatogram purification (5 to 30%EtOAc/ hexane), obtain 0.21g 1-benzyl-3-(4-cyano group-phenyl)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate and by product 1-benzyl-4,5,7,8-tetrahydrochysene-1H-1,7: 1 mixtures of 2,6-, tri-azepines-Azulene-6-t-butyl formate.The mixture of compound (0.21g) is dissolved in to 7mL CH 2cl 2in, and add 7mLTFA.Mixture is stirring at room 1 hour, and concentrated under vacuum.Crude product is dissolved in to CH 2cl 2in, and use
Figure S04833737820060524D000722
550A plastic resin treatment.Stir after 2 hours, mixture is filtered and concentrated in a vacuum.Use C 18reversed-phase column carries out chromatogram purification, obtains 0.14g as this title mixture of its tfa salt.MS (ESI): C 21h 20n 4accurate calculation quality, 328.17; Measured value, m/z 329.1[M+H] +, 351.1[M+Na] +.
1H NMR(500MHz，CD 3OD)：7.83-7.81(m，2H)，7.76-7.74(m，2H)，7.36-7.28(m，3H)，7.19-7.17(m，2H)，5.46(s，2H)，3.39-3.37(m，4H)，3.15-3.09(m，4H).
Embodiment 55
Figure S04833737820060524D000723
1-(the chloro-benzyl of 4-)-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .1-(the chloro-benzyl of 4-)-3-phenyl-4.5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.the 1-preparing to C to 0.13g embodiment 43 steps A (the chloro-benzyl of 4-)-3-trifyl-4,5,7,8-tetrahydrochysene-1H-1, adds 300 μ L water, 0.11g K in the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate in 3mLTHF 2cO 3, 44.9mg phenyl-boron dihydroxide and 20.0mg PdCl 2dppf.Mixture is heated 18 hours at 100 ℃.Mixture is also concentrated in a vacuum by diatomite filtration.At SiO 2upper chromatogram purification (hexane is to 45%EtOAc/ hexane), obtains the needed compound of 16.1mg.MS (ESI): C 25h 28clN 3o 2accurate calculation quality, 437.19; Measured value, m/z 438.2[M+H] +.
step B.as embodiment 26 step B, compound (16.1mg) is converted into this title compound (7.1mg) above.MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.57-7.54(m，2H)，7.44-7.40(m，2H)，7.35-7.31(m，1H)，7.30-7.26(m，3H)，7.04(d，J＝8.5Hz，2H)，5.32(s，2H)，2.99-2.93(m，4H)，2.85-2.82(m，2H)，2.77-2.73(m，2H)，1.97(br s，1H).
Embodiment 56
Figure S04833737820060524D000731
1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.the 1-preparing to C to 142.7mg embodiment 43 steps A (the chloro-benzyl of 4-)-3-trifyl-4,5,7,8-tetrahydrochysene-1H-1, adds 0.17g K in the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate in 3mL THF 3pO 4, 54.9mg 4-chlorophenylboronic acid and 22.1mg PdCl 2dppf.By mixture reflux 48 hours.Mixture, by diatomite filtration, is used to toluene rinsing, and filtrate is concentrated in a vacuum.At SiO 2upper chromatogram purification (hexane is to 75%EtOAc/ hexane), obtains the needed compound of 6.7mg.MS (ESI): C 25h 27cl 2n 3o 2accurate calculation quality, 471.15; Measured value, m/z 472.1[M+H] +.
step B.the same with embodiment 26 step B, compound (6.7mg) is converted into this title compound (5.0mg) above.MS (ESI): C 20h 19cl 2n 3accurate calculation quality, 371.10; Measured value, m/z 372.1[M+H] +.
1H NMR(5O0MHz，CDCl 3)：7.48(d，J＝8.5Hz，2H)，7.38(d，J＝8.5Hz，2H)，7.29(d，J＝8.5Hz，2H)，7.03(d，J＝8.5Hz，2H)，5.30(s，2H)，3.02-2.96(m，4H)，2.84-2.80(m，2H)，2.79-2.76(m，2H).
Embodiment 57
1-benzyl-3-phenyl-6-propyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As embodiment 35, by 1-benzyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 44, and 0.09g) He 23 μ L propionic aldehyde are prepared this title compound (0.05g) for 2,6-, tri-azepines-Azulene.MS (ESI): C 23h 27n 3accurate calculation quality, 345.22; Measured value, m/z 346.3[M+H] +.
1H NMR(400MHz，CD 3OD)：7.56-7.54(m，2H)，7.47-7.28(m，6H)，7.21-7.19(m，2H)，5.44(s，2H)，3.70-3.66(m，2H)，3.41-3.07(m，8H)，1.86-1.76(m，2H)，1.03(t，J＝7.3Hz，3H).
Embodiment 58
Figure S04833737820060524D000742
1-benzyl-6-sec.-propyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As embodiment 35, by 1-benzyl-3-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 44, and 0.07g) He 22 μ L acetone are prepared this title compound (0.03g) for 2,6-, tri-azepines-Azulene.MS (ESI): C 23h 27n 3accurate calculation quality, 345.22; Measured value, m/z 346.3[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.52(m，2H)，7.50-7.27(m，6H)，7.22-7.20(m，2H)，5.47(s，2H)，3.77-3.61(m，3H)，3.29-3.28(m，3H)，3.24-3.08(m，3H)，1.40(d，J＝6.0Hz，6H).
Embodiment 59
Figure S04833737820060524D000751
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .5-oxo-azepan-Isosorbide-5-Nitrae-dicarboxylic acid uncle 1--butyl ester 4-ethyl ester.
By 4-oxo-piperidines-1-t-butyl formate (35mmol, 7.0g) at anhydrous Et 2solution in O (50mL) stirs in the 200mL three-necked flask being equipped with two addition funnel.Solution is cooled to-25 ℃.With 90 minutes by anhydrous Et 2ethyl diazoacetate (46.5mmol, 4.89mL) in O (10mL) and anhydrous Et 2bF in O (10mL) 3oEt 2(36.7mmol, 4.65mL) simultaneously but be added in solution independently.Compound is stirred other 1 hour and is slowly heated to room temperature.Then, by 30%K 2cO 3the aqueous solution is added drop-wise in mixture until gas is overflowed stops.Organic layer is separated, at Na 2sO 4above be dried and concentrate.Resistates is passed through to chromatography purification (SiO 2, 5 to 20%EtOAc/ hexanes), obtain needed compound (7.5g).
step is oxo-azepan-1-formic acid tertiary butyl ester B.4-.
In solution to the product of steps A in Isosorbide-5-Nitrae-dioxs (50mL), add 1N NaOH (40.83mmol, 40.83mL).By compound in stirred overnight at room temperature.Then solution is acidified to pH4-5 with 3NHCl.Mixture is first used to Et 2o then uses CH 2cl 2extraction, does not have product residual until TLC shows in water layer.By the organic layer merging at Na 2sO 4upper dry and concentrated in a vacuum, obtain needed compound (7.46g).MS (ESI): C 11h 19nO 3accurate calculation quality, 213.14; Measured value, m/z 236.2[M+Na] +.
step is (the chloro-phenyl of 4-)-4,5,7 C.3-, 8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in the solution of the compound (7.46g, 35.0mmol) that tosic acid (0.033mg, 0.18mmol) and morpholine (3.4mL, 38mmol) are added to step B in benzene (15mL).Reaction mixture is used to Dean Rodney Stark instrument reflux 20 hours.Reaction mixture is cooled to room temperature, obtains intermediate enamine, described enamine can be used and without being further purified.To enamine at CH 2cl 2(30mL) in 0 ℃ of solution in, add triethylamine (27.5mmol, 3.80mL), then add 4-chlorobenzoyl nitrogen (27.5mmol, 3.50mL) at CH 2cl 2(10mL) solution in.Reaction mixture is heated to room temperature and stirs 16 hours.Mixture is poured into water, and layer is separated.By organic layer at Na 2sO 4above be dried and concentrate.Gained EtOH (120mL) dilution for oily matter, be cooled to 0 ℃, and process (75mmol, 2.4mL) with hydrazine.Reaction mixture is heated to room temperature, and stirs 16 hours.Mixture is concentrated, and resistates is carried out to purifying by SFC, generate needed mixture (1.2g).MS (ESI): C 18h 22clN 3o 2accurate calculation quality, 347.14; Measured value, m/z 346.0[M-H] -.
1h NMR (500MHz, CD 3oD): 7.40-7.35 (m, 4H), 3.62-3.59 (m, 2H), 3.54-3.51 (m, 2H), 2.96-2.93 (m, 2H), 2.81-2.77 (m, 2H), 1.20 (s, 9H). this reaction also generates 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1,2,5-, tri-azepines-Azulene-5-t-butyl formate (1.5g).MS (ESI): C 18h 22clN 3o 2accurate calculation quality, 347.14; Measured value, m/z 346.0[M-H] -.
1H NMR(500MHz，CD 3OD)：7.65.(d，J＝8.2Hz，1H)，7.47-7.41(m，3H)，4.67-4.45(m，2H)，3.71-3.65(m，2H)，2.90-2.89(m，2H)，1.90-1.87(m，2H)，1.18(s，9H).
step is benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae D.1-, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in 0 ℃ of solution to the product (0.10g, 0.29mmol) of step C in DMF (2mL), add NaH (60% dispersion in oil, 92mg, 2.3mmol).Solution is heated to room temperature 1 hour, then adds benzyl (2.3mmol).Reaction mixture is stirred 16 hours, then concentrated.By residue diluted with water, then use CH 2cl 2extraction.By organic layer salt water washing, at Na 2sO 4upper dry, then concentrated.Crude product is passed through to SiO 2chromatogram purification, generates needed ester, and described ester is directly used in next step.In addition, also obtain 2-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 25h 28clN 3o 2accurate calculation quality, 437.19; Measured value, m/z 438.4[M+H] +. 1HNMR(500MHz，CDCl 3)：7.50-7.48(m，2H)，7.40-7.38，(m，2H)，7.33-7.26(m，3H)，7.13-7.11(m，2H)，5.33(s，2H)，3.55-3.51(m，4H)，2.86-2.77(m，4H)，1.47(s，9H).
step e.the product of step D is dissolved in to 9: 1 CH 2c 2/ MeOH (4mL).Add Et 2excessive 1N HCl in O, and gained mixture is stirred 2 hours.With MS, monitor reaction process, until there is no obvious parent material.Reaction mixture is concentrated, obtain needed product (51mg).MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.2 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.56-7.53(m，2H)，7.51-7.48(m，2H)，7.38-7.29(m，3H)，7.20-7.19(m，2H)，5.48(s，2H)，3.42-3.37(m，4H)，3.20-3.18(m，2H)，3.10-3.08(m，2H).
The other method that scheme 5 is summarized is described below:
step F .3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 6,7-tetrahydro-indazole-5-[1,3] dioxolane.according to the described method of step C above, by 5.0g Isosorbide-5-Nitrae-dioxa-spiral shell [4.5] last of the ten Heavenly stems-8-ketone, the chloro-Benzoyl chloride of 4.5mL 4-and 3.0mL hydrazine, prepare needed compound (5.0g).
1H NMR(500MHz，CDCl 3)：7.53-7.50(m，2H)，7.36-7.33(m，2H)，4.02(s，4H)，2.91(s，2H)，2.89(t，J＝6.6Hz，2H)，2.01(t，J＝6.6Hz，2H).
step is benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae G.1-, 6,7-hydrogen-indazole-5-[1,3] dioxolane.with bromotoluene (1.9mL), replace benzyl chloride and use K 2cO 3(6.1g) replace NaH, according to step, D describes, and by the compound of 4.0g step F, prepares needed compound (3.93g).
1H NMR(500MHz，CDCl 3)：7.67-7.64(m，2H)，7.39-7.27(m，5H)，7.21-7.18(m，2H)，5.29(s，2H)，4.05-3.98(m，4H)，2.95(s，2H)，2.71(t，J＝6.6Hz，2H)，1.98(t，J＝6.6Hz，2H).
step is benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae H.1-, 6,7-tetrahydro-indazole-5-ketoxime.solution reflux by the compound of 3.87g step G in 80mL THF and 5mL 1M HCl 16 hours.In vacuum, remove volatile matter, and add water (300mL).By adding 1M NaOH that mixture is adjusted to pH9, then use CH 2cl 2extraction.To merge extract salt water washing, then, in a vacuum except desolventizing, obtain 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 6,7-tetrahydro-indazole-5-ketone.By this product (3.13g) solution-treated of hydroxylamine hydrochloride (3.0g) in 20mL pyridine.Reaction mixture is stirred 14 hours in room temperature, then water (300mL) dilution, and stir other 1 hour.Mixture, in filtration on paper, is then washed solid with EtOAc, and dry in a vacuum, generate the needed compound of 2.48g.
1h NMR (500MHz, acetone-d 6): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H), 6.91-9.87 (m, 2H), 6.85-6.81 (m, 1H), 6.77-6.73 (m, 2H), 4.87 (s, 2H), 3.21 (s, 2H), (2.31 t, J=6.6Hz, 2H), 2.09 (t, J=6.6Hz, 2H).
step is benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae I.1-, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.by the compound of step H (78.2mg) at 15mL CH 2cl 2in solution be cooled to 0 ℃, then add diisobutylaluminium hydride (the 1.5M solution in toluene, 0.75mL).Mixture is heated to room temperature and stirs 12 hours.Add water (0.2mL) and NaF (0.40g), and mixture is stirred 1 hour.Mixture is passed through to diatomite filtration, and filtrate is concentrated, generate this title compound of 66.7mg and 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, the mixture of 2,5-, tri-azepines-Azulene.MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.0[M+H] +.
Unless otherwise indicated, the method Preparation Example 60 to 102 of describing with embodiment 59 step D and E.
Embodiment 60
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene
As embodiment 59 step D and E, with 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1,2,5-, tri-azepines-Azulene-5-t-butyl formate (0.1g), the isomer of embodiment 59 step C, as initial compounds, prepares this title compound (0.068g).Reaction also generates 2-benzyl-3-(the chloro-phenyl of 4-)-2,6,7,8-tetrahydrochysene-4H-1,2,5-, tri-azepines-Azulene-5-t-butyl formate.MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.2[M+H] +. 1HNMR(500 MHz，CD 3OD)：7.51-7.30(m，4H)，7.37-7.29(m，3H)，7.29-7.21(m，3H)，5.45(s，2H)，4.32(s，2H)，3.53-3.50(m，2H)，3.06-3.03(m，2H)，2.04-1.99(m，2H).
Embodiment 61
Figure S04833737820060524D000782
3-(the chloro-phenyl of 4-)-1-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With methyl-iodide (0.21mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.028g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-methyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 14h 16clN 3accurate calculation quality, 261.10; Measured value, m/z 262.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.69-7.65(m，4H)，4.07(s，3H)，3.69-3.67(m，2H)，3.58-3.56(m，2H)，3.44-3.42(m，2H)，3.05-3.04(m，2H).
Embodiment 62
3-(the chloro-phenyl of 4-)-2-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-methyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 61) is prepared this title compound (0.011g).MS (ESI): C 14h 16clN 3accurate calculation quality, 261.10; Measured value, m/z 262.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.45(m，2H)，7.28-7.26(m，2H)，3.60(s，3H)，3.31-3.29(m，2H)，3.21(m，2H)，3.04-3.02(m，2H)，2.72-2.70(m，2H).
Embodiment 63
3-(the chloro-phenyl of 4-)-1-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With iodoethane (0.27mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.035g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-ethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 15h 18clN 3accurate calculation quality, 275.12; Measured value, m/z 276.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.34(m，4H)，7.11(q，J＝7.3Hz，2H)，3.38-3.36(m，2H)，3.27-3.24(m，2H)，3.15-3.13(m，2H)，2.94-2.92(m，2H)，1.30(t，J＝7.3Hz，3H).
Embodiment 64
Figure S04833737820060524D000801
3-(the chloro-phenyl of 4-)-2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-ethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 63) is prepared this title compound (0.021g).MS (ESI): C 15h 18clN 3accurate calculation quality, 275.12; Measured value, m/z 276.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.46(d，J＝8.6Hz，2H)，7.24(d，J＝8.6Hz，2H)，3.90(q，J＝7.2Hz，2H)，3.31-3.29(m，2H)，3.20-3.19(m，2H)，3.06-3.04(m，2H)，2.69-2.67(m，2H)，1.17(t，J＝7.2Hz，3H).
Embodiment 65
Figure S04833737820060524D000802
3-(the chloro-phenyl of 4-)-1-propyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With propyl iodide (0.33mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.031g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-propyl group-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 16h 20clN 3accurate calculation quality, 289.13; Measured value, m/z 290.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.35(m，4H)，4.03(t，J＝7.2Hz，2H)，3.37-3.35(m，2H)，3.27-3.24(m，2H)，3.15-3.13(m，2H)，2.95-2.93(m，2H)，1.76-1.69(m，2H)，0.84(t，J＝7.4Hz，3H).
Embodiment 66
Figure S04833737820060524D000811
3-(the chloro-phenyl of 4-)-2-propyl group-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-propyl group-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 65) is prepared this title compound (0.016g).MS (ESI): C 16h 20clN 3accurate calculation quality, 289.13; Measured value, m/z 290.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45(d，J＝8.5Hz，2H)，7.23(d，J＝8.5Hz，2H)，3.83(d，J＝7.2Hz，2H)，3.30-3.28(m，2H)，3.20-3.19(m，2H)，3.05-3.03(m，2H)，2.68-2.66(m，2H)，1.62-1.18(m，2H)，0.65(t，J＝7.4Hz，3H).
Embodiment 67
Figure S04833737820060524D000812
1-butyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 1-butyl iodide (0.038mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.033g).In alkylation step, reaction also generates 2-butyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 17h 22clN 3accurate calculation quality, 303.15; Measured value, m/z304.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.34(m，4H)，4.07(t，J＝7.2Hz，2H)，3.37-3.35(m，2H)，3.27-3.25(m，2H)，3.14-3.12(m，2H)，2.95-2.92(m，2H)，1.69-1.66(m，2H)，1.22-1.20(m，2H)，0.86(t，J＝7.4Hz，3H).
Embodiment 68
Figure S04833737820060524D000821
2-butyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 2-butyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 67) is prepared this title compound (0.018g).MS (ESI): C 17h 22clN 3accurate calculation quality, 303.15; Measured value, m/z304.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.46(d，J＝8.4Hz，2H)，7.25(d，J＝8.4Hz，2H)，3.91-3.88(m，2H)，3.32-3.30(m，2H)，3.21-3.19(m，2H)，3.07-3.05(m，2H)，2.70-2.68(m，2H)，1.58-1.52(m，2H)，1.06-1.03(m，2H)，0.68(t，J＝7.4Hz，3H).
Embodiment 69
Figure S04833737820060524D000822
3-(the chloro-phenyl of 4-)-1-(2-cyclohexyl-ethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the bromo-2-cyclohexyl of 1-ethane (0.053mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.056g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 28clN 3accurate calculation quality, 357.20; Measured value, m/z358.2 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.46-7.34(m，4H)，4.08(t，J＝7.6Hz，2H)，3.37-3.35(m，2H)，3.27-3，25(m，2H)，3.13-3.11(m，2H)，2.94-2.92(m，2H)，1.68-1.20(m，7H)，1.18-1.05(m，4H)，O.93-0.86(m，2H).
Embodiment 70
Figure S04833737820060524D000831
3-(the chloro-phenyl of 4-)-2-(2-cyclohexyl-ethyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 69) is prepared this title compound (0.026g).MS (ESI): C 21h 28clN 3accurate calculation quality, 357.20; Measured value, m/z 358.2[M+H] +. 1HNMR(500MHz，CD 3OD)：7.46(d，J＝8.5Hz，2H)，7.23(d，J＝8.5Hz，2H)，3.90(t，J＝7.3Hz，2H)，3.30-3.28(m，2H)，3.20-3.19(m，2H)，3.05-3.03(m，2H)，2.69-2.67(m，2H)，1.48-1.41(m，5H)，1.36-1.33(m，2H)，1.03-1.00(m，3H)，0.95-0.89(m，1H)，0.81-0.67(m，2H).
Embodiment 71
Figure S04833737820060524D000832
3-(the chloro-phenyl of 4-)-1-styroyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With (2-chloroethyl) benzene (0.045mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.048g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-styroyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.52-7.47(m，4H)，7.28-7.21(m，3H)，7.03-7.01(m，2H)，4.39(t，J＝6.4Hz，2H)，3.20-3.18(m，2H)，3.13-3.10(m，2H)，2.95-2.93(m，2H)，2.91-2.89(m，2H)，2.69-2.67(m，2H).
Embodiment 72
Figure S04833737820060524D000841
3-(the chloro-phenyl of 4-)-2-styroyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2 styroyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 71) is prepared this title compound (0.020g).MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.36(m，2H)，7.19-7.14(m，3H)，6.83-6.79(m，4H)，4.14(t，J＝6.7Hz，2H)，3.41-3.39(m，2H)，3.26-3.24(m，2H)，3.19-3.17(m，2H)，3.01-2.98(m，2H)，2.69-2.67(m，2H).
Embodiment 73
Figure S04833737820060524D000842
3-(the chloro-phenyl of 4-)-1-(the fluoro-3-methyl-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the fluoro-3-methyl-benzyl of 4-bromine (0.09g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.002g).MS (ESI): C 21h 21clFN 3accurate calculation quality, 369.14; Measured value, m/z 370.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.49-7.47(m，2H)，7.45-7.42(m，2H)，7.07-7.01(m，1H)，7.00-6.95(m，1H)，6.95-6.90(m，1H)，5.31(s，2H)，2.97-2.91(m，4H)，2.89-2.84(m，2H)，2.82-2.77(m，2H)，2.22(s，3H).
Embodiment 74
Figure S04833737820060524D000851
3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 3-methyl-benzyl chlorine (0.6mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.004g).MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.31-7.26(m，2H)，7.26-7.21(m，2H)，6.99(t，J＝7.5Hz，1H)，6.88(d，J＝7.1Hz，1H)，6.76(s，1H)，6.67(d，J＝7.1Hz，1H)，5.13(s，2H)，2.79-2.73(m，4H)，2.69-2.65(m，2H)，2.63-2.60(m，2H)，2.09(s，3H).
Embodiment 75
Figure S04833737820060524D000852
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 4-fluorobenzyl chloride (0.5mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.003g).MS (ESI): C 20h 19clFN 3accurate calculation quality, 355.13; Measured value, m/z 356.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.40-7.37(m，2H)，7.35-7.32(m，2H)，7.08-7.04(m，2H)，6.98-6.94(m，2H)，5.26(s，2H)，2.89-2.86(m，4H)，2.80-2.78(m，2H)，2.73-2.70(m，2H).
Embodiment 76
Figure S04833737820060524D000861
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 3-fluorobenzyl chloride (0.5mL), replace benzyl chlorine, by 3-(the chloro-phenyl of 4-)-4,5,7, tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.01g).MS (ESI): C 20h 19clFN 3accurate calculation quality, 355.13; Measured value, m/356.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.42-7.37(m，2H)，7.35-7.32(m，2H)，7.28-7.21(m，1H)，6.93-6.88(m，1H)，6.84(d，J＝7.7Hz，1H)，6.75-6.71(m，1H)，5.29(s，2H)，2.89-2.85(m，4H)，2.79-2.76(m，2H)，2.74-2.70(m，2H).
Embodiment 77
Figure S04833737820060524D000862
3-(the chloro-phenyl of 4-)-1-(4-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 4-methyl-benzyl chlorine (0.45g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.74g) prepare this title compound (0.013g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(4-methyl-benzyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z352.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.36(m，2H)，7.34-7.31(m，2H)，7.03(d，J＝8.0Hz，2H)，6.90(d，J＝8.0Hz，2H)，5.21(s，2H)，2.83-2.67(m，4H)，2.75-2.72(m，2H)，2.69-2.67(m，2H)，2.20(s，3H).
Embodiment 78
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 3,4-difluoro benzyl bromide (0.4mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.07g) prepare this title compound (0.002g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 3,4-bis-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.41-7.38(m，2H)，7.36-7.33(m，2H)，7.22-7.20(m，1H)，7.07-7.02(m，1H)，6.96-6.92(m，1H)，5.26(s，2H)，3.06-3.02(m，4H)，2.94-2.91(m，2H)，2.87-2.84(m，2H).
Embodiment 79
3-(the chloro-phenyl of 4-)-1-(3-nitro-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 3-nitrobenzyl bromine (0.09g), replace benzyl chloride, and use Cs 2cO 3(0.2g) replace NaH, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.005g).MS (ESI): C 20h 19clN 4o 2accurate calculation quality, 382.12; Measured value, m/z 383.1[M+H] +.
1H NMR(500MHz，CD 3OD)：8.07-8.05(m，1H)，7.91-7.87(m，1H)，7.50(t，J＝7.9Hz，1H)，7.44-7.38(m，3H)，7.36-7.33(m，2H)，5.41(s，2H)，2.88-2.85(m，4H)，2.82-2.79(m，2 H)，2.73-2.71(m，2H).
Embodiment 80
3-(the chloro-phenyl of 4-)-1-(the fluoro-4-methyl-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6 three azepines-Azulene
With the fluoro-4-methyl-benzyl of 3-bromine (0.9g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.003g).MS (ESI): C 21h 21clFN 3accurate calculation quality, 369.14; Measured value, m/z 370.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.47(m，2H)，7.44-7.42(m，2H)，7.19(t，J＝7.6Hz，1H)，6.84-6.81(m，1H)，6.78-6.75(m，1H)，5.33(s，2H)，2.95-2.92(m，4H)，2.87-2.84(m，2H)，2.81-2.78(m，2H)，2.22(s，3H).
Embodiment 81
Figure S04833737820060524D000882
3-(the chloro-phenyl of 4-)-1-(3,4-dimethyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 3,4-dimethyl benzyl chlorine (0.6mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.003g).MS (ESI): C 22h 24clN 3accurate calculation quality, 365.17; Measured value, m/z 366.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.40-7.38(m，2H)，7.35-7.32(m，2H)，6.98-6.96(m，1H)，6.90-6.86(m，1H)，6.72-6.69(m，1H)，5.30(s，1H)，5.19(s，1H)，2.90-2.87(m，2H)，2.86-2.82(m，2H)，2.77-2.73(m，2H)，2.72-2.68(m，2H)，2.21(s，3H)，2.17(s，3H).
Embodiment 82
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-methyl valerate
With 5-chloro pentane acid methyl esters (0.90mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.15g) prepare this title compound (0.0042g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 19h 24clN 3o 2accurate calculation quality, 361.16; Measured value, m/z362.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.54-7.51(m，2H)，7.31-7.29(m，2H)，3.95(t，J＝7.0Hz，2H)，3.60(s，3H)，3.03-3.01(m，2H)，2.93-2.91(m，4H)，2.56-2.53(m，2H)，2.16(t，J＝7.4Hz，2H)，1.67-1.62(m，2H)，1.41-1.38(m，2H).
Embodiment 83
Figure S04833737820060524D000892
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-valeric acid
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl] (embodiment 82,0.009g) are dissolved in 9: 1 THF/MeOH of 1mL, and process with 2mL 1MNaOH for-methyl valerate.After stirring at room 5 hours, in a vacuum except desolventizing.By 1mL 1N HCl acidifying for aqueous residue, and by EtOAc extraction (3x) for mixture.To merge organic layer at Na 2sO 4upper dry, concentrated, and dry in valve tube.Then resistates is dissolved in to 1mL9: 1 CH 2cl 2in/MeOH, and use Et 23mL 1N HCl in O processes.After 4 hours, remove in a vacuum volatile matter.Thick oily matter is passed through to preparation TLC purifying (9: 1 CH 2cl 2/ 2M NH 3solution in MeOH), generate this title compound of 0.002g.MS (ESI): C 18h 22clN 3o 2accurate calculation quality, 347.14; Measured value, m/z 348.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.55-7.53(m，4H)，7.35-7.32(m，2H)，3.98(t，J＝7.0Hz，2H)，3.38-3.35(m，2H)，3.28-3.26(m，2H)，3.13-3.10(m，2H)，2.77-2.74(m，2H)，2.09-2.06(m，2H)，1.71-1.66(m，2H)，1.41-1.37(m，2H).
Embodiment 84
Figure S04833737820060524D000901
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-penta-1-alcohol.
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl] (embodiment 82,0.009g) are dissolved in 9: 1 Et for-methyl valerate 2o/CH 2cl 2(3mL), in, then solution is slowly added to the hydrogenation chlorine lithium (2mg) that stirring at the anhydrous Et of 5mL 2in suspension in O.After stirring at room 6 hours, will react with 2mL water and end.Mixture is processed with 2mL 1N NaOH, then used again 2mL water treatment.Then mixture is passed through to diatomite filtration.Organic layer is separated, at MgSO 4upper dry, and concentrated.After being further dried by valve tube, gained oily matter is dissolved in to 9: 1 CH of 2mL 2cl 2in/MeOH, and use Et 23mL1N HCl in O processes.After 4 hours, in a vacuum except desolventizing.Thick oily matter is passed through to preparation TLC purifying (9: 1 CH 2c 2/ 2M NH in MeOH 3), generating this title compound of 0.001g, it is colorless oil.MS (ESI): C 18h 24clN 3the accurate calculation quality of O, 333.16; Measured value, m/z334.2[M+H] +. 1hNMR (500MHz, CD 3oD): 7.54-7.52 (m, 2H), 7.32-7.30 (m, 2H), 3.95 (t, J=7.1Hz, 2H), 3.44 (t, J=6.6Hz, 2H), 3.13-3.09 (m, 2H), 3.03-3.00 (m, 2H), 2.98-2.95 (m, 2H), 2.61-2.58 (m, 2H), 1.70-1.64 (m, 2H), 1.40-1.35 (m, 2H), 1.20-1.16 (m, 2H).
Embodiment 85
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-methyl valerate.
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 82) is prepared this title compound (0.0051g).MS (ESI): C 19h 24clN 3o 2accurate calculation quality, 361.16; Measured value, m/z 362.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.40(m，4H)，4.13(t，J＝7.0Hz，2H)，3.63(s，3H)，3.04-3.03(m，2H)，2.97-2.95(m，4H)，2.79-2.76(m，2H)，2.34(t，J＝7.4Hz，2H)，1.81-1.77(m，2H)，1.61-1.58(m，2H).
Embodiment 86
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-valeric acid
As embodiment 83, by 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl] (embodiment 85,0.014g) are hydrolyzed and slough protection, generate this title compound (0.0014g) for-methyl valerate.MS (ESI): C 18h 22clN 3o 2accurate calculation quality, 347.14; Measured value, m/z 348.0[M+H] +. 1hNMR (500MHz, CD 3oD): 7.49-7.43 (m, 4H), 4.18 (t, J=7.0Hz, 2H), 3.45-3.43 (m, 2H), 3.25-3.22 (m, 2H), 3.17-3.16 (m, 2H), 3.04-3.01 (m, 2H), 2.28-2.24 (m, 2H), 1.84-1.82 (m, 2H), 1.60-1.57 (m, 2H).
Embodiment 87
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-penta-1-alcohol
As embodiment 84, by 5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl] (embodiment 85, and 0.015g) reduction, generates this title compound (0.0063g), and it is colorless oil for-methyl valerate.MS (ESI): C 18h 24clN 3the accurate calculation quality of O, 333.16; Measured value, m/z 334.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.40(m，4H)，4.13(t，J＝7.2Hz，2H)，3.53(t，J＝6.4Hz，2H)，3.04-3.01(m，2H)，2.97-2.92(m，4H)，2.78-2.75(m，2H)，1.82-1.75(m，2H)，1.57-1.51(m，2H)，1.41-1.34(m，2H).
Embodiment 88
Figure S04833737820060524D000921
3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-methyl-butyrate
With 4-chloro-butyric acid methyl esters (0.8mL), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1g) prepare this title compound (0.003g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(3-methoxycarbonyl-propyl group)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 18h 22clN 3o 2accurate calculation quality, 347.14; Measured value, m/z 348.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.31(m，4H)，4.07(t，J＝6.6Hz，2H)，3.52(s，3H)，2.97-2.94(m，2H)，2.88-2.84(m，4H)，2.70-2.66(m，2H)，2.25(t，J＝6.6Hz，2H)，1.98-1.95(m，2H).
Embodiment 89
Figure S04833737820060524D000922
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-methyl-butyrate
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-(3-methoxycarbonyl-propyl group)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 88) is prepared this title compound (0.003g).MS (ESI): C 18h 22clN 3o 2accurate calculation quality, 347.14; Measured value, m/z 348.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.45-7.42(m，2H)，7.23-7.20(m，2H)，3.91(t，J＝6.9Hz，2H)，3.44(s，3H)，3.04-3.00(m，2H)，2.93-2.86(m，4H)，2.52-2.49(m，2H)，2.07(t，J＝7.OHz，2H)，1.88-1.80(m，2H).
