CN1223656A

CN1223656A - Spiro-piperidine derivatives and their use as therapeutic agents

Info

Publication number: CN1223656A
Application number: CN 97195632
Authority: CN
Inventors: R·巴克尔; N·R·库尔蒂斯; J·M·埃利奥特; T·哈里森; G·J·霍林沃斯; P·S·杰克森; J·J·库拉戈斯基; E·M·瑟瓦尔德; C·J·斯温; B·J·维廉斯
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 1996-06-21
Filing date: 1997-06-17
Publication date: 1999-07-21

Abstract

Substituted spiro-piperidine derivatives of structural formula (I) are tachykinin receptor antagonists of use, for example, in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

Description

Spiro-piperidine derivatives and as the purposes of therapeutical agent

The present invention relates to the aza cyclic cpds, they can be used as tachykinin antagenists.More particularly, The compounds of this invention is spiral shell-substituted azetidine analog derivative.

International (PCT) application WO94/20500 (publication on September 15th, 1994) discloses the Spiroazacyclic derivative as the P substance antagonist.Especially, WO94/20500 relates to and contains 1, the spirocyclic piperidine derivatives of 8-diaza spiro [5.5] undecane parent nucleus.

We have further found the non-peptide of a class at present, and they are effective tachykinin antagenists, particularly the P substance antagonist.In addition, record by for example conventional hepatomicrosome analysis, The compounds of this invention demonstrates has very high liver stability.

Further, because it has unique cyclopropyl ether moiety, a preferred group The compounds of this invention has the very oral bioavailability of high level, simultaneously to people NK ₁Acceptor has high avidity.

The invention provides formula I compound and pharmacologically acceptable salt thereof:

Wherein

R ¹Expression hydrogen, hydroxyl, C _1-6Alkyl, C _2-6Alkenyl, C _3-7Cycloalkyl, C _3-7Cycloalkyl C _1-4Alkyl, C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _1-6Alkoxy C _1-4Alkyl, C _1-6Alkoxy C _1-4Alkoxyl group, fluoro C _1-6Alkoxy C _1-4Alkyl, C _2-6Alkenyloxy, C _3-7Cycloalkyloxy, C _3-7Cycloalkyl C _1-4Alkoxyl group, phenoxy group, benzyloxy, cyano group, halogen, NR ^aR ^b, SR ^a, SOR ^a, SO ₂R ^a, OSO ₂R ^a, NR ^aCOR ¹⁴, COR ^a, CO ₂R ^aOr CONR ^aR ^b, R wherein ^aAnd R ^bRepresent hydrogen, C independently of one another _1-4Alkyl or fluoro C _1-4Alkyl;

R ²Expression hydrogen, halogen, C _1-6Alkyl or C _1-6Alkoxyl group;

Or work as R ²With R ¹When adjoining, they can connect into and contain the saturated or unsaturated ring of one or two 5-that is selected from nitrogen, oxygen and sulphur or 6-unit, and this ring can at random be selected from C _1-4Alkyl, CF ₃,=O or=substituting group of S replaces;

R ³Expression hydrogen, halogen, C _1-6Alkyl, fluoro C _1-6Alkyl, C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _3-7Cycloalkyl, C _3-7Cycloalkyl C _1-4Alkyl, cyano group, SR ^a, SOR ^a, SO ₂R ^a, NR ^aR ^b, NR ^aCOR ¹⁴, COR ^a, CO ₂R ^a, CONR ^aR ^bOr by cyano group, CO ₂R ^aOr CONR ^aR ^bThe C that replaces _1-4Alkyl, wherein R ^aAnd R ^bDefinition as mentioned;

R ⁴Expression hydrogen, halogen, C _1-6Alkyl, C _1-6Alkoxyl group, CF ₃, OCF ₃, NO ₂, CN, SR ^a, SOR ^a, SO ₂R ^a, CO ₂R ^a, CONR ^aR ^b, C _2-5Alkenyl, C _2-6Alkynyl or by C _1-4The C that alkoxyl group replaces _1-4Alkyl, wherein R ^aAnd R ^bDefinition as mentioned;

R ⁵Expression hydrogen, halogen, C _1-6Alkyl, CF ₃Or by C _1-4The C that alkoxyl group replaces _1-6Alkoxyl group;

R ⁶Expression hydrogen, COR ^a, CO ₂R ^a, COCONR ^aR ^b, COCO ₂R ^a, at random be selected from the C that following substituting group replaces _1-6Alkyl: CO ₂R ^a, CONR ^aR ^b, hydroxyl, CN, COR ^a, NR ^aR ^b, C (NOH) NR ^aR ^b, CONH phenyl (C _1-4Alkyl), COCO ₂R ^a, CONHNR ^aR ^b, C (S) NR ^aR ^b, CONR ^aC _1-6Alkyl R ¹², CONR ¹³C _2-6Alkenyl, CONR ¹³C _2-6Alkynyl, COCONR ^aR ^b, CONR ^aC (NR ^b) NR ^aR ^b, CONR ^aHeteroaryl and at random by one, two or three are selected from C _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group, halogen and trifluoromethyl replaces;

Or R ⁶Expression-CH ₂C ≡ CCH ₂NR ⁷R ⁸Group, R wherein ⁷And R ⁸Be defined as follows;

Or R ⁶Expression is contained the 5-unit of 1,2 or 3 nitrogen-atoms or the C of 6-unit heterocyclic substituted _1-6Alkyl, this C _1-6Alkyl can at random be replaced by the oxygen base, described 5-unit or 6-unit heterocycle can be at random by=O or=S replaces or at random by formula ZNR ⁷R ⁸Group replace, wherein

Z is C _1-6Alkylidene group or C _3-6Cycloalkyl;

R ⁷Be hydrogen or C _1-4Alkyl, C _3-7Cycloalkyl, C _3-7Cycloalkyl C _1-4Alkyl or by C _1-4The C that alkoxyl group or hydroxyl replace _2-4Alkyl;

R ⁸Be hydrogen or C _1-4Alkyl, C _3-7Cycloalkyl, C _3-7Cycloalkyl C _1-4Alkyl or by C _1-4Alkoxyl group, hydroxyl or contain one or two heteroatomic 4,5 or 6 yuan of cyclosubstituted C of heterolipid that are selected from N, O and S _2-4Alkyl;

Or R ⁷, R ⁸And coupled nitrogen-atoms forms 4 to 7 yuan of heterolipid rings, this heterolipid ring at random is selected from hydroxyl or is at random replaced by one or two group of the C1-4 alkoxyl group of C1-4 alkoxyl group or hydroxyl replacement, this ring at random contains two keys, and this ring can at random contain aerobic or sulphur annular atoms, group S (O) or S (O) ₂Or can be used as NH or NR ^cSecond nitrogen-atoms of the part of part, wherein R ^cFor at random by hydroxyl or C _1-4The C that alkoxyl group replaces _1-4Alkyl;

Or R ⁷, R ⁸And coupled nitrogen-atoms forms the non-aromatics azabicyclo system that contains 6 to 12 annular atomses;

Or Z, R ⁷Reach coupled nitrogen-atoms and form the heterolipid ring that contains 4 to 7 annular atomses, described heterolipid ring can at random contain the aerobic annular atoms;

R ⁹And R ¹⁰Represent hydrogen, halogen, C independently of one another _1-6Alkyl, CH ₂OR ^e, oxo, CO ₂R ^aOr CONR ^aR ^b, R wherein ^aAnd R ^bDefinition as mentioned, R ^eExpression hydrogen, C _1-6Alkyl or phenyl;

R ¹²Expression OR ^a, CONR ^aR ^bOr heteroaryl;

R ¹³Expression hydrogen or C _1-6Alkyl;

R ¹⁴Expression C _1-6Alkyl, C _1-6Alkoxyl group, fluoro C _1-6Alkyl or phenyl;

X is Sauerstoffatom or two hydrogen atoms; And

Intermittent line is represented two arbitrarily keys.

In special group formula I compound and pharmacologically acceptable salt thereof,

R ¹Expression, C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _1-6Alkoxy C _1-4Alkyl, fluoro C _1-6Alkoxy C _1-4Alkyl, C _2-6Alkenyloxy, C _3-7Cycloalkyloxy, phenoxy group, benzyloxy, cyano group, halogen or NR ^aR ^b, R wherein ^aAnd R ^bRepresent hydrogen or C independently of one another _1-4Alkyl;

R ³Expression halogen, C _1-6Alkyl, fluoro C _1-6Alkyl, C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _3-7Cycloalkyl, C _3-7Cycloalkyl C _1-4Alkyl or cyano group;

R ⁴Expression hydrogen, halogen, C _1-6Alkyl, C _1-6Alkoxyl group, CF ₃, OCF ₃, NO ₂, CN, SR ^a, SOR ^a, SO ₂R ^a, CO ₂R ^a, CONR ^aR ^b, C _2-6Alkenyl, C _2-6Alkynyl or by C _1-4The C that alkoxyl group replaces _1-4Alkyl, wherein R ^aAnd R ^bRepresent hydrogen or C independently of one another _1-4Alkyl;

X is two hydrogen atoms.

In a preferred class formula I compound, R ¹Expression hydroxyl, C _1-6Alkyl, C _2-6Alkenyloxy, C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _2-6Alkenyloxy, C _3-7Cycloalkyloxy, C _3-7Cycloalkyl C _1-4Alkoxyl group, cyano group, NR ^aR ^b, SR ^a, OSO ₂R ^a, or R ¹With radicals R ²Form the 5-unit saturated rings that contains a Sauerstoffatom together.

In a particularly preferred class formula I compound, R ¹Be C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group or C _3-7Cycloalkyloxy, particularly methoxyl group, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 2,2-difluoroethoxy, 2-fluorine oxyethyl group, ring propoxy-or cyclobutoxy group.More particularly, R ¹Be methoxyl group or ring propoxy-.

In further preferred The compounds of this invention, R ¹Be the ring propoxy-.

In another preferred class formula I compound, R ²Be hydrogen, fluorine or chlorine atom, particularly hydrogen atom.

In a further preferred class formula I compound, R ³Be hydrogen, halogen, fluoro C _1-6Alkyl, fluoro C _1-6Alkoxyl group, cyano group, NR ^aR ^bOr NR ^aCOR ¹⁴(R wherein ¹⁴Be preferably methyl, methoxyl group, trifluoromethyl or phenyl).

In a preferred class formula I compound again, R ³Be halogen atom or fluoro C _1-6Alkoxyl group, particularly fluorine, trifluoromethoxy or 2,2, the 2-trifluoro ethoxy.More particularly, R ³Be trifluoromethoxy.

In a further preferred class formula I compound, R ⁴Be hydrogen atom or fluorine atom.

At another preferably in the class formula I compound, R ⁵Be hydrogen atom.

In a further preferred class formula I compound, R ⁶Be hydrogen atom.

In a preferred class formula I compound again, R ⁶Be the C of the 5-unit heterocyclic substituted that contains 2 or 3 nitrogen-atoms of definition as mentioned _1-6Alkyl, particularly CH ₂, CH (CH ₃) and CH ₂CH ₂, CH more especially ₂

Especially, 5-unit ring is for being selected from the heterocycle of following radicals:

Particularly preferred heterocycle is selected from:

In another preferred class formula I compound, R ⁹And R ¹⁰One of be hydrogen, particularly R ⁹And R ¹⁰Both are hydrogen atom.

In a further preferred class formula I compound, X represents two hydrogen atoms.

Preferably, two keys of being represented by intermittent line do not exist.

One group of preferred The compounds of this invention be formula (I is compound and pharmacologically acceptable salt thereof a):

R wherein ¹, R ², R ³, R ⁴With intermittent line as the definition relevant with formula I.

For the formula I compound, Z (if present) can be straight chain, side chain or cyclic group.Preferred Z contains 1 to 4 carbon atom, most preferably 1 or 2 carbon atom.Particularly preferred Z group is CH ₂

For formula I compound, R ⁷Can suitably be C _1-4Alkyl or by hydroxyl or C _1-2The C that alkoxyl group replaces _2-4Alkyl; R ⁸Can suitably be C _1-4Alkyl or by hydroxyl or C _1-2The C that alkoxyl group replaces _2-4Alkyl; Or R ⁷And R ⁸Form azetidinyl, pyrrolidyl, piperidyl, morpholino, thiomorpholine generation, Piperazino together with coupled nitrogen-atoms or on nitrogen-atoms by C _1-4The Piperazino that alkyl replaces or by hydroxyl or C _1-2The C that alkoxyl group replaces _2-4Alkyl.

As group NR ⁷R ⁸When expression contained the heterolipid ring of 4 to 7 annular atomses and described ring and contains a pair of key, particularly preferred group was the 3-tetramethyleneimine.

As group NR ⁷R ⁸When representing that non-aromatics azabicyclo is, this class ring system can contain 6 to 12 annular atomses, preferably contains 7 to 10 annular atomses.Suitable ring comprises 5-azabicyclo [2.1.1] hexyl, 5-azabicyclo [2.2.1] heptyl, 6-azabicyclo [3.2.1] octyl group, 2-azabicyclo [2.2.2] octyl group, 6-azabicyclo [3.2.2] nonyl, 6-azabicyclo [3.3.1] nonyl, 6-azabicyclo [3.2.2] decyl, 7-azabicyclo [4.3.1] decyl, 7-azabicyclo [4.4.1] undecyl and 8-azabicyclo [5.4.1] dodecyl, particularly 5-azabicyclo [2.2.1] heptyl and 6-azabicyclo [3.2.1] octyl group.

Work as R ⁸Expression is contained one or two heteroatomic 5 or 6 yuan of cyclosubstituted C of heterolipid that are selected from N, O and S _2-4During alkyl, suitable ring comprises pyrrolidino, piperidino-(1-position only), Piperazino, morpholino or thiomorpholine generation.Be preferably the nitrogen that contains the heterolipid ring especially, especially pyrrolidino or morpholino ring.