Embodiment 90
Figure S04833737820060524D000931
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-butyric acid
As embodiment 83, by 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl] (embodiment 89, and 0.006g) hydrolysis, generates this title compound (0.005g) for-methyl-butyrate.MS (ESI): C 17h 20clN 3o 2accurate calculation quality, 333.12; Measured value, m/z 334.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.55-7.52(m，2H)，7.35-7.33(m，2H)，3.98(t，J＝6.8Hz，2H)，3.12-3.09(m，2H)，3.03-2.96(m，4H)，2.62-2.59(m，2H)，2.03-1.97(m，4H).
Embodiment 91
Figure S04833737820060524D000932
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-butyric acid
As embodiment 83, by 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl] (embodiment 88, and 0.009g) hydrolysis, generates this title compound (0.003g) for-methyl-butyrate.MS (ESI): C 17h 20clN 3o 2accurate calculation quality, 333.12; Measured value, m/z 334.1[M+H] +, m/z332.0[M-H] -.
1H NMR(400MHz，CD 3OD)：7.46-7.44(m，4H)，4.17(t，J＝7.1Hz，2H)，3.11-3.08(m，2H)，3.05-2.98(m，4H)，2.83-2.79(m，2H)，2.18-2.15(m，2H)，2.07-2.03(m，2H).
Embodiment 92
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-Ding-1-alcohol
As embodiment 84, by 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl] (embodiment 89, and 0.006g) reduction, generates this title compound, and it is white solid (0.001g) for-methyl-butyrate.MS (ESI): C 17h 22clN 3the accurate calculation quality of O, 319.15; Measured value, m/z 320.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.45-7.41(m，2H)，7.22-7.20(m，2H)，3.89-3.84(m，2H)，3.32-3.29(m，2H)，2.94-2.91(m，2H)，2.85-2.81(m，4H)，2.47-2.43(m，2H)，1.63-1.58(m，2H)，1.24-1.17(m，2H).
Embodiment 93
Figure S04833737820060524D000942
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-Ding-1-alcohol
As embodiment 84, by 4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl] (embodiment 88, and 0.02g) reduction, generates this title compound, and it is white solid (0.007g) for-methyl-butyrate.MS (ESI): C 17h 22clN 3the accurate calculation quality of O, 319.15; Measured value, m/z 320.2[M+H] +. 1HNMR(400MHz，CD 3OD)：7.36-7.31(m，4H)，4.05(t，J＝7.2Hz，2H)，3.45(t，J＝6.4Hz，2H)，2.96-2.94(m，2H)，2.89-2.84(m，4H)，2.70-2.66(m，2H)，1.77-1.68(m，2H)，1.46-1.39(m，2H).
Embodiment 94
3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 3,4-bis-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 78) is prepared this title compound (0.001g).MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.1[M+H] +. 1HNMR(500MHz，CD 3OD)：7.41-7.36(m，2H)，7.15-7.10(m，2H)，7.07-7.01(m，1H)，6.77-6.72(m，1H)，6.65-6.62(m，1H)，5.06(s，2H)，3.17-3.15(m，2H)，09-3.05(m，2H)，2.99-2.97(m，2H)，2.62-2.59(m，2H).
Embodiment 95
Figure S04833737820060524D000952
3-(the chloro-phenyl of 4-)-2-(4-methyl-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59 step e, by 3-(the chloro-phenyl of 4-)-2-(4-methyl-benzyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 77) is prepared this title compound (0.005g).MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2[M+H] +. 1H NMR(500MHz，CD 3OD)：7.36-7.33(m，2H)，7.10-7.01(m，2H)，6.95(d，J＝7.8Hz，2H)，6.69(d，J＝8.0Hz，2H)，5.01(s，2H)，2.92-2.90(m，2H)，2.83-2.80(m，4H)，2.46-2.43(m，2H)，2.16(s，3H).
Embodiment 96
3-(the chloro-phenyl of 4-)-1-(the fluoro-4-methoxyl group-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the fluoro-4-methoxy-benzyl of 3-bromine (0.25g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.35g) prepare this title compound (0.021g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(the fluoro-4-methoxyl group-benzyl of 3-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 21clFN 3the accurate calculation quality of O, 385.14; Measured value, m/z 386.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.47(m，2H)，7.47-7.42(m，2H)，7.06-7.02(m，1H)，6.90-6.86(m，2H)，5.29(s，2H)，3.84(s，3H)，3.35-3.29(m，2H)，2.94-2.92(m，4H)，2.88-2.85(m，2H)，2.80-2.77(m，2H). 13C NMR(125MHz，CD 3OD)：154.2，152.2，149.1，148.1，143.5，134.2，132.9，131.1，131.0，130.5，129.1，123.3，118.7，115.0，114.8，114.4，56.2，52.4，49.9，28.8，27.3.
Embodiment 97
Figure S04833737820060524D000962
3-(the chloro-phenyl of 4-)-2-(the fluoro-4-methoxyl group-benzyl of 3-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 59, step e, by 3-(the chloro-phenyl of 4-)-2-(the fluoro-4-methoxyl group-benzyl of 3-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6 t-butyl formate (embodiment 96), prepares this title compound (0.017g).MS (ESI): C 21h 21clFN 3the accurate calculation quality of O, 385.14; Measured value, m/z386.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.45(m，2H)，7.21-7.18(m，2H)，6.95-6.92(m，1H)，6.67-6.63(m，2H)，5.08(s，2H)，3.81(s，3H)，3.31-3.30(m，2H)，3.01-2.98(m，2H)，2.94-2.88(m，4H)，2.55-2.52(m，2H). 13C NMR(125MHz，CD 3OD)：154.9，153.8，153.0，148.9，142.5，136.6，133.0，132.1，130.5，130.0，129.4，124.3，120.7，116.0，115.8，115.1，57.1，53.3，51.3，32.7，28.0.
Embodiment 98
Figure S04833737820060524D000971
3-(the chloro-phenyl of 4-)-1-(4-nitro-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 4-nitrobenzyl bromine (0.3g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3g) prepare this title compound (0.004g).MS (ESI): C 20h 19clN 4o 2accurate calculation quality, 382.12; Measured value, m/z383.1[M+H] +.
1H NMR(400MHz，CD 3OD)：8.23-8.19(m，2H)，7.51-7.47(m，2H)，7.45-7.47(m，2H)，7.32(d，J＝8.6Hz，2H)，5.52(s，2H)，2.98-2.95(m，4H)，2.89-2.85(m，2H)，2.83-2.79(m，2H).
Embodiment 99
Figure S04833737820060524D000972
4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-aniline
3-(the chloro-phenyl of 4-)-1-(4-nitro-benzyl)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 98,70mg) are dissolved in the anhydrous EtOH of 25mL, and process with 10% palladium on carbon (20mg) for 2,6-, tri-azepines-Azulene-6-t-butyl formate.Under 30 psi, by mixture hydrogenation 4 hours.Mixture is passed through to diatomite filtration.Filtrate is concentrated and is dried by valve tube, generate 55mg 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.Intermediate aniline is dissolved in 1mL MeOH, and uses Et 25mL 1N HCl in O processes.After 6 hours, remove in a vacuum volatile matter.Gained is yellow semi-solid by preparation TLC (9: 1 CH 2c 1-22M NH in/MeOH 3), generating this title compound of 0.007g, it is faint yellow solid.MS (ES1): C 20h 22n 4accurate calculation quality, 318.18; Measured value, m/z 319.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.47(m，2H)，7.44-7.41(m，2H)，7.37-7.34(m，1H)，6.94-6.90(m，2H)，6.68-6.65(m，2H)，5.23(s，2H)，3.11-3.06(m，4H)，2.99-2.96(m，2H)，2.91-2.88(m，2H).
Embodiment 100
Figure S04833737820060524D000981
N-[4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-phenyl]-Toluidrin
To 0.022g 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydrochysene-1H-1, adds 1 equivalent triethylamine in the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 99) in DMF (1mL).After 5 minutes, add 1 equivalent methylsulfonyl chloride and mixture is stirred and spent the night.To react water and end, and extract (3x) with EtOAc.Merging organic layer at Na 2sO 4upper dry, and concentrated.Gained oily matter, by preparation TLC purifying (50%EtOAc/ hexane), is generated to 1-(4-methanesulfonamido-benzyl)-3-phenyl-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.Then this list methanesulfonates is dissolved in to 9: 1 CH 2cl 2/ MeOH (2mL), and use Et 23mL 1N HCl in O processes.After 6 hours, in vacuum, remove volatile matter.Gained oily matter is passed through to preparation TLC purifying (9: 1 CH 2cl 22M NH in/MeOH 3), generating this title compound of 0.004g, it is white solid.MS (ESI): C 21h 24n 4o 2the accurate calculation quality of S, 396.16; Measured value, m/z397.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.47(m，2H)，7.42(t，J＝7.7Hz，2H)，7.37-7.34(m，1H)，7.22-7.20(m，2H)，7.13-7.10(m，2H)，5.34(s，2H)，2.97-2.93(m，4H)，2.92(s，3H)，2.90-2.87(m，2H)，2.82-2.78(m，2H).
Embodiment 101
Figure S04833737820060524D000991
N, N-[4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-phenyl]-bis-Toluidrins
1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 99,0.05mmol) are dissolved in 1mL DMF, and process with 1 equivalent triethylamine for 2,6-, tri-azepines-Azulene-6-t-butyl formate.After 5 minutes, add 1.5 equivalent methylsulfonyl chlorides, and mixture is stirred and spent the night.To react water and end, and extract (3x) with EtOAc.Merging organic layer at Na 2sO 4upper dry, and concentrated.Gained oily matter, by TLC purifying (50%EtOAc/ hexane), is generated to 1-(4-bis-methanesulfonamido-benzyl)-3-phenyl-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.Then intermediate is dissolved in to 9: 1 CH of 2mL 2cl 2in/MeOH, and use Et 23mL 1N HCl in O processes.After 6 hours, in vacuum, remove desolventizing.Thick oily matter is passed through to preparation TLC purifying (9: 1 CH 2cl 2/ 2MNH in MeOH 3), generating this title of 0.006g mixture, it is white solid.MS (ESI): C 22h 26n 4o 4s 2accurate calculation quality, 474.14; Measured value, m/z 475.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.47(m，2H)，7.44-7.40(m，2H)，7.37-7.35(m，1H)，7.22-7.20(m，2H)，7.13-7.11(m，2H)，5.34(s，2H)，2.97-2.94(m，4H)，2.92(s，6H)，2.89-2.87(m，2H)，2.82-2.80(m，2H).
Embodiment 102
Figure S04833737820060524D000992
1-benzyl-3-p-methylphenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As embodiment 59 step C to E, with 4-methyl-Benzoyl chloride (11mmol), replace 4-chloro-benzoyl chloride, by 4-oxo-azepan-1-t-butyl formate (embodiment 59, step B, 10mmol), prepare this title compound (0.2g).MS (ESI): C 21h 23n 3accurate calculation quality, 317.19; Measured value, m/z 318.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.34-7.33(m，2H)，7.29-7.26(m，2H)，7.24-7.21(m，3H)，7.10-7.09(m，2H)，5.40(s，2H)，3.33-3.27(m，4H)，3.11-3.09(m，2H)，3.00-2.98(m，2H)，2.30(s，3H).
Embodiment 103
3-(the chloro-phenyl of 4-)-1-thiophene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .1-(4-chloro-phenyl-)-2-diazo-ethyl ketone.to diazomethane (33.2mmmol) at Et 2in solution in O (70mL), add triethylamine (33.2mmol).Mixture is cooled to 0 ℃, and slowly adds 4-chloro-benzoyl chloride (30mmol) at Et 2solution in O (30mL).Then mixture is heated to room temperature, and stirs 1 hour.After mixture is filtered, limpid filtrate is concentrated, generate thick required compound (5.4g).
step is (the chloro-phenyl of 4-)-4,5,7 B.3-, 8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.to 4-oxo-piperidinyl-1-t-butyl formate (20mmol) at Et 2in 0 ℃ of mixture in O (150mL), add BF 3et 2o (30mmol) is at Et 2solution in O (150mL), then adds compound (21mmol) prepared by steps A at Et 2solution in O (150mL). after having added, mixture is heated to 25 ℃, and stirs 1 hour.Add NaHCO 3saturated aqueous solution (200mL), and layer is separated.Organic layer is concentrated, and by gained MeOH (100mL) dilution for resistates.Add hydrazine, and mixture is stirred 16 hours at 25 ℃.By purified by flash chromatography (EtOAc/CH 2cl 2), generate needed compound (1.8g).
step C.product prepared by step B (0.2mmol) mixes in DMF (2mL) with 2-chloromethyl-thiophene (0.3mmol), then adds Cs 2cO 3(0.3mmol).Mixture is stirred 16 hours at 25 ℃.Concentrate and pass through SiO 2after chromatogram purification (EtOAc/ hexane), obtain 3-(the chloro-phenyl of 4-)-1-thiophene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.By this intermediate CH 2cl 2(10mL) TFA in (1mL) processes 4 hours.After reaction mixture is concentrated, obtain title compound (0.029g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-thiophene-2-ylmethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 18h 18clN 3the accurate calculation quality of O, 343.09; Measured value, m/z 344.1 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.46-7.44(m，2H)，7.41-7.39(m，2H)，7.29(dd，J＝5.1，1.1Hz，1H)，7.00(dd，J＝3.5.1.1Hz，1H)，6.91(dd，J＝5.1，3.5Hz，1H)，5.52(s，2H)，3.36-3.34(m，2H)，3.30-3.28(m，2H)，3.24-3.18(m，2H)，2.99-2.97(m，2H).
Unless otherwise indicated, by the method Preparation Example 104 to 155 of describing in embodiment 103.
Embodiment 104
Figure S04833737820060524D001011
1-benzyl-3-thiophene-2-base-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With thiophene-2-carbonyl chloride (5mmol), replace 4-chloro-benzoyl chloride, and replace 2-chloromethyl-thiophene with benzyl chloride (0.3mmol), described in embodiment 103, by 3-thiophene-2-base-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate is prepared this title compound (28mg).MS (ESI): C 18h 19n 3the accurate calculation quality of S, 309.13; Measured value, m/z 310.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.27-7.01(m，8H)，5.28(s，2H)，3.26-3.24(br m，2H)，3.18-3.16(br m，2H)，3.11-3.09(br m，2H)，2.96-2.94(br m，2H).
Embodiment 105
3-(the chloro-phenyl of 4-)-1-(3-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 3-methoxyl group-benzyl chloride (1.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 1mmol) prepare this title compound (0.095g).MS (ESI): C 21h 22clN 3the accurate calculation quality of O, 367.15; Measured value, m/z 368.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60(d，J＝8.5Hz，2H)，7.56(d，J＝8.5Hz，2H)，7.32(d，J＝7.9Hz，1H)，6.92(dd，J＝8.2，2.1Hz，1H)，6.84(s，1H)，6.80(d，J＝8.2Hz，1H)，5.57(s，2H)，3.79(s，3H)，3.48-3.46(br m，2H)，3.44-3.42(br m，2H)，3.33-3.31(br m，2H)，3.16-3.14(brm，2H).
Embodiment 106
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 2-fluorobenzyl chloride (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.042g).MS (ESI): C 20h 19clFN 3accurate calculation quality, 355.13; Measured value, m/z 356.2 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.55-7.48(brm，4H)，7.39-3.37(br m，1H)，7.20-7.14(m，3H)，5.54(s，2H)，3.48-3.46(br m，2H)，3.40-3.38(br m，2H)，3.31-3.29(br m，2H)，3.13-3.11(br m，2H).
Embodiment 107
3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2-methyl-benzyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.03g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(2-methyl-benzyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z352.2 [M+H] +.
1H NMR(400MHz，CD 3OD)：7.56(d，J＝8.5Hz，2H)，7.49(d，J＝8.5Hz，2H)，7.23-7.15(m，3H)，6.58(d，J＝7.5，1H)，5.50(s，2H)，3.42-3.39(br m，4H)，3.15-3.12(br m，4H)，2.40(s，3H).
Embodiment 108
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2,4-difluoro benzyl bromide (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.030g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,4-bis-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.52-7.49(br m，4H)，7.27-7.24(br m，1H)，7.01-6.99(br m，2H)，5.52(s，2H)，3.51-3.49(br m，2H)，3.43-3.40(br m，2H)，3.34-3.31(br m，2H)，3.11-3.09(br m，2H).
Embodiment 109
3-(the chloro-phenyl of 4-)-1-(2-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2-methoxy-benzyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3mmol) prepare this title compound (0.06g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(2-methoxyl group-benzyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 22clN 3the accurate calculation quality of O, 367.15; Measured value, m/z 368.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.45-7.43(m，2H)，7.30-7.27(m，2H)，7.18-7.17(m，1H)，6.80-6.77(m，2H)，6.61-6.59(m，1H)，5.26(s，2H)，3.80(s，3H)，2.92-2.86(m，4H)，2.74-2.69(m，4H).
Embodiment 110
Figure S04833737820060524D001041
1-(the chloro-benzyl of 2-) 3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 2-chlorobenzyl chloride (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.01g).MS (ESI): C 17h 22clN 3the accurate calculation quality of O, 371.10; Measured value, m/z 372.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.43-7.41(m，2H)，7.32-7.30(m，2H)，7.32(d，J＝8.6Hz，2H)，6.76(d，J＝8.6Hz，2H)，5.23(s，2H)，2.94-2.91(br m，4H)，2.79-7.77(br m，2H)，2.73-7.71(br m，2H).
Embodiment 111
Figure S04833737820060524D001042
1-fourth-3-thiazolinyl-3-(4-nitrogen-phenyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 1-fourth-3-thiazolinyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.028g).MS (ESI): C 17h 22clN 3the accurate calculation quality of O, 301.13; Measured value, m/z 302.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.40-7.37(m，2H)，7.31-7.28(m，2H)，6.75-6.67(m，1H)，5.02-5.00(br m，2H)，4.07(t，J＝7.3Hz，2H)，2.99-2.97(br m，2H)，2.91-2.89(br m，2H)，2.80-2.78(br m，2H)，2.71-2.69(br m，2H)，2.48(q，J＝7.3Hz，2H).
Embodiment 112
1-(the bromo-benzyl of 2-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 2-bromo benzyl bromo (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.035g) .MS (ESI): C 20h 19brClN 3accurate calculation quality, 415.05; Measured value, m/z 418.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.69(d，J＝7.8Hz，1H)，7.53-7.27(m，6H)，6.78(d，J＝7.8Hz，1H)，5.58(s，2H)，3.50-3.48(br m，4H)，3.19-3.17(br m，4H).
Embodiment 113
1-(the bromo-benzyl of 4-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 4-bromo benzyl bromo (0.3mmol), replace 2-n-formyl sarcolysine base-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3mmol) prepare this title compound (0.032g).MS (ESI): C 20h 19brClN 3accurate calculation quality, 415.05; Measured value, m/z418.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.40(m，6H)，6.92(d，J＝8.4Hz，2H)，5.28(s，2H)，3.32-3.30(br m，4H)，3.03-3.01(brm，4H).
Embodiment 114
3-(the chloro-phenyl of 4-)-1-(2-ethyl-butyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the bromo-2-ethyl-butane of 1-(0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.010g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 19h 26clH 3accurate calculation quality, 331.18; Measured value, m/z 332.3[M+H] +.
1H NMR(400MHz，CD 3OD)：7.50-7.48(br m，4H)，4.11-4.09(br m，2H)，3.71-3.69(br m，2H)，3.33-3.31(br m，2H)，3.26-3.24(br m，2H)，3.06-3.04(br m，2H)，1.91-1.89(m，1H)，1.36-1.34(m，4H)，0.93(t，J＝7.3Hz，6H).
Embodiment 115
3-(the chloro-phenyl of 4-)-1-(the chloro-thiophene-2-of 5-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the chloro-thiophene-2-of 5-ylmethyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.029g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(the chloro-thiophene-2-of 5-ylmethyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 18h 17cl 2n 3the accurate calculation quality of S, 377.05; Measured value, m/z 378.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.54-7.51(m，2H)，7.49-7.46(m，2H)，3.91(d，J＝3.8Hz，1H)，6.86(d，J＝3.8Hz，1H)，5.51(s，2H)，3.45-3.44(m，2H)，3.38-3.61(m，2H)，3.27-3.25(m，2H)，3.07-3.05(m，2H).
Embodiment 116
Figure S04833737820060524D001071
1-(the bromo-benzyl of 3-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With 3-bromobenzyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.04g).MS (ESI): C 20h 19brClN 3accurate calculation quality, 415.05; Measured value, m/z 416.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-6.86(m，8H)，5.36(s，2H)，3.30-3.27(br m，4H)，3.06-3.04(m，4H).
Embodiment 117
Figure S04833737820060524D001072
3-(the chloro-phenyl of 4-)-1-cyclohexyl methyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With cyclohexyl methyl bromine (2mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 170mg) prepare this title compound (0.09g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-cyclohexyl methyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 26clN 3accurate calculation quality, 343.18; Measured value, m/z 344.3[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37(d，J＝6.6Hz，2H)，7.32(d，J＝6.6Hz，2H)，3.94(d，J＝7.3Hz，2H)，3.44-3.40(br m，2H)，3.35-3.32(br m，2H)，3.17-3.14(br m，2H)，3.01-2.99(br m，2H)，1.74-1.53(m，4 H)，1.52(d，J＝11.2Hz，2H)，1.17-1.10(m，3H)，0.94-0.90(m，2H).
Embodiment 118
3-(the chloro-phenyl of 4-)-1-isobutyl--Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With isobutyl bromide (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.031g).In alkylation step, reaction also generates 3-(4-chloro-phenyl-)-2-isobutyl--4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 17h 22clN 3accurate calculation quality, 303.15; Measured value, m/z304.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.64(d，J＝6.6Hz，2H)，7.56(d，J＝6.6Hz，2H)，4.20(d，J＝7.4Hz，2H)，3.72-3.69(br m，2H)，3.62-3.60(br m，2H)，3.44-3.42(br m，2 H)，3.29-3.27(brm，2H)，2.35(m，1H)，1.14(d，J＝6.7Hz，6H).
Embodiment 119
Figure S04833737820060524D001082
1-benzo [1,3] dioxole-5-ylmethyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
With benzo [1,3] dioxole-5-ylmethyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.035g).In alkylation step, reaction also generates 2-benzo [1,3] dioxole-5-ylmethyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 20clN 3o 2accurate calculation quality, 381.12; Measured value, m/z 382.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.32(m，4H)，6.67-6.65(m，1H)，6.54-6.61(m，2H)，5.81(s，2H)，5.16(s，2H)，2.81-2.79(m，4H)，2.76-2.74(m，2H)，2.68-2.66(m，2H).
Embodiment 120
Figure S04833737820060524D001091
3-(the chloro-phenyl of 4-)-1-(tetrahydrochysene-pyrans-4-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With toluene-4-sulfonic acid tetrahydrochysene-pyrans-4-base methyl esters (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound.This title compound obtaining is and 3-(the chloro-phenyl of 4-)-2-(tetrahydrochysene-pyrans-4-ylmethyl)-2,4,5,6,7,8-six hydrogen-1,2: 1 mixtures (25mg) of 2,6-, tri-azepines-Azulene.The data of mixture: MS (ESI): C 19h 24clN 3the accurate calculation quality of O, 345.16; Measured value, m/z 346.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.47-7.23(m，4H)，4.10-3.78(m，4H)，3.37-3.14(m，8H)，3.06-2.67(m，2H)，2.02-1.93(m，1H)，1.42-0.97(m，4H).
Embodiment 121
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,6-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
With 2,6-difluorobenzyl chlorine (1.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 1mmol) prepare this title compound (0.07g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,6-bis-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.34-7.30(m，5H)，6.93-6.90(m，2H)，5.34(s，2H)，3.59-3.57(m，2 H)，3.39-3.37(m，4H)，2.94-2.92(m，2H).
Embodiment 122
Figure S04833737820060524D001101
3-(the chloro-phenyl of 4-)-2-cyclohexyl methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2 cyclohexyl methyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 117) is prepared this title compound (0.06g).MS (ESI): C 20h 26clN 3accurate calculation quality, 343.18; Measured value, m/z 334.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39(d，J＝8.5Hz，2H)，7.31(d，J＝8.5Hz，2H)，4.10(d，J＝7.3Hz，2H)，3.49-3.47(br m，2H)，3.37-3.35(br m，2H)，3.21-3.19(br m，2H)，3.03-3.01(br m，2H)，1.88-1.61(m，4 H)，1.52-1.49(m，2H)，1.17-1.10(m，3H)，0.94-0.90(m，2H).
Embodiment 123
Figure S04833737820060524D001102
3-(the chloro-phenyl of 4-)-1-(4-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 4-methoxy-benzyl chlorine (1.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 1mmol) prepare this title compound (0.1g).MS (ESI): C 21h 22clN 3the accurate calculation quality of O, 367.15; Measured value, m/z 368.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.41-7.39(m，2H)，7.31(d，J＝7.7Hz，2H)，6.70(d，J＝7.7Hz，2H)，5.36(s，2H)，3.60(s，3H)，3.33-3.31(br m，2H)，3.21-3.1 9(br m，2H)，3.1 8-3.1 6(br m，2H)，2.96-2.94(brm，2H).
Embodiment 124
3-(the chloro-phenyl of 4-)-1-(3-methyl-butyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With the bromo-3-methyl-butane of 1-(0.3mmol), replace 2-n-formyl sarcolysine base-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.030g).MS (ESI): C 18h 24clN 3accurate calculation quality, 317.17; Measured value, m/z 318.3[M+H] +.
1H NMR(400MHz，CD 3OD)：7.56-7.54(m，4H)，4.34(s，2H)，3.57-3.55(br m，2H)，3.44-3.42(br m，2H)，3.40-3.38(br m，2H)，3.29-3.27(br m，2H)，1.79-1.77(br m，1H)，1.02(d，J＝4.5Hz，6H).
Embodiment 125
Figure S04833737820060524D001112
3-(the chloro-phenyl of 4-)-1-(2-trifluoromethyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2-trifluoromethyl benzyl bromine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.04g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(2-trifluoromethyl-benzyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 19clF 3n 3accurate calculation quality, 405.12; Measured value, m/z 406.1[M+H] +. 1HNMR(400MHz，CD 3OD)：7.45(d，J＝7.7Hz，2H)，7.25-7.24(br m，3H)，7.18-7.16(br m，3H)，6.46-6.44(br m，1H)，5.43-5.41(s，2H)，3.14-3.11(br m，4H)，2.89-2.87(br m，4H).
Embodiment 126
Figure S04833737820060524D001121
3-(the chloro-phenyl of 4-)-2-(2-methyl-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(2-methyl-benzyl)-4,5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 107) is prepared this title compound (0.020g).MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.47(d，J＝8.4Hz，2H)，7.24(d，J＝8.4Hz，2H)，7.15(m，3H)，6.60(d，J＝7.6Hz，1H)，5.23(s，2H)，3.46-3.44(m，2H)，3.36-3.34(m，2H)，3.21-3.19(m，2H)，2.89-2.87(m，2H)，2.13(s，3H).
Embodiment 127
2-benzyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene.
According to the deprotection method in embodiment 103 step C, by 2-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 59, step D) is prepared this title compound (0.018g).MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.30-7.28(m，2H)，7.20-7.15(m，3H)，7.03-7.01(m，2H)，6.91-6.89(m，2H)，5.06(s，2H)，3.03-3.01(m，2H)，2.94-2.90(m，4H)，2.51-2.49(m，2H).
Embodiment 128
3-(the chloro-phenyl of 4-)-1-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
To 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.4mmol) in the solution in toluene (3mL), add 4-methoxyl group-2-methyl-benzyl chloride (0.9mmol) and cyano group methylene radical-tri--normal-butyl phosphine (1mmol).Mixture is heated 16 hours at 110 ℃.At concentrated and purifying (SiO 2, EtOAc/ hexane) after, 3-(the chloro-phenyl of 4-)-1-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae obtained, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (54mg).Meanwhile, also obtain other regional isomer 3-(the chloro-phenyl of 4-)-2-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (86mg).By 3-(the chloro-phenyl of 4-)-1-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (20mg) is used CH 2cl 2(10mL) TFA (1mL) processes 4 hours.After reaction mixture is concentrated, obtain this title compound (0.02g).MS (ESI): C 22h 24clN 3the accurate calculation quality of O, 381.16; Measured value, m/z 382.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.37(m，2H)，7.34-7.32(m，2H)，6.68-6.66(br m，1H)，6.54-6.52(br m，1H)，6.37(d，J＝8.3Hz，1H)，5.21(s，2H)，2.81-2.79(m，4H)，2.71-2.69(m，4H).
Embodiment 129
Figure S04833737820060524D001141
3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,4-bis-)-4,5,7,8-tetrahydrochysene-2H-1, (embodiment 108 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.016g).MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.54(d，J＝8.0Hz，2H)，7.49(d，J＝8.0Hz，2H)，6.96-6.88(m，3H)，5.27(s，2H)，3.46-3.44(br m，2H)，3.34-3.32(br m，2H)，3.23-3.21(br m，2H)，2.86-2.84(br m，2H).
Embodiment 130
Figure S04833737820060524D001142
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl]-furans-2-ethyl formate
With the chloro-furans-2-of 5-ethyl formate (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.008g). in alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-1-(5-ethoxy carbonyl-furans-2-ylmethyl)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 22clN 3o 3accurate calculation quality, 399.13; Measured value, m/z 400.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44(d，J＝8.4Hz，2H)，7.30(d，J＝8.4Hz，2H)，7.00(d，J＝3.5Hz，1H)，6.21(d，J＝3.5Hz，1H)，5.09(s，2H)，4.21(q，J＝7.1Hz，2H)，3.21-3.19(m，2H)，3.11-3.09(m，2H)，2.96-2.94(m，2H)，2.61-2.59(m，2H)，1.24(t，J＝7.1Hz，2H).
Embodiment 131
Figure S04833737820060524D001151
3-(the chloro-phenyl of 4-)-2-isobutyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method of embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-isobutyl--4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 118, step C) is prepared this title compound (0.010g).MS (ESI): C 17h 22clN 3accurate calculation quality, 303.15; Measured value, m/z 304.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.58-7.56(m，2H)，7.37-7.34(m，2H)，3.81(d，J＝7.5Hz，2H)，3.42-3.40(m，2H)，3.34-3.30(m，2H)，3.18-3.15(m，2H)，2.81-2.78(m，2H)，2.02-2.00(m，1H)，0.74(d，J＝6.7Hz，6H).
Embodiment 132
Figure S04833737820060524D001152
3-(the chloro-phenyl of 4-)-2-(2-methoxyl group-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(2-methoxyl group-benzyl)-4,5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 109) is prepared this title compound (0.040g).MS (ESI): C 21h 22clN 3o 3accurate calculation quality, 399.13; Measured value, m/z 368.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.26(d，J＝6.5Hz，2H)，7.12(t，J＝7.6Hz，1H)，7.03(d，J＝6.5Hz，2H)，6.80(t，J＝7.6Hz，1H)，6.71(d，J＝7.6Hz，1H)，6.62(d，J＝7.6Hz，1H)，5.08(s，2H)，2.99-2.97(m，2H)，2.89-2.87(m，4H)，2.49-2.47(m，2H).
Embodiment 133
2-benzyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
To 2-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1, adds lithium aluminum hydride (100mg) in the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate (0.1mmol) (embodiment 59, step D) in THF (25mL).By mixture reflux 4 hours.Add water (1mL), mixture is filtered and filtrate is concentrated.Purifying (SiO 2, EtOAc/ hexane) after, 2 benzyls-3-phenyl-2 obtained, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.By intermediate CH 2cl 2(5mL) dilution, and add TFA (1mL).By reaction mixture stirring at room 4 hours.Reaction mixture is concentrated, obtain this title compound (0.018g).MS (ESI): C 20h 21n 3accurate calculation quality, 303.17; Measured value, m/z 304.3[M+H] +.
1H NMR(400MHz，CD 3OD)：7.38-7.35(m，3H)，7.19-7.18(m，3H)，7.12-7.10(m，2H)，5.13(s，2H)，3.35-3.21(br m，6H)，3.34-3.30(br m，2H)，2.81-2.79(br m，2H).
Embodiment 134
3-(the chloro-phenyl of 4-)-1-Propargyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2-propynyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.014g).MS (ESI): C 16h 16clN 3accurate calculation quality, 285.10; Measured value, m/z 286.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.32(m，4H)，7.13(t，J＝6.4Hz，1H)，5.48(d，J＝6.4Hz，2H)，2.93-2.91(m，4H)，2.84-2.81(m，2H)，2.68-2.65(m，2H).