Shi Yi ZNR especially ⁷R ⁸Part comprises that wherein Z is CH ₂Or CH ₂CH ₂And NR ⁷R ⁸Those groups for amino, methylamino-, dimethylamino, diethylin, azetidinyl, pyrrolidino and morpholino.

Especially, Z is preferably CH ₂And NR ⁷R ⁸Be dimethylamino, azetidinyl or pyrrolidino, particularly dimethylamine.

When any variable appeared at formula I more than once or appear in any substituting group, definition under its every kind situation and the definition under any other situation were separate.

Just as used herein, term " alkyl " or " alkoxyl group " as group or group part is meant the straight or branched group.Suitable examples of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl and the tertiary butyl.Suitable alkoxyl group example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.

Just as used herein, term " fluoro C _1-6Alkyl " and " fluoro C _1-6Alkoxyl group " be meant the C that wherein one or more (particularly 1 to 3) hydrogen atoms are replaced by fluorine atom _1-6Alkyl or C _1-6Alkoxyl group.Similarly, term " fluoro C _1-4Alkyl " be meant the C that wherein one or more (particularly 1 to 3) hydrogen atoms are replaced by fluorine atom _1-4Alkyl.Preferred especially fluoro C _1-3Alkyl and fluoro C _1-3Alkoxyl group, for example CF ₃, CH ₂CH ₂F, CH ₂CHF ₂, CH ₂CF ₃, OCF ₃, OCH ₂CH ₂F, OCH ₂CHF ₂Or OCH ₂CF ₃, CF the most particularly ₃, OCF ₃And OCH ₂CF ₃

Here the cycloalkyl of indication is represented as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Suitable cycloalkylalkyl can be as the cyclopropyl methyl.

Similarly, the cycloalkyloxy of indication is represented as ring propoxy-or cyclobutoxy group here.

Just as used herein, term " alkenyl " and " alkynyl " as group or group part is meant the straight or branched group.Suitable alkenyl comprises vinyl and allyl group.Suitable alkynyl is a propargyl.

Just as used herein, be meant as the term " heteroaryl " of group or group part and contain 1 to 4 heteroatomic 5-or 6-unit hetero-aromatic ring that is selected from N, O and S.The special example of this class group comprises: pyrryl, furyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl isothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, triazolyl, oxadiazole base, thiadiazolyl group, triazinyl and tetrazyl.

When this class was used, term " halogen " was meant fluorine, chlorine, bromine and iodine.Except as otherwise noted, optimal halogen is fluorine and chlorine, wherein preferred fluorine.

Specilization compound in the scope of the invention comprises following compounds and pharmaceutical salts thereof:

(6S, 5R)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R, 3S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(±)-(6S*, 5R*, 3S*)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R, 3S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-7-(1,2,4-triazolyl-3-methylene radical)-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R)-3-(2-isopropoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R, 3S)-3-(2-isopropoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R)-3-(2-allyloxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R)-3-(5-trifluoromethoxy-2,3-Dihydrobenzofuranes-7-yl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R, 3S)-3-(5-trifluoromethoxy-2,3-Dihydrobenzofuranes-7-yl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R)-3-(2-methoxyl group-5-(2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R, 3S)-3-(2-methoxyl group-5-(2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R)-3-(2,5-two (2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R, 3S)-3-(2, two (2,2, the 2-trifluoro ethoxy) phenyl of 5-)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R, 3S)-3-(2-difluoro-methoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(6S, 5R, 3S)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(6S, 5R, 3S)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-fluorophenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

Further specilization compound in the scope of the invention comprises following compounds and salt thereof:

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-7-benzyl-3-[2-methoxyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3, two (the phenyl)-1-oxa-s of 6--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-7-benzyl-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(±)-(3R*, 5R*, 6S*)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone.

Further again specilization compound in the scope of the invention comprises following compounds and pharmaceutical salts thereof:

(3S, 5R, 6S)-3-(2-ring propoxy--5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

The present invention further aspect, the formula I compound can the preparation of its pharmaceutical acceptable salt, particularly with its acid salt form preparation.

As being used for medicine, formula I compound salt should be non-toxicity pharmacologically acceptable salt.But other salt also can be used for the preparation of The compounds of this invention or its non-toxicity pharmacologically acceptable salt.The suitable pharmacologically acceptable salt of The compounds of this invention comprises acid salt, they can be by getting as solution and pharmaceutically acceptable acid solution mixing system with The compounds of this invention, and described pharmaceutically acceptable acid comprises hydrochloric acid, fumaric acid, tosic acid, toxilic acid, succsinic acid, acetate, citric acid, tartrate, carbonic acid, phosphoric acid or sulfuric acid.Amido salt also can comprise quaternary ammonium salt, and wherein amino nitrogen atom can have suitable organic group, as alkyl, alkenyl, alkynyl or aralkyl moiety.Further, when The compounds of this invention had acidic moiety, suitable pharmacologically acceptable salt can comprise metal-salt, an alkali metal salt (as sodium or sylvite) and alkaline earth salt (as calcium and magnesium salts).

Described salt can form by ordinary method, for example with product and one or more normal suitable acid-respons of free alkali form, this is reflected at the solvent that do not dissolve described salt or as carrying out in the solvent of water, described water can separate in vacuum or by lyophilize, this water also can be in suitable ion exchange resin, the anionresin in the existing salt is become another kind of negatively charged ion and separates.

Scope of the present invention comprises the prodrug of above-mentioned formula I compound.Usually, the functionality derivative that this class prodrug is the formula I compound, they can easily convert required formula I compound in vivo.At " the Design ofProdrugs " that edit as H.Bundgaard, Elsevier has described the ordinary method of selecting and prepare suitable prodrug in 1985.

Prodrug can be the pharmacology inertia derivative of biologically active substance (" parent drug " or " parent molecule "), in order to discharge active medicine, described pharmacology inertia derivative need be changed in vivo, and this pharmacology inertia derivative has the transmission performance that is better than the parent drug molecule.The body internal conversion can be the result of some metabolic processes, and the chemistry of described metabolic process such as carboxylic acid, phosphoric acid or sulfuric ester or enzymic hydrolysis are perhaps as susceptibility reduction or oxidation.

The scope of the invention comprises formula I compound solvate and salt thereof, as hydrate.

The compounds of this invention has at least three asymmetric centers, therefore can have enantiomorph and diastereomer.All these isomer and composition thereof should be understood to include within the scope of the invention.

Wherein do not exist arbitrarily two preferred formula I of key and (I a) compound has 3-, 5-, 6-position stereochemistry is as embodiment 124 (being 3-(S), 5-(R) and 6-(S)) compound.The example is suc as formula shown in (I b):

Wherein do not exist any two keys a particularly preferred class formula I and (I a) compound has stereochemistry 3-(R), 5-(R) and 6-(S) (as embodiment 214 compounds), promptly suc as formula shown in (I c):

For example, 3 of embodiment 214 (R) compound has bigger effectiveness than its 3 (S) epimer (embodiment 124).

Should be appreciated that various substituent preferred definition described here can adopt separately or, can be applicable to the fixed pattern of The compounds of this invention in conjunction with adopting, also can be applicable to by formula (I a), the preferred compound represented of formula (I b) and formula (I c).

The present invention further provides pharmaceutical composition, this pharmaceutical composition comprises one or more formula I compounds relevant with pharmaceutically acceptable carrier or vehicle.

Preferably, for per os, non-enteron aisle or rectal administration, or by sucking or being blown into administration, the present composition can be a presented in unit dosage form, as tablet, pill, capsule, pulvis, granule, solution or suspension or suppository.

For the preparation solids composition, as tablet, form composition in advance in order to form the homogeneous mixture that contains The compounds of this invention or the solid of its nontoxic pharmacologically acceptable salt, main active ingredient can be mixed with pharmaceutical carrier and other medicines solvent or diluent.The for example conventional composition in flakes of described pharmaceutical carrier is as W-Gum, lactose, sucrose, sorbyl alcohol, talcum, stearic acid, Magnesium Stearate, Lin Suanergai or natural gum; Described solvent or diluent such as water.So-called these homogeneous phases form composition in advance, and its implication is meant that activeconstituents is evenly dispersed in the composition very much, thereby composition can easily be divided into equivalent unit dosage, as tablet, pill and capsule.Then this solid is formed in advance composition and be divided into above-mentioned 0.1 the presented in unit dosage form that contains to about 500mg activeconstituents of the present invention.The tablet of novel composition or pill can contain coating or contain other compound, thereby the advantage that can have the effect lengthening is provided.For example, tablet or pill can contain that make up a prescription in inside and the outside composition that makes up a prescription, and the latter is the former sealing.Two kinds of compositions can be by the intestines layer separately, and this intestines layer is used for stoping disintegration under one's belt and allows internal component to contact with duodenum or delay discharging.Many materials can be used for intestines layer or casing, and this class material can comprise the mixture of many polymeric acids and polymeric acid, and described polymeric acid can contain shellac, fine jade ceryl alcohol and cellulose ethanoate.

Wherein can mix novel composition of the present invention and be applicable to that per os or the liquid form by drug administration by injection comprise hydration solution, suitable fragrance syrup, water or oil suspension, and the fragrance emulsion that contains edible oil (as Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil), also comprise elixir and similar pharmaceutical carrier.The suitable dispersion or the suspension agent that are used for hydration suspension comprise synthetic or natural gum, as tragacanth gum, kordofan gum, diatom salt, glucose glycan, Xylo-Mucine, methylcellulose gum, Polyvinylpyrolidone (PVP) or gelatin.

Can comprise that those contain the formula I compound as composition of active components by the drug administration by injection preferred compositions, described formula I compound can contain tensio-active agent (or wetting agent or tensio-active agent) or exist with emulsion form (as water-in-oil or O/w emulsion).

Especially, suitable tensio-active agent comprises non-reagents for anion, as polyoxyethylene sorbitol (as Tween ^TM20,40,60,80 or 85) and other sorbyl alcohol (as Span ^TM20,40,60,80 or 85).The composition that contains tensio-active agent can comprise 0.05 to 5% tensio-active agent easily, and preferred 0.1 to 2.5%.People should be appreciated that if necessary, can add other composition (as mannitol) or other pharmaceutically acceptable carrier.

Suitable emulsion can be utilized commercial fats emulsion preparation, as Intralipid ^TM, Liposyn ^TM, Infonutrol ^TM, Lipofundin ^TMAnd Lipiphysan ^TMActiveconstituents both may be dissolved in the premix emulsion composition, may be dissolved in oil (as soya-bean oil, sunflower oil, Oleum Gossypii semen, sesame oil, Semen Maydis oil or Prunus amygdalus oil) again and mixed in formed emulsion and the water with phosphatide (as egg phosphatide, soybean phospholipid or soybean lecithin).Should be appreciated that in order to regulate the tension force of emulsion, can add other composition, as glycerine or glucose.Suitable emulsion can typically contain the oil up to 20%, and for example 5 to 20%.Fats emulsion can preferably contain the oil droplet of 0.1 to 1.0 μ m, 0.1 to 0.5 μ m particularly, and its pH is 5.5 to 8.0.

Particularly preferred emulsion compositions is that those pass through formula I compound and Intralipid ^TMOr its composition (as soya-bean oil, egg phosphatide, G ﹠ W) mixes and the emulsion compositions that makes.

The composition that is used to suck or be blown into administration can comprise pharmaceutically acceptable emulsion and suspension, hydration or organic solvent or its mixture and powder.The liquid or solid composition can contain aforesaid suitable pharmaceutically acceptable vehicle.Preferably, for local or be administered systemically, composition can be by oral administration or by the administration of nasal respiration route.Preferably, the composition in the aseptic acceptable solvent can atomize by utilizing rare gas element.Fogged emulsion can directly be breathed or spraying gun can link to each other with mask, tent or intermittent type positive pressure respirator by spraying gun.Solution, suspension or pulvis can be preferably by the devices that transmits preparation in a suitable manner, per os or nasal administration.

The present invention further provides the method that preparation contains the pharmaceutical composition of formula I compound, this method comprises the formula I compound is combined with pharmaceutically acceptable carrier or vehicle.

The formula I compound is many in treatment to be to have suitable value aspect the clinical disease of special type there to be excessive tachykinin (particularly P material) activity.

Thus, for example excessively tachykinin (particularly P material) is active relevant with many central nervous system diseases.This class disease comprises: the mental state disease, as depressed or dysthymia disorders more especially, as ictal or recurrent master dysthymia disorders and depression or the two poles of the earth disease separately, as the two poles of the earth I type disease, the two poles of the earth II type disease and circulation thymopathy; Anxiety disorder, as have or do not have the Phobias that agoraphobia, agoraphobia not have the Phobias medical history, special phobia is as special Zoophpbia, social phobia, obsessive-compulsive disorder, catatonia comprises post-traumatic stress disorder and acute catatonia, and the generalization anxiety disorder; Dissociation of sensibility disease and other psychosis are as schizophreniform diseases, dissociation of sensibility disease, paranoea, brief mental disorder, the property shared mental disorder and the mental disorder relevant with vain hope or illusion; Delerium, dementia and amnesia and other identification or neurodegenerative disease, as alzheimer's disease, senile dementia, alzheimer's type dementia, vascular dementia and other dementia, as the dementia that causes by HIV disease, injury of head, parkinsons disease, Hang Ting Dun Shi disease, Pi Keshi disease, Creutzfeldr-Jakob disease or multiple etiology; The outer motion disease of parkinsons disease and other triquetrum, the movement disorders that causes as pharmacotherapy, the position that for example the acute dystonia of neuroleptic inductive, neuroleptic inductive are acutely cathisophobiaed, the retardance dyskinesia of neuroleptic inductive and medication cause trembles; By using the following drug-induced disease relevant with material: alcohol, Amphetamine (or amphetamine-type material), caffeine, hemp, Cocaine, hallucinogenic agent, inhalation and aerosol propellants, nicotine, opioid, phenylglycidine derivative, tranquilizer, soporific and anxiolytic, the described disease relevant with material comprises: pharmacological dependence and abuse, poisoning, de-addiction, poisoning delerium, de-addiction delerium, persistence dementia, psychosis, emotionality disease, anxiety disorder, sexual dysfunction and sleep disease; Epilepsy; The Down syndromes; Take off neurospongium tip disease, as MS and ALS and other neuropathology disease, as Peripheral nerve disease, the neuropathy that causes of diabetes and chemotherapy for example, and postherpetic neuralgia, trigeminal neuralgia, merogenesis neurodynia or intercostal neuralgia and other neurodynia; And by cerebrovascular disease acute or that the chronic brain blood vessel injury causes, as cerebrum block formation, subarachnoid hemorrhage or cerebral edema.