Embodiment 135
Figure S04833737820060524D001171
3-(the chloro-phenyl of 4-)-1-pentafluorophenyl group methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6 three azepines-Azulene
With pentafluorophenyl group methyl chloride (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.02g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-pentafluorophenyl group methyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-Azaazulenes-6-t-butyl formate.MS (ESI): C 20h 15clF 5n 3accurate calculation quality, 427.09; Measured value, m/z 428.1[M+H] +. 1HNMR(500MHz，CD 3OD)：7.30(br s，4H)，5.34(s，2H)，3.01(br s，4H)，2.90-2.88(m，2H)，2.71-2.69(m，2H).
Embodiment 136
Figure S04833737820060524D001172
3-(the chloro-phenyl of 4-)-2-thiophene-2-ylmethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to the method for describing in embodiment 103, by 3-(the chloro-phenyl of 4-)-2-thiophene-2-ylmethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate is prepared this title compound (0.010g).MS (ESI): C 18h 18clN 3the accurate calculation quality of S, 343.09; Measured value, m/z 344.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60-7.58(m，2H)，7.38-7.35(m，2H)，7.32(dd，J＝5.1，1.1Hz，1H)，6.92(dd，J＝5.1，3.5Hz，1H)，6.78(dd，J＝3.5，1.1Hz，1H)，5.41 (s，2H)，3.47-3.45(m，2H)，3.37-3.35(m，2H)，3.23-3.21(m，2H)，2.85-2.83(m，2H).
Embodiment 137
Figure S04833737820060524D001181
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4,6-tri-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2,4,6-trifluoro-benzyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.027g).MS (ESI): C 20h 17clF 3n 3accurate calculation quality, 391.11; Measured value, m/z 392.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.30-7.26(m，4H)，6.80-6.78(br m，2H)，5.25(s，2H)，2.94-2.92(m，4H)，2.82-2.80(m，2H)，2.66-2.62(m，2H).
Embodiment 138
Figure S04833737820060524D001182
2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-benzonitrile
With the chloro-benzonitrile of 2-(0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.032g).MS (ESI): C 21h 19clN 4accurate calculation quality, 362.13; Measured value, m/z 363.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.81(d，J＝7.6Hz，1H)，7.68-7.66(br m，1H)，7.54-7.51(m，3H)，7.46(d，J＝8.4Hz，2H)，7.23(d，J＝7.6Hz，1H)，5.64(s，2H)，3.51-3.49(br m，2H)，3.43-3.41(br m，2H)，3.31-3.29(br m，2H)，3.13-3.11(br m，2H).
Embodiment 139
Figure S04833737820060524D001191
3-(the chloro-phenyl of 4-)-2-(the chloro-thiophene-2-of 5-ylmethyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(the chloro-thiophene-2-of 5-ylmethyl)-4,5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 115) is prepared this title compound (0.009g).MS (ESI): C 18h 17cl 2n 3the accurate calculation quality of S, 377.05; Measured value, m/z 378.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.47-7.44(m，2H)，7.22-7.20(m，2H)，6.65(d，J＝3.8Hz，1H)，6.44(d，J＝3.8Hz，1H)，5.17(s，2H)，3.32-3.30(m，2H)，3.21-3.19(m，2H)，3.07-3.05(m，2H)，2.70-2.68(m，2H).
Embodiment 140
Figure S04833737820060524D001192
3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,6-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(the fluoro-benzyl of 2,6-bis-)-4; 5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 121, step C) is prepared this title compound (0.036g).MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.42(m，2H)，7.27-7.23(m，3H)，6.79(m，2H)，5.14(s，2H)，3.27-3.25(m，2H)，3.21-3.18(m，2H)，3.02-3.00(m，2H)，2.69-2.67(m，2H).
Embodiment 141
Figure S04833737820060524D001201
3-(the chloro-phenyl of 4-)-2-(2-trifluoromethyl-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method of embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(2-trifluoromethyl-benzyl)-4,5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 125) is prepared this title compound (0.021g).MS (ESI): C 21h 19clF 3n 3accurate calculation quality, 405.12; Measured value, m/z 406.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.69(d，J＝7.8Hz，1H)，7.59(t，J＝7.2Hz，1H)，7.53-7.46(m，3H)，7.27(d，J＝8.1，2H)，6.83(d，J＝7.2Hz，1H)，5.47(s，2H)，3.51-3.49(br m，2H)，3.42-3.40(br m，2H)，3.31-3.29(br m，2H)，2.94-2.92(br m，2H).
Embodiment 142
Figure S04833737820060524D001202
3-(the chloro-phenyl of 4-)-1-naphthalene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With naphthalene-2-ylmethyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.043g).MS (ESI): C 24h 22clN 3accurate calculation quality, 387.15; Measured value, m/z 388.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.74-7.69(m，3H)，7.45-7.38(m，5H)，7.34-7.32(m，1H)，7.18-7.16(m，2H)，5.43(s，2H)，3.04(m，2H)，2.99-2.97(m，2H)，2.87-2.85(m，4H).
Embodiment 143
Figure S04833737820060524D001211
3-(the chloro-phenyl of 4-)-2-(2-ethyl-butyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(2-ethyl-butyl)-4,5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 114) is prepared this title compound (0.012g).MS (ESI): C 19h 26clN 3accurate calculation quality, 331.18; Measured value, m/z 332.2[M+H] +.
1H NMR(400MHz，CD 3OD)：7.50-7.25(br m，4H)，3.76-3.74(m，2H)，3.33-3.31(br m，2H)，3.22-3.20(br m，2H)，3.09-3.07(br m，2H)，2.73-2.71(br m，2H)，1.56-1.54(m，1H)，1.16-1.14(m，4H)，0.82-0.55(m，6H).
Embodiment 144
Figure S04833737820060524D001212
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-furans-2-ethyl formate
According to the deprotection method in embodiment 103 step C; by 3-(the chloro-phenyl of 4-)-1-(5-ethoxy carbonyl-furans-2-ylmethyl)-4; 5; 7; 8-tetrahydrochysene-1H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 130) is prepared this title compound (0.017g).MS (ESI): C 21h 22clN 3o 3accurate calculation quality, 399.13; Measured value, m/z 400.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.32(m，4H)，7.06(d，J＝3.5Hz，1H)，6.41(d，J＝3.5Hz，1H)，5.34(s，2H)，4.21(q，J＝7.1Hz，2H)，3.26-3.24(m，2H)，3.19-3.17(m，2H)，3.13-3.11(m，2H)，2.86-2.84(m，2H)，1.24(t，J＝7.1Hz，2H).
Embodiment 145
Figure S04833737820060524D001221
3-(the chloro-phenyl of 4-)-1-naphthalene-1-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 1-naphthalene-methyl chloride (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.015g).In alkylation step, reaction also generates 3-(4-chloro-phenyl-)-2-naphthalene-1-ylmethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 24h 22clN 3accurate calculation quality, 387.15; Measured value, m/z 388.1[M+H] +. 1hNMR (500MHz, CD 3oD): 7.79-7.18 (m, 11H), 5.74 (d, J=7.3Hz, 2H), 3.42 (s, 2H), 3.21-3.19 (br m, 2H), 3.10-3.08 (br m, 2H), 2.92-2.90 (br m, 2H), 2.84-2.82 (br m, 2H).
Embodiment 146
Figure S04833737820060524D001222
2-benzo [1,3] dioxole-5-ylmethyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 2-benzo [1,3] dioxole-5-ylmethyl-3-(the chloro-phenyl of 4-)-4; 5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 119) is prepared this title compound (0.021g).MS (ESI): C 21h 20clN 3o 2accurate calculation quality, 381.12; Measured value, m/z 382.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.34(m，2H)，7.11-7.10(m，2H)，6.57(d，J＝7.9Hz，1H)，6.31-6.29(m，2H)，5.79(s，2H)，4.95(s，2H)，3.55-3.40(m，1H)，2.82-2.80(m，5H)，2.42-2.41(m，2H).
Embodiment 147
Figure S04833737820060524D001231
[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-methyl acetate
With 2-methyl bromoacetate (1.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 1mmol) prepare this title compound (0.09g) .MS (ESI): C 16h 18clN 3o 2accurate calculation quality, 319.11; Measured value, m/z 320.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.31(d，J＝8.1Hz，2H)，7.26(d，J＝8.1Hz，2H)，4.93(s，2H)，3.56(s，3H)，3.27-3.25(br m，2H)，3.19-3.17(br m，2H)，3.04-3.03(br m，2H)，2.90-2.88(brm，2H).
Embodiment 148
Figure S04833737820060524D001232
2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-N-methyl-ethanamide
To 3-(the chloro-phenyl of 4-)-1-methylamino formyl radical methyl-4; 5,7,8-tetrahydrochysene-1H-1; in the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate (44mg) (embodiment 147) in THF (0.5mL), add the 8%NaOH aqueous solution (0.3mL).Mixture, stirring at room 16 hours, is then used to 1N HCl (0.5mL) acidifying.By mixture CH 2cl 2(2 * 2mL) extraction. merging organic layer salt water washing, at Na 2sO 4above be dried and concentrate.By resistates CH 3cN (0.5mL) dilutes and uses DCC (26mg) and HOBt (18mg) to process.In room temperature, after 2 hours, add methylamine hydrochloride (70mg) at H 2solution in O (0.3mL).By mixture stirring at room 16 hours.Reaction mixture is concentrated, by resistates SiO 2chromatogram purification (EtOAc/ hexane), generates 3-(the chloro-phenyl of 4-)-1-methylamino formyl radical methyl-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.By this intermediate CH 2cl 2(10mL) TFA in (1mL) processes 4 hours, and solution is concentrated, obtains this title compound (0.015g).MS (ESI): C 16h 19clN 4the accurate calculation quality of O, 318.12; Measured value, m/z 319.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.41-7.32(m，4H)，5.94(br s，1H)，4.70(s，2H)，2.98-2.90(m，4H)，2.77-2.71(m，7H).
Embodiment 149
3-(the chloro-phenyl of 4-)-2-pentafluorophenyl group methyl-2,4,5,6,7,8-, six hydrogen-1,2,6 three azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2 pentafluorophenyl group methyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6 t-butyl formate (embodiment 135) is prepared this title compound (0.016g).MS (ESI): C 20h 15clF 5n 3accurate calculation quality, 427.09; Measured value, m/z 428.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.43(m，2H)，7.26-7.23(m，2H)，5.15(s，2H)，2.91-2.89(m，2H)，2.83-2.81(m，2H)，2.79-2.77(m，2H)，2.46-2.44(m，2H).
Embodiment 150
Figure S04833737820060524D001242
3-(the chloro-phenyl of 4-)-1-(3,4,5-trimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 3,4,5-trimethoxy benzyl chloride (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.006g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(3,4,5-trimethoxy-benzyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 23h 26clN 3o 3accurate calculation quality, 427.17; Measured value, m/z 428.1[M+H] +.1HNMR(500MHz，CD 3OD)：7.51-7.49(m，2H)，7.46-7.44(m，2H)，6.44(s，2H)，5.32(s，2H)，3.78(s，6H)，3.74(s，3H)，2.95-2.89(m，6H)，2.81-2.79(m，2H).
Embodiment 151
Figure S04833737820060524D001251
3-(the chloro-phenyl of 4-)-2-naphthalene-1-ylmethyl-2,45,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-naphthalene-1-ylmethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 145) is prepared this title compound (0.015g).MS (ESI): C 24h 22clN 3accurate calculation quality, 387.15; Measured value, m/z 388.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.78-7.75(m，2H)，7.67(d，J＝8.3Hz，1H)，7.41-7.39(m，2H)，7.00(td，J＝8.0，1.0Hz，1H)，7.21-7.19(m，2H)，7.02-7.01(m，2H)，6.69-6.67(dd，J＝7.1，1.0Hz，1H)，5.56(s，2H)，3.31-3.29(m，2H)，2.90-2.88(m，4H)，2.49-2.47(m，2H).
Embodiment 152
Figure S04833737820060524D001261
3-(the chloro-phenyl of 4-)-1-(2,6-dimethyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 2,6-dimethyl benzyl chlorine (0.3mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (0.018g).MS (ESI): C 22h 24clN 3accurate calculation quality, 365.17; Measured value, m/z 366.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.45(m，4H)，7.17-7.15(br m，1H)，7.11-7.09(m，2H)，5.51(s，2H)，3.43-3.41(br m，2H)，3.39-3.37(br m，2H)，3.31-3.29(br m，2H)，3.10-3.08(br m，2H)，2.31(s，3H).
Embodiment 153
3-(the chloro-phenyl of 4-)-2-(3,4,5-trimethoxy-benzyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C; by 3-(the chloro-phenyl of 4-)-2-(3; 4; 5-trimethoxy-benzyl)-4; 5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 150) is prepared this title compound (25mg) .MS (ESI): C 23h 26clN 3o 3accurate calculation quality, 427.17; Measured value, m/z 428.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.36(m，2H)，7.13-7.11(m，2H)，6.07(s，2H)，5.00(s，2H)，3.59(s，9H)，2.90-2.70(m，6H)，2.46-2.44(m，2H).
Embodiment 154
Figure S04833737820060524D001271
1-(3,4-, bis--benzyloxy-benzyl)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6 three azepines-Azulene
With two (benzyloxy) benzyl chlorides (0.3mmol) of 3,4-, replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.2mmol) prepare this title compound (22mg).In alkylation step, reaction also generates 2-(3,4-, bis--benzyloxy-benzyl)-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-2H-1,2,6 three azepines-Azulene-6-t-butyl formate.MS (ESI): C 34h 32clN 3o 2accurate calculation quality, 549.22; Measured value, m/z 550.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.16(m，14H)，6.86(d，J＝8.3Hz，1H)，6.65(d，J＝1.9Hz，1H)，6.56(dd，J＝8.3，1.9Hz，1H)，5.13(s，2H)，4.99(s，2H)，4.97(s，2H)，2.78-2.76(m，2H)，2.73-2.71(m，2H)，2.65(m，4H).
Embodiment 155
Figure S04833737820060524D001272
2-(3,4-, bis--benzyloxy-benzyl)-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method in embodiment 103 step C, by 2-(3,4-, bis--benzyloxy-benzyl)-3-(the chloro-phenyl of 4-)-4; 5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 154) is prepared this title compound (20mg).MS (ESI): C 34h 32clN 3o 2accurate calculation quality, 549.22; Measured value, m/z 550.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.43-7.30(m，12H)，7.07-7.05(m，2H)，6.89-6.87(m，1H)，6.47-6.46(m，2H)，5.09(s，2H)，5.04(s，2H)，5.01(s，2H)，2.99-2.97(m，2H)，2.93-2.91(m，2H)，2.88-2.86(m，2H)，2.52-2.50(m，2H).
Embodiment 156
3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-phenol
By 3-(the chloro-phenyl of 4-)-1-(3-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 105,0.1mmol) at CH for 2,6-, tri-azepines-Azulene 2cl 2(5mL) solution in is cooled to 0 ℃, and adds 1M BBr 3at CH 2cl 2(0.5mL) solution in.Mixture is heated to 25 ℃.After 2 hours, add NaHCO 3saturated aqueous solution.Layer is separated, and EtOAc for water layer (2 * 5mL) is extracted.By the organic layer obtaining at Na 2sO 4be dried and concentrate.By purified by flash chromatography (2MNH 3solution/CH in MeOH 2cl 2), generate this title compound (10mg).MS (ESI): C 20h 20clN 3Oaccurate calculation quality, 353.13; Measured value, m/z354.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.40-7.38(m，2H)，7.35-7.32(m，2H)，7.03(t，J＝7.9Hz，1H)，6.57(dd，J＝8.1，2.0Hz，1H)，6.49(d，J＝8.1Hz，1H)，6.39-6.37(br m，1H)，5.20(s，2H)，2.81-2.78(br m，4H)，2.74-2.72(br m，2H)，2.70-2.68(br m，2H).
Embodiment 157
Figure S04833737820060524D001282
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-phenol
Described in embodiment 156, by (the chloro-phenyl of 4-)-1-(4 methoxyl groups-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 123,0.1mmol) prepare this title compound (10mg) for 2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 20clN 3the accurate calculation quality of O, 353.13; Measured value, m/z 354.1[M+H] +.
1H NMR(500 MHz，CD 3OD)：7.39-7.37(m，2H)，7.34-7.31(m，2H)，6.89-6.86(m，2H)，6.64-6.61(m，2H)，5.16(s，2H)，2.77-2.75(br m，6H)，2.67-2.65(br m，2H).
Embodiment 158
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-3-methyl-phenol
Described in embodiment 156, by (the chloro-phenyl of 4-)-1-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 128,34mg) prepare this title compound (8mg) .MS (ESI): C for 2,6-, tri-azepines-Azulene-6-t-butyl formate 21h 22clN 3the accurate calculation quality of O, 367.15; Measured value, m/z368.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.37(m，2H)，7.33-7.32(m，2H)，6.54-6.52(br m，1H)，6.41-6.39(br m，1H)，6.28(d，J＝8.3Hz，1H)，5.17(s，2H)，2.83-2.78(m，4H)，2.71-2.67(m，2H).
Embodiment 159
Figure S04833737820060524D001292
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-benzene-1,2-diphenol
By 1-(3,4-, bis--benzyloxy-benzyl)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-t-butyl formate (embodiment 154,0.1m mol) is at CH 2cl 2(5mL) solution in is cooled to 0 ℃, and adds 1M BBr 3at CH 2cl 2(0.5mL) solution in.Mixture is heated to room temperature, and stirring at room 1 hour.The throw out forming is filtered and collected, wash with water, and dry under vacuum, generate this title mixture (25mg).MS (ESI): C 20h 20clN 3o 2accurate calculation quality, 369.12; Measured value, m/z 370.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.42(m，4H)，7.39-7.37(m，2H)，6.63(d，J＝8.1Hz，1H)，6.50(d，J＝2.1Hz，1H)，6.45(dd，J＝8.1，2.1Hz，1H)，5.18(s，2H)，3.29-3.25(m，4H)，3.06-3.04(m，2H)，2.97-2.95(m，2H).
Embodiment 160
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] the fluoro-phenol of-2-
BBr 3(0.13mL) be slowly added to 0.022g 3-(4-chloro-phenyl-)-1-(the fluoro-4-methoxyl group-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes (embodiment 96) are at CH 2cl 2(20mL) in 0 ℃ of solution in.After 1 hour, mixture is heated 18 hours in room temperature.And then reaction is cooled to 0 ℃, and by adding the saturated NaHCO of 5mL 3the aqueous solution is by the stopping of reaction.Use methyl alcohol CH 2cl 2aqueous layer extracted (2x).To merge organic layer at Na 2sO 4above be dried and concentrate.By preparation TLC (9: 1 CH for thick oily matter 2cl 2/ 2M NH 3solution in MeOH) purifying, generates this title compound (0.016g), and it is brown solid.MS (ESI): C 20h 19clFN 3the accurate calculation quality of O, 371.12; Measured value, m/z 372.1[M+H] +.
1H NMR(400MHz，CD 3OD)：7.50-7.42(m，4H)，6.86-6.79(m，3H)，5.26(s，2H)，3.31-3.26(m，2H)，2.96-2.95(m，4H)，2.90-2.87(m，2H)，2.81-2.79(m，2H). 13C NMR(100MHz，CD 3OD)：154.2，151.8，149.6，146.1，146.0，143.8，134.8，133.4，131.1，130.3，130.2，129.7，124.0，119.1，115.6，115.4，53.1，50.4，29.0，27.5.
Embodiment 161
Figure S04833737820060524D001311
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl] the fluoro-phenol of-2-
Described in embodiment 160, by 3-(the chloro-phenyl of 4-)-2-(the fluoro-4-methoxyl group-benzyl of 3-)-2,4,5,6,7,8-, six hydrogen-1,2, (embodiment 97, and 0.12g) demethylation generates this title compound (0.027g), and it is pale solid for 6 three azepines-Azulene.MS (ESI): C 20h 19clFN 3the accurate calculation quality of O, 371.12; Measured value, m/z 372.0[M+H] +. 1HNMR(500MHz，CD 3OD)：7.48-7.44(m，2H)，7.21-7.18(m，2H)，6.75(t，J＝8.6Hz，1H)，6.61-6.58(m，1H)，6.53-6.50(m1H)，5.04(s，2H)，3.31-3.30(m，2H)，3.01-2.99(m，2H)，2.94-2.88(m，4H)，2.55-2.52(m，2H). 13C NMR(125 MHz，CD 3OD)：154.2，153.7，152.3，146.5，146.4，142.4，136.6，133.1，130.6，130.5，130.1，124.5，120.7，119.2，116.0，115.9，53.4，51.2，32.6，28.0.
Embodiment 162
Figure S04833737820060524D001312
2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] phenol
Described in embodiment 156, by 3-(the chloro-phenyl of 4-)-1-(2 methoxyl groups-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 109,0.1mmol) prepare this title compound (13mg) for 2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 20clN 3the accurate calculation quality of O, 353.13; Measured value, m/z 354.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.37(d，J＝6.5Hz，2H)，7.33(d，J＝6.5Hz，2H)，7.19(t，J＝7.6Hz，1H)，7.10(d，J＝7.6Hz，1H)，6.91(d，J＝7.6Hz，1H)，6.62(t，J＝7.6 Hz，1H)，5.12(s，2H)，2.91-2.80(br m，6H)，2.68-2.66(m，2H).
Embodiment 163
Figure S04833737820060524D001321
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl]-3-methyl-phenol
Described in embodiment 156, by (the chloro-phenyl of 4-)-2-(4-methoxyl group-2-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 128,42mg) prepare this title compound (14mg) for 2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 22clN 3the accurate calculation quality of O, 367.15; Measured value, m/z 368.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.33-7.30(m，2H)，7.07-7.06(m，2H)，6.43(d，J＝2.3Hz，1H)，6.36(dd，J＝8.4，2.3Hz，1H)，6.30(d，J＝8.4Hz，1H)，4.96(s，2H)，2.89-2.86(m，2H)，2.82-2.77(m，4H)，2.44(m，2H)，1.89(s，3H).
Embodiment 164
Figure S04833737820060524D001322
2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-ylmethyl]-phenol
As embodiment 156, by 3-(the chloro-phenyl of 4-)-2-(2-methoxyl group-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 132,30mg) prepare this title compound (8mg) for 2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 20clN 3the accurate calculation quality of O, 353.13; Measured value, m/z 354.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.62(d，J＝6.5Hz，2H)，7.36-7.34(m，3H)，7.13(d，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，1H)，6.82(t，J＝8.0Hz，1H)，5.08(s，2H)，3.11-3.00(br m，6H)，2.60-2.58(m，2H).
Embodiment 165
1-benzyl-3-(the chloro-phenyl of 4-)-6-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
To 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 59, step e for 2,6-, tri-azepines-Azulene; 0.1mmol) in the solution in 1,2-ethylene dichloride (5mL), add acetic acid (0.2mmol), formaldehyde (37% aqueous solution, 0.037mL) and NaBH (OAc) 3(0.2mmol).Mixture stirring at room 15 hours.By mixture CH 2cl 2dilution, and use saturated NaHCO 3solution washing (2x).To merge organic layer at Na 2sO 4upper dry, filter, and concentrated in a vacuum.At SiO 2upper chromatogram purification (2M NH 3solution/CH in MeOH 2cl 2), generate this title compound of 0.015g.MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2[M+H] +.
1H NMR(400MHz，CDCl 3)：7.45-7.42(m，2H)，7.32-7.29(m，2H)，7.26-7.19(m，3H)，7.03-7.01(br m，2H)，5.27(s，2H)，2.75-2.68(m，4H)，2.64-2.58(m，4H)，2.36(s，3H).
Unless otherwise indicated, by the method synthetic example 166 to 169 of describing in embodiment 165.
Embodiment 166
Figure S04833737820060524D001332
1-benzyl-3-(the chloro-phenyl of 4-)-6-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With acetaldehyde (0.2mmol), replace formaldehyde, prepare this title compound (18mg).MS (ESI): C 22h 24clN 3accurate calculation quality, 365.17; Measured value, m/z 366.2[M+H] +.
1H NMR(400MHz，CDCl 3)：7.45-7.43(m，2H)，7.31-7.29(m，2H)，7.26-7.19(m，3H)，7.03-7.01(br m，2H)，5.26(s，2H)，2.74-2.71(m，10H)，1.01(t，J＝7.1Hz，3H).
Embodiment 167
Figure S04833737820060524D001341
3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
To 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1mmol) at CH 2cl 2(5mL) in the solution in, add TFA (1mL).By mixture stirring at room 16 hours.After concentrated, obtain intermediate 3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.According to the method for describing in embodiment 165, with 3,4-dimethoxy-phenyl aldehyde (0.2mmol), replace formaldehyde, intermediate (0.1mmol) is converted into this title compound (16mg).MS (ESI): C 22h 24clN 3o 2accurate calculation quality, 397.16; Measured value, m/z398.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.35(brm，4H)，7.91(d，J＝1.8Hz，1H)，6.82-6.80(dd，J＝8.1，1.8Hz，1H)，6.76-6.74(d，J＝8.1Hz，1H)，3.83-3.80(s，6H)，2.84-2.82(m，4H)，2.71-2.69(m，4H).
Embodiment 168
Figure S04833737820060524D001342
1-butyl-3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 3,4-dimethoxy-phenyl aldehyde (0.2mmol), replace formaldehyde, by 1-butyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 67,14mg) prepare this title compound (8mg) for 2,6-, tri-azepines-Azulene.MS (ESI): C 26h 32clN 3o 2accurate calculation quality, 453.22; Measured value m/z454.2[M+H] +. 1hNMR (400MHz, CDCl 3): 7.38 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 7.20 (s, 1H), 6.91-6.90 (br m, 1H), 6.81 (d, J=8.2Hz, 1H), 6.75 (d, J=8.2Hz, 1H), 3.98 (t, J=7.3Hz, 2H), 3.82 (d, J=7.0Hz, 6H), 3.66 (s, 2H), 2.78-2.72 (br m, 8H), 1.67 (m, 2H), 1.27 (m, 2H), 0.86 (t, J=7.3Hz, 6H).
Embodiment 169
1-benzyl-3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 3,4-dimethoxy-phenyl aldehyde (o.2mmol), replace formaldehyde, by 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 59, step e for 2,6-, tri-azepines-Azulene; 0.1mmol) prepare this title compound (12mg).MS (ESI): C 29h 30clN 3o 2accurate calculation quality, 487.20; Measured value, m/z 488.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.44-7.43(m，2H)，7.30-7.29(m，2H)，7.25-7.22(m，2H)，7.20-7.18(m，1H)，7.03-7.02(m，2H)，6.86(d，J＝1.7Hz，1H)，6.76-6.71(m，2H)，5.25(s，2H)，3.79(s，6H)，3.63(s，2H)，2.72(s，4H)，2.68-2.66(m，4H).
Embodiment 170
Figure S04833737820060524D001352
[1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-methyl acetate
To 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 59, step e for 2,6-, tri-azepines-Azulene; 1mmol) in the solution in acetone (3mL), add Na 2cO 3(2mmol) and methyl bromoacetate (2mmol).By mixture stirring at room 1 hour.Concentrated also purifying (SiO 2, 2M NH 3solution/CH in MeOH 2cl 2) after, obtain this title compound (60mg).MS (ESI): C 23h 24clN 3o 2accurate calculation quality, 409.16; Measured value, m/z410.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.44-7.42(m，2H)，7.31-7.29(m，2H)，7.25-7.23(br m，2H)，7.20-7.18(br m，1H)，7.02-6.99(br m，2H)，5.26(s，2H)，3.64(s，2H)，3.41(s，2H)，2.81-2.79(br m，4H)，2.75-2.73(br m，2H)，2.70-2.68(br m，2H).
Embodiment 171
2-[1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-ethanol
To [1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-methyl acetate, (embodiment 170,16mg) in the solution in THF (1mL), add lithium aluminum hydride (100mg).By mixture stirring at room 16 hours.By adding H 2o (0.1mL) is by the stopping of reaction.Concentrated also purifying (SiO 2, 2M NH 3solution/CH in MeOH 2cl 2), generate this title compound (5mg).MS (ESI): C 22h 24clN 3the accurate calculation quality of O, 381.16; Measured value, m/z 382.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.50-7.20(m，7H)，7.04(d，J＝7.2Hz，1H)，5.29(s，2H)，3.07-3.04(m，2H)，2.89-2.77(m，10H).
Embodiment 172
Figure S04833737820060524D001362
3-(the chloro-phenyl of 4-)-1-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
By 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3mmol) at CH 2cl 2(5mL) phenyl-boron dihydroxide for solution (0.6mmol) in, pyridine (0.6mmol) and venus crystals (II) (4.5mmol) are processed.Mixture stirring at room 16 hours.Concentrated also purifying (SiO 2, EtOAc/ hexane) after, intermediate 3-(the chloro-phenyl of 4-)-1-phenyl-Isosorbide-5-Nitrae obtained, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.Then, by this intermediate CH 2cl 2(10mL) dilution, and add TFA (1mL).Mixture stirring at room 4 hours.Mixture is concentrated, and by residue purified (SiO 2, 2M NH 3solution/CH in MeOH 2cl 2), generate this title compound (40mg).MS (ESI): C 19h 18clN 3accurate calculation quality, 323.12; Measured value, m/z 324.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.46-7.40(m，4H)，7.36-7.32(m，5H)，3.09-3.07(br m，4H)，3.00-2.98(br m，2H)，3.92-2.90(br m，2H).
Embodiment 173
Figure S04833737820060524D001371
3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7,8,9-six hydrogen-1H-1,2,6-, tri-azepines-cyclopenta cyclooctene
steps A .3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,7,8.9-, six hydrogen-1,2,6-, tri-azepines-cyclopenta cyclooctene-6-t-butyl formate.to 4-oxo-azepan-1-t-butyl formate, (embodiment 59, step B; 0.915g) at Et 2in 0 ℃ of solution in O (30mL), add BF 3et 2o (0.733mL), then adds that 1-(4-chloro-phenyl-)-(embodiment 103, steps A for 2-diazo-ethyl ketone; 4.5mmol) at Et 2solution in O (30mL). mixture is heated to 25 ℃, and stirs 1 hour.Add saturated NaHCO 3the aqueous solution (40mL), and organic layer is separated and concentrated.By gained MeOH (50mL) dilution for resistates, and process (1.5mL) with hydrazine.Reaction mixture is stirred 16 hours at 25 ℃.Concentrate and use purified by flash chromatography (SiO 2, EtOAc/CH 2c1 2), generate needed ester.
step is (the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-Isosorbide-5-Nitrae B.3-, 5,7,8,9-, six hydrogen-1,2,6-, tri-azepines-cyclopenta cyclooctene-6-t-butyl formate.the solution of product prepared by steps A (0.2mmol) in DMF (2mL) is processed with 2-methyl-benzyl chlorine (0.3mmol), then uses Cs 2cO 3(0.3mmol) process.Mixture is stirred 16 hours at 25 ℃.Concentrate and carry out chromatography purification (SiO 2, EtOAc/ hexane), generate target intermediate.
step C.(2M is at Et for product prepared by the step B HCl for solution in MeOH (20mL) 2solution in O, 1mL) processes 16 hours.Concentrate and carry out chromatography purification (SiO 2, 2M NH 3solution/CH in MeOH 2cl 2) after, obtain this title compound (24mg).Reaction also generates 3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7,8,9-six hydrogen-1H-1,2,7-, tri-azepines-cyclopenta cyclooctene (20mg).MS (ESI): C 22h 24clN 3accurate calculation quality, 365.17; Measured value, m/z 366.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.51-7.50(m，2H)，7.42-7.40(m，2H)，7.14-7.05(m，3H)，6.58(d，J＝7.6Hz，1H)，5.42(s，2H)，3.25(t，J＝5.6Hz，2H)，3.13(t，J＝5.6Hz，2H)，3.01(t，J ＝5.6Hz，2H)，2.89(t，J＝5.6Hz，2H)，2.30(s，3H)，1.78-1.76(m，2H).
Embodiment 174
Figure S04833737820060524D001381
3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7,8,9-six hydrogen-1H-1,2,7-, tri-azepines-cyclopenta cyclooctene
As described in embodiment 173, obtain this title compound (20mg).MS (ESI): C 22h 24clN 3accurate calculation quality, 365.17; Measured value, m/z366.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.46(m，2H)，7.39-7.36(m，2H)，7.14-7.05(m，3H)，6.55-6.54(m，1H)，5.39(s，2H)，3.02-3.00(m，2H)，2.98-2.96(m，4H)，2.80-2.78(m，2H)，2.30-2.28(s，3H)，1.99-1.97(m，2H).
Embodiment 175
Figure S04833737820060524D001391
3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine.
As described in embodiment 173, by 3-oxo-tetramethyleneimine-1-t-butyl formate (0.858g) with 1-(4-chloro-phenyl-)-(embodiment 103, steps A for 2-diazo-ethyl ketone; 5.79mmol) prepare this title compound (22mg).MS (ESI): C 17h 22clN 3the accurate calculation quality of O, 337.13; Measured value, m/z 338.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.62-7.60(m，2H)，7.36-7.34(m，2H)，7.14-7.06(m，3H)，6.76(d，J＝7.5Hz，1H)，5.33(s，2H)，4.09(s，2H)，3.38(t，J＝6.1Hz，2H)，3.10(t，J＝6.1Hz，2H)，2.25(s，3H).
Embodiment 176
2,3-phenylbenzene-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .3-oxo-2-phenyl-2,3,4,5,7,8-, six hydrogen-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in the solution of the compound (3.13g) of preparing to embodiment 59 steps A in 80mL EtOH, add 1.2mL phenylhydrazine.By gained solution reflux 3 days, be then cooled to room temperature, then in a vacuum except desolventizing.By resistates at SiO 2upper chromatogram purification (0 to80%EtOAc/ hexane), generates the needed compound of 3.13g.MS (ESI): C 18h 23n 3o 3accurate calculation quality, 329.17; Measured value, m/z 330.2[M+H] +.
step is phenyl-3-trifyl oxygen base-4 B.2-, 5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.to the above-claimed cpd stirring (1.79g) at 35mL CH 2cl 2in solution in add 3.0mL i-Pr 2nEt and 3.05g N-phenyl trifluoromethanesulfonate methylsulfonyl imines.By mixture reflux 24 hours, then concentrated in a vacuum.At SiO 2upper chromatogram purification (0 to 75%EtOAc/ hexane), generates the needed compound of 1.88g.MS (ESI): C 19h 22f 3n 3o 5the accurate calculation quality of S, 461.12; Measured value, m/z 407.1[M+H] +.
step C.2,3-phenylbenzene-4,5.7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in solution to above-claimed cpd (0.28g) in 5mL Isosorbide-5-Nitrae-diox, add 0.29g K 3pO 4, 104.3mg phenyl-boron dihydroxide and 43.0mg PdCl 2dppf.Mixture is heated 3 hours at 80 ℃.Add other phenyl-boron dihydroxide (0.10g) and PdCl 2dppf (26mg), and temperature is increased to 100 ℃.After other 12 hours, mixture is poured in water (100mL), and used CH 2cl 2extraction (3 * 20mL). will merge organic layer by diatomite filtration, and filtrate is concentrated in a vacuum.At SiO 2upper chromatogram purification (0 to20%EtOAc/ hexane), generates the needed compound of 158.8mg.MS (ESI): C 24h 27n 3o 2accurate calculation quality, 389.21; Measured value, m/z390.2[M+H] +.
step D.in solution to the above-claimed cpd stirring (158.8mg) in 5mL EtOH, add 2mL 1.0M HCl at Et 2solution in O.Compound is stirring at room 12 hours, and concentrated in a vacuum, generate this title compound of 75.6mg.MS (ESI): C 19h 19n 3accurate calculation quality, 289.16; Measured value, m/z 290.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.41-7.38(m，3H)，7.36-7.32(m，3H)，7.23-7.18(m，4H)，3.49-3.45(m，2H)，3.38-3.34(m，2H)，3.26-3.23(m，2H)，2.96-2.93(m，2H).
Embodiment 177
2-cyclohexyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A. hydrochloric acid cyclohexyl hydrazine.in solution to pimelinketone (1.25mL) in hexane (8mL), add 1.59g carboxylamine (carbazate) tert-butyl ester.By compound reflux 10 minutes, be then cooled to room temperature. remove by filter the white depositions of formation, and used the washing of low temperature hexane.Then by white solid BH 3(solution of 1.0M in THF 12mL) is processed.In stirring at room, after 20 minutes, mixture is processed with 16mL 6N HCl.Mixture is 110 ℃ of heating 20 minutes, then concentrated in a vacuum.Resistates is processed with 30mL THF.From this mixture, filter and collect this title compound (1.82g), it is white solid.MS (ESI): C 6h 14n 2accurate calculation quality, 114.12; Measured value, m/z 115.1[M+H] +.
1H NMR(500MHz，CDCl 3)：3.05-2.99(m，1H)，2.11-2.09(m，2H)，1.88-1.86(m，2H)，1.72-1.69(m，1H)，1.37-1.19(m，5H).
step is cyclohexyl-3-trifyl oxygen base-4 B.2-, 5,7,8-hydrogen-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 176 steps A and B, the hydrochloric acid cyclohexyl hydrazine of preparing by steps A replaces phenylhydrazine, prepares needed compound.Hydrazonium salt is used before use
Figure S04833737820060524D001411
550 resin neutralizations.
step is cyclohexyl-3-phenyl-4 C.2-, 5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in the solution of the compound of preparing to 126mg steps A in 3mL Isosorbide-5-Nitrae-dioxs, add 229mg K 3pO 4, 131mg phenyl-boron dihydroxide and 7.5mg dppf.Then add PdCl 2dppf (22mg) also spends the night mixture reflux.Mixture is concentrated in a vacuum, and resistates is dissolved in toluene.Solution is passed through to diatomite filtration, and filtrate is concentrated, generate 202mg oily matter.At SiO 2upper chromatogram purification (5 to 25%EtOAc/ hexane), generates the needed compound of 98.7mg.MS (ESI): C 24h 33n 3o 2accurate calculation quality, 395.26; Measured value, m/z 396.2[M+H] +.
step D.as described in embodiment 43 step e, above-claimed cpd (98.7mg) is converted into this title compound (71.0mg), and by crude product at SiO 2(2 to 8%2MNH for upper chromatogram purification 3solution/EtOAc in MeOH).MS (ESI): C 19h 25n 3accurate calculation quality, 295.20; Measured value, m/z 296.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.59-7.49(m，3H)，7.35-7.29(m，2H)，3.97-3.88(m，1H)，3.44-3.38(m，2H)，3.34-3.27(m，2H)，3.20-3.14(m，2H)，2.81-2.73(m，2H)，1.99-1.76(m，6H)，1.65(brs，1H)，1.28-1.17(m，3H).
Embodiment 178
Figure S04833737820060524D001412
3-(the chloro-phenyl of 4-)-2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 129mg 2-cyclohexyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 177, step B) and 173mg 4-chlorophenylboronic acid, prepare this title compound (48mg).MS (ESI): C 19h 24clN 3accurate calculation quality, 329.17; Measured value, m/z 330.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.60-7.53(m，2H)，7.36-7.27(m，2H)，3.94.-3.83(m，1H)，3.43-3.36(m，2H)，3.34-3.26(m，2H)，3.2-3.12(m，2H)，2.80-2.72(m，2H)，1.98-1.76(m，6H)，1.67(brs，1H)，1.32-1.17(m，3H).
Embodiment 179
Figure S04833737820060524D001421
2-cyclohexyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
As described in embodiment 177 step C and D; with 130mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 177 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; step B) and 132mg 4-trifluoromethyl phenyl boronic acid, prepare this title compound (68mg).MS (ESI): C 20h 24f 3n 3accurate calculation quality, 363.19; Measured value, m/z 364.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.90-7.84(m，2H)，7.57-7.50(m，2H)，4.64(br s，2H)，3.94-3.85(m，1H)，3.33-3.05(m，4H)，2.93-2.72(m，2H)，2.00-1.76(m，6H)，1.67(br s，1H)，1.38-1.17(m，3H).
Embodiment 180
Figure S04833737820060524D001431
2-cyclopentyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-cyclopentyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 176 steps A and B, with hydrochloric acid cyclopentyl hydrazine (replacing pimelinketone with cyclopentanone, according to the method preparation of embodiment 177 steps A), replace phenylhydrazine, with the trimethyl carbinol, replace EtOH, add 3 equivalent triethylamines simultaneously, prepare needed triflate.
step B.according to the method for embodiment 177 step C and D, use 109mg phenyl-boron dihydroxide, by the product (101mg) of steps A, prepare this title compound (52mg).MS (ESI): accurate calculation quality C 18h 23n 3, 281.19; Measured value, m/z 282.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.58-7.48(m，3H)，7.36-7.30(m，2H)，4.50(m，1H)，3.44-3.38(m，2H)，3.34-3.27(m，2H)，3.22-3.16(m，2H)，2.81-2.75(m，2H)，2.06-1.84(m，6H)，1.65-1.54(m，2H).
Embodiment 181
Figure S04833737820060524D001432
3-(the chloro-phenyl of 4-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 215mg 2-cyclopentyl-3-trifyl oxygen base-4,5; 7,8 tetrahydrochysenes-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 296mg 4-chlorophenylboronic acid, prepare this title compound (74mg).MS (ESI): C 18h 22clN 3accurate calculation quality, 315.15; Measured value, m/z 316.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.59-7.53(m，2H)，7.36-7.30(m，2H)，4.48(m，1H)，3.44-3.37(m，2H)，3.34-3.27(m，2H)，3.22-3.15(m，2H)，2.81-2.74(m，2H)，2.06-1.84(m，6H)，1.65-155(m，2H).
Embodiment 182
Figure S04833737820060524D001441
2-cyclopentyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 200mg 2-cyclopentyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 185mg 4-fluorophenyl boric acid, prepare this title compound (113mg).MS (ESI): C 18h 22fN 3accurate calculation quality, 299.18; Measured value, m/z 300.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.45-7.39(m，2H)，7.35-7.29(m，2H)，4.53(m，1H)，3.48-3.42(m，2H)，3.36-3.28(m，2H)，3.28-3.23(m，2H)，2.84-2.78(m，2H)，2.08-1.85(m，6H)，1.67-1.56(m，2H).
Embodiment 183
Figure S04833737820060524D001442
2-(1-ethyl-propyl group) 3-(the fluoro-phenyl of 3-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-(1-ethyl-propyl group)-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 176 steps A and B, with hydrochloric acid (1-ethyl-propyl group) hydrazine (as described in embodiment 177 steps A, being prepared by propione), replace phenylhydrazine, prepare needed triflate.Hydrazine is neutralized with the NaH in DMF before use.
step B.as described in embodiment 177 step C and D, the triflate of preparing by 150mg steps A and 138mg 3-fluorophenyl boric acid, prepare this title compound (82mg).MS (ESI): C 18h 24fN 3accurate calculation quality, 301.20; Measured value, m/z302.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.61-7.55(m，1H)，7.31-7.25(m，1H)，7.16-7.12(m，1H)，7.10-7.05(m，1H)，3.85-3.77(m，1H)，3.45-3.40(m，2H)，3.35-3.29(m，2H)，3.23-3.18(m，2H)，2.82-2.76(m，2H)，1.97-1.80(m，2H)，1.79-1.70(m，2H)，0.71(t，J＝7.4Hz，3H).
Embodiment 184
Figure S04833737820060524D001451
2-(1-ethyl-propyl group)-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
As described in embodiment 177 step C and D; with 150mg 2-(1-ethyl-propyl group)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 183 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 138mg 3-fluorophenyl boric acid, prepare this title compound (93mg).MS (ESI): C 18h 24fN 3accurate calculation quality, 301.20; Measured value, m/z 302.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.44-7.30(m，4H)，3.92-3.85(m，1H)，3.51-3.43(m，2H)，3.38-3.33(m，2H)，3.30-3.24(m，2H)，2.86-2.78(m，2H)，1.98-1.85(m，2H)，1.84-1.73(m，2H)，0.73(t，J＝7.4Hz，3H).
Embodiment 185
Figure S04833737820060524D001461
2-(1-ethyl-propyl group)-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D; with 150mg 2-(1-ethyl-propyl group)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 183 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 126mg 3 thienylboronic acid, prepare this title compound (95mg).MS (ESI): accurate calculation quality C 16h 23n 3s, 289.16; Measured value, m/z 290.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.68-7.64(m，1H)，7.52-7.48(m，1H)，7.12-7.07(m，1H)，3.93-3.86(m，1H)，3.44-3.39(m，2H)，3.34-3.28(m，2H)，3.22-3.17(m，2H)，2.85-2.79(m，2H)，1.95-1.84(m，2H)，1.79-1.69(m，2H)，0.71(t，J＝7.4Hz，3H).
Embodiment 186
2-(1-ethyl-propyl group)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D; with 150mg 2-(1-ethyl-propyl group)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 183 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 120mg phenyl-boron dihydroxide, prepare this title compound (40mg).MS (ESI): C 18h 25n 3accurate calculation quality, 283.20; Measured value, m/z 284.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.48-7.38(m，3H)，7.24-7.19(m，2H)，3.77-3.70(m，1H)，3.36.3.31(m，2H)，3.24-3.19(m，2H)，3.14-3.09(m，2H)，2.71-2.65(m，2H)，1.85-1.75(m，2H)，1.68-1.58(m，2H)，0.61(t，J＝7.4Hz，3H).
Embodiment 187
Figure S04833737820060524D001471
3-(the chloro-phenyl of 4-)-2-(the fluoro-ethyl of 2,2,2-tri-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-(the fluoro-ethyl of 2,2,2-tri-)-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 176 steps A and B, with 2,2,2-trifluoro ethyl hydrazine, replace phenylhydrazine, prepare needed triflate.
step B.as described in embodiment 177 step C and D, the triflate of preparing by 304mg steps A and 407mg 4-chlorophenylboronic acid, prepare this title compound (40mg) .MS (ESI): C 15h 15clF 3n 3accurate calculation quality, 329.09; Measured value, m/z330.0[M+H] +.
1H NMR(500MHz，CDCl 3)：7.62-7.52(m，2H)，7.40-7.29(m，2H)，4.70(q，J＝8.6Hz，2H)，3.44-3.37(m，2H)，3.36-3.25(m，2H)，3.22-3.13(m，2H)，2.83-2.73(m，2H).
Embodiment 188
2-(the fluoro-ethyl of 2,2,2-tri-)-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D; with 288mg 2-(2; the fluoro-ethyl of 2,2-tri-)-3-trifyl oxygen base-4,5; 7; 8-tetrahydrochysene-2H-1, (embodiment 187 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 468mg 4-trifluoromethyl phenyl boronic acid, prepare this title compound (128mg).MS (ESI): C 16h 15f 6n 3accurate calculation quality, 363.12; Measured value, m/z 364.0[M+H] +. 1HNMR(500MHz，CDCl 3)：7.93-7.83(m，2H)，7.62-7.54(m，2H)，4.75(q，J＝8.6 Hz，2H)，3.47-3.39(m，2H)，3.38-3.27(m，2H)，3.24-3.15(m，2H)，2.87-2.76(m，2H).
Embodiment 189
Figure S04833737820060524D001481
2-sec.-propyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-sec.-propyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 176 steps A and B, with hydrochloric acid Iproniazid, replace phenylhydrazine, with the trimethyl carbinol, replace EtOH, add 3 equivalent triethylamines simultaneously, prepare needed triflate.
step B.as described in embodiment 177 step C and D, the triflate of preparing by 172mg steps A and 147mg phenyl-boron dihydroxide, prepare this title compound (93mg).MS (ESI): C 16h 21n 3accurate calculation quality, 255.17; Measured value, m/z256.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.58-7.49(m，3H)，7.36-7.30(m，2H)，4.40(m，1H)，3.45-3.40(m，2H)，3.34-3.28(m，2H)，3.23-3.18(m，2H)，2.82-2.75(m，2H)，1.40(d，J＝6.9Hz，6H).
Embodiment 190
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 159mg 2-sec.-propyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 189, steps A) and 156mg 4-fluorophenyl boric acid, prepare this title compound (92mg).MS (ESI): C 16h 20fN 3accurate calculation quality, 273.16; Measured value, m/z 274.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.42-7.35(m，2H)，7.33-7.27(m，2H)，4.37(m，1H)，3.46-3.39(m，2H)，3.34-3.28(m，2H)，3.23-3.18(m，2H)，2.81-2.74(m，2H)，1.41(d，J＝6.9Hz，6H).
Embodiment 191
2-(1-ethyl-propyl group)-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D; with 148mg 2-(1-ethyl-propyl group)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 183 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 122mg 2-thienyl boric acid, prepare this title compound (35mg).MS (ESI): C 16h 23n 3the accurate calculation quality of S, 289.16; Measured value, m/z 290.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.72-7.67(m，1H)，7.25-7.21(m，1H)，7.13-7.09(m，1H)，4.01-3.94(m，1H)，3.43-3.38(m，2H)，3.34-3.28(m，2H)，3.20-3.14(m，2H)，2.86-2.80(m，2H)，1.95-1.85(m，2H)，1.79-1.69(m，2H)，0.71(t，J＝7.4Hz，3H).
Embodiment 192
Figure S04833737820060524D001492
2-cyclopentyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 200mg 2-cyclopentyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 169mg 3 thienylboronic acid, prepare this title compound (114mg).MS (ESI): C 16h 21n 3the accurate calculation quality of S, 287.15; Measured value, m/z 288.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.68-7.63(m，1H)，7.56-7.51(m，1H)，7.17-7.12(m，1H)，4.58(m，1H)，3.43-3.37(m，2H)，3.34-3.28(m，2H)，3.19-3.14(m，2H)，2.86-2.80(m，2H)，2.04-1.85(m，6H)，1.67-1.57(m，2H).
Embodiment 193
2-ethyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-ethyl-3-trifyl oxygen base-4,5,7,8-hydrogen-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 176 steps A and B, with oxalic acid ethyl hydrazine, replace phenyl hydrazine, with the trimethyl carbinol, replace EtOH, add 3 equivalent triethylamines simultaneously, prepare needed triflate.
step B.as described in embodiment 177 step C and D, the triflate of preparing by 198mg steps A and 122mg phenyl-boron dihydroxide, prepare this title compound (106mg).MS (ESI): C 15h 19n 3accurate calculation quality, 241.16; Measured value, m/z242.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.61-7.54(m，3H)，7.43-7.39(m，2H)，4.11(q，J＝7.1Hz，2H)，3.49-3.44(m，2H)，3.37-3.32(m，2H)，3.28-3.22(m，2H)，2.89-2.82(m，2H)，1.33(t，J＝7.1Hz，3H).
Embodiment 194
Figure S04833737820060524D001502
2-ethyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 208mg 2-ethyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 193, steps A) and 211mg 4-fluorophenyl boric acid, prepare this title compound (114mg).MS (ESI): C 15h 18fN 3accurate calculation quality, 259.15; Measured value, m/z 260.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.41-7.35(m，2H)，7.32-7.26(m，2H)，3.99(q，J＝7.1Hz，2H)，3.43-3.38(m，2H)，3.33-3.28(m，2H)，3.18-3.12(m，2H)，2.80-2.75(m，2H)，1.27(t，J＝7.1Hz，3H).
Embodiment 195
2-ethyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 177 step C and D, with 148mg 2-ethyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 193, steps A) and 306mg 2-thienyl boric acid, prepare this title compound (101mg).MS (ESI): accurate calculation quality C 13h 17n 3s, 247.11; Measured value, m/z 248.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.62-7.57(m，1H)，7.16-7.11(m，1H)，7.10-7.05(m，1H)，3.98(q，J＝7.1Hz，2H)，3.33-3.27(m，2H)，3.24-3.18(m，2H)，3.07-3.01(m，2H)，2.80-2.73(m，2H)，1.22(t，J＝7.1Hz，3H).
Embodiment 196
Figure S04833737820060524D001512
2-(the chloro-phenyl of 3-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-(the chloro-phenyl of 3-)-3-phenyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with (the chloro-phenyl of 3-) hydrazine, replace phenylhydrazine; use 102.1mg phenyl-boron dihydroxide; as described in embodiment 43 step D; by 142.7mg 2-(the chloro-phenyl of 3-)-3-trifyl oxygen base-4; 5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 176 steps A and B preparation) is prepared needed compound (53.9mg).MS (ESI): C 24h 26clN 3o 2accurate calculation quality, 423.17; Measured value, m/z 424.1[M+H] +
step B.as described in embodiment 26 step B, compound (53.9mg) is converted into this title compound (37.6mg) above.MS (ESI): C 19h 18clN 3accurate calculation quality 323.12; Measured value, m/z 324.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.38-7.32(m，4H)，7.16-7.09(m，4H)，6.96-6.93(m，1H)，3.09-3.05(m，2H)，3.02-2.98(m，2H)，2.97-2.94(m，2H)，2.65-2.62(m，2H)，2.07(br s，1H).
Embodiment 197
Figure S04833737820060524D001521
2-(the fluoro-phenyl of 3-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 1; 4-diox is as solvent; as embodiment 196 describes; by 339.2mg 2-(the fluoro-phenyl of 3-)-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (as described in embodiment 176 steps A and B, by the preparation of (the fluoro-phenyl of 3-) hydrazine) is prepared this title compound (37.6mg).MS (ESI): C 19h 18fN 3accurate calculation quality, 307.15; Measured value, m/z 308.1[M+H] +.
1H NMR(400MHz，CDCl 3)：7.39-7.35(m，3H)，7.20-7.14(m，3H)，7.00-6.96(m，1H)，6.94-6.86(m，2H)，3.13-3.09(m，2H)，3.06-3.02(m，2H)，3.01-2.96(m，2H)，2.69-2.66(m，2H).
Embodiment 198
Figure S04833737820060524D001531
2-(the chloro-phenyl of 2-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 1; 4-diox is as solvent; as described in embodiment 196; by 199.8mg 2-(the chloro-phenyl of 2-)-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (as described in embodiment 176 steps A and B, by the preparation of (the chloro-phenyl of 2-) hydrazine) is prepared this title compound (17.2mg).MS (ESI): C 19h 18clN 3accurate calculation quality, 323.12; Measured value, m/z 324,1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.37-7.34(m，2H)，7.29-7.24(m，5H)，7.14-7.10(m，2H)，3.12-3.09(m，2H)，3.04-2.99(m，4H)，2.74-2.71(m，2H)，2.13(br s，1H).
Embodiment 199
Figure S04833737820060524D001532
2-phenyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-phenyl-3-thiophene-2-base-4,5,7,8-tetrahydrochysene-2H-1,2.6-tri-azepines-Azulene-6-t-butyl formate.to 199.8mg 2-phenyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1, adds 0.6mL 2M Na in the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 176, step B) in 3.5mL DMF 2cO 3the aqueous solution and 75.6mg thiophene-2-boric acid.Add PdCl 2dppf (20.2mg), and mixture is heated 16 hours at 80 ℃.Mixture is poured in water (50mL), used CH 2cl 2extraction (3 * 15mL), and it is concentrated in a vacuum to merge organic layer.At SiO 2upper chromatogram purification (0 to50% EtOAc/ hexane), generates the needed compound of 58.9mg, and it is white solid .MS (ESI): C 22h 25n 3o 2the accurate calculation quality of S, 395.17; Measured value, m/z 396.1[M+H] +.
step B.as described in embodiment 26 step B, compound (58.9mg) is converted into this title compound (28.1mg) above.MS (ESI): C 17h 17n 3the accurate calculation quality of S, 295.11; Measured value, m/z 296.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.36(dd，J＝5.2，1.3Hz，1H)，7.32-7.23(m，5H)，7.01(dd，J＝5.2，3.3Hz，1H)，6.85(dd，J＝3.3，1.3Hz，1H)，3.11-3.08(m，2H)，3.03-2.99(m，4H)，2.76-2.73(m，2H)，2.12(brs，1H).
Embodiment 200
Figure S04833737820060524D001541
3-(the fluoro-phenyl of 4-)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
As described in embodiment 199, by 207.0mg 2-phenyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 176, step B) and 98.5mg 4-fluorophenyl boric acid are prepared this title compound (70.0mg).MS (ESI): accurate calculation quality C 19h 18fN 3, 307.15; Measured value, m/z 308.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.28-7.24(m，2H)，7.22-7.16(m，3H)，7.13-7.10(m，2H)，7.05-7.01(m，2H)，3.12-3.08(m，2H)，3.05-3.02(m，2H)，3.01-2.98(m，2H)，2.68-2.64(m，2H).
Embodiment 201
3-(the chloro-phenyl of 4-)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 196, by 164.0mg 2-phenyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 176, step B) and 63.8mg 4-chlorophenylboronic acid are prepared this title compound (9.3mg).MS (ESI): C 19h 18clN 3accurate calculation quality, 323.12; Measured value, m/z 324.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.33-7.25(m，4H)，7.23-7.16(m，3H)，7.09-7.06(m，2H)，3.10-3.07(m，2H)，3.03-3.00(m，2H)，2.99-2.96(m，2H)，2.66-2.63(m，2H).
Embodiment 202
Figure S04833737820060524D001551
3-(the chloro-phenyl of 3-)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 199, by 192.3mg 2-phenyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 176, step B) and 84.7mg 3-chlorophenylboronic acid, prepare this title compound (37.5mg).MS (ESI): C 19h 18clN 3accurate calculation quality, 323.12; Measured value, m/z 324.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.32-7.16(m，8H)，7.01-6.98(m，1H)，3.12-3.08(m，2H)，3.05-3.02(m，2H)，3.01-2.98(m，2H)，2.69-2.66(m，2H).
Embodiment 203
2-phenyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With DME as solvent; as described in embodiment 199; by 188.9mg 2-phenyl-3-trifyl oxygen base-4; 5,7,8-tetrahydrochysene-2H-1; 2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 176, step B) and 93.3mg ptolylboronic acid, prepare this title compound (17.5mg).MS (ESI): C 20h 21n 3accurate calculation quality, 303.17; Measured value, m/z 304.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.26-7.23(m，2H)，7.21-7.16(m，3H)，7.15-7.12(m，2H)，7.04-7.01(m，2H)，3.11-3.07(m，2H)，3.04-3.00(m，2H)，2.98-2.96(m，2H)，2.68-2.65(m，2H)，2.35(s，3H).
Embodiment 204
Figure S04833737820060524D001561
2,3-phenylbenzene-4,5,6,7-tetrahydrochysene-2H-pyrazolo [4,3-c] pyridine
steps A .2,3-phenylbenzene-2,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-t-butyl formate.to 156.6mg 2-phenyl-3-trifyl oxygen base-2, and 4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-t-butyl formate (as described in embodiment 176 steps A and B, to 4-oxo-piperidines-1, the preparation of 3-dicarboxylic acid 1-tert-butyl ester 3-methyl esters) at THF/H 2o (10: in the solution Isosorbide-5-Nitrae mL), add 148.4mg K 2cO 3with 56.2mg phenyl-boron dihydroxide.Add PdCl 2dppf (23.4mg), and by compound reflux 16 hours.Mixture is concentrated in a vacuum. by resistates at SiO 2upper chromatogram purification (0 to 75%EtOAc/ hexane), generates the needed ester of 45.6mg, and it is pale solid.MS (ESI): C 23h 25n 3o 2accurate calculation quality, 375.19; Measured value, m/z 376.2[M+H] +.
step B.as described in embodiment 26 step B, compound (45.6mg) is converted into this title compound (24.5mg) above.MS (ESI): C 18h 17n 3accurate calculation quality, 275.14; Measured value, m/z 276.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.34-7.22(m，8H)，7.16-7.12(m，2H)，3.96(s，2H)，3.23(t，J＝6.0Hz，2H)，2.88(t，J＝6.0Hz，2H).
Embodiment 205
Figure S04833737820060524D001571
3-phenyl-2-(3-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
steps A .3-phenyl-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 177 step C; by 279.1mg 3-trifyl oxygen base-2-(3-trifluoromethyl-phenyl)-4; 5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate is (as described in embodiment 176 steps A and B; by the preparation of (3-trifluoromethyl-phenyl)-hydrazine) and 0.21g phenyl-boron dihydroxide, prepare needed compound (172.0mg).MS (ESI): C 25h 26f 3n 3o 2accurate calculation quality, 457.20; Measured value, m/z 458.1[M+H] +.
step B.as described in embodiment 26 step B, compound (172.0mg) is converted into this title compound (106.4mg) above.MS (ESI): C 20h 18f 3n 3accurate calculation quality, 357.15; Measured value, m/z 358.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.53(s，1H)，7.44-7.41(m，1H)，7.39-7.29(m，5H)，7.17-7.13(m，2H)，3.12-3.09(m，2H)，3.06-3.02(m，2H)，3.00-2.97(m，2H)，2.69-2.66(m，2H).
Embodiment 206
3-(4-methoxyl group-phenyl)-2-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 199, by 198.3mg 2-phenyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 176, step B) and 94.7mg 4-anisole ylboronic acid, prepare this title compound (43.6mg).MS (ESI): C 20h 21n 3the accurate calculation quality of O, 319.17; Measured value, m/z 320.2[M+H] +.
1H NMR(500MHz，CDCl 3)：7.28-7.24(m，2H)，7.21-7.17(m，3H)，7.07(d，J＝8.8Hz，2H)，6.87(d，J＝8.8Hz，2H)，3.81(s，3H)，3.11-3.08(m，2H)，3.04-3.01(m，2H)，3.00-2.97(m，2H)，2.68-2.65(m，2H).
Embodiment 207
2-(the chloro-phenyl of 4-)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 204; by 201.1mg 2-(4-chloro-phenyl-)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate is (as described in embodiment 176 steps A and B; by the preparation of (the chloro-phenyl of 4-) hydrazine) and 65.1mg phenyl-boron dihydroxide, prepare this title compound (50.4mg).MS (ESI): C 19h 18clN 3accurate calculation quality, 323.12; Measured value, m/z 324.1[M+H] +.
1H NMR(500MHz，CDCl 3)：7.39-7.34(m，3H)，7.22-7.19(m，2H)，7.15-7.11(m，4H)，3.11-3.07(m，2H)，3.04-3.00(m，2H)，2.99-2.96(m，2H)，2.67-2.64(m，2H).
Embodiment 208
6-methyl-2,3-phenylbenzene-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
To 33.5mg 2,3-phenylbenzene-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (embodiment 176, step D) is at 5mL CH 2cl 2in solution in add 0.15g paraformaldehyde and 0.15gNaBH (OAc) 3.Mixture, stirring at room 12 hours, and is diluted with 20mL 1M NaOH.Stir after 3 hours, by mixture CH 2cl 2extraction (2 * 10mL), and it is concentrated to merge organic layer.At SiO 2upper chromatogram purification (0 to 5%2M NH 3solution/CH in MeOH 2cl 2), generating this title compound of 22.3mg, it is white solid.MS (ESI): C 20h 21n 3accurate calculation quality, 303.17; Measured value, m/z 304.2[M+H] +.
1H NMR(500 MHz，CDCl 3)：7.35-7.30(m，3H)，7.27-7.21(m，2H)，7.20-7.16(m，3H)，7.15-7.12(m，2H)，3.06-3.02(m，2H)，2.83-2.79(m，2H)，2.72-2.67(m，4H)，2.50(s，3H).
Embodiment 209
Figure S04833737820060524D001591
2-sec.-propyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 204mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 194mg 4-aminomethyl phenyl boric acid, as described in embodiment 177 step C and D, prepare this title compound (129mg).MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.28(d，J＝7.7Hz，2H)，7.12(d，J＝7.7Hz，2H)，4.32(m，1H)，3.34-3.33(m，2H)，3.12-3.10(m，2H)，2.70-2.68(m，2H)，2.33(s，3H)，1.30(d，J＝6.6Hz，6H).
Embodiment 210
Figure S04833737820060524D001592
3-(4-ethyl-phenyl)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 202mg 2-sec.-propyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 189, steps A) and 212mg 4-ethylphenyl boric acid; as described in embodiment 177 step C and D, prepare this title compound (134mg).MS (ESI): C 18h 25n 3accurate calculation quality 283.20; Measured value, m/z 284.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44(d，J＝7.7Hz，2H)，7.31(d，J＝7.7Hz，2H)，4.52(m，1H)，3.50-3.48(m，2H)，3.36-3.34(m，2H)，2.85-2.83(m，2H)，2.75(q，J＝7.7Hz，2H)，1.47(d，J＝6.6Hz，6H)，1.29(t，J＝7.7Hz，3H).
Embodiment 211
3-(the chloro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 205mg 2-sec.-propyl-3-trifyl oxygen base-4; 5; 7,8-tetrahydrochysene-2H-1,2; (embodiment 189 for 6-tri-azepines-Azulene-6-t-butyl formate; steps A) and 332mg 2-(the chloro-phenyl of 4-)-benzo [1,3,2] dioxo bora cyclopentenes (dioxaborole); as described in embodiment 177 step C and D, prepare this title compound (82mg).MS (ESI): C 16h 20clN 3accurate calculation quality, 289.13; Measured value, m/z290.4[M+H] +, 292.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57(d，J＝8.5Hz，2H)，7.33(d，J＝8.5Hz，2H)，4.36(m，1H)，3.44-3.40(m，2H)，3.20-3.18(m，2H)，2.81-2.76(m，2H)，1.40(d，J＝6.6Hz，6H).