Neurodynia (particularly P material) activity also relates to nociception and pain.Therefore, The compounds of this invention can be used for preventing or treating the disease of the main pain of symptom, comprise the damage of soft tissue and tip, as acute wound, osteoarthritis, rheumatoid arthritis, flesh skeleton pain (particularly pain after the wound), spinal pain, myofascitis pain syndromes, headache, vulvectomy P﹠B; The degree of depth and visceral pain,, oral cavity pain (as toothache) painful, stomachache, gynaecology's pain (as dysmenorrhoea), and work pain as pained, myalgia, eyes; With the neural pain relevant with root damage, as with the pain of peripheral nerve disease-related, for example nerve is held back and brachial plexus avulsion, amputation, Peripheral nerve disease, trigeminal neuralgia, irregularities face bitterly, nerve root injury and arachnoiditis; The pain relevant, i.e. cancer pain with cancer; Central nervous system pain is as the pain that is caused by marrow or brain stem injury; Sciatica; Ankylosing spondylitis, gout; And scar pain.

Tachykinin (particularly P material) antagonist also can be used for treating respiratory disease, particularly those and the excessive relevant disease of mucus secretion, for example chronic obstruction airway disease, bronchopneumonia, chronic bronchitis, gallbladder cystic fibrosis and edema, grow up airway misery syndromes and bronchospasm; Diseases associated with inflammation is as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritus and sunburn; Anaphylaxis is as eczema and rhinitis; Anaphylactic disease is as toxicodendron; Ophthalmic diseases is as conjunctivitis, youth membranous conjunctivitis etc.; The ophthalmic diseases relevant with hyperplasia is as proliferative vitreous body retinopathy; Tetter is as contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis.

Tachykinin (particularly P material) antagonist also can be used for treating tumour, comprises mammary cancer, neuroganglion blastoma and small cell tumor, as small cell lung cancer.

Tachykinin (particularly P material) also can be used for treating stomach and intestine (GI) disease, comprise diseases associated with inflammation and GI passage disease, as gastritis, gastro-duodenal ulcer, cancer of the stomach, gastric lymphoma, with the relevant disease of splanchnic nerve unit control, ulcerative colitis, the Crohn disease, irritable bowel syndrome and vomiting, comprise acute, retardance or advanced vomiting, as by chemotherapy, radiation, toxin, virus or infectation of bacteria, gestation, the vomiting that vestibular disease causes is as motion sickness, dizzy, giddy and Meniere disease, surgery, migraine, pressure change between cranium, stomach oesophagus reflection disease and hyperchlorhydria, eat and drink immoderately, gastroxia, meniere's or gastric disorder causing nausea, heartburn and maldigestion.

Tachykinin (particularly P material) also can be used for treating various other somatocyte diseases relevant with depression; Sympathetic reflex dystrophy is as shoulder/hand syndromes; Opposite immune response, as the rejection of transplanted tissue with immunostimulant or suppress relevant disease, as the plasma extravasation that systemic lupus erythematosus is caused by the cytokine chemotherapy, vesical dysfunction is as urocystitis, the excessive and incontinence of bladder detrusor reflection; Fibrous tissue forms and collagen diseases, as Scleroderma and acidophilia fascioliasis; The blood flow disease that is caused by vasorelaxation and vasospasm disease is as angina, vascular headache, migraine and Reynaud disease; And propagate with the headache in the pain or the nociception, particularly migraine of any above-mentioned disease-related.

Formula I compound of the present invention has value at postoperative pain and nausea and vomiting aspect, operation back that the above-mentioned disease combined aspects of treatment also has value, particularly therapeutic combination.

Formula I compound of the present invention can be used in particular for treatment vomiting, comprises acute, retardance or advanced vomiting, as the vomiting that is caused by pressure change between chemotherapy, radiation, toxin, gestation, vestibular disease, motion, operation, migraine and cranium.The most especially, the formula I compound can be used for the vomiting that treatment is caused by antitumor (cytotoxin) agent (comprising the employed conventional dose of cancer chemotherapy), and is used for the treatment of the vomiting that is caused by other medicament (as rolipram).

The example of this based chemotherapy medicament comprises: alkylating reagent has the compound of alkylating as mustargen, aziridine cpd, alkyl sulfonate esters and other, as nitrourea, cis-platinum and dacarbazine; Antimetabolite is as folic acid, purine or pyrimidine antagonist; Mitotic inhibitor is as vinca alkaloids and podophyllotoxin derivative; And cytotoxicity antibiotic.

The special case description of chemotherapeutic agents is at D.J.Stewart in Nausea and Vomiting:Recent Research and Clinical Advances, Eds.J.Kucharczyk et al., CRC Press Inc., Boca Raton, Florida, USA (1991) pp177-203, particularly pp188.Chemotherapeutic agents commonly used comprises cis-platinum, dacarbazine (DTIC), dactinomycin, mustargen, streptozotocin, endoxan, carmustine (BCNU), chlorethyl cyclohexyl nitrosourea (CCNU), Zorubicin, zhengdingmeisu, procarbazine, mitomycin, cytosine arabinoside, etoposide, methotrexate, 5 FU 5 fluorouracil, vinealeucoblastine(VLB), vincristine(VCR), bleomycin and Chlorambucil [people such as R.J.Gralla, CancerTreatment Report (1984) 68 (1), 163-172].

The formula I compound also can be used for treatment by radioactive vomiting, and described radiation comprises as in radiotherapy or the radiation vomiting of treatment in the cancer, and is included in the radiotherapy in the treatment of operation back nausea and vomiting.

People should be appreciated that the formula I compound can exist with other healing potion bonded form, when alleviating vomiting, separately or the mixed preparation that uses in order.This class mixed preparation can exist as the form of paired packing.

Further aspect of the present invention comprises and 5-HT ₃Antagonist or other emesis medicine bonded formula I compound, described 5-HT ₃The red siron of antagonist such as Austria, granisetron or a bent siron, described other emesis medicine such as dopamine antagonist (as Reglan or domperidone) or GABA _BReceptor antagonist (as Spinax).In addition, separately or with other one or more emesis therapeutical agent bonded formula I compounds can with anti-inflammatory corticosteroid bonded form administration, described anti-inflammatory corticosteroid such as dexamethasone, Betamethasone Valerate, triamcinolone, adcortyl A, 9-go fluorine fluocinonide, budesonide or other as United States Patent (USP) 2,789, and 118,2,990,401,3,048,581,3,126,375,3,929,768,3,996,359,3,928,326 and 3, those disclosed anti-inflammatory corticosteroid in 749,712.Sai Misong (Decadron particularly preferably ^TM).Moreover, the formula I compound can with the administration of chemotherapeutic agents bonded mode, described chemotherapeutics alkylating reagent described above, antimetabolite, mitotic inhibitor or cytotoxicity antibiotic.Usually, the present dosage form that has that is used for this class bonded known treatment medicament all is fit to.