Embodiment 212
Figure S04833737820060524D001602
4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
With 205mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 211mg 4-cyano-phenyl boric acid, as described in embodiment 177 step C and D, prepare this title compound (95mg).MS (ESI): C 17h 20n 4accurate calculation quality, 280.17; Measured value, m/z 281.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57(d，J＝8.5Hz，2H)，7.33(d，J＝8.5Hz，2H)，4.36(m，1H)，3.42-3.40(m，2H)，3.19-3.17(m，2H)，2.79-2.77(m，2H)，1.40(d，J＝6.6Hz，6H).
Embodiment 213
Figure S04833737820060524D001611
2-sec.-propyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
With 199mg 2-sec.-propyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 189, steps A) and 265mg 4-trifluoromethyl phenyl boronic acid; as described in embodiment 177 step C and D, prepare this title compound (103mg).MS (ESI): C 17h 20f 3n 3accurate calculation quality, 323.16; Measured value, m/z 324.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.86(d，J＝8.0Hz，2H)，7.55(d，J＝8.0Hz，2H)，4.34(m，1H)，3.43-3.40(m，2H)，3.20-3.18(m，2H)，2.80-2.78(m，2H)，1.40(d，J＝6.6Hz，6H).
Embodiment 214
2-ethyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 201mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 198mg 4-aminomethyl phenyl boric acid, as described in embodiment 177 step C and D, prepare this title compound (136mg).MS (ESI): C 16h 21n 3accurate calculation quality, 255.17; Measured value, m/z 256.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38(d，J＝8.OHz，2H)，7.25(d，J＝8.0Hz，2H)，4.67(br s，1H)，4.05(q，J＝7.1Hz，2H)，3.92-3.41(m，2H)，3.28-3.18(m，3H)，2.89-2.80(m，2H)，2.43(s，3H)，1.29(t，J＝7.1Hz，3H).
Embodiment 215
Figure S04833737820060524D001621
The 2-tertiary butyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-(tertiary butyl)-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with the tertiary fourth hydrazine of hydrochloric acid, replace phenylhydrazine, with the trimethyl carbinol, replace EtOH, add 3 equivalent triethylamines simultaneously, as described in embodiment 176 steps A and B, prepare needed triflate.
step B.the triflate of preparing by 200mg steps A and 166mg phenyl-boron dihydroxide, as described in embodiment 177 step C and D, prepare this title compound (53mg).MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.5[M+H] +, 214.4[M-tBu] +.
1H NMR(500MHz，CD 3OD)：7.49-7.47(m，3H)，7.32-7.30(m，2H)，3.41-3.39(m，2H)，3.253.23(m，2H)，3.18-3.15(m，2H)，2.52-2.520(m，2H)，1.41(s，9H).
Embodiment 216
Figure S04833737820060524D001622
The 2-tertiary butyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 204mg 2-(tertiary butyl)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 215, steps A) and 194mg 4-fluorophenyl boric acid; as described in embodiment 177 step C and D, prepare this title compound (88mg).MS (ESI): C 17h 22fN 3accurate calculation quality, 287.18; Measured value, m/z 288.4[M+H] +, 232.4[M- tbu] +.
1H NMR(500MHz，CD 3OD)：7.37-7.33(m，2H)，7.26-7.22(m，2H)，3.41-3.38(m，2H)，3.26-3.24(m，2H)，3.18-3.15(m，2H)，2.53-2.51(m，2H)，1.42(s，9H).
Embodiment 217
Figure S04833737820060524D001631
2-cyclopentyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 204.3mg 2-cyclopentyl-3-trifyl oxygen base-4; 5; 7; 8 tetrahydrochysenes-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 204.1mg 4-aminomethyl phenyl boric acid; as described in embodiment 177 step C and D, prepare this title compound (70.4mg).MS (ESI): C 19h 25n 3accurate calculation quality, 295.42; Measured value, m/z 296.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37(d，J＝7.9Hz，2H)，7.21(d，J＝7.9Hz，2H)，4.50(m，1H)，3.43-3.40(m，2H)，3.32-3.28(m，2H)，3.20-3.17(m，2H)，2.80-2.77(m，2H)，2.43(s，3H)，2.04-1.86(m，6H)，1.64-1.55(m，2H).
Embodiment 218
Figure S04833737820060524D001632
2-cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 269.2mg 2-cyclopentyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 359.2mg 4-trifluoromethyl phenyl boronic acid; as described in embodiment 177 step C and D, prepare this title compound (45.2mg).MS (ESI): C 19h 22f 3n 3accurate calculation quality, 349.49; Measured value, m/z 350.3[M+H] +. 1HNMR(500MHz，CD 3OD)：7.87(d，J＝7.9Hz，2H)，7.55(d，J＝7.9Hz，2H)，4.48(m，1H)，3.43-3.40(m，2H)，3.21-3.17(m，2H)，2.81-2.77(m，2H)，2.07-1.86(m，6H)，1.66-1.57(m，2H).
Embodiment 219
Figure S04833737820060524D001641
3-(the chloro-phenyl of 3-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 204.4mg 2-cyclopentyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 234.5mg 3-chlorophenylboronic acid; as described in embodiment 177 step C and D, prepare this title compound (34.9mg).MS (ESI): C 18h 22clN 3accurate calculation quality, 315.84; Measured value, m/z 316.4[M+H] +.
1H NMR(500MHz，CO 3OD)：7.57-7.52(m，2H)，7.37-7.35(m，1H)，7.29-7.26(m，1H)，4.46(m，1H)，3.43-3.39(m，2H)，3.20-3.16(m，2H)，2.80-2.76(m，2H)，2.06-1.86(m，6H)，1.66-1.57(m，2H).
Embodiment 220
Figure S04833737820060524D001642
2-cyclopentyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 299.2mg 2-cyclopentyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 329.2mg 4-anisole ylboronic acid; as described in embodiment 177 step C and D, prepare this title compound (34.9mg).MS (ESI): C 19h 25n 3the accurate calculation quality of O, 311.42; Measured value, m/z312.3[M+H] +.
1H NMR(500MHz，CD 3OD)：7.26-7.23(m，2H)，7.11-7.08(m，2H)，4.51(m，1H)，3.87(s，3H)，3.43-3.40(m，2H)，3.20-3.16(m，2H)，2.80.-2.76(m，2H)，2.02-1.86(m，6H)，1.64-1.55(m，2H).
Embodiment 221
2-(3,3-dimethyl-cyclopentyl)-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
steps A .2-(3,3-dimethyl-cyclopentyl)-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with hydrochloric acid (3,3-dimethyl-cyclopentyl)-hydrazine, replace phenylhydrazine, with the trimethyl carbinol, replace EtOH, add 3 equivalent triethylamines simultaneously, as described in embodiment 176 steps A and B, prepare needed triflate.
step B.the triflate of preparing by 197.5mg steps A and 150mg phenyl-boron dihydroxide, as described in embodiment 177 step C and D, prepare this title compound (92.8mg).MS (ESI): C 20h 27n 3accurate calculation quality, 309.45; Measured value, m/z 310.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.58-7.50(m，3H)，7.34-7.31(m，2H)，4.66-4.58(m，1H)，3.44-3.40(m，2H)，3.32-3.28(m，2H)，3.21-3.17(m，2H)，2.81-2.77(m，2H)，2.21-2.03(m，2H)，2.01-1.95(m，1H)，1.80-1.73(m，2H)，1.48-1.39(m，1H)，1.16(s，3H)，0.92(s，3H).
Embodiment 222
Figure S04833737820060524D001661
2-(3,3-dimethyl-cyclopentyl)-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 201.7mg 2-(3; 3-dimethyl-cyclopentyl)-3-trifyl oxygen base-4; 5; 7,8-tetrahydrochysene-2H-1,2; (embodiment 221 for 6-tri-azepines-Azulene-6-t-butyl formate; steps A) and 180mg 4-fluorophenyl boric acid, as described in embodiment 177 step C and D, prepare this title compound (52.6mg).MS (ESI): C 20h 26fN 3accurate calculation quality, 327.44; Measured value, m/z 328.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.34(m，2H)，7.33-7.28(m，2H)，4.62-4.53(m，1H)，3.44-3.39(m，2H)，3.31-3.29(m，2H)，3.21-3.17(m，2H)，2.80-2.75(m，2H)，2.20-2.03(m，2H)，2.00-1.94(m，1H)，1.80-1.73(m，2H)，1.49-1.41(m，1H)，1.16(s，3H)，0.93(s，3H).
Embodiment 223
Figure S04833737820060524D001662
3-(the chloro-phenyl of 4-)-2-(3,3-dimethyl-cyclopentyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 203.3mg 2-(3; 3-dimethyl-cyclopentyl)-3-trifyl oxygen base-4; 5; 7,8-tetrahydrochysene-2H-1,2; (embodiment 221 for 6-tri-azepines-Azulene-6-t-butyl formate; steps A) and 204.1mg4-chlorophenylboronic acid, as described in embodiment 177 step C and D, prepare this title compound (25.6mg).MS (ESI): C 20h 26clN 3accurate calculation quality, 343.89; Measured value, m/z 344.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57(d，J＝8.5Hz，2H)，7.32(d，J＝8.5Hz，2H)，4.62-4.54(m，1H)，3.43-3.39(m，2H)， 3.32-3.28(m，2H)，3.20-3.16(m，2H)，2.79-2.75(m，2H)，2.19-2.03(m，2H)，1.99-1.94(m，1H)，1.80-1.73(m，2H)，1.49-1.40(m，1H)，1.16(s，3H)，0.94(s，3H).
Embodiment 224
2-cyclohexyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 206.5mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 177, step B) and 193.2mg 4-fluorophenyl boric acid; as described in embodiment 177 step C and D, prepare this title compound (17.2mg).MS (ESI): C 19h 24fN 3accurate calculation quality, 313.41; Measured value, m/z 314.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37-7.28(m，4H)，3.91-3.84(m，1H)，3.43-3.38(m，2H)，3.32-3.27(m，2H)，3.18-3.14(m，2H)，2.78-2.74(m，2H)，1.96-179(m，6H)，1.69-1.63(m，1H)，1.30-1.19(m，3H).
Embodiment 225
Figure S04833737820060524D001672
2-cyclohexyl-3-(the fluoro-phenyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 205.2mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 177 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; step B) and 224.9mg 3; 4-difluorophenyl boric acid, as described in embodiment 177 step C and D, prepares this title compound (42.7mg).MS (ESI): C 19h 23f 2n 3accurate calculation quality, 331.40; Measured value, m/z 332.5 [M+H] +.
1H NMR(500MHz，CD 3OD)：7.51-7.44(m，1H)，7.34-7.28(m，1H)，7.17-7.13(m，1H)，3.91-3.84(m，1H)，3.42-3.38(m，2H)，3.18-3.14(m，2H)，2.78-2.74(m，2H)，1.96-1.78(m，6H)，1.70-1.64(m，1H)，1.32-1.19(m，3H).
Embodiment 226
Figure S04833737820060524D001681
2-cyclohexyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 203.8mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 177, step B) and 181.6mg 4-aminomethyl phenyl boric acid; as described in embodiment 177 step C and D, prepare this title compound (60.2mg).MS (ESI): C 20h 27n 3accurate calculation quality, 309.45; Measured value, m/z 310.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.37(d，J＝7.7Hz，2H)，7.19(d，J＝7.7Hz，2H)，3.97-3.89(m，1H)，3.44-3.39(m，2H)，3.31-3.26(m，2H)，3.20-3.15(m，2H)，2.80-2.75(m，2H)，1.96-1.78(m，6H)，1.70-1.62(m，1H)，1.28-1.18(m，3H).
Embodiment 227
Figure S04833737820060524D001682
2-cyclohexyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 207mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 177, step B) and 224.1mg 4-anisole ylboronic acid; as described in embodiment 177 step C and D, prepare this title compound (96.8mg).MS (ESI): C 20h 27n 3the accurate calculation quality of O, 325.45; Measured value, m/z 326.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.25(d，J＝8.7Hz，2H)，7.11(d，J＝8.7Hz，2H)，4.00-3.92(m，1H)，3.87(s，3H)，3.45-3.40(m，2H)，3.22-3.17(m，2H)，2.81-2.75(m，2H)，1.96-1.65(m，7H)，1.29-1.19(m，3H).
Embodiment 228
4-(2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
With 203.8mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 177, step B) and 198mg 4-cyano-phenyl boric acid; as described in embodiment 177 step C and D, prepare this title compound (135.4mg).MS (ESI): C 20h 24n 4accurate calculation quality, 320.43; Measured value, m/z321.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.93(d，J＝8.5Hz，2H)，7.53(d，J＝8.5Hz，2H)，3.92-3.84(m，1H)，3.43-3.38(m，2H)，3.19-3.15(m，2H)，2.80-2.75(m，2H)，1.98-1.80(m，6H)，1.71-1.64(m，1H)，1.32-1.20(m，3H).
Embodiment 229
3-(the chloro-phenyl of 3-)-2-cyclohexyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 199.3mg 2-cyclohexyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 177, step B) and 216.2mg 3-chlorophenylboronic acid; as described in embodiment 177 step C and D, prepare this title compound (14.4mg).MS (ESI): C 19h 24clN 3accurate calculation quality, 329.87; Measured value, m/z 330.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.54(m，2H)，7.35(s，1H)，7.28-7.25(m，1H)，3.91-3.84(m，1H)，3.43-3.38(m，2H)，3.19-3.14(m，2H)，2.79-2.74(m，2H)，1.97-1.80(m，6H)，1.71-1.64(m，1H)，1.28-1.19(m，3H).
Embodiment 230
Figure S04833737820060524D001701
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] and-phenyl }-methyl-amine
By 1-(the bromo-benzyl of 4-)-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 113 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.04mmol), t-butyl carbamate (0.05mmol), sodium phenylate trihydrate (0.05mmol), the mixture of three (dibenzalacetone) two palladiums (0) (0.001mmol) He three-tertiary butyl phosphines (0.05mmol) in dry toluene (3mL) are at N 2under atmosphere, in 6 hours, 70 ℃ heating of 100 ℃ of heating, within 15 hours and 100 ℃, heat 2.5 hours.Be cooled to after room temperature, reaction mixture is directly prepared to TLC purifying (2: 1 hexane/EtOAc), generate 0.008g 1-(uncle 4--butoxy carbonyl amino-benzyl)-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate, is then used DMF (1mL) dilution, and process with NaH (60%, 1.5 equivalent).After 15 minutes, add methyl-iodide (1.5 equivalent).After 1 hour, reaction H 2o ends, and by EtOAc extraction (2x) for mixture.To merge organic layer at Na 2sO 4and concentrated.Then gained semisolid is dissolved in to CH 2cl 2/ MeOH (9: 1,1mL) in, and (1N is at Et with HCl 2solution in O, 4mL) processes.Mixture is stirring at room 3 hours, then concentrated.Gained oily matter is prepared to TLC purifying (10%2M NH 3solution/CH in MeOH 2cl 2), generating this title compound of 0.002mg, it is white solid.MS (ESI): C 21h 23clN 4accurate calculation quality, 366.16; Measured value, m/z 367.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.32(m，4H)，6.84(d，J＝8.6Hz，1H)，6.48-6.45(m，2H)，5.12(s，2H)，2.84-2.81(m，4H)，2.79-2.77(m，2H)，2.69-2.66(m，2H)，2.63(s，3H).
Embodiment 231
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [4,3-c] pyridine
steps A .2-sec.-propyl-3-trifyl oxygen base-2,4,6,7-tetrahydrochysene-pyrazolo [4,3-c] pyridine-5-t-butyl formate.the method of describing according to embodiment 189 steps A, from 4-oxo-piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl esters starts, and prepares needed triflate.
step B.the triflate of preparing by 221mg steps A and 140mg 4-fluorophenyl boric acid, as described in embodiment 177 step C and D, prepare this title compound (26mg).MS (ESI): C 15h 18fN 3accurate calculation quality, 259.32; Measured value, m/z 260.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.39(m，2H)，7.33-7.28(m，2H)，4.48(m，1H)，4.15(s，2H)，3.58(t，J＝6.3Hz，2H)，3.08(t，J＝6.3Hz，2H)，1.42(d，J＝6.6Hz，6H).
Embodiment 232
Figure S04833737820060524D001712
2-cyclopentyl-3-furans-3-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 202mg 2-cyclopentyl-3--trifyl oxygen base-4,5,7; 8--tetrahydrochysene-2H-1, (embodiment 180 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 149mg 3-furans boric acid, according to embodiment 180, prepare this title compound (101mg).MS (ESI): C 16h 21n 3the accurate calculation quality of O, 271.17; Measured value, m/z 272.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.73-7.72(m，2H)，6.57-6.56(m，1H)，4.64(m，1H)，3.40-3.38(m，2H)，3.16-3.14(m，2H)，2.86-2.84(m，2H)，2.03-1.91(m，6H)，1.66-1.64(m，2H).
Embodiment 233
Figure S04833737820060524D001721
2-cyclopentyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 200mg 2-cyclopentyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 180 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 282mg 2-thienyl boric acid, according to embodiment 180, prepare this title compound (83mg).MS (ESI): C 16h 21n 3the accurate calculation quality of S, 287.15; Measured value, m/z 288.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.70-7.68(m，1H)，7.24-7.22(m，1H)，7.15-7.14(m，1H)，4.64(m，1H)，3.41-3.39(m，2H)，3.16-3.15(m，2H)，2.85-2.83(m，2H)，2.01-1.88(m，6H)，1.64-1.60(m，2H).
Embodiment 234
Figure S04833737820060524D001722
The 2-tertiary butyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 204mg 2-(tertiary butyl)-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 215 for 2,6 three azepines-Azulene-6-t-butyl formate; steps A) and 177mg 3 thienylboronic acid, according to embodiment 215, prepare this title compound (83mg).MS (ESI): C 15h 21n 3the accurate calculation quality of S, 275.15; Measured value, m/z 276.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.59-7.57(m，1H)，7.43-7.42(m，1H)，7.08-7.06(m，1H)，3.38-3.36(m，2H)，3.25-3.23(m，2H)，3.13-3.11(m，2H)，2.56-2.54(m，2H)，1.43(s，9H).
Embodiment 235
The 2-tertiary butyl-3-furans-3-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 203mg 2-(tertiary butyl)-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 215 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 154mg 3-furans boric acid, according to embodiment 215, prepare this title compound (60mg).MS (ESI): C 15h 21n 3the accurate calculation quality of O, 259.17; Measured value, m/z 260.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.69-7.68(m，1H)，7.61(br s，1H)，6.50-6.49(m，1H)，3.38-3.36(m，2H)，3.27-3.25(m，2H)，3.13-3.11(m，2H)，2.63-2.61(m，2H)，1.50(s，9H).
Embodiment 236
Figure S04833737820060524D001732
2-cyclopentyl-3-(the fluoro-phenyl of 3,4-bis-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-Azaazulenes
With 209mg 2-cyclopentyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 180, steps A) and 218mg 3; 4-difluorophenyl boric acid, according to embodiment 180, prepares this title compound (70mg).MS (ESI): C 18h 21f 2n 3accurate calculation quality, 317.17; Measured value, m/z318.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.45(m，1H)，7.36-7.32(m，1H)，7.18-7.17(m，1H)，4.49(m，1H)，3.43-3.41(m，2H)，3.21-3.19(m，2H)，2.80-2.78(m，2H)，2.15-1.87(m，6H)，1.66-1.61(m，2H).
Embodiment 237
3-(the chloro-phenyl of 4-)-1-cyclobutyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-1-cyclobutyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 238), prepares this title compound (0.01g). (MS (ESI): C 17h 20clN 3accurate calculation quality, 301.13; Measured value, m/z302.4[M+H] +. 1HNMR(500MHz，CD 3OD)：7.54-7.48(m，4H)，5.15-5.05(m，1H)，3.47-3.46(m，2H)，3.35-3.30(m，4H)，3.22-3.21(m，2H)，2.70-2.60(m，2H)，2.50-2.40(m，2H)，1.90-1.80(m，2H).
Embodiment 238
Figure S04833737820060524D001742
3-(the chloro-phenyl of 4-)-2-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
In 25 ℃ to 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.40mmol) in the solution in DMF (2mL), add NaH (60% suspension in oil, 60mg).After 10 minutes, mixture is heated to 80 ℃, and adds chlorine tetramethylene (1.5mmol).Mixture is heated 16 hours in this temperature.Mixture is concentrated, and carry out chromatogram purification (SiO 2, EtOAc/ hexane), generate 3-(the chloro-phenyl of 4-)-2-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.Deprotection method according in embodiment 103 step C, obtains this title compound (0.030mg) by described ester.In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-1-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 17h 20clN 3accurate calculation quality, 301.13; Measured value, m/z 302.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.52-7.51(m，2H)，7.30-7.29(m，2H)，4.70-4.60(m，1H)，3.40-3.89(m，2H)，3.27-3.21(m，4H)，2.79-2.76(m，2H)，2.60-2.50(m，2H)，2.30-2.20(m，2H)，1.81-1.65(m，2H).
Embodiment 239
Figure S04833737820060524D001751
3-(the chloro-phenyl of 4-)-1-cyclohexyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 238, with bromo-hexanaphthene (1.5mmol), replace chloro-tetramethylene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.40mmol) prepare this title compound (15mg).MS (ESI): C 19h 24clN 3, 329.17; Measured value, m/z 330.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.41(m，4H)，4.30-4.27(m，1H)，3.44-3.42(m，2H)，3.31-3.26(m，4H)，2.98-2.96(m，2H)，1.93-1.84(m，5H)，1.70-1.65(m，1H)，1.46-1.40(m，2H)，1.24-1.89(m，2H).
Embodiment 240
Figure S04833737820060524D001752
The 2-tertiary butyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 203mg 2-(tertiary butyl)-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 215 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 176mg 2-thienyl boric acid, according to embodiment 215, prepare this title compound (83mg).MS (ESI): C 15h 21n 3the accurate calculation quality of S, 275.15; Measured value, m/z 276.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.56(m，1H)，7.08-7.06(m，1H)，7.01-7.00(m，1H)，3.29-3.27(m，2H)，3.17-3.14(m，2H)，2.51-2.48(m，2H)，1.37(s，9H).
Embodiment 241
Figure S04833737820060524D001761
3-(the fluoro-phenyl of the chloro-3-of 4-)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 146mg 2-cyclopentyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 180 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and the chloro-4-fluorophenyl of 168mg 3-boric acid, according to embodiment 180, prepare this title compound (31mg).MS (ESI): C 18h 21clFN 3accurate calculation quality, 333.14; Measured value, m/z 334.4[M+H] +, 336.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.31(m，2H)，7.22-7.18(m，1H)，4.37(m，1H)，3.31-3.28(m，2H)，3.07-3.03(m，2H)，2.67-2.64(m，2H)，2.11-1.78(m，6H)，1.56-1.47(m，2H).
Embodiment 242
Figure S04833737820060524D001762
2-sec.-propyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 206mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 219mg 4-anisole ylboronic acid, according to embodiment 189, prepare this title compound (148mg).MS (ESI): C 17h 23n 30 accurate calculation quality, 285.18; Measured value, m/z 286.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.30-7.28(m，2H)，7.13-7.11(m，2H)，4.68(m，1H)，4.47(m，1H)，3.87(s，3H)，3.47-3.44(m，1H)，3.25-3.23(m，1H)，2.89-2.81(m，2H)，1.43(d，J＝6.6Hz，6H).
Embodiment 243
Figure S04833737820060524D001771
2-sec.-propyl-3-(4-trifluoromethoxy-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 278mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 402mg 4-Trifluoromethoxyphen-l boric acid, according to embodiment 189, prepare this title compound (196mg).MS (ESI): C 17h 20f 3n 3the accurate calculation quality of O, 339.36; Measured value, m/z 340.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.53-7.45(m，4H)，4.66(br s，1H)，4.40(J＝6.68Hz，1H)，3.45-3.43(m，1H)，3.23-3.21(m，1H)，2.88-2.79(m，2H)，1.42(d，J＝6.7Hz，6H).
Embodiment 244
Figure S04833737820060524D001772
2-sec.-propyl-3-(4-sec.-propyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 270mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 311mg 4-isopropyl benzene ylboronic acid, according to embodiment 189, prepare this title compound (177mg).MS (ESI): C 19h 27n 3accurate calculation quality, 297.44; Measured value, m/z 298.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.35-7.34(m，2H)，7.19-7.17(m，2H)，4.57(br s，1H)，4.38-4.32(m，1H)，3.36-3.34(m，1H)，3.15-3.13(m，1H)，2.90(m，1H)，2.79-2.70(m，2H)，1.31(d，J＝13.3Hz，6H)，1.20(d，J＝6.9Hz，6H).
Embodiment 245
Figure S04833737820060524D001781
3-(the 4-tertiary butyl-phenyl)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 215mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 268mg 4-tert.-butylbenzene ylboronic acid, according to embodiment 189, prepare this title compound (28mg).MS (ESI): C 20h 29n 3accurate calculation quality, 311.24; Measured value, m/z 312.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.61-7.59(m，2H)，7.27-7.25(m，2H)，4.40(m，1H)，3.43-3.40(m，2H)，3.19-3.17(m，2H)，2.79-2.77(m，2H)，1.50-1.25(m，15H).
Embodiment 246
Tolyl-2 between 2-sec.-propyl-3-, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 219mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 209mg 3-aminomethyl phenyl boric acid, according to embodiment 189, prepare this title compound (24mg).MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.41(m，1H)，7.34-7.33(m，1H)，7.13-7.10(m，2H)，4.37(m，1H)，3.42-3.40(m，2H)，3.19-3.17(m，2H)，2.78-2.76(m，2H)，2.42(s，3H)，1.38(d，J＝6.7Hz，6H).
Embodiment 247
Figure S04833737820060524D001791
2-sec.-propyl-3-o-tolyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 207mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 198mg 2-aminomethyl phenyl boric acid, according to embodiment 189, prepare this title compound (80mg).MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.40(m，2H)，7.36-7.33(m，1H)，7.19-7.18(m，1H)，4.66(br s，2H)，4.10(m，1H)，4.00-3.66(m，2H)，2.76-2.61(m，2H)，2.13(s，3H)，1.45-1.29(m，6H).
Embodiment 248
3-(the chloro-phenyl of 3,4-bis-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 200mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 189, steps A) and 268mg 3; 4-dichlorophenyl boric acid, according to embodiment 189, prepares this title compound (60mg).MS (ESI): C 16h 19c l2n 3accurate calculation quality, 323.10; Measured value, m/z 324.4[M+H] +, 326.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.72-7.71(m，1H)，7.53-7.52(m，1H)，7.29-7.27(m，1H)，4.64(brs，2H)，4.32(m，1H)，3.86-3.57(m，2H)，3.31-3.08(m，2H)，2.84-2.75(m，2H)，1.39(d，J＝6.6Hz，6H).
Embodiment 249
Figure S04833737820060524D001801
2-benzyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-benzyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with hydrochloric acid benzyl hydrazine, replace hydrochloric acid Iproniazid, according to embodiment 189 steps A, prepare needed triflate.
step B.the triflate of preparing by 230mg steps A and 234mg 4-fluorophenyl boric acid, as described in embodiment 177 step C and D, prepare this title compound (29mg).MS (ESI): C 20h 20fN 3accurate calculation quality, 321.39; Measured value, m/z322.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.31-7.19(m，7H)，6.97-6.93(m，2H)，5.20(s，2H)，3.45-3.40(m，2H)，3.35-3.30，(m，2H)，3.20-3.15(m，2H)，2.83-2.78(m，2H).
Embodiment 250
Figure S04833737820060524D001802
2-sec.-propyl-3-thiophene-2-base-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 208mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 187mg 2-thienyl boric acid, according to embodiment 189, prepare this title compound (46mg).MS (ESI): C 14h 19n 3the accurate calculation quality of S, 261.13; Measured value, m/z 262.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.70-7.69(m，1H)，7.25-7.23(m，1H)，7.15-7.14(m，1H)，4.65(br s，2H)，4.55-4.49(m，1H)，3.8-3.6(m，2H)，3.23-3.10(m，2H)，2.93-2.83(m，2H)，1.44-1.36(m，6H).
Embodiment 251
3-(the chloro-phenyl of 2-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 266mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 292mg 2-chlorophenylboronic acid, according to embodiment 189, prepare this title compound (90mg).MS (ESI): C 16h 20clN 3accurate calculation quality, 289.13; Measured value, m/z 290.4[M+H] +, 292.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.65-7.63(m，1H)，7.58-7.49(m，2H)，7.41-7.39(m，1H)，4.66(br s，2H)，4.16(m，1H)，4.00-3.44(m，2H)，3.0-2.6(m，2H)，1.47-1.38(m，6H).
Embodiment 252
Figure S04833737820060524D001812
1-[4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-phenyl]-ethyl ketone
With 255mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 341mg 4-acetylbenzene ylboronic acid, according to embodiment 189, prepare this title compound (168mg).MS (ESI): C 18h 23n 3the accurate calculation quality of O, 297.18; Measured value, m/z298.5[M+H] +.
1H NMR(500MHz，CD 3OD)：8.17-8.15(m，1H)，7.69-7.67(m，1H)，7.51-7.49(m，1H)，7.37-7.35(m，1H)，4.65(br s，1H)，4.46-4.38(m，1H)，4.00-3.50(m，2H)，3.48-3.42(m，1H)，3.25-3.17(m，1H)，3.13-2.81(m，2H)，2.67(s，1.5H)，1.55(s，1.5H)，1.44-1.40(m，6H).
Embodiment 253
2-sec.-propyl-3-(4-nitro-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 274mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 189 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 321mg 4-nitrophenyl boric acid, according to embodiment 189, prepare this title compound (34mg).MS (ESI): C 16h 20n 4o 2accurate calculation quality, 300.16; Measured value, m/z 301.4[M+H] +.
1H NMR(500MHz，CD 3OD)：8.42-8.40(m，2H)，7.62-7.60(m，2H)，4.37(m，1H)，3.43-3.41(m，2H)，3.21-3.18(m，2H)，2.82-2.79(m，2H)，1.41(d，J＝8.2Hz，6H).
Embodiment 254
Figure S04833737820060524D001822
3-(the chloro-phenyl of 4-)-1-suberyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With chloro-suberane (1.0mmol), replace chloro-tetramethylene, according to embodiment 238, by 3-(the chloro-phenyl of 4-)-4,5,7,8 tetrahydrochysenes-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.30mmol) prepare this title compound (22mg).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-suberyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes-6-t-butyl formate.MS (ESI): C 20h 26clN 3accurate calculation quality, 343.18; Measured value, m/z 344.4[M+H] +. 1HNMR(500MHz，CD 3OD)：7.40-7.34(m，4H)，4.31-4.27(m，1H)，3.39-3.37(m，2H)，3.28-3.26(m，2H)，3.17-3.16(m，2H)，2.95-2.92(m，2H)，2.04-2.01(m，2H)，1.92-1.90(m，2H)，1.77-1.75(m，2H)，1.63-1.53(m，6H).
Embodiment 255
3-(the chloro-phenyl of 4-)-1-encircles octyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With chloro-cyclooctane (1.0mmol), replace chloro-tetramethylene, according to embodiment 238, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.30mmol) prepare this title compound (47mg).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-and encircles octyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 21h 28clN 3accurate calculation quality, 357.20; Measured value, m/z 358.5[M+H] +. 1HNMR(500MHz，CD 3OD)：7.50-7.44(m，4H)，4.49-4.45(m，1H)，3.51-3.48(m，2H)，3.38-3.36(m，2H)，3.33-3.32(m，2H)，3.05-3.04(m，2H)，2.21-2.18(m，2H)，1.97-1.88(m，4H)，1.72-1.64(m，8H).
Embodiment 256
2-benzyl-3-(the chloro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,5-, tri-azepines-Azulene
As described in embodiment 60, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.1g) prepare this title compound (0.023g).MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.47-7.44(m，2H)，7.25-7.19(m，5H)，6.94-6.92(m，2H)，5.17(s，2H)，3.66(s，2H)，3.21-3.19(m，2H)，2.93-2.90(m，2H)，1.93-1.84(s，2H).
Embodiment 257
2-ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 213mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 232mg 4-ethylphenyl boric acid, according to embodiment 193, prepare this title compound (140mg).MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.40-7.39(m，2H)，7.27-7.26(m，2H)，4.65(br s，2H)，4.05-4.00(m，2H)，3.8-3.6(m，2H)，3.18-3.00(m，2H)，2.88-2.81(m，2H)，2.76-2.71(m，2H)，1.32-1.24(m，6H).
Embodiment 258
Figure S04833737820060524D001842
4-(2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
With 205mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-Azaazulenes-6-t-butyl formate; steps A) and 218mg 4-cyano-phenyl boric acid, according to embodiment 193, prepare this title compound (47mg).MS (ESI): C 16h 18n 4accurate calculation quality, 266.15; Measured value, m/z 267.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.93-7.91(m，2H)，7.58-7.56(m，2H)，4.03(q，J＝7.2Hz，2H)，3.43-3.40(m，2H)，3.18-3.16(m，2H)，2.82-2.80(m，2H)，1.29(t，J＝7.2Hz，3H).
Embodiment 259
Figure S04833737820060524D001851
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-6-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 35, by 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (embodiment 190) and paraformaldehyde are prepared this title compound (113mg).MS (ESI): C 17h 22fN 3accurate calculation quality, 287.18; Measured value, m/z288.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.42-7.40(m，2H)，7.34-7.30(m，2H)，4.42(m，1H)，3.77-3.74(m，1H)，3.67-3.62(m，2H)，3.36-3.34(m，1H)，3.27-3.21(m，3H)，3.03(s，3H)，2.92-2.89(m，1H)，2.80-2.76(m，1H)，1.49-1.29(m，6H).
Embodiment 260
Figure S04833737820060524D001852
3-(the fluoro-phenyl of 4-)-2,6-di-isopropyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 35, by 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (embodiment 190) and acetone are prepared this title compound (92mg).MS (ESI): C 19h 26fN 3accurate calculation quality, 315.21; Measured value, m/z 316.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.42-7.39(m，2H)，7.33-7.30(m，2H)，4.40(m，1H)，3.78-3.74(m，2H)，3.68-3.63(m，1H)，3.36-3.21(m，4H)，2.99-2.94(m，1H)，2.80-2.76(m，1H)，1.54-1.37(m，12H).
Embodiment 261
Figure S04833737820060524D001861
2-ethyl-3-(4-sec.-propyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 205mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 245mg 4-isopropyl benzene ylboronic acid, according to embodiment 193, prepare this title compound (131mg).MS (ESI): C 18h 25n 3accurate calculation quality, 283.20; Measured value, m/z 284.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.46(m，2H)，7.34-7.33(m，2H)，4.12(q，J＝7.3Hz，2H)，3.50-3.45(m，2H)，3.36-3.33(m，2H)，3.27-3.25(m，2H)，3.01(m，1H)，2.87-2.85(m，2H)，1.34(t，J ＝7.3Hz，3H)，1.31(d，J＝6.9Hz，6H).
Embodiment 262
Figure S04833737820060524D001862
2-ethyl-3-(4-methoxyl group-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 219mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 241mg 4-anisole ylboronic acid, according to embodiment 193, prepare this title compound (134mg).MS (ESI): C 16h 21n 3the accurate calculation quality of O, 271.17; Measured value, m/z 272.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.33(m，2H)，7.15-7.12(m，2H)，4.12(q，J＝7.3Hz，2H)，3.88(s，3H)，3.49-3.47(m，2H)，3.36-3.34(m，2H)，3.28-3.25(m，2H)，2.88-2.85(m，2H)，1.35(t，J＝7.3Hz，3H).
Embodiment 263
2-ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-ethyl-3-(4-trifluoromethyl-phenyl)-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in the round-bottomed flask of 25mL, add 216mg 2-ethyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 193, steps A), 139mg 4-trifluoromethyl phenyl boronic acid, 17mg Bu 4n +br -, 6mg dppf and 17mg PdCl 2(dppf).Add toluene (5mL), then add 0.8mL 2M Na 2cO 3the aqueous solution, and mixture is heated 12 hours in 120 ℃ under nitrogen atmosphere.Mixture is passed through to diatomite filtration, and filtrate is concentrated in a vacuum, generate 294mg chocolate viscosity oily matter.At SiO 2upper chromatogram purification (0 to 25%EtOAc/ hexane) generates the needed product of 177mg.MS (ESI): C 21h 26f 3n 3o 2accurate calculation quality, 409.20; Measured value, m/z 410.5[M+H] +.
step B.according to embodiment 43 step e, prepare this title compound (149mg).MS (ESI): C 16h 18f 3n 3accurate calculation quality, 309.15; Measured value, m/z 310.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.90-7.89(m，2H)，7.65-7.63(m，2H)，4.67(br s，2H)，4.10(q，J＝7.2Hz，2H)，4.00-3.56(m，2H)，3.36-3.24(m，2H)，2.95-2.85(m，2H)，1.33(t，J＝7.2Hz，3H).
Embodiment 264
Figure S04833737820060524D001881
2-ethyl-3-o-tolyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 206mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 95mg 2-aminomethyl phenyl boric acid, according to embodiment 263, prepare this title compound (138mg).MS (ESI): C 16h 21n 3accurate calculation quality, 255.17; Measured value, m/z 256.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.49-7.42(m，2H)，7.38-7.35(m，1H)，7.25-7.24(m，1H)，4.69(br s，2H)，4.03-3.17(m，5H)，2.76-2.68(m，2H)，2.15(s，3H)，1.28(t，J＝7.2Hz，3H).
Embodiment 265
3-(2-oxygen-phenyl)-2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 227mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 120mg 2-chlorophenylboronic acid, according to embodiment 263, prepare this title compound (73mg).MS (ESI): C 15h 18clN 3accurate calculation quality, 275.12; Measured value, m/z 276.4[M+H] +, 278.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.64-7.62(m，1H)，7.58-7.48(m，2H)，7.41-7.39(m，1H)，3.97-3.86(m，2H)，3.44-3.42(m，2H)，3.20-3.17(m，2H)，2.70-2.63(m，2H)，1.26(t，J＝7.2Hz，3H).
Embodiment 266
2-ethyl-3-(the fluoro-phenyl of 2-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
With 205mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 97mg 2-fluorophenyl boric acid, according to embodiment 263, prepare this title compound (121mg).MS (ESI): C 15h 18fN 3accurate calculation quality, 259.15; Measured value, m/z 260.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.61-7.55(m，1H)，7.39-7.30(m，3H)，4.01-3.91(m，2H)，3.43-3.41(m，2H)，3.18-3.16(m，2H)，2.79-2.73(m，2H)，1.28(t，J＝9.0Hz，3H).
Embodiment 267
Figure S04833737820060524D001892
3-(the chloro-phenyl of 2,4-bis-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 230mg 2-sec.-propyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 189, steps A) and 308mg 2; 4-dichlorophenyl boric acid, according to embodiment 189, prepares this title compound (37mg).MS (ESI): C 16h 19cl 2n 3accurate calculation quality, 323.10; Measured value, m/z324.4[M+H] +, 326.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.73-7.72(m，1H)，7.54-7.51(m，1H)，7.37-7.35(m，1H)，4.65(br s，1H)，4.11-4.05(m，1H)，3.43-3.40(m，2H)，3.29-3.16(m，3H)，2.70-2.63(m，2H)，1.39-1.32(m，6H).
Embodiment 268
Figure S04833737820060524D001901
[4-(2-ethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-phenyl]-dimethylamine
With 205mg 2-ethyl-3-trifyl oxygen base-4,5,7; 8-tetrahydrochysene-2H-1, (embodiment 193 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and 115mg 4-dimethylaminophenyl boric acid, according to embodiment 263, prepare this title compound (57mg).MS (ESI): C 17h 24n 4accurate calculation quality, 284.20; Measured value, m/z 285.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.87-7.85(m，2H)，7.65-7.63(m，2H)，4.67(br s，2H)，4.06(q，J＝9.0Hz，2H)，4.00-3.62(m，2H)，3.36(s，6H)，3.32-3.29(m，2H)，3.18-2.81(m，2H)，1.31(t，J＝9.0Hz，3H).
Embodiment 269
Figure S04833737820060524D001902
6-benzyl-3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
As shown in embodiment 35, by 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (embodiment 190) and phenyl aldehyde are prepared this title compound (115mg).MS (ESI): C 23h 26fN 3accurate calculation quality, 363.21; Measured value, m/z 364.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.58-7.55(m，2H)，7.53-7.51(m，3H)，7.37-7.33(m，2H)，7.31-7.27(m，2H)，4.52(s，2H)，4.34(m，1H)，3.80-3.75(m，1H)，3.68-3.64(m，1H)，3.35-3.16(m，4H)，2.83-2.80(m，2H)，1.38(t，J＝6.7Hz，6H).
Embodiment 270
Figure S04833737820060524D001911
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-6-(3-phenyl-propyl group)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 35, by 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (embodiment 190) and 3-phenyl-propionic aldehyde, prepare this title compound (142mg).MS (ESI): C 25h 30fN 3accurate calculation quality, 391.24; Measured value, m/z392.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.45-7.41(m，2H)，7.35-7.26(m，6H)，7.22-7.19(m，1H)，4.46(m，1H)，3.79-3.76(m，1H)，3.67-3.63(m，1H)，3.46-3.43(m，1H)，3.35-3.29(m，5H)，2.90-2.87(m，1H)，2.83-2.73(m，3H)，2.19-2.12(m，2H)，1.44(t，J＝6.7Hz，6H).
Embodiment 271
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-6-styroyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
As described in embodiment 35, by 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene (embodiment 190) and phenylacetic aldehyde are prepared this title compound (104mg).MS (ESI): C 24h 28fN 3accurate calculation quality, 377.23; Measured value, m/z 378.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.41-7.27(m，9H)，4.39(m，1H)，3.88-3.84(m，1H)，3.73-3.71(m，1H)，3.56-3.52(m，3H)，3.45-3.20(m，3H)，3.17-3.14(m，2H)，2.89-2.84(m，2H)，1.41(t，J＝6.6Hz，6H).
Embodiment 272
Figure S04833737820060524D001921
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,7,8-tetrahydrochysene-2H-1, this compound of 2,6-, tri-azepines-Azulene-6-t-butyl formate obtains as intermediate in the described step of embodiment 190.MS (ESI): C 21h 28fN 3o 2accurate calculation quality, 373.46; Measured value, m/z374.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.24-7.13(m，4H)，4.24(m，1H)，3.62-3.55(m，2H)，3.49-3.42(m，2H)，3.01-2.93(m，2H)，2.52-2.44(m，2H)，1.50-1.45(m，9H)，1.39(d.J＝6.9Hz，6H).
Embodiment 273
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion
steps A .5-oxo-azepan-Isosorbide-5-Nitrae-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.by dry, N 2purge, 500-mL, three necks and the round-bottomed flask that is equipped with magnetic stirring bar pack 4-oxo-piperidines-1-t-butyl formate (20g, 0.10mol) and BF into 3-Et 2o (14mL, 0.11mol) is at Et 2solution in O (200mL), and mixture is refrigerated to-5 ℃.Slowly add ethyl diazoacetate (13.7mL, 0.13mol) with 1 hour, generate violent gas simultaneously and overflow.During adding, internal temperature is remained on to 0 ℃--5 ℃.To react at 0 ℃ and stir 1 hour, then at 0 ℃ with 30%Na 2cO 3the aqueous solution is slowly ended.PH is adjusted between 7 and 8, then H 2o (30mL) is added in mixture.By EtOAc extraction (2 * 75mL) for organic layer, at Na 2sO 4upper dry, be concentrated into orange.Thick oily matter is carried out to filtering chromatogram method purifying (SiO 2: external diameter 14cm, high 8cm; 10 to 30%EtOAc/ hexanes), regain this title compound, it is faint yellow oily matter (85%).MS (ESI): C 14h 23nO 5accurate calculation quality; Measured value, m/z without, unstable.HPLC (method B): R t=8.53 minutes.
1H NMR(400MHz，CDCl 3)：4.25-2.03(m，11H)，1.47-1.45(d，J＝7.8Hz，9H)，1.31-1.24(m，3H).
step is oxo-2 B.3-, 3,4,5,7,8-, six hydrogen-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in flask in the outfit of 1L, single neck, round bottom with magnetic stirring bar, by 5-oxo-azepan-1, hydrazine (3.0mL, 0.095mol) in 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (24.42g, 85.0mmol) and EtOH (250mL) mixes.Gained reaction mixture refluxed heating 4 hours, then concentrated, generate needed pyrazoles, it is white product, thick productive rate 95%.By thick pyrazoles for next step and without being further purified.MS (ESI): C 12h 19n 3o 3accurate calculation quality, 253.14; Measured value, m/z 254.1[M+H] +.HPLC (method B): R t=6.48 minutes.
1H NMR(400MHz，CDCl 3)：3.64-3.54(m，4H)，2.91-2.86(m，2H)，2.70-2.65(m，2H)，1.49(s，9H).
step is trifyl oxygen base-4 C.3-, 5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in flask in the outfit of 250mL, single neck, round bottom with magnetic stirring bar, N-phenyl trifluoromethanesulfonate methylsulfonyl imines (50g, 0.14mol) is suspended in 100mL pyridine, then in room temperature, add solid 3-oxo-2,3,4,5,7,8-, six hydrogen-1H-1,2,6-tri-azepines-Azulene-6-t-butyl formate (35.4g, 0.14mol).Reaction mixture, 1, forms homogeneous solution after hour, and continues to stir in room temperature spend the night (15 hours).By solvent vaporising under vacuum, then resistates at Et 2o (500mL) and 1M K 2cO 3(300mL) between the aqueous solution, distribute.Organic layer is separated, use K 2cO 3(1mol/L, 300mL) washs three times, then uses salt solution (200mL) washing once, at MgSO 4upper dry, and evaporation, generate white solid product (50.2g, 0.13mol, 93%), use it for next step reaction and without being further purified.MS (ESI): C 13h 18f 3n 3o 5the accurate calculation quality of S, 385.09; M/z measured value, 384.0[M-H] -.HPLC (method B): R t=9.55 minutes.
1H NMR(500MHz，CDCl 3)：9.52(s，1H)，3.70-3.50(m，4H)，3.00-2.85(m，2H)，2.70-2.60(m，2H)，1.49(s，9H).
step is benzyl-3-trifyl oxygen base-4 D.1-, 5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.in the flask that comprises magnetic stirring bar of 1L, three necks, round bottom, under nitrogen atmosphere by 3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (48g, 0.125mol) is dissolved in the anhydrous THF of 500mL.Solution is cooled to 0 ℃, and adds solid potassium tert-butoxide (15.4g, 0.137mol) in batches.Reaction mixture is stirred to 10 minutes limpid to form, uniform solution.By feed hopper, use 10 minutes and add bromotoluene (23.4g, 0.137mol).By gained mixture in stirred overnight at room temperature (15 hours).Make solvent evaporation, and resistates is dissolved in EtOAc (300mL) again.Organic layer is first used to H 2o (2 * 200mL) then uses salt solution (200mL) washing, at MgSO 4upper dry, filter and concentrate.By crude product via SiO 2plug filters purifying with cushion, generates pure white solid product (44.5g, 94mmol, 75%).MS (ESI): C 20h 24f 3n 3o 5the accurate calculation quality of S, 475.14; Measured value, m/z 476.2[M+H] +.HPLC (method B): R t=10.90 minutes.
1H NMR(500MHz，CDCl 3)：7.40-7.25(m，5H)，7.10-7.05(m，2H)，5.22-5.15(m，2H)，3.60-3.50(m，4H)，2.80-2.60(m，4H)，1.47-1.42(m，9H).
step e .2-(the chloro-phenyl of 4-)-benzo [1,3,2] dioxo bora cyclopentenes (dioxaborole).in flask in the outfit of 250mL, single neck, round bottom with Dean Rodney Stark water trap and condenser, by 4-chlorophenylboronic acid (17.5g, 0.112mol) and the solution reflux of catechol (12.3g, 0.112mol) in toluene (150mL) 4 hours.Solution is cooled to room temperature, so be settled out white solid.Make solvent evaporation, and by crude product (25.8g, 0.112mol, 100%) like this for next reaction without being further purified.HPLC (method B): R t=6.00 and 7.50 minutes.
1H NMR(500MHz，CDCl 3)：8.01(d，J ＝8.1Hz，2H)，7.47(d，J＝8.1Hz，2H)，7.34-7.29(m，2H)，7.15-7.11(m，2H).
step F .1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7.8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.under nitrogen atmosphere, in the flask of 1L, three necks, round bottom, add Pd (dppf) Cl 2(2.8g, 3.4mmol), 1,1 '-bis-(diphenylphosphino) ferrocene (0.96g, 1.73mmol), Bu 4n +br -(2.78g, 8.6mmol), Na 2cO 3(36.5g, 344mmol) and 2-(the chloro-phenyl of 4-)-benzo [1,3,2] dioxo bora cyclopentenes (23.8g, 103mmol).Via syringe, add 1-benzyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-1H-1, the solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate (41g, 86mmol) in toluene (250mL), then adds H 2o (250mL).Reaction mixture refluxed heating 3 hours, be then cooled to room temperature.By EtOAc for organic layer (200mL) dilution, then use 1M K 2cO 3washing is until the colour stable of water layer.By salt solution for organic layer (200mL) washing, at MgSO 4dry, filter and concentrate.By the crude product so obtaining via short SiO 2fill in row cushion and filter purifying, generate this title compound (34.5,79mmol, 92%), it is white solid.MS (ESI): C 25h 28clN 3o 2accurate calculation quality, 437.19; Measured value, m/z438.1, [M+H] +.HPLC (method B): R t=10.89 minutes.
1H NMR(400MHz，CDCl 3)：7.50-7.45(m，2H)，7.40-7.36(m，2H)，7.36-7.25(m，3H)，7.13-7.10(m，2H)，5.35.5.33(m，2H)，3.56-3.50(m，4H)，2.83-2.75(m，4H)，1.28-1.25(m，9H).
step is benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae G.1-, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.in the flask of 500mL, single neck, round bottom, 1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (34g, 77mmol) is dissolved in CH 2cl 2(100mL).Add carefully trifluoroacetic acid (70mL).By compound of reaction stirring at room 2 hours.Make solvent evaporation, resistates is dissolved in to CH again 2cl 2(200mL).Slowly add NaHCO 3saturated aqueous solution is until CO 2till stopping selecting.By water layer CH 2cl 2(2 * 200mL) extraction.Obtain organic layer, at MgSO 4upper dry, filter and concentrate.By crude product recrystallization from hot EtOAc, generate pure white solid product (24g, 71mmol, 91%).MS (ESI): C 20h 20clN 3accurate calculation quality, 337.13; Measured value, m/z 338.3[M+H] +.HPLC (method B): R t=7.53 minutes.
1H NMR(400MHz，CDCl 3)：7.48-7.44(m，2H)，7.44-7.38(m，3H)，7.38-7.27(m，3H)，7.14-7.06(m，2H)，5.36(s，2H)，3.30-3.16(m，4H)，3.10-2.98(m，4H).
step is benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae H.1-, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion.in the flask of 500mL, single neck, round bottom, 1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-tri-azepines-Azulene 7 (10g, 30mmol) is suspended in MeOH (70mL), and mixture is heated until homogeneous solution forms.Drip the solution of citric acid monohydrate compound (7.5g, 36mmol) in MeOH (10mL).By gained homogeneous solution reflux 20 minutes, be then cooled to room temperature, make solvent evaporation form oily matter.By EtOAc for oily matter (200mL) dilution, and reflux.In this hot solution, slowly add MeOH to form slurries.Slurries are cooled to room temperature, filter the solid of collecting precipitation, with EtOAc washing, dry under vacuum, generation Citrate trianion (based on 11: 1 ratio that HNMR analyzes, 9.1g).Filtrate is concentrated, by adding other 0.5 equivalent citric acid, form other 2g product.Merging productive rate is 71%.
1H NMR(500MHz，D 2O)：7.35-7.22(m，4H)，7.22-7.15(m，3H)，7.0-6.92(m，2H)，5.22(s，2H)，3.22-3.14(m，4H)，3.0-2.92(m，2H)，2.88-2.80(m，2H)，2.69(d，J＝15Hz，2H)，2.57(d，J＝15Hz，2H).
Embodiment 274
Figure S04833737820060524D001961
3-(4 '-chloro-biphenyl-4-yl)-2-(the fluoro-ethyl of 2,2,2-tri-)-2,4,5,6,7,8-six hydrogen-1,2,6 three azepines-Azulene
This title compound (18mg) is also obtained by embodiment 187 step B.MS (ESI): C 21h 19clF 3n 3accurate calculation quality, 405.12; Measured value, m/z 406.1[M+H] +, 408.0[M+H] +.
1H NMR(500MHz，CD 3OD)：7.74-7.72(m，2H)，7.61-7.59(m，2H)，7.41-7.35(m，4H)，4.70-4.55(m，3H)，3.85-3.30(m，3H)，3.25-3.05(m，2H)，2.82-2.74(m，2H).
Embodiment 275
Figure S04833737820060524D001962
3-(4 '-chloro-biphenyl-4-yl)-2-cyclopentyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
This title compound (33mg) is also obtained by embodiment 181.MS (ESI): C 24h 26clN 3accurate calculation quality, 391.18; Measured value, m/z 392.1[M+H] +, 394.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.81-7.80(m，2H)，7.70-7.68(m，2H)，7.50-7.41(m，4H)，4.65-4.53(m，3H)，3.85-3.67(m，2H)，3.30-3.10(m，2H)，2.88(br s，2H)，2.01-1.91(m，6H)，1.63-1.60(m，2H).
Embodiment 276
2-cyclobutyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-cyclobutyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with hydrochloric acid cyclobutyl hydrazine (as described in embodiment 177 steps A, being prepared by cyclobutanone), replace phenylhydrazine, and replace EtOH with the trimethyl carbinol, add 3 equivalent triethylamines simultaneously, as described in embodiment 176 steps A and B, prepare needed triflate.
step B.the product of preparing by 189mg steps A and and 73mg phenyl-boron dihydroxide, according to embodiment 263, prepare this title compound (118mg).MS (ESI): C 17h 21n 3accurate calculation quality, 267.17; Measured value, m/z 268.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60-7.50(m，3H)，7.34-7.30(m，2H)，4.71-4.63(m，2H)，4.00-3.40(m，2H)，3.24-3.22(m，3H)，3.00-2.80(m，2H)，2.68-2.59(m，2H)，2.30-2.24(m，2H)，2.30-2.24(m，2H)，1.84-1.71(m，2H).
Embodiment 277
Figure S04833737820060524D001972
2-cyclobutyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 263, with 198mg 2-cyclobutyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 276, steps A) and 88mg4-fluorophenyl boric acid, prepare this title compound (122mg).MS (ESI): C 17h 20fN 3accurate calculation quality, 285.16; Measured value, m/z 286.4[M+H] +,
1H NMR(500MHz，CD 3OD)：7.35-7.27(m，4H)，4.65-4.59(m，2H)，3.95-3.3.40(m，2H)，3.32-3.05(m，3H)，3.00-2.75(m，2H)，2.67-2.59(m，2H)，2.29-2.23(m，2H)，1.84-1.73(m，2H).
Embodiment 278
Figure S04833737820060524D001981
2-cyclobutyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 263, with 192mg 2-cyclobutyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 276, steps A) and 83mg 4-aminomethyl phenyl boric acid, prepare this title compound (117mg).MS (ESI): C 18h 23n 3accurate calculation quality, 281.19; Measured value, m/z 282.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.41-7.32(m，2H)，7.23-7.13(m，2H)，4.71-4.65(m，2H)，4.00-3.41(m，2H)，3.32-3.05(m，3H)，2.95-2.79(m，2H)，2.67-2.58(m，2H)，2.43(s，3H)，2.28-2.23(m，2H)，1.84-1.71(m，2H).
Embodiment 279
2-cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 263, with 201mg 2-cyclobutyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 276, steps A) and 122mg4-trifluoromethyl phenyl boronic acid, prepare this title compound (73mg).MS (ESI): C 18h 20f 3n 3accurate calculation quality, 335.16; Measured value, m/z 336.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.86-7.85(m，2H)，7.52-7.50(m，2H)，4.654.58(m，1H)，3.45-3.41(m，2H)，3.22-3.20(m，2H)，2.81-2.79(m，2H)，2.67-2.62(m，2H)，2.30-2.24(m，2H)，1.84.-1.74(m，2H).
Embodiment 280
Figure S04833737820060524D001991
4-(2-cyclobutyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
According to embodiment 263, with 172mg 2-cyclobutyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 276, steps A) and 172mg4-cyano-phenyl boric acid, prepare this title compound (28mg).MS (ESI): C 18h 20the accurate calculation quality of N4,292.17; Measured value, m/z 293.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.92-7.90(m，2H)，7.50-7.48(m，2H)，4.65-4.58(m，1H)，3.42-3.40(m，2H)，3.21-3.19(m，2H)，2.81-2.78(m，2H)，2.66-2.62(m，2H)，2.30-2.25(m，2H)，1.85-1.74(m，2H).
Embodiment 281
Figure S04833737820060524D001992
2-cyclopropyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .N ,-cyclobutyl-hydrazine t-butyl formate.to 1.37g 3-(4-cyano group-phenyl)-oxirane-2-t-butyl formate at Et 2in solution in O (8mL), add 1.2mL cyclopropylamine.By mixture ageing 2 hours, then concentrated in a vacuum.At SiO 2on carry out chromatogram purification (0 to 25%EtOAc/ hexane), generate unpurified light yellow solid, it is distilled under high vacuum in 50 ℃ of oil baths, generate the needed compound of 641mg. 1HNMR(500MHz，CDCl 3)：6.31(br s，1H)，3.49(br s，1H)，2.74(br s，1H)，1.48(s，9H)，0.52-0.48(m，4H).
step B. hydrochloric acid cyclopropyl hydrazine.the product of preparing to steps A (636mg) is at CH 2cl 2(10mL) in the solution in, add the 9mL 4.0MHCl in Isosorbide-5-Nitrae-dioxs.By mixture ageing 12 hours, then concentrated in a vacuum, generate this title compound of 507mg. 1H NMR(500MHz，CD 3OD)：2.61-2.57(m，1H)，0.71-0.59(m，4H).
step is cyclopropyl-3-trifyl oxygen base-4 C.2-, 5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with hydrochloric acid cyclopropyl hydrazine, replace phenylhydrazine, and replace EtOH with the trimethyl carbinol, add 3 equivalent triethylamines simultaneously, as described in embodiment 176 steps A and B, prepare needed triflate.
step D.according to embodiment 263, with 208mg 2-cyclopropyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate and 84mg phenyl-boron dihydroxide are prepared this title compound (128mg).MS (ESI): C 16h 19n 3accurate calculation quality, 253.16; Measured value, m/z 254.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.44(m，5H)，3.57-3.54(m，1H)，3.42-3.40(m，2H)，3.17-3.14(m，2H)，2.93-2.84(m，2H)，0.91-0.85(m，4H).
Embodiment 282
Figure S04833737820060524D002001
2-cyclopropyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 281, with 200mg 2-cyclopropyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 281, step C) and 92mg 4-fluorophenyl boric acid, prepare this title compound (134mg).MS (ESI): C 16h 18fN 3accurate calculation quality, 271.15; Measured value, m/z 272.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.51-7.47(m，2H)，7.31-7.27(m，2H)，3.55-3.51(m，1H)，3.41-3.39(m，2H)，3.23-3.14(m，2H)，3.00-2.83(m，2H)，0.93-.084(m，4H).
Embodiment 283
Figure S04833737820060524D002011
2-(1-ethyl-propyl group)-3-(the fluoro-3-methyl-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 183; with 59mg 2-(1-ethyl-propyl group)-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1, (embodiment 183 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; steps A) and the fluoro-3-aminomethyl phenyl of 19mg 4-boric acid, prepare this title compound (34mg).MS (ESI): C 19h 26fN 3accurate calculation quality, 315.21; Measured value, m/z 316.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.27-7.18(m，3H)，4.69-4.65(m，1H)，3.93-3.89(m，1H)，3.50-3.27(m，5H)，3.00-2.80(m，2H)，2.35(s，3H)，1.95-1.87(m，2H)，1.83-1.76(m，2H)，0.81-0.68(m，6H).
Embodiment 284
2-cyclopropyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 281, with 200mg 2-cyclopropyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 281, step C) and 90mg 4-aminomethyl phenyl boric acid, prepare this title compound (133mg).MS (ESI): C 17h 21n 3accurate calculation quality, 267.17; Measured value, m/z 268.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.42-7.34(m，4H)，4.68-4.65(m，2H)，3.80-3.30(m，6H)，2.97(br s，2H)，2.44(s，3H)，0.94-0.91(m，4H).
Embodiment 285
Figure S04833737820060524D002021
2-cyclopropyl-3-thiene-3-yl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 281, with 200mg 2-cyclopropyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 281, step C) and 84mg 3 thienylboronic acid, prepare this title compound (134mg).MS (ESI): C 14h 17n 3the accurate calculation quality of S, 259.11; Measured value, m/z 260.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.64-7.63(m，2H)，7.31-7.29(m，1H)，4.65(br s，1H)，3.70-3.60(br s，1H)，3.57-3.52(m，1H)，3.40-3.38(m，1H)，3.19(brs，1H)，3.13-3.11(m，1H)，2.99-2.96(m，1H)，2.91-2.89(m，1H)，0.93-0.88(m，4H).
Embodiment 286
4-(2-cyclopropyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzonitrile
According to embodiment 281, with 200mg 2-cyclopropyl-3-trifyl oxygen base-4,5; 7,8-tetrahydrochysene-2H-1,2; 6-tri-azepines-Azulene-6-t-butyl formate (embodiment 281, step C) and 97mg 4-cyano-phenyl boric acid, prepare this title compound (91mg).MS (ESI): C 17h 18the accurate calculation quality of N4,278.15; Measured value, m/z 279.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.94-7.92(m，2H)，7.71-7.70(m，2H)，4.66(br s，1H)，3.71-3.68(m，1H)，3.47(br s，1H)，3.39-3.19(m，4H)，3.01-2.88(m，2H)，0.96-0.90(m，4H).
Embodiment 287
Figure S04833737820060524D002031
6-benzyl-2-sec.-propyl-3-phenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine
steps A. trifluoromethanesulfonic acid 6-benzyl-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridin-3-yl ester.according to embodiment 189 steps A, the product that replaces embodiment 59 steps A to prepare with 1-benzyl-3-oxo-piperidine-4-ethyl formate, prepares needed triflate.
step B.with the fluoro-methylsulfonic acid 6-benzyl-2-of 200mg tri-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridin-3-yl ester and 85mg phenyl-boron dihydroxide, as described in EXAMPLE Example 263, prepare this title compound (54mg).MS (ESI): C 22h 25n 3accurate calculation quality, 331.20; Measured value, m/z 332.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60-7.48(m，7H)，7.39-7.37(m，2H)，4.59-4.48(m，3H)，4.44-4.34(m，2H)，3.81-3.79(m，1H)，3.46-3.40(m，1H)，2.94-2.84(m，2H)，1.46-1.29(m，6H).
Embodiment 288
2-sec.-propyl-3-phenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine
In the solution of the compound (98mg) of preparing to embodiment 287 step B in 5mL EtOH, add 98mg 10%Pd/C, then add 0.14mL 1，4-cyclohexadiene.Compound is positioned under nitrogen atmosphere, and heats 5 hours in 80 ℃ of oil baths.Filtering mixt, and filtrate is concentrated in a vacuum, generate 67mg viscosity colorless oil.At SiO 2on carry out chromatogram purification (0 to 8%2M NH 3solution/EtOAc in MeOH), generate this title compound of 59mg.This product (59mg) is dissolved in to Et 2o, and use Et 2excessive 1.0MHC in O processes 30 minutes.In vacuum, except desolventizing, generate the corresponding hydrochloride of 68mg.MS (ESI): C 15h 19n 3accurate calculation quality, 241.16; Measured value, m/z 242.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.48(m，3H)，7.38-7.36(m，2H)，4.53(m，1H)，4.40-4.32(m，2H)，3.47(t，J＝6.2Hz，2H)，2.82(t，J ＝6.2Hz，2H)，1.41(d，J＝6.7Hz，6H).
Embodiment 289
Figure S04833737820060524D002041
6-benzyl-2-sec.-propyl-3-thiene-3-yl--4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4c] pyridine
According to embodiment 287, with the fluoro-methylsulfonic acid 6-benzyl-2-of 300mg tri-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridin-3-yl ester and 133mg 3 thienylboronic acid, prepare this title compound (69mg).MS (ESI): C 20h 23n 3the accurate calculation quality of S, 337.16; Measured value, m/z 338.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.66-7.65(m，1H)，7.60-7.57(m，3H)，7.55-7.53(m，3H)，7.21-7.20(m，1H)，4.65-4.52(m，3H)，4.42-4.33(m，2H)，3.82-3.79(m，1H)，3.44-3.40(m，1H)，2.94-2.91(m，2H)，1.46-1.35(m，6H).
Embodiment 290
6-benzyl-2-sec.-propyl-3-p-methylphenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine
According to embodiment 287, with the fluoro-methylsulfonic acid 6-benzyl-2-of 300mg tri-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridin-3-yl ester and 141mg 4-aminomethyl phenyl boric acid, prepare this title compound (67mg).MS (ESI): C 23h 27n 3accurate calculation quality, 345.22; Measured value, m/z 346.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60-7.58(m，2H)，7.54-7.53(m，3H)，7.37-7.35(m，2H)，7.28-7.24(m，2H)，4.58-4.49(m，3H)，4.42-4.33(m，2H)，3.81-3.78(m，1H)，3.45-3.41(m，1H)，2.90-2.82(m，2H)，2.41(s，3H)，1.42-1.29(m，6H).