When people such as F.D.Tattersall, when testing in the ferret model of the vomiting that causes by cis-platinum that J.Pharmacol., (1993) 250, R5-R6 describe, can find that compound of the present invention can alleviate retch and the vomiting that is caused by cis-platinum.

The formula I compound also can be used in particular for treating pain or nociception and/or inflammation and with as neuropathy (neuropathy that causes as diabetes and chemotherapy), zoster after reach the relevant disease of other neurodynia, asthma, osteoarthritis, rheumatoid arthritis and headache (comprise migraine, acute or chronic tension headache, bunchiness headache, temporomandibular joint bitterly and upper jaw bone antrodynia).

The formula I compound also can be used in particular for treating dysthymia disorders, comprises depressive illness, as independent outbreak or the adult depressive illness of recurrent and spirit depressing disease, depressibility neurosis and neural official energy dysthymia disorders; Melancholy depressed, comprise apocleisis, lose weight, insomnia and early awakening disease, and ideomotor movement is slow; Atypia dysthymia disorders (or active dysthymia disorders) comprises appetite increase, hypersomnia, ideomotor movement excitement or excitement, anxiety disorder and phobia; Seasonal emotion disease; Or the two poles of the earth disease or manic dysthymia disorders, as the two poles of the earth I type disease, the two poles of the earth II type disease and cyclothymosis.

The present invention further provides the formula I compound that is used for the treatment of.

According to further or other aspect, the invention provides formula I application of compound at the excessively relevant physiology disease medicament of preparation treatment and tachykinin (particularly P material).

The present invention also provides the method for the excessively relevant physiology disease of treatment or prevention and tachykinin (particularly P material), and this method comprises that the patient to the needs treatment gives with the formula I compound of reduction tachykinin amount or contains the formula I compound compositions.

The further aspect according to the present invention need utilize The compounds of this invention and one or more to be applicable to the above-mentioned any disease of pharmaceutically active agents combined treatment of treatment special disease.Formula I compound and other medicines promoting agent can carry out simultaneously the patient, order or in conjunction with administration.For example, in order to treat respiratory disease (as asthma), the formula I compound can be used in combination with bronchodilator, described bronchodilator such as β ₂-adrenergic receptor agonist or the tachykinin antagenists that the NK-2 acceptor is worked.Formula I compound and bronchodilator can carry out simultaneously the patient, order or in conjunction with administration.

Similarly, The compounds of this invention can use with leukotriene antagonist, described leukotriene antagonist such as leukotriene D ₄Antagonist (as be selected from european patent application 0480717 and 0604114 and United States Patent (USP) 4,859,692 and 5,270,324 in those disclosed compound).This combination can be used in particular for treating respiratory disease, as asthma, chronic bronchitis and cough.

The invention provides the method for treatment respiratory disease (as asthma) thus, this method comprises that the patient to the needs treatment gives with the formula I compound of significant quantity and the bronchodilator of significant quantity.

The present invention also provides the composition that comprises formula I compound, bronchodilator and pharmaceutically acceptable carrier.

People should be appreciated that The compounds of this invention can use with other antimigraine, described antimigraine such as Ergotamine or 5-HT for treatment or prevention of migraine ₁Agonist, particularly sumatriptan, naratriptan, zolmatriptan or rizatriptan.

Similarly, for treatment action hyperpathia, The compounds of this invention can use with D-aspartic acid N-methyl ester (as dizocilpine) agonist.

For treatment or prevention of lower urinary tract diseases associated with inflammation (particularly urocystitis), The compounds of this invention can use with antiphlogistic drug (as bradykinin receptor antagonists).

The present invention also provides the composition that can contain formula I compound, bronchodilator and pharmaceutically acceptable carrier.

People should be appreciated that, for treatment or prevent irritation or nociception, The compounds of this invention can use with other anodyne, described anodyne such as paracetamol (Paracetamol), acetylsalicylic acid and other NSAIDs, particularly opium anodyne, especially morphine.Special antiphlogistic drug can comprise diclofenac, ibuprofen, indomethacin, ketoprofen, naprosine, piroxicam and sulindac.Can be used for to comprise morphine, morphine monomethyl ether, paracodin, diacetylmorphine, dihydrocodeinone, hydromorphone, levorphan, Oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, Pethidine, methadone, Aden's first Numorphan Oral, dextropropoxyphene and pentazocine or its pharmacologically acceptable salt with the suitable opium anodyne of The compounds of this invention bonded.The preferably salt of these opium anodyne comprises, morphine sulfate, Srm-Rhotaard, morphine tartrate, codeine phosphate, codeine sulfate, two dihydrocodeine bitartrates, diamorphine hydrochloride, two Hydrocodone Tartrates, the hydrochloric acid hydromorphone, levorphanol tartrate, the hydrochloric acid Oxymorphone, alfentanil hydrochloride, Buprenorphine hcl, butorphanol tartrate, the citric acid fentanyl, pethidine hydrochloride, methadone hydrochloride, hydrochloric acid Aden first Numorphan Oral, PROPOXY PHEN HCL napsylate (2-naphthene sulfonic acid (1: 1) monohydrate) dextropropoxyphene and pentazocine hydrochloride.

Thus, further aspect of the present invention provides the pharmaceutical composition that contains The compounds of this invention and anodyne and at least a pharmaceutically acceptable carrier or vehicle.

The present invention further or other aspect, the invention provides the product that contains The compounds of this invention and anodyne, this product can be used as simultaneously, separately or order be used for the treatment of or prevent irritation or nociceptive mixed preparation.

People should be appreciated that The compounds of this invention can use with other antidepressant or medicament antianxity for treatment dysthymia disorders or anxiety disorder.

The antidepressive of suitable type comprises NRI, selective serotonin reuptake inhibitor (SSRIs), oxidase inhibitor (MAOIs), monoamine oxidase reverse inhibitor (RIMAs) thrombotonin and NRI (SNRIs), corticotropin releasing factor (CRF) (CRF) antagonist, α-adrenoceptor antagonist and atypia antidepressive.

Suitable NRI comprises tertiary amine three cyclisation things and secondary amine three cyclisation things.The suitable example of tertiary amine three cyclisation things comprises: amitriptyline, chlorimipramine, P-3693A, imipramine and trimeproprimine and pharmacologically acceptable salt thereof.The suitable example of secondary amine three cyclisation things comprises: chlorine piperazine oxygen , desmethylimipramine, maprotiline, nortriptyline and protriptyline and pharmacologically acceptable salt thereof.

The suitable selectivity serotonin reuptake inhibitors comprises: fluoxetine, fluvoxamine, paroxetine and Sertraline and pharmacologically acceptable salt thereof.

Suitable oxidase inhibitor comprises: U-10387, Phenelzine, Tranylcypromine and Si Lai Jimmy and pharmacologically acceptable salt thereof.

Suitable monoamine oxidase reverse inhibitor comprises: moclobemide and pharmacologically acceptable salt thereof.

Be used for suitable thrombotonin of the present invention and NRI and comprise Wen Lafa star and pharmacologically acceptable salt thereof.

Suitable CRF antagonist is included in those compounds of describing among International Patent Application WO 94/13643, WO94/13644, WO 94/13661, WO 94/13676 and the WO 94/13677.

Suitable atypia antidepressive comprises: Bupropion, lithium, nefazodone, Trazodone and vicilan and pharmacologically acceptable salt thereof.

A suitable class antianxiety agent comprises benzodiazepine class and 5-HT _1AAgonist or antagonist, particularly 5-HT _1APartial agonist, and corticotropin releasing factor (CRF) (CRF) antagonist.

Suitable benzodiazepine class comprises: Xanax, zeisin, rancedon, chlorazepate, stable, halazepam, Wypax, oxazepan and W-4020 and pharmacologically acceptable salt thereof.

Suitable 5-HT _1AReceptor stimulant or antagonist comprise: 5-HT particularly _1AAcceptor portion agonist buspirone, flesinoxan, gepirone hydrochloride and Yi Sha is fallen and pharmacologically acceptable salt.

Thus, of the present invention further aspect, the invention provides a kind of pharmaceutical composition, said composition comprises The compounds of this invention and antidepressant or antianxiety agent and at least a pharmaceutically acceptable carrier or vehicle.

The present invention further or other aspect, the invention provides a kind of The compounds of this invention and antidepressive or antianxiety agent product of comprising, this product can be used as simultaneously, separately or order be used for the treatment of or prevent the mixed preparation of dysthymia disorders and/or anxiety disorder.

People should be appreciated that for treatment or prevention food obstacle comprise obesity, Bulimia nerovsa disease and mandatory food obstacle, The compounds of this invention can use with other anoretic.

The invention provides thus in preparation and be used for the treatment of or prevent the formula I compound in the medicine of food obstacle disease and the application of anoretic.

The present invention also provides the method that is used for the treatment of or prevents food obstacle disease, and this method comprises that the patient to the needs treatment gives with a certain amount of formula I compound and a certain amount of anoretic, makes them can provide effective result together.

Of the present invention further aspect, the invention provides a kind of pharmaceutical composition, said composition comprises formula I compound and anoretic and at least a pharmaceutically acceptable carrier or vehicle.

People should be appreciated that formula I compound and anoretic can be used as simultaneously, separately or in proper order are used for the treatment of or prevent the mixed preparation form existence of food obstacle disease.This class mixed preparation can exist as the form of paired packing.

The present invention further or other aspect, the invention provides a kind of product that contains formula I compound and anoretic, this product can be used as simultaneously, separately or order be used for the treatment of or prevent the mixed preparation of food obstacle disease.

In the further embodiment of the present invention, this scheme provide preparation be used for the treatment of or the prevention of obesity disease drug in the formula I compound and the application of anoretic.

The present invention also provides and has been used for the treatment of or the method for obesity prevention, and this method comprises that the patient to the needs treatment gives with a certain amount of formula I compound and a certain amount of anoretic, makes them can provide effective result together.

In another embodiment of the present invention, this scheme provides in preparation and has been used for the treatment of or prevents formula I compound in the Bulimia nerovsa disease drug and anoretic to use.

The present invention also provides the method that is used for the treatment of or prevents Bulimia nerovsa disease, and this method comprises that the patient to the needs treatment gives with a certain amount of formula I compound and a certain amount of anoretic, makes them can provide effective result together.

In the further embodiment of the present invention, this scheme provides in preparation and has been used for the treatment of or prevents the formula I compound in the mandatory food obstacle medicine and the application of anoretic.

The present invention also provides the method that is used for the treatment of or prevents mandatory food obstacle, and this method comprises that the patient to the needs treatment gives with a certain amount of formula I compound and a certain amount of anoretic, makes them can provide effective result together.

In other embodiments of the present invention, this scheme provides in preparation and has been used for alleviating the formula I compound of the total body fat quality medicine of fat Mammals and the application of anoretic.

The present invention also provides and has been used to alleviate the total body fat method for quality of fat Mammals (particularly people), this method comprises that the patient to the needs treatment gives with a certain amount of formula I compound and a certain amount of anoretic, makes them can provide effective result together.

Be used for The compounds of this invention blended suitable anoretic including, but not limited to aminorex, amfecloral, amphetamine, Benzphetamine Hydrochloride, chlorphentermine, clobenzorex, Lipociden, Clominorex, clortermine, isopropylhexedrine., dexfenfluramine, Dextrofenfluramine, Diethylpropion, diphemethoxidine, the N-N-ethylamphetamine, fenbutrazate, S-768, fenisorex, Perphoxene, fludorex, McN 1231, the chaff methyl amphetamine, Levamphetamine, piperazine acetic acid benzyl ester, SaH-42548, metamfepyramone, methyl amphetamine, pseudonorephedrine, phenpentermine, antapentan, Preludin, Phentermine, Phenylpropanolamine, picilorex and western mine-laying department and pharmacologically acceptable salt thereof.

Particularly preferred anoretic comprises amphetamine and derivative thereof, as amphetamine, Benzphetamine Hydrochloride, chlorphentermine, clobenzorex, Lipociden, clortermine, dexfenfluramine, Dextrofenfluramine, Diethylpropion, N-N-ethylamphetamine, S-768, Perphoxene, chaff methyl amphetamine, Levamphetamine, metamfepyramone, methyl amphetamine, pseudonorephedrine, phenpentermine, antapentan, Preludin, Phentermine, Phenylpropanolamine, picilorex and western mine-laying department and pharmacologically acceptable salt thereof.

Particularly preferred suitable class anoretic is the halogeno-benzene propanamine derivatives, comprises chlorphentermine, Lipociden, clortermine, dexfenfluramine, S-768, picilorex and western mine-laying department and pharmacologically acceptable salt thereof.

Being used for mixing the preferred especially halogeno-benzene propanamine derivatives of using with The compounds of this invention comprises: S-768 and dexfenfluramine and pharmacologically acceptable salt thereof.

People should be appreciated that The compounds of this invention can use with selective serotonin reuptake inhibitor (SSRI) bonded form for treatment or obesity prevention.

The present invention provides a kind of thus and has been used for the treatment of or the application of prevention of obesity disease drug Chinese style (I) compound and SSRI in preparation.

The present invention also provides and has been used for the treatment of or the method for obesity prevention, and this method comprises that the patient to the needs treatment gives with a certain amount of formula I compound and a certain amount of SSRI, makes them can provide effective result together.

Of the present invention further aspect, the invention provides a kind of pharmaceutical composition, said composition comprises formula I compound and SSRI and at least a pharmaceutically acceptable carrier or vehicle.