Embodiment 291
Figure S04833737820060524D002051
6-benzyl-3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4c] pyridine
According to embodiment 287, with the fluoro-methylsulfonic acid 6-benzyl-2-of 300mg tri-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridin-3-yl ester and 146mg 4-fluorophenyl boric acid, prepare this title compound (72mg).MS (ESI): C 22h 24fN 3accurate calculation quality, 349.20; Measured value, m/z 350.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60-7.57(m，2H)，7.55-7.53(m，3H)，7.43-7.40(m，2H)，7.32-7.27(m，2H)，4.59-4.34(m，5H)，3.81-3.79(m，1H)，3.46-3.40(m，1H)，2.90-2.85(m，2H)，1.43-1.36(m，6H).
Embodiment 292
Figure S04833737820060524D002052
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine
According to embodiment 288, with 153mg 6-benzyl-3-(the fluoro-phenyl of 4-)-2-sec.-propyl-4,5,6,7-tetrahydrochysene-2H pyrazolo [3,4-c] pyridine replaces the product of embodiment 287 step B, prepares this title compound (101mg).MS (ESI): C 15h 18fN 3accurate calculation quality, 259.15; Measured value, m/z 260.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.42-7.28(m，4H)，4.50-4.47(m，1H)，4.35(br s，2H)，3.49-3.46(m，2H)，2.81-2.79(m，2H)，1.42-1.36(m，6H).
Embodiment 293
Figure S04833737820060524D002061
2-sec.-propyl-3-p-methylphenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine
According to embodiment 288, with 163mg 6-benzyl-2-sec.-propyl-3-p-methylphenyl-4,5,6,7-tetrahydrochysene-2H-pyrazolo [3,4-c] pyridine replaces the product of embodiment 287 rapid B, prepares this title compound (114mg).MS (ESI): accurate calculation quality C 16h 21n 3, 255.17; Measured value, m/z 256.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.43-7.32(m，2H)，7.30-7.20(m，2H)，4.52(m，1H)，4.39-4.31(m，2H)，3.47(t，J＝6.2Hz，2H)，2.80(t，J＝6.2Hz，2H)，1.42(d，J＝6.6Hz，6H.
Embodiment 294
Figure S04833737820060524D002062
2-cyclopentyl-3-(the fluoro-phenyl of 4-)-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A. three fluoro-methylsulfonic acid 2-cyclopentyl-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester.with 2,2,7,7-tetramethyl--5-oxo-azepan-4-ethyl formate is (as shown in embodiment 59 steps A, by 2,2, the preparation of 6,6-tetramethyl--piperidin-4-one-) replace 5-oxo-azepan-Isosorbide-5-Nitrae-dioctyl phthalate tert-butyl ester 4-ethyl ester, as described in embodiment 180 steps A, prepare needed fluoroform acid esters.
step B.with the fluoro-methylsulfonic acid 2-of 216mg tri-cyclopentyl-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester and 103mg 4-fluorophenyl boric acid, as described in embodiment 263 steps A, prepare this title compound.Product (134mg) is dissolved in to Et 2o, and use Et 2excessive 1.0M HCl in O processes 30 minutes.In vacuum, except desolventizing, generate the corresponding HCl salt of 146mg.MS (ESI): C 22h 30fN 3accurate calculation quality, 355.24; Measured value, m/z 356.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.36-7.26(m，4H)，4.47-4.41(m，1H)，3.15(s，2H)，2.71(s，2H)，2.03-1.88(m，6H)，1.61-1.57(m，2H)，1.44(s，6H)，1.35(s，6H).
Embodiment 295
Figure S04833737820060524D002071
2-cyclopentyl-5,5,7,7-tetramethyl--3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
With the fluoro-methylsulfonic acid 2-of 263mg tri-cyclopentyl-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester and 110mg phenyl-boron dihydroxide, as described in embodiment 294, prepare this title compound (129mg).MS (ESI): C 22h 31n 3accurate calculation quality, 337.25; Measured value, m/z 338.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.56-7.49(m，3H)，7.32-7.30(m，2H)，4.51-4.44(m，1H)，3.12(s，2H)，2.72(s，2H)，2.03-1.88(m，6H)，1.61-1.57(m，2H)，1.45(s，6H)，1.35(s，6H).
Embodiment 296
Figure S04833737820060524D002072
2-sec.-propyl-5,5,7,7-tetramethyl--3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A. three fluoro-methylsulfonic acid 2-sec.-propyl-5,5,7,7-tetramethyl--2,4.5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester.with sec.-propyl hydrazine, replace cyclopentyl hydrazine, as described in embodiment 294 steps A, prepare required triflate.
step B.with the fluoro-methylsulfonic acid 2-of 196mg tri-sec.-propyl-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester and 87mg phenyl-boron dihydroxide, as described in embodiment 294 step B, prepare this title compound (98mg).MS (ESI): C 20h 29n 3accurate calculation quality, 311.24; Measured value, m/z 312.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.52(m，3H)，7.32-7.31(m，2H)，4.34(m，1H)，3.11(s，2H)，2.71(s，2H)，1.49-1.34(m，18H).
Embodiment 297
Figure S04833737820060524D002081
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5,5,7,7-tetramethyl--2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the fluoro-methylsulfonic acid 2-of 196mg tri-sec.-propyl-5,5,7,7-tetramethyl--2,4,5,6,7,8 six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester and 100mg 4-fluorophenyl boric acid, as described in embodiment 296, prepare this title compound (100mg).MS (ESI): C 20h 28fN 3accurate calculation quality, 329.23; Measured value, m/z 330.5[M+H] +.
1H NMR(500 MHz，CD 3OD)：7.36-7.27(m，4H)，4.31(m，1H)，3.10(s，2H)，2.70(s，2H)，1.47-1.34(m，18H).
Embodiment 298
2-sec-butyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-sec-butyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.with hydrochloric acid sec-butyl hydrazine (as described in embodiment 177 steps A, being prepared by 2-butanone), replace hydrochloric acid sec.-propyl hydrazine, according to embodiment 189 steps A, prepare needed triflate.
step B.the triflate of preparing by 216mg steps A and 106mg phenyl-boron dihydroxide, as described in embodiment 263, prepare this title compound (97mg).MS (ESI): C 17h 23n 3accurate calculation quality, 269.38; Measured value, m/z 270.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.58-7.50(m，3H)，7.35-7.31(m，2H)，4.15-4.07(m，1H)，3.50-3.18(m，6H)，2.88-2.73(m，2H)，1.97-1.86(m，1H)，1.74-1.65(m，1H)，1.43(d，J＝6.8Hz，3H)，0.64(t，J＝7.4Hz，3H).
Embodiment 299
Figure S04833737820060524D002091
2-sec-butyl-3-(the fluoro-phenyl of 4-)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
The triflate of preparing by 245mg embodiment 298 steps A and 153mg 4-fluorophenyl boric acid, as described in embodiment 263, prepare this title compound (71mg).MS (ESI): C 17h 22fN 3accurate calculation quality, 287.38; Measured value, m/z 288.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.41-7.35(m，2H)，7.34-7.28(m，2H)，4.12-4.03(m，1H)，3.51-3.20(m，6H)，2.90-2.73(m，2H)，1.97-1.87(m，1H)，1.75-1.65(m，1H)，1.44(d，J＝6.6Hz，3H)，0.66(t，J＝7.4Hz，3H).
Embodiment 300
2-sec-butyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
The triflate of preparing by 249mg embodiment 298 steps A and 129mg 4-aminomethyl phenyl boric acid, as described in embodiment 263, prepare this title compound (116mg).MS (ESI): C 18h 25n 3accurate calculation quality, 283.41; Measured value, m/z284.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.42-7.37(m，2H)，7.27-7.21(m，2H)，4.23-4.12(m，1H)，3.55-3.23(m，6H)，2.92-2.75(m，2H)，2.43(s，3H)，1.98-1.88(m，1H)，1.77-1.68(m，1H)，1.46(d，J＝6.6Hz，3H)，0.67(t，J＝7.4Hz，3H).
Embodiment 301
2-sec-butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
The triflate of preparing by 257mg embodiment 298 steps A and 175mg 4-trifluoromethyl phenyl boronic acid, as described in embodiment 263, prepare this title compound (71mg).MS (ESI): C 18h 22f 3n 3accurate calculation quality, 337.38; Measured value, m/z 338.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.91-7.85(m，2H)，7.61-7.54(m，2H)，4.11-4.03(m，1H)，3.52-3.20(m，6H)，2.93-2.75(m，2H)，1.99-1.88(m，1H)，1.75-1.65(m，1H)，1.45(d，J＝6.6Hz，3H)，0.65(t，J＝7.4Hz，3H).
Embodiment 302
Figure S04833737820060524D002102
2-cyclopentyl-3-(the fluoro-phenyl of 4-)-6-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to embodiment 208, by the product of 216mg embodiment 182 preparations, prepare this title compound (186mg).This product is dissolved in to Et 2o, and use Et 2excessive 1.0M HCl in O processes, and generates corresponding HCl salt.MS (ESI): C 19h 24fN 3accurate calculation quality, 313.41; Measured value, m/z 314.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.38-7.34(m，2H)，7.31-7.26(m，2H)，4.47(m，1H)，3.75-3.69(m，1H)，3.64-3.57(m，1H)，3.33-3.15(m，4H)，3.02(s，3H)，2.91-2.83(m，1H)，2.78-2.71(m，1H)，2.04-1.84(m，6H)，1.65-1.54(m，2H).
Embodiment 303
Figure S04833737820060524D002111
4-(2-sec.-propyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-yl)-benzamide.
The triflate of preparing by 206mg embodiment 189 steps A and 135mg 4-benzamide boric acid, as shown in embodiment 263, prepare this title compound (26mg).MS (ESI): accurate calculation quality C 17h 22n 4o, 298.38; Measured value, m/z 299.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.93-7.89(m，2H)，7.37-7.34(m，2H)，6.16(br s，1H)，5.81(br s，1H)，4.27(m，1H)，3.05-3.00(m，2H)，2.97-2.88(m，4H)，2.51-2.46(m，2H)，1.41(d，J＝6.6Hz，6H).
Embodiment 304
Figure S04833737820060524D002112
2-sec.-propyl-3-[4-(1H-TETRAZOLE-5-yl)-phenyl]-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-sec.-propyl-3-[4-(1H-TETRAZOLE-5-yl)-phenyl]-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.by 3-(4-cyano group-phenyl)-2-sec.-propyl-4,5,7,8-tetrahydrochysene-2H-1, the toluene solution of 2,6-, tri-azepines-Azulene-6-t-butyl formate (intermediate in embodiment 212) and azide tributyl tin reflux 48 hours.Mixture is concentrated, and by resistates at SiO 2on carry out purifying (0 to 75%EtOAc/ hexane), generate the needed tetrazolium of 89mg, it is glassy mass.
The product that step B. prepares steps A is dissolved in diox, with HCl (solution in 4M diox, 1mL) processes, and by mixture in stirring at room.After 48 hours, by solution decantation, by the washing of solid Yong diox, and dry under vacuum, generate this title compound of 60mg.MS (ESI): C 17h 21N 7accurate calculation quality, 323.40; Measured value, m/z324.4[M+H] +.
1H NMR(500MHz，CD 3OD)：8.24-8.20(m，2H)，7.58-7.55(m，2H)，4.42(m，1H)，3.44-3.40(m，2H)，3.34-3.30(m，2H)，3.21-3.17(m，2H)，2.84-2.80(m，2H)，1.42(d，J＝6.8，6H).
Embodiment 305
Figure S04833737820060524D002121
6-benzyl-3-(the fluoro-phenyl of 4-)-2-sec.-propyl-8-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A. three fluoro-methylsulfonic acid 6-benzyl-2-sec.-propyl-8-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-3-base ester.with 1-benzyl-6-methyl-5-oxo-azepan-4-ethyl formate (as described in embodiment 59 steps A, by 1-benzyl-3-methyl-piperidin-4-one-, prepared) replacement 5-oxo-azepan-1,4-dioctyl phthalate tert-butyl ester 4-ethyl ester, as described in embodiment 189 steps A, prepare needed triflate.
step B.as described in embodiment 287 step B, the triflate of being prepared by 151mg steps A and 110mg 4-fluorophenyl boric acid are prepared this title compound (29mg).MS (ESI): C 24h 28fN 3accurate calculation quality, 377.50; Measured value, m/z 378.5[M+H] +.
1H NMR(500MHz，CDCl 3)：7.41-7.37(m，2H)，7.33-7.29(m，2H)，7.27-7.18(m，3H)，7.16-7.10(m，2H)，4.24(m，1H)，3.78(d，J＝13.4Hz，1H)，3.70(d，J＝13.4Hz，1H)，3.19-3.12(m，1H)，2.78-2.68(m，3H)，2.55-2.43(m，3H)，1.40(d，J＝6.6，3H)，1.37(d，J＝6.6，3H)，1.33(d，J＝7.1，3H).
Embodiment 306
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-8-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .3-methyl-4-oxo-piperidines-1-t-butyl formate.in-78 ℃ of solution to 4-oxo-piperidines-1-t-butyl formate in THF (100mL), add LDA (50mL, the solution of 1.8M in THF) and stir 1 hour simultaneously.Then add methyl-iodide (5mL), mixture is slowly heated to room temperature, and stir 24 hours.By adding NH 4c1 saturated aqueous solution (20mL) is by the stopping of reaction.Mixture is poured into H 2in O (800mL), with EtOAc extraction, and concentrated.At SiO 2on carry out chromatogram purification (120g, 0 to 10%EtOAc/ hexane), generate the needed product of 3.83g, it is pale solid. 1HNMR(500MHz，CDCl 3)：4.23-4.14(m，2H)，3.31-3.21(m，1H)，2.61-2.37(m，4H)，1.50(s，9H)，1.05(d，J＝6.6Hz，3H).
step is sec.-propyl-8-methyl-3-trifyl oxygen base-4 B.2-, 5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 59 steps A, product prepared by steps A (2.01g) is processed with ethyl diazoacetate (1.5mL).Then as described in embodiment 189 steps A, resulting materials (2.90g) is converted into needed triflate (2.68g).Reaction also generates 0.60g 2-isopropyl-4-methyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.
step C.as described in embodiment 263 steps A, by triflate and the 1.36g 4-fluorophenyl boric acid of 2.68g step B, prepare this title compound (1.62g).By coupling product 50mL CH 2cl 2in TFA (20mL) process 16 hours.Mixture is concentrated, and by 1M NaOH (50mL) dilution for resistates, and use CH 2cl 2(50mL, 3x) extraction.To merge organic layer at Na 2sO 4above be dried and concentrate, generate needed material.MS (ESI): C 17h 22fN 3accurate calculation quality, 287.18; Measured value, m/z 288.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.18-7.05(m，4H)，4.16(m，1H)，3.08-2.97(m，2H)，2.96-2.83(m，2H)，2.78-2.71(m，1H)，2.49-2.31(m，2H)，1.34(d，J＝6.6Hz，3H)，1.31(d，J＝6.6Hz，3H)，1.29(d，J＝7.3Hz，3H).
Embodiment 307
Figure S04833737820060524D002141
3-(the fluoro-phenyl of 4-)-2-isopropyl-4-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
As described in embodiment 177 step C and D, the triflate of being prepared by 0.60g embodiment 306 step B and 0.57g 4-fluorophenyl boric acid, prepare this title compound (154mg).MS (ESI): C 17h 22fN 3accurate calculation quality, 287.18; Measured value, m/z288.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.25-7.20(m，2H)，7.17-7.12(m，2H)，4.15(m，1H)，3.35-3.30(m，1H)，3.08-3.03(m，1H)，3.00-2.85(m，3H)，2.77-2.71(m，1H)，2.57-2.51(m，1H)，1.39(d，J＝6.6Hz，3H)，1.36(d，J＝6.6Hz，3H)，1.15(d，J＝7.3Hz，3H).
Embodiment 308
2-cyclopentyl-3-(the fluoro-phenyl of 4-)-7-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
steps A .2-methyl-4-oxo-piperidines-1-t-butyl formate.solution Isosorbide-5-Nitrae-dioxa-8-aza-spiro [4.5] decane-8-t-butyl formate (2.97g) in TMEDA (2.2mL) is cooled to-78 ℃, and drip secondary BuLi (solution of 1.8M in THF, 13mL).Gained yellow solution is placed 1 hour at-78 ℃.Add methyl-iodide (1.5mL), and with 16 hours, mixture is heated to room temperature by-78 ℃.Reaction mixture is poured in water (800mL), and extracted with EtOAc.To merge organic layer H 2o, salt water washing, and at Na 2sO 4upper dry.At SiO 2on carry out chromatogram purification (330g, 5 to 20%EtOAc/ hexanes), generate 1.65g 7-methyl isophthalic acid, 4-dioxa-8-aza-spiro [4.5] decane-8-t-butyl formate.A plurality of aliquots containigs of described ester are merged to (2.29g), with the 5mL concentrated hydrochloric acid in 10mL diox, process, and 65 ℃ of heating 6 hours.Except desolventizing, resistates is dissolved in to CH 2cl 2, and process with two-tertiary butyl sodium bicarbonate (1.0g).After 5d, by mixture NaHCO 3saturated aqueous solution and H 2o dilution, and use CH 2cl 2extraction.At SiO 2on carry out purifying (120g, 5 to 15%EtOAc/ hexanes), generate the required product of 1.40g, it is white solid.
1H NMR(500MHz，CDCl 3)：4.69-4.59(m，1H)，4.21-4.12(m，1H)，3.30-3.20(m，1H)，2.66-2.57(m，1H)，2.47-2.36(m，1H)，2.32-2.23(m，1H)，2.22-2.15(m，1H)，1.42(s，9H)，1.11(d，J＝7.1Hz，3H).
step is cyclopentyl-7-methyl-3-trifyl oxygen base-4 B.2-, 5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.as described in embodiment 59, product prepared by steps A (1.40g) is processed with ethyl diazoacetate.As described in embodiment 180 steps A, resulting materials (1.0g) is converted into needed triflate (0.78g).Reaction also generates 2-cyclopentyl-5-methyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.
Step C. is as described in embodiment 263, and the triflate of being prepared by 301mg step B and 185mg 4-fluorophenyl boric acid, prepare this title compound (160.4mg).Reaction also generates 2-cyclopentyl-3-(the fluoro-phenyl of 4-)-5-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.By SFC chromatography by isomer separation.MS (ESI): C 19h 24fN 3accurate calculation quality, 313.41; Measured value, m/z314.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.25-7.21(m，2H)，7.18-7.12(m，2H)，4.22(m，1H)，3.24-3.18(m，1H)，3.03-2.92(m，2H)，2.76-2.67(m，2H)，2.60-2.52(m，1H)，2.45-2.39(m，1H)，2.16-1.82(m 6H)，1.59-1.47(m，2H)，1.25(d，J＝6.3Hz，3H).
Embodiment 309
Figure S04833737820060524D002151
2-cyclopentyl-3-(the fluoro-phenyl of 4-)-5-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 308, prepare this title compound (3.8mg).MS (ESI): C 19h 24fN 3accurate calculation quality, 313.41; Measured value, m/z 314.4[M+H] +. 1H NMR(500MHz，CDCl 3)：7.24-7.19(m，2H)，7.18-7.13(m，2H)，4.31(m，1H)，3.42-3.35(m，1H)，3.09-2.90(m，4H)，2.57-2.45(m，2H)，2.14-1.80(m6H)，1.58-1.48(m，2H)，1.22(d，J＝6.3Hz，3H).
Embodiment 310
Figure S04833737820060524D002161
2-cyclopentyl-7-methyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
The triflate of being prepared by 193mg embodiment 308 step B and 117mg 4-aminomethyl phenyl boric acid, prepare this title compound (64mg).MS (ESI): C 20h 27n 3accurate calculation quality, 309.45; Measured value, m/z 310.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.28-7.25(m，2H)，7.17-7.13(m，2H)，4.39(m，1H)，3.21-3.16(m，1H)，3.03-2.92(m，2H)，2.74-2.67(m，2H)，2.59-2.52(m，1H)，2.49-2.43(m，1H)，2.40(s，3H)，2.17-1.82(m，6H)，1.59-1.47(m，2H)，1.24(d，J＝6.3Hz，3H).
Embodiment 311
Figure S04833737820060524D002162
2-sec.-propyl-7-methyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 260mg 2-sec.-propyl-7-methyl-3-trifyl oxygen base-4; 5; 7; 8-tetrahydrochysene-2H-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (as described in embodiment 308, replacing cyclopentyl hydrazine with sec.-propyl hydrazine) and 101mg phenyl-boron dihydroxide; as described in embodiment 263, prepare this title compound (102mg).Reaction also generates 2-sec.-propyl-5-methyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.5[M+H] +.
1H NMR(600MHz，CD 3OD)：7.58-7.52(m，3H)，7.36-7.35(m，2H)，4.43(m，1H)，3.65-3.57(m，1H)，3.51-3.48(m，1H)，3.23-3.11(m，3H)，2.87-2.82(m，2H)，2.76-2.73(m，1H)，1.48(d，J＝6.4Hz，3H)，1.43-1.40(m，6H).
Embodiment 312
2-sec.-propyl-5-methyl-3-phenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 311, prepare this title compound (28mg), and carry out purifying by SFC chromatography.MS (ESI): C 17h 23n 3accurate calculation quality, 269.19; Measured value, m/z 270.4[M+H] +.
1H NMR(600MHz，CD 3OD)：7.58-7.52(m，3H)，7.35-7.33(m，2H)，4.40(m，1H)，3.63-3.59(m，1H)，3.5-3.47(m，1H)，3.31-3.19(m，3H)，2.80-2.68(m，2H)，1.43-1.39(m，6H)，1.34(d，J＝6.6Hz，3H).
Embodiment 313
Figure S04833737820060524D002172
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-7-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 260mg 2-sec.-propyl-7-methyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate and 115mg 4-fluorophenyl boric acid, as described in embodiment 311, prepare this title compound (127mg).Reaction also generates 3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.MS (ESI): C 17h 22fN 3accurate calculation quality, 287.18; Measured value, m/z 288.5[M+H] +.
1H NMR(600MHz，CD 3OD)：7.39-7.37(m，2H)，7.32-7.28(m，2H)，4.36(m，1H)，3.61-3.56(m，1H)，3.50-3.47(m，1H)，3.20-3.06(m，3H)，2.85-2.80(m，1H)，2.73-2.69(m，1H)，1.46(d，J＝6.6Hz，3H)，1.41-1.38(m，6H).
Embodiment 314
Figure S04833737820060524D002181
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5-methyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
As described in embodiment 311, prepare this title compound (36mg), and on SFC, carry out purifying.MS (ESI): C 17h 22fN 3accurate calculation quality, 287.18; Measured value, m/z288.5[M+H] +.
1H NMR(600MHz，CD 3OD)：7.37-7.35(m，2H)，7.31-7.28(m，2H)，4.33(m，1H)，3.61-3.58(m，1H)，3.48-3.45(m，1H)，3.27-3.13(m，3H)，2.77-2.65(m，2H)，1.41-1.37(m，6H)，1.34(d，J＝6.6Hz，3H).
Embodiment 315
Figure S04833737820060524D002182
P-tolyl-2 of 2-sec.-propyl-7-methyl-3-, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With 260mg 2-sec.-propyl-7-methyl-3-trifyl oxygen base-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate and 112mg 4-aminomethyl phenyl boric acid are prepared this title compound (127mg) as described in embodiment 311.Reaction also generates 2-sec.-propyl-5-methyl-3-p-methylphenyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.MS (ESI): C 18h 25n 3accurate calculation quality, 283.20; Measured value, m/z 284.5[M+H] +.
1H NMR(600MHz，CD 3OD)：7.38-7.36(m，2H)，7.22-7.20(m，2H)，4.41(m，1H)，3.60-3.56(m，1H)，3.50-3.45(m，1H)，3.21-3.06(m，3H)，2.84-2.70(m，2H)，1.46(d，J＝6.6Hz，3H)，1.42-1.37(m，6H).
As described in embodiment 238, Preparation Example 316 to 323, simultaneously according to explanation, carry out certain adjustment.
Embodiment 316
Figure S04833737820060524D002191
3-(the chloro-phenyl of 4-)-1-pyridin-4-yl methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With hydrochloric acid 4-chloromethyl-pyridine (0.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3mmol) prepare this title compound (0.02g).MS (ESI): C 19h 19clN 4accurate calculation quality, 338.13; Measured value, m/z 339.3[M+H] +.
1H NMR(500MHz，CDCl 3)：8.49-8.48(m，2H)，7.43-7.41(m，2H)，7.33-7.31(m，2H)，6.90-6.89(m，2H)，5.28(s，2H)，2.92-2.87(m，2H)，2.75-2.73(m，1H)，2.66-2.64(m，1H).
Embodiment 317
3-(the chloro-phenyl of 4-)-1-pyridine-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With hydrochloric acid 2-chloromethyl-pyridine (0.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.4mmol), prepare this title compound (0.01g).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-pyridine-2-ylmethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 19h 19clN 4accurate calculation quality, 338.13; Measured value, m/z 339.3[M+H] +.
1H NMR(500MHz，CDCl 3)：8.49-8.48(m，1H)，7.56-7.54(m，1H)，7.44-7.42(m，2H)，7.32-7.30(m，2H)，7.19-7.11(m，1H)，6.84-6.82(m，1H)，5.39(s，2H)，2.93-2.87(m，4H)，2.76-2.74(m，4H).
Embodiment 318
Figure S04833737820060524D002201
3-(the chloro-phenyl of 4-)-2-pyridine-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-Azaazulenes
According to embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-pyridine-2-ylmethyl-4,5,7,8-tetrahydrochysene-2H-1,2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 317) is prepared this title compound (0.011g).MS (ESI): accurate calculation quality C 19h 19clN4,338.13; Measured value, m/z 339.3[M+H] +.
1H NMR(500MHz，CDCl 3)：8.44-8.43(m，1H)，7.56-7.55(m，1H)，7.32-7.27(m，2H)，7.11-7.07(m，3H)，6.81-6.77(m，1H)，5.20(s，2H)，2.98-2.96(m，2H)，2.89-2.86(m，4H)，2.48-2.46(m，2H).
Embodiment 319
3-(the chloro-phenyl of 4-)-1-pyridin-3-yl methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With hydrochloric acid 3-chloromethyl-pyridine (0.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3mmol) prepare this title compound.This title compound is conduct and 3-(the chloro-phenyl of 4-)-2-pyridin-3-yl methyl-2,4,5,6,7,8-, six hydrogen-1, and 2: 1 mixtures (25mg) of 2,6-, tri-azepines-Azulene obtain.The data of mixture: MS (ESI): C 19h 19clN 4accurate calculation quality, 338.13; Measured value, m/z 339.4[M+H] +.
1H NMR(500MHz，CDCl 3)：8.47-8.14(m，2H)，7.42-7.03(m，6H)，5.39-5.07(two s，2H)，2.97-2.84(m，2H)，2.72-2.43(m，2H).
Embodiment 320
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl]-methyl benzoate
With 4-brooethyl-methyl benzoate (0.5mmol), replace 2-chloromethyl-thiophene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.3mmol) prepare this title compound (0.03g).MS (ESI): C 22h 22clN 3o 2accurate calculation quality, 395.14; Measured value, m/z 396.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.63-7.19(m，7H)，7.03-7.02(m，2H)，5.27(s，2H)，3.15(s，2H)，2.79-2.67(m，8H).
Embodiment 321
Figure S04833737820060524D002221
3-(the chloro-phenyl of 4-)-1-(tetrahydrochysene-pyrans-4-yl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1; 2,6 three azepines-Azulene
With the chloro-tetrahydrochysene-pyrans of 4-(1.5mmol), replace chloro tetramethylene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.40mmol) prepare this title compound.This title compound obtaining is and 3-(the chloro-phenyl of 4-)-2-(tetrahydrochysene-pyrans-4-yl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, the mixture of 2: 1 (10mg) of 2,6 three azepines-Azulene.The data of mixture: MS (ESI): C 18h 22clN 3the accurate calculation quality of O, 331.15; Measured value, m/z 332.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.42(m，1H)，7.36-7.30(m，4H)，7.20-7.18(m，1H)，4.36-4.33(m，1H)，3.97-3.94(m，3H)，3.87-3.86(m，1H)，3.51-3.49(m，3H)，3.28-3.25(m，1H)，2.90-2.75(m，8H)，2.66-2.64(m，2H)，2.39-2.37(m，1H)，2.19-2.10(m，3H)，1.74-1.71(m，2H)，1.65-1.62(m，1H).
Embodiment 322
Figure S04833737820060524D002222
3-(the chloro-phenyl of 4-)-1-(4-methyl-cyclohexyl base)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With the bromo-4-methyl-cyclohexyl of 1-alkane (1.0mmol), replace chloro tetramethylene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.30mmol) prepare this title compound (11mg).In alkylation step, reaction also generates 3-(the chloro-phenyl of 4-)-2-(4-methyl-cyclohexyl base)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene-6-t-butyl formate.MS (ESI): C 20h 26clN 3accurate calculation quality, 343.18; Measured value, m/z 344.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.40-7.34(m，4H)，4.10-4.06(m，1H)，3.39-3.37(m，2H)，3.28-3.26(m，2H)，3.17-3.15(m，2H)，2.94-2.91(m，2H)，1.96-1.89(m，2H)，1.83-1.76(m，4H)，1.52-1.10(m，2H)，0.91-0.87(m，4H).
Embodiment 323
Figure S04833737820060524D002231
2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl] and-ethyl }-dimethyl-amine
With hydrochloric acid (the chloro-ethyl of 2-)-dimethyl-amine (0.66mmol), replace chloro tetramethylene, by 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, StepB for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.33mmol) prepare this title compound.This title compound obtaining is the mixture of 2: 1 (10mg) with { 2-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-ethyl }-dimethyl-amine.The data of mixture: MS (ESI): C 17h 23clN 4accurate calculation quality, 318.16; Measured value, m/z 319.4[M+H] +. 1HNMR(500MHz，CD 3OD)：7.50-7.45(m，2H)，7.37-7.33(m，2H)，4.51-4.49(m，1.3H)，4.27-4.26(m，0.7H)，3.63-3.61(m，1.3H)，3.48-3.42(m，2H)，3.33-3.29(m，2H)，3.24-3.23(m，2H)，3.14-3.12(m，0.7H)，3.00-2.98(m，1.3H)，2.91(s，4H)，2.84(s，2H)，2.75-2.73(m，0.7H).
Embodiment 324
Figure S04833737820060524D002232
3-(the chloro-phenyl of 4-)-1-(1-oxygen base-pyridine-2-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
By 3-(the chloro-phenyl of 4-)-2-pyridine-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1, (embodiment 317 for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.1mmol) heat 1 hour in 80 ℃ with the mixture of mCPBA (0.1g) in ethylene dichloride (10mL).Add NaHCO 3saturated aqueous solution (20mL), and layer is separated.Organic layer is concentrated, and MeOH for resistates (5mL) is diluted.Add hydrochloric acid (1M, 2mL), and mixture is stirred 16 hours at 25 ℃.After concentrated, with purified by flash chromatography (2M NH 3/ CH 2cl 2in MeOH), generate required compound (34mg).MS (ESI): C 19h 19clN 4the accurate calculation quality of O, 354.12; Measured value, m/z 355.2[M+H] +. 1HNMR(500MHz，CDCl 3)：8.20-8.19(m，1H)，7.41-7.39(m，2H)，7.33-7.31(m，2H)，7.18-7.15(m，2H)，6.69-6.67(m，1H)，5.50(s，2H)，3.10-3.03(m，2H)，2.93-2.86(m，2H).
Embodiment 325
2-[1-benzyl-3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1,2,6-, tri-azepines-Azulene-6-yl]-ethanamide
1-benzyl-3-(the chloro-phenyl of 4-)-1-pyridin-3-yl methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1, (embodiment 59, step e for 2,6-, tri-azepines-Azulene; 0.05mmol), the bromo-ethanamide of 2-(8mg) and Na 2cO 3(15mg) mixture in acetone (2mL) stirs 16 hours in 25 ℃.After concentrated, with purified by flash chromatography (2M NH 3/ at CH 2cl 2in MeOH), generate required compound (6mg).M S (ESI): C 22h 23clN 4the accurate calculation quality of O, 394.16; Measured value, m/z 395.3[M+H] +. 1HNMR(500MHz，CDCl 3)：8.49-8.48(m，1H)，7.56-7.54(m，1H)，7.44-7.42(m，2H)，7.32-7.30(m，2H)，7.19-7.11(m，1H)，6.84-6.82(m，1H)，5.39(s，2H)，2.93-2.87(m，2H)，2.76-2.74(m，2H).
Embodiment 326
Figure S04833737820060524D002251
3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-propionitrile
To 3-(the chloro-phenyl of 4-)-4,5,7,8-tetrahydrochysene-1H-1, (embodiment 103, step B for 2,6-, tri-azepines-Azulene-6-t-butyl formate; 0.05mmol), NaOH (50% aqueous solution, 0.2mL) and Bu 4nHSO 4(0.005mmol) mixture in ethylene dichloride (5mL) adds the bromo-propionitrile of 3-(0.1mmol).Mixture is stirred 16 hours at 25 ℃.And 80 ℃ of heating 1 hour.After concentrated, by purified by flash chromatography (EtOAc/ hexane), generate 3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-propionitrile-6-t-butyl formate.According to the deprotection method of describing in embodiment 103 step C, by this ester deprotection, generate this title compound (9mg).In alkylation step, reaction also generates 3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-propionitrile-6-t-butyl formate.MS (ESI): C 16h 17the accurate calculation quality of ClN4,300.11; Measured value, m/z 301.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.44-7.37(m，4H)，4.39-4.37(t，J＝6.1Hz，2H)，3.41-3.39(m，2H)，3.29-3.27(m，2H)，3.24-3.22(m，2H)，2.99-2.96(m，2H)，2.95-2.92(t，J＝6.1Hz，2H).
Embodiment 327
Figure S04833737820060524D002252
3-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-propionitrile
According to the deprotection method of describing in embodiment 103 step C, by 3-[3-(the chloro-phenyl of 4-)-5,6; 7; 8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-2-yl]-propionitrile-6-t-butyl formate (embodiment 326) prepares this title compound (0.004g).MS (ESI): C 16h 17clN 4accurate calculation quality, 300.11; Measured value, m/z 301.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.50-7.48(m，2H)，7.31-7.30(m，2H)，4.14-4.11(t，J＝6.1Hz，2H)，3.32-3.31(m，2H)，3.23-3.21(m，2H)，3.09-3.07(m，2H)，2.86-2.84(t，J＝6.1Hz，2H)，2.72-2.70(m，2H).
Embodiment 328
Figure S04833737820060524D002261
3-(the chloro-phenyl of 4-)-2-suberyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method of describing in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-suberyl-2,4,5; 6,7,8-, six hydrogen-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 254, step C) is prepared this title compound (0.010g).MS (ESI): C 20h 26ClN 3accurate calculation quality, 343.18; Measured value, m/z 344.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.60-7.58(m，2H)，7.33-7.31(m，2H)，4.10-4.06(m，1H)，3.41-3.39(m，2H)，3.31-3.29(m，2H)，3.18-3.16(m，2H)，2.78-2.75(m，2H)，2.10-2.05(m，2H)，1.91-1.87(m，2H)，1.80-1.76(m，2H)，1.60-1.58(m，4H)，1.40-1.39(m，2H).
Embodiment 329
Figure S04833737820060524D002262
3-(the chloro-phenyl of 4-)-2-encircles octyl group-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method of describing in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-, encircle octyl group-2,4,5; 6,7,8-, six hydrogen-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 255, step C) is prepared this title compound (0.017g).MS (ESI): C 21h 28clN 3accurate calculation quality, 357.20; Measured value, m/z 358.5[M+H] +.
1H NMR(500MHz，CD 3OD)：7.61-7.58(m，2H)，7.34-7.32(m，2H)，4.24-4.21(m，1H)，3.41-3.39(m，2H)，3.31-3.29(m，2H)，3.18-3.16(m，2H)，2.78-2.76(m，2H)，2.15-2.11(m，2H)，1.81-1.77(m，4H)，1.57-1.46(m，6H)，1.31-1.29(m，2H).
Embodiment 330
Figure S04833737820060524D002271
3-(the chloro-phenyl of 4-)-2-(4-methyl-cyclohexyl base)-2,4,5,6,7,8-six hydrogen-1,2,6-, tri-azepines-Azulene
According to the deprotection method of describing in embodiment 103 step C, by 3-(the chloro-phenyl of 4-)-2-(4-methyl-cyclohexyl base)-2,4,5; 6,7,8-, six hydrogen-1; 2,6-, tri-azepines-Azulene-6-t-butyl formate (embodiment 322, step C) is prepared this title compound (0.007g).MS (ESI): C 20h 26clN 3accurate calculation quality, 343.18; Measured value, m/z 344.4[M+H] +.
1H NMR(500MHz，CD 3OD)：7.59-7.57(m，2H)，7.33-7.31(m，2H)，3.95-3.92(m，1H)，3.37-3.35(m，2H)，3.31-3.29(m，2H)，3.18-3.16(m，2H)，2.78-2.75(m，2H)，2.10-1.95(m，2H)，1.90-1.77(m，4H)，1.05-0.91(m，6H)，
Embodiment 331
Figure S04833737820060524D002272
2-benzyl-3-(the chloro-phenyl of 4-)-2,4,5,6-tetrahydrochysene-pyrrolo-[3,4-c] pyrazoles
In-78 ℃ to LDA, (solution of 1.80M in THF 20mmol) drips the solution of 3-oxo-tetramethyleneimine-1-t-butyl formate (10mmol) in THF (10mL) in the solution in THF (100mL).After 20 minutes, add the solution of 4-chlorobenzyl chloride (15mmol) in THF (10mL).Then, mixture is heated to 25 ℃ and stir 16 hours.Add NaHCO 3saturated aqueous solution (100mL), organic layer is separated and concentrated, generate 3-(the chloro-benzyl of 4-)-4-oxo-tetramethyleneimine-1-t-butyl formate.By EtOH (10mL) dilution for this resistates (1/8 part, about 1.25mmol), and with hydrochloric acid benzyl hydrazine (1.5mmol) and K 2cO 3(5mmol) process.Mixture is stirred 16 hours at 25 ℃.Concentrate and use purified by flash chromatography (EtOAc/CH 2cl 2), generate 2-benzyl-3-(the chloro-phenyl of 4-)-2,6-dihydro-4H-pyrrolo-[3,4-c] pyrazoles-5-t-butyl formate.By described ester and TFA (2mL) at CH 2cl 2(10mL) solution in stirs 4 hours at 25 ℃.Concentrate and use purified by flash chromatography (2M NH 3solution/CH in MeOH 2cl 2), generate required compound (10mg).MS (ESI): C 18h 16clN 3accurate calculation quality, 309.10; Measured value, m/z 310.4[M+H] +.
1H NMR(500MHz，CDCl 3)：7.37-7.21(m，7H)，7.08-7.05(m，2H)，5.29(s，2H)，4.09(s，2H)，4.04(s，2H).
Embodiment 332
1-(the chloro-benzyl of 4-)-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-Azaazulenes
In embodiment 59 step D, with 4-chlorobenzyl bromine (0.1g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.15g), preparation is as this title compound (0.017g) of hydrochloride.MS (ESI): C 20h 19cl 2n 3accurate calculation quality, 371.10; Measured value, m/z 372.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.57-7.50(m，4H)，7.41-7.33(m，2H)，7.27-7.19(m，2H)，5.45(s，2H)，4.34(s，2H)，3.57-3.53(m，2H)，3.08-3.03(m，2H)，2.08-2.02(m，2H).
Embodiment 333
Figure S04833737820060524D002291
3-(the chloro-phenyl of 4-)-1-(4-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene
In embodiment 59 step D, with 4-methyl-benzyl bromine (0.09g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.15g), preparation is as this title compound (0.011g) of hydrochloride.MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.46-7.39(m，2H)，7.21-7.18(m，2H)，6.98-6.95(m，2H)，6.77-6.74(m，2H)，5.08(s，2H)，3.97(s，2H)，3.46-3.43(m，2H)，2.96-2.92(m，2H)，2.17(s，3H)，2.01-1.97(m，2H).
Embodiment 334
Figure S04833737820060524D002292
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-Azaazulenes
In embodiment 59 step D, with 3,4-difluoro benzyl bromide (0.06g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.07g), prepare this title compound (0.005g).MS (ESI): C 20h 18clF 2n 3accurate calculation quality, 373.12; Measured value, m/z 374.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.39-7.34(m，4H)，7.16-7.10(m，1H)，6.98-6.97(m，1H)，6.89-6.88(m，1H)，5.27(s，2H)，3.81(s，2H)，3.09-3.06(m，2H)，2.80-2.76(m，2H)，1.75-1.70(m，2H).
Embodiment 335
3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene
In embodiment 59 step D, with 3-methyl-benzyl bromine (0.06g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.1g), prepare this title compound (0.012g).MS (ESI): C 21h 22clN 3accurate calculation quality, 351.15; Measured value, m/z 352.2[M+H] +.
1H NMR(500MHz，CD 3OD)：7.49-7.43(m，4H)，7.19(t，J＝7.6Hz，1H)，7.08(d，J＝7.6Hz，1H)，7.00(s，1H)，6.92(d，J＝7.3Hz，1H)，5.34(s，2H)，3.88(s，2H)，3.16-3.13(m，2H)，2.88-2.85(m，2H)，2.30(s，3H)，1.80-1.77(m，2H).
Embodiment 336
Figure S04833737820060524D002302
3-(the chloro-phenyl of 4-)-1-(the fluoro-4-methyl-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5 three azepines-Azulene
In embodiment 59 step D, with 3-fluoro-4-methyl-benzyl bromine (0.09g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.1g), prepare this title compound (0.002g).MS (ESI): C 21h 21clFN 3accurate calculation quality, 369.14; Measured value, m/z 370.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.49-7.43(m，4H)，7.19(t，J＝7.9Hz，1H)，6.88-6.80(m，2H)，5.34(s，2H)，3.88(s，2H)，3.16-3.13(m，2H)，2.87-2.85(m，2H)，2.23(d，J＝1.5Hz，3H)，1.81-1.78(m，2H).
Embodiment 337
Figure S04833737820060524D002311
3-(the chloro-phenyl of 4-)-1-(the fluoro-3-methyl-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,5-, tri-azepines-Azulene
In embodiment 59 step D, with 4-fluoro-3-methyl-benzyl bromine (0.09g), replace benzyl chloride, by 3-(the chloro-phenyl of 4-)-4,6,7,8-tetrahydrochysene-1H-1, (embodiment 59, step C for 2,5-, tri-azepines-Azulene-5-t-butyl formate; 0.1g) prepare this title compound (0.001g).MS (ESI): C 21h 21clFN 3accurate calculation quality, 369.14; Measured value, m/z 370.1[M+H] +.
1H NMR(500MHz，CD 3OD)：7.48-7.43(m，4H)，7.08-7.06(m，1H)，6.99-6.97(m，2H)，5.32(s，2H)，3.88(s，2H)，3.16-3.14(m，2H)，2.89-2.86(m，2H)，2.22(d，J＝1.6Hz，3H)，1.80(m，2H).
Embodiment 338
Figure S04833737820060524D002312
3-(the fluoro-phenyl of 4-)-2-sec.-propyl-5,7-dimethyl-2,4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene
With being similar to above-mentioned method, prepare this title compound.
test method
medicine in-vitro is of science
1. couple 5-HT 7the avidity of receptor binding site
By singular competition radioligand, in conjunction with test, assess the compounds of this invention to 5-HT 7the avidity of receptor binding site.Test is to carry out on the film of being prepared by HEK-293 cell, and described cell has been used rat 5-HT 7aacceptor has carried out stable transfection (GB:NM022938).From culture plate, to getting cell, be suspended in Tris-HCl (50mM, pH7.5), and by centrifugal collection (1000rpm, 5 minutes).By cell precipitation thing homogenize in 50mMTris-HCl (pH 7.5), 5mM EDTA (Polytron 15 seconds, arranges 5).After centrifugal (15,000rpm, 25 minutes), film (135 μ g protein/mL) is resuspended in identical damping fluid, and under the test compound improving constantly in concentration existence, at room temperature and 1nM[ 3h] 5-CT cultivates 60 minutes.At 10Mm 5-HT, there is the non-specific binding of giving a definition.With cell harvester (Packard), by fast filtering, stop cultivating.In TopCount-NXT (Packard), calculate radioactivity.
Forming S type suppresses curve and carrys out matching (GraphPadPrism) by nonlinear regression analysis.Calculate IC 50value (generating 50% concentration suppressing of specificity radioligand combination).According to Cheng and Prussoff (Biochem.Pharmacol. (1973) 22:3099-3108), obtain K ivalue.To test in triplicate.
In DMSO, prepare medicine stock solution (10mM) (the final analysis concentration of DMSO is no more than 0.4%).In analysis buffer, prepare drug dilution liquid.Data presentation is in table 1 below.
2. the effect of pair adenylate cyclase activity
In adenylate cyclase enzyme test, assess the vitro functional matter of the compounds of this invention.Using rat 5-HT 7athe HEK-293 cell of acceptor stable transfection is taped against on 96 hole flat boards.Cell is washed with 200 μ L DNEM/F12, and cultivate 10 minutes with 80 μ L 2mM 3-isobutyl-1-methylxanthines.For other 10 minutes, add compound (10 μ L).Subsequently, add 5-CT (10 μ L).After 20 minutes, by adding 20 μ L 0.5N HCl to stop cultivating.Flat board is cultivated 30 minutes at 4 ℃.Adopt commercial reagent box (Perkin Elmer), use 125i-cAMP, measures the cAMP content in 20 μ L supernatant liquors.Use GrapPad Prism, by nonlinear regression analysis, calculate the S type curve of best fitted.
R5-HT 7athe adenylate cyclase activity that 5-CT-in/HEK-293 cell stimulates is implemented example 59 compounds to be suppressed, the pK of assessment bbe about 8, with by [ 3h] 5-CT is in conjunction with the K of test determination ibe worth very consistent.
3. couple 5-HT 2Athe avidity of receptor binding site
Use [ 3h] ketanserin is as radioligand, by competitive radioligand with in conjunction with test, assesses compound to rat 5-HT 2Athe avidity of acceptor.(Schotte, the people such as A., Psychopharmacology (1996) 124:57-73) as described in the prior art, tests deriving from the film of rat layer.In brief, by cerebral tissue (rat layer) homogenize in the Tris-HCl damping fluid (50mM, pH7.4) of 20 volumes/weight in wet base tissue.By the whole film fragments of centrifugal collection, and wash by centrifugal (in 4 ℃ with centrifugal 25 minutes of 25,000g) subsequently.Film is resuspended to and contains 1nM[ 3h] in the Tris-HCl damping fluid (50mM, pH7.4) of ketanserin.Under existing, 10 μ M risperidones assess non-specific binding.By pre-soaked on the Whatmang of 0.1% polymine F/B strainer fast filtering, and carry out once washing step with the ice-cold Tris-HCl damping fluid (pH7.4) of 1mL, stop cultivating.The pK of all compounds ivalue is all to pass through pK i=-log K icalculate, wherein K i(Biochem Pharmacol. (1973) the 22:3099-3108) (IC calculating according to the method for Cheng and Prusoff 50/ (1+[S]/K d), [S]=1nM wherein; K d=0.42nM).All values in table 1 all Shi YinMWei unit is listed.Data presentation is in following table 1.
4. couple 5HT 2the avidity of receptor binding site
Employment restructuring 5-HT 2A(GB:X57830), 5-HT 2Band 5-HT (GB:Z36748) 2C(GB:M81778) acceptor carries out receptors bind.Use [ 3h] ketanserin (h5-HT 2A) or [ 3h] mesulergine (h5-HT 2Band h5-HT 2C), by competitive radioligand with in conjunction with test, assess compound to 3 kinds of different people 5-HT 2the avidity of receptor subtype.On film, test, described film is by using h5-HT 2Athe NIH3T3 of stable transfection or use h5-HT 2Band h5-HT 2Cthe CHO of stable transfection makes.The K of all compounds ivalue is all (Cheng and Prusoff, Biochem.Pharmacol. (1973) the 22:3099-3108) (IC calculating according to the formula of Cheng and Prusoff 50/ (1+[S]/K d), [S]=1nM (5-HT wherein 2A), 4nM (5-HT 2B) and 3nM (5-HT 2C); K d=0.4nM (5-HT 2A), 3.5nM (5-HT 2B) and 3nM (5-HT 2C).Data presentation is in following table 1.
5. for 5-HT 2the external function test (intracellular Ca2+) of acceptor
(the people such as Porter as described in the prior art, 1999, Jerman, people .Eur.J.Pharmacol. (2001) 414:23-30 such as J.C.), the fluorescence imaging plate reader (FLIPR) that use is analyzed based on calcium, measures these compounds to different 5-HT 2the vitro functional matter of receptor subtype. by 5-HT 2the G albumen of acceptor YuGq family connects, and then activates Phospholipase C, induction phosphoinositide metabolism and raising intracellular calcium concentration.The same cell that use is described in a upper joint (receptors bind) is to carry out FLIPR experiment.
Table 1. binding affinity (nM)
Embodiment K i 5-HT 7 K i 5-HT 2A K i 5-HT 2B K i 5-HT 2C
1 120 NT NT NT
17 70 NT NT NT
18 25 NT NT NT
22 45 NT NT NT
26 18 NT NT NT
38 pK b7.8 NT NT NT
47 7 9 64 24
57 15 NT NT NT
59 6 280 160 74
64 19 18 NT NT
74 5 100 94 180
75 7 200 100 320
76 8 210 350 690
87 33 NT NT NT
98 40 NT NT NT
100 30 NT NT NT
103 7.7 60 44 150
104 9 80 52 360
108 9 NT 100 800
111 17 NT NT NT
114 32 NT 90 400
117 20 NT NT NT
118 8 20 NT NT
119 39 NT NT NT
120 40 NT NT NT
131 120 7 4.2 50
133 125 2.3 3.5 10
160 7 300 350 3500
165 4 100 310 180
166 8 80 560 590
167 75 NT 350 10000
172 37 NT NT NT
174 40 NT NT NT
177 80 7 7 110
178 85 3 3 NT
180 10 1.5 1.4 12
181 37 1.5 1.8 11
182 90 0.74 1.4 18
183 240 7 54 70
184 120 1 17 15
186 61 1 24 20
190 16 10 22 51
191 30 NT NT NT
192 20 2.5 0.9 15
209 6 1.1 1.4 12
210 7 2 0.75 20
211 8.5 5 0.5 18
212 93 25 12 425
213 12 7.5 4.7 80
214 5 NT 2 170
215 30 8 95 NT
216 70 6 20 17
217 25 1 0.65 10
218 75 1.7 1.8 15
220 55 1.3 0.55 6.8
232 20 25 0.50 66
233 15 4 25 16
236 950 7 4.5 32
238 40 1 0.50 13
241 310 9 9.5 38
242 21 8 1.3 45
253 75 NT 25 625
255 60 NT NT NT
257 9 NT 2 110
273 5 400 NT NT
276 90 3 2.5 90
277 150 0.9 3 40
278 35 0.1 0.2 10
279 80 0.8 1 45
280 3300 1.5 6 120
282 100 6 20 200
283 5000 10 60 150
284 10 1 2 60
285 29 60 6 500
286 335 50 80 5000
298 50 5 6.5 60
299 35 1.7 9 26
300 10 0.3 0.8 12
301 40 1.6 3 100
302 100 0.2 1.3 21.5
305 600 20 60 2200
306 120 1 22 39
308 5200 2 3 162
309 130 30 15 130
310 475 0.2 0.4 30
311 80 140 100 3000
313 30 100 40 1000
315 12 9 3 300
316 9.1 60 530 5000
NT=does not record

Claims (38)

1. there is the compound that serotonin receptor regulates active formula (II):
Figure FSB0000113077250000011
Wherein
M is 1 or 2;
P is 1 or 2, and condition is that p is not 1 in the situation that m is 1;
Q is 0 or 1;
R is 0,1,2,3,4 or 5;
R 3be-C 1-4alkyl;
Ar is phenyl; Quilt-C 1-6alkyl ,-OC 1-6alkyl ,-CN ,-(C=O) C 1-6alkyl, halogen ,-CF 3or-OCF 3the phenyl replacing; Furyl; Or thienyl;
ALK is C 1-8alkylidene group, C 2-8alkylene group or C 2-8alkynylene, described group be optionally independently selected from following substituting group monosubstituted, two replace or three replacements :-OH ,-CN ,-NH 2,-C (=O) NH 2,-COOH and-COOC 1-6alkyl;
CYC is hydrogen, phenyl, 4-, 5-, 6-, 7-benzo [1,3] dioxa cyclopentenyl, THP trtrahydropyranyl, pyridyl, furyl, thienyl, the non-aromatic carbocyclic ring of 3-8 unit, naphthyl, and described phenyl is optionally by R qmonosubstituted, two replacements or three replace;
R qto be selected from following group :-OH ,-C 1-6alkyl ,-OC 1-6alkyl ,-O benzyl ,-NO 2, NH 2the SO of ,-(N-H) 2-C 1-6alkyl ,-N-(SO 2c 1-6alkyl) 2, halogen ,-CF 3,-OCF 3,-COOH and-COOC 1-6alkyl;
R 1be selected from H and C 1-7alkyl, described C 1-7alkyl is optionally by R pmonosubstituted, two replacements or three replace;
R pbe selected from following groups :-OH ,-NH 2,-C (=O) NH 2, phenyl ,-OC 1-6alkyl and-COOC 1-6alkyl;
Or its pharmacologically acceptable salt.
2. the compound of claim 1, wherein m is 1.
3. the compound of claim 1, wherein m+p is 2 or 3.
4. the compound of claim 1, wherein q is 1.
5. the compound of claim 1, wherein r is 0,1 or 2.
6. the compound of claim 1, wherein r is 4.
7. the compound of claim 1, wherein R 3be selected from methyl, ethyl, propyl group, sec.-propyl, butyl.
8. the compound of claim 1, wherein R 3it is methyl.
9. the compound of claim 1, wherein Ar is selected from phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 3-cyano-phenyl, 4-cyano-phenyl, 3-acetylphenyl, 4-acetylphenyl, 3, 4-difluorophenyl, 3, 4-dichlorophenyl, 2, 3-difluorophenyl, 2, 3-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-chloro-phenyl-, the chloro-4-fluorophenyl of 3-, the fluoro-4-chloro-phenyl-of 3-, the fluoro-3-aminomethyl phenyl of 4-, furans-2-base, furans-3-base, thiophene-2-base and thiene-3-yl-.
10. the compound of claim 1, wherein the optional ALK replacing is selected from methylene radical, ethylidene, propylidene, butylidene, the sub-tertiary butyl, pentylidene, 1-ethyl propylidene, 2-ethyl propylidene, 2-ethyl butylidene, isopropylidene, Aden-3-thiazolinyl, isobutylidene, 3-methyl butylidene, acrol and sub-Propargyl.
The compound of 11. claims 1, wherein ALK is selected from methylene radical, methoxycarbonyl methyl, ethylidene, propylidene, 3-methoxycarbonyl propylidene, 3-carboxyl propylidene, butylidene, the sub-tertiary butyl, 4-hydroxy butylidene, 4-methoxycarbonyl butylidene, 4-carboxyl butylidene, pentylidene, 5-hydroxyl pentylidene, 1-ethyl propylidene, 2-ethyl propylidene, 2-ethyl butylidene, isopropylidene, Aden-3-thiazolinyl, isobutylidene, 3-methyl butylidene, sub-Propargyl and 2-cyano group ethylidene.
The compound of 12. claims 1, wherein CYC is selected from hydrogen, phenyl, naphthalene-1 or 2-base, thiophene-2-base, thiene-3-yl-, furans-2-base, furans-3-base, pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
The compound of 13. claims 1, wherein the optional CYC replacing is selected from hydrogen, phenyl, pyridyl, cyclobutyl, cyclopentyl, cyclohexyl, thiophene-2-base, thiene-3-yl-, THP trtrahydropyranyl, furans-2-base, furans-3-base and naphthalene-1 or 2-base.
The compound of 14. claims 1, wherein CYC is selected from hydrogen, phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4 difluorobenzene base, 2,4 dichloro benzene base, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-3,5-dimethylphenyl, 2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl, cyclobutyl, cyclohexyl, cyclopentyl, the fluoro-3-aminomethyl phenyl of 4-, 3-nitrophenyl, 4-nitrophenyl, 4-methyl-3-fluorophenyl, 3,4-3,5-dimethylphenyl, 4-methoxyl group-3-fluorophenyl, 4-methoxyl group-2-aminomethyl phenyl, 3-aminophenyl, 4-aminophenyl, 4-methoxycarbonyl phenyl, 3-methylsulfonyl amino-phenyl, 4-methylsulfonyl amino-phenyl, 3-diformazan sulfuryl amino-phenyl, 4-diformazan sulfuryl amino-phenyl, thiophene-2-base, thiene-3-yl-, 5-chlorothiophene-2-base, benzo [1,3] dioxole-4 or 5-base, tetrahydropyrans-2, 3 or 4-base, furans-2-base, furans-3-base, naphthalene-1 or 2-base, 3,4-benzyloxy phenenyl, 2-hydroxy phenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 4-hydroxy-2-methyl phenyl, 4 -hydroxyl -3-fluorophenyl and 3,4-dihydroxy phenyl.
The compound of 15. claims 1, wherein R 1be selected from hydrogen and C 1-3alkyl, each group is optionally by R pmonosubstituted, two replacements or three replace.
The compound of 16. claims 1, wherein optionally by R pthe R replacing 1be selected from hydrogen, methyl, ethyl, propyl group and sec.-propyl.
The compound of 17. claims 1, wherein R 1be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, 3-hydroxypropyl, methoxycarbonyl methyl, carbamyl ylmethyl, styroyl, hydrocinnamyl and hydroxyethyl.
18. are selected from the compound of following claim 1:
1-benzyl-3-(the fluoro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzyl-3-phenyl-6-propyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
5-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-yl]-penta-1-alcohol;
3-(the chloro-phenyl of 4-)-1-(4-nitro-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
N-[4-(3-phenyl-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl)-phenyl]-Toluidrin;
3-(the chloro-phenyl of 4-)-1-thiophene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzyl-3-thiophene-2-base-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-fourth-3-thiazolinyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(2-ethyl-butyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-cyclohexyl methyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-isobutyl--Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzo [1,3] dioxole-5-ylmethyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(tetrahydrochysene-pyrans-4-ylmethyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] the fluoro-phenol of-2-;
1-benzyl-3-(the chloro-phenyl of 4-)-6-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzyl-3-(the chloro-phenyl of 4-)-6-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-6-(3,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-phenyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(2-methyl-benzyl)-4,5,6,7,8,9-six hydrogen-1H-1,2,7-, tri-azepines-cyclopenta cyclooctene;
3-(the chloro-phenyl of 4-)-1-encircles octyl group-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene; With
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion;
19. are selected from the compound of following claim 1
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(3-methyl-benzyl)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-azepine-Azulene;
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 3-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-thiophene-2-ylmethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzyl-3-thiophene-2-base-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-(the fluoro-benzyl of 2,4-bis-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
4-[3-(the chloro-phenyl of 4-)-5,6,7,8-tetrahydrochysene-4H-1,2,6-, tri-azepines-Azulene-1-ylmethyl] the fluoro-phenol of-2-;
1-benzyl-3-(the chloro-phenyl of 4-)-6-methyl isophthalic acid, 4,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
1-benzyl-3-(the chloro-phenyl of 4-)-6-ethyl-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene; With
1-benzyl-3-(the chloro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion.
20. are selected from the compound of following claim 1:
1-benzyl-3-(the fluoro-phenyl of 4-)-Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene;
3-(the chloro-phenyl of 4-)-1-isobutyl--Isosorbide-5-Nitrae, 5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
Compound 1-benzyl-3-(4-chloro-phenyl-)-Isosorbide-5-Nitrae of 21. claims 1,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene.
Compound 1-benzyl-3-(4-chloro-phenyl-)-Isosorbide-5-Nitrae of 22. claims 1,5,6,7,8-, six hydrogen-1,2,6-, tri-azepines-Azulene Citrate trianion.
The compound of 23. claims 1, wherein said pharmacologically acceptable salt is effective amino additive salt.
The compound of 24. claims 1, wherein said pharmacologically acceptable salt is selected from hydrobromate, hydrochloride, vitriol, hydrosulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluceptate, Lactobionate and lauryl sulfonate.
25. pharmaceutical compositions, described composition contain pharmaceutically acceptable carrier and treatment significant quantity according to the compound of claim 1.
26. are selected from the purposes in the medicine of the following CNS illness being mediated by serotonin receptor according to the compound of claim 1 in preparation treatment or prevention in Mammals: somnopathy, depressive and/or anxiety, generalized anxiety disorder, schizophrenia, two-phase sexual dysfunction, psychotic disease mental disorder, obsession, mood disorder, stress after wound, migraine, pain, eating disorder, obesity, sexual dysfunction, metabolic disturbance, hormone imbalances, alcohol abuse, addictive disorders, feel sick, inflammation, the hypertension of nervus centralis impact, sleep/Arousal disorders, jet lag and diel rhythm are abnormal.
The purposes of 27. claims 26, it is abnormal that the wherein said CNS illness being mediated by serotonin receptor is selected from depressive and/or anxiety, dyssomnias and diel rhythm.
The compound of 28. claims 1 is selected from the purposes in the medicine of the following disease being mediated by serotonin receptor or illness in preparation treatment and prevention in Mammals: ypotension, peripheral blood vessel obstacle, cardiovascular shock, ephrosis, gastric motility disorder, diarrhoea, spastic colon, easily swash property enteropathy, ischemic, septic shock, the urinary incontinence.
The purposes of the compound of 29. claims 1 in preparing the medicine for the treatment of or prevent to be selected from the following illness in eye being mediated by serotonin receptor in Mammals: glaucoma, optic neuritis, diabetic retinopathy, retinal edema and age-related macular degeneration.
The purposes of the compound of 30. claims 1 in preparing the medicine for the treatment of or prevent to be selected from the following disease being mediated by serotonin receptor or illness in Mammals: depressive and/or anxiety, sleep/Arousal disorders, jet lag, migraine, the urinary incontinence, gastric motility disorder and Yi Ji enteropathy.
The compound of 31. claims 1 is selected from the purposes in the medicine of the following disease being mediated by serotonin receptor or illness in preparation treatment or prevention in Mammals: after depressive and/or anxiety, generalized anxiety disorder, schizophrenia, two-phase sexual dysfunction, psychotic disease mental disorder, obsession, mood disorder, wound stress, somnopathy, sexual dysfunction, eating disorder, migraine, addictive disorders and peripheral vascular disease.
The method of 32. preparation formulas (XVI) compound or pharmaceutically acceptable salt thereof, described method comprises the step that formula (XXXV) compound is reacted with formula (XIV):
Wherein G is-C 1-6alkyl ,-COOC 1-6alkyl ,-(C=O) C 1-6alkyl or benzyl, described benzyl is unsubstituted or quilt-OC 1-6alkyl or-C 1-6alkyl replaces;
X is C1, Br, I, OMs or OTs;
M, p, q, r, ALK and CYC are as defined in claim 1;
R 3be-C 1-4alkyl, allyl group, propargyl or benzyl, described each group is optionally by-C 1-3alkyl ,-OH or halogen replace.
The method of 33. claims 32, wherein said formula (XXXV) compound is by processing formula (XIII) compound to make with fluoroform sulfonyl agent:
The method of 34. preparation formulas (II) compound, wherein described formula (XVI) compound is reacted at least one step with production (II) compound subsequently:
Wherein
Ar and R 1defined in claim 1.
The method of 35. preparation formulas (XXXV) compound or pharmaceutically acceptable salt thereof, described method comprises the step that formula (XIII) compound is reacted with fluoroform sulfonyl agent:
Figure FSB0000113077250000073
Wherein
G is-C 1-6alkyl ,-COOC 1-6alkyl ,-(C=O) C 1-6alkyl or benzyl, described benzyl is unsubstituted or quilt-OC 1-6alkyl or-C 1-6alkyl replaces;
M, p and r are as defined in claim 1;
R 3be-C 1-4alkyl, allyl group, propargyl or benzyl, described each group is optionally by-C 1-3alkyl ,-OH or halogen replace;
Or their enantiomorph, diastereomer, hydrate, solvate, pharmacologically acceptable salt, ester or acid amides.
The method of 36. preparation formulas (II) compound, wherein described formula (XXXV) compound is reacted at least one step with production (II) compound subsequently:
Figure FSB0000113077250000081
Wherein
Q, Ar, CYC, ALK and R 1defined in claim 1.
37. use isotopic labelings are so that the compound of the claim 1 that can survey by positron emission tomoscan or single photon emission computed tomography.
The purposes of the compound of 38. claims 1 in the medicine for the preparation of the adjustable disease of research thrombotonin, described medicine is for using 18f-mark or 11the compound of the claim 1 of C-mark, as positron emission tomoscan molecular probe.
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CN1269800A (en) * 1997-09-08 2000-10-11 詹森药业有限公司 Tetrahydro Gamma-carbolines

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