People should be appreciated that formula I compound and SSRI can be used as simultaneously, separately or in proper order are used for the treatment of or the mixed preparation form of obesity prevention exists.This class mixed preparation can exist as the form of paired packing.

The present invention further or other aspect, the invention provides a kind of product that contains formula I compound and SSRI, this product can be used as simultaneously, separately or order is used for the treatment of or the mixed preparation of obesity prevention.

In other embodiment of the present invention, this scheme provides in preparation and has been used for alleviating the formula I compound of the total body fat quality medicine of fat Mammals (particularly people) and the application of SSRI.

The present invention also provides and has been used to alleviate the total body fat method for quality of fat Mammals (particularly people), this method comprises gives with a certain amount of formula I compound and a certain amount of SSRI Mammals, makes them can provide effective result together.

Of the present invention further aspect, the invention provides a kind of total body fat quality pharmaceutical composition of fat Mammals (particularly people) that alleviates, said composition comprises formula I compound and SSRI and at least a pharmaceutically acceptable carrier or vehicle.

Be used for comprising: fluoxetine, fluvoxamine, paroxetine and Sertraline and pharmacologically acceptable salt thereof with the suitable selective serotonin reuptake inhibitor of The compounds of this invention blended.

Just as used herein, " obesity " is meant that Mammals wherein has the disease that is at least 25.9 body-mass index (BMI), and described body-mass index is divided by height square (kg/m by body weight ²) calculate.Usually, the people's of normal type BMI is between 19.9 to 25.9.

Here the obesity of indication can any reason cause, no matter be genetic cause or environment reason.Can cause fat or the disease example of fat reason comprises overfeeding and Bulimia nerovsa, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndromes, Frohlich syndromes, type II diabetes, GH-deficiency, normal mutation and of short and small stature, Turner syndromes and other demonstrate that metabolic activity reduces or as the pathology disease that energy expenditure increases of forbidding of total free-fat mass percent, as suffer from the leukemic children of acute lymphocytoblast.

(obesity) " treatment " is meant mammiferous BMI is reduced to less than about 25.9, and kept this body weight at least 6 months.Treatment can suitably make mammiferous food or energy take in reduction.

(obesity) " prevention " is meant if treated administration before the obesity outbreak, but the generation of obesity prevention.Moreover, treat on the obese person if begun, but then can expect the development of the medicine sequela of the medicine sequela of this treatment obesity prevention or obesity prevention, described sequela such as arteriosclerosis, type II diabetes, polycystic ovarian disease, cardiovascular disorder, osteoarthritis, tetter, hypertension, insulin resistant, hypercholesteremia, this triglyceride level blood and chololithiasis.

Therefore, on the one hand, the present invention relates to suppress and/or suppress fully fat mammiferous steatogenesis, promptly suppress and/or suppress fully the excessive gathering of lipid in the lipocyte, this excessive gathering is the principal character of human or animal's obesity, also relates to losing weight; And on the other hand, the present invention relates to alleviate the symptom of disease, as prevent the generation of polycystic ovarian disease or stop the development of polycystic ovarian disease, thereby make the patient no longer fat, increase the sensitivity and/or the reduction of Regular Insulin or eliminate demand or the use of diabetic subject's (as suffering from the grow up diabetes of outbreak or the patient of type II diabetes) Regular Insulin.

Further aspect of the present invention comprises uses the formula I compound, obtains food biotics (change of 24 hour cadence time) effect, alleviates 24 hours rhythm diseases of Mammals.The invention further relates to the formula I compound is used to block the time change effect of Mammals to light.

The invention further relates to the formula I compound is used for improving or improving mammiferous sleep quality, increase particularly that sleep is renderd a service and the length of one's sleep is kept in raising, and be used for prevention and treatment sleep disease and sleep disordered.

In preferred embodiments, the invention provides and a kind ofly be used to make 24 hour cadence time of subject in advance or the method for time retardation, this method comprises gives with an amount of formula I compound or pharmaceutically acceptable salt thereof the subject.

The administration of the subject being carried out an amount of formula I compound can be used for prevention or treats following disease, thereby obtains the chronobiology effect and/or alleviate the interference of 24 hour cadence time: the disorder of sleep-raw meat feel timetable; The circadian rhythm that high-speed flight causes destroys; Break tour; The people of operating schedule disorder; The people of resident, nurse, firefighter, police or its need of work vigilance and night or insomnia at night; The people of different time sleep have perhaps been deprived owing to work or responsibility; The animal worker; Infantry or its occupation need other armed personnel of great vigilance, and because professional behavior and the people of sleep deprivation; Submariner, perhaps restricted personnel owing to research, exploration or seabed work purpose; Miner, caver, researchist or be limited in subterranean some personnel; The personnel that cosmonaut, lunar space or planet around the earth in the track or solar system skin are executed the task or task and the personnel that undergo training for this reason; Permanent or temporary transient those the impaired personnel of blind person or visual impairment personnel or resolution light and dark ability; The mental patient; The insomniac; Need maintain those personnel of the senseless state that medical treatment, psychosis or other reason cause; The clinicist in the arctic or the Antarctica or live in people in the abnormal weather of light; Suffers from seasonal emotion disease (SAD), winter melancholia or the hypochondriacal people of other form; Senior people; Alzheimer's disease patient or suffer from the people of other form dementia; The patient who needs the drug dose treatment at circadian rhythm round-robin appropriate time; Suffer from the people that postpone or do sth. in advance syndromes the length of one's sleep, or suffer from the people of the syndromes non-24 hour length of one's sleep; And suffer from main or less important insomnia or with the patient of the relevant insomnia of circadian rhythm.The compounds of this invention can be used for as prevention or treatment and circadian rhythm relative disease, also can be used for preventing or treat with across time zone or mentality and the physical disease relevant with circulation shift work timetable.

In preferred embodiments, the invention provides a kind of prevention or treatment Mammals circadian rhythm disease, comprise time zone change (circadian rhythm that high-speed flight causes destroys) syndromes, break tour sleep disordered, postpone the syndromes length of one's sleep, syndromes and non-24 hours sleep-raw meats were felt that disease, this method comprise and were given the formula I compound or pharmaceutically acceptable salt thereof of using effective dose to Mammals the length of one's sleep in advance.

In another preferred embodiment, the invention provides a kind of method of circadian rhythm clipping time among the subject that shortens after sleep-awake circulation change, this method comprises gives with suitable dosage formula I compound or pharmaceutically acceptable salt thereof the subject.

In a more preferred embodiment, the invention provides the method for the circadian rhythm destruction that a kind of alleviation traveller (particularly Mammals) high-speed flight causes, this method comprises gives with the formula I compound or pharmaceutically acceptable salt thereof that increases vigilance dosage the traveller.The purpose of the present embodiment is that auxiliary health carries out physiological regulation, sleep when passing through several time zones with change and food habits.

In another embodiment preferred, (for example the shift work personnel will change over night daytime to the invention provides a kind of subject's of resetting internal physiological tempo clock, vice versa) method, this method comprises gives with suitable dosage formula I compound or pharmaceutically acceptable salt thereof the subject.

The invention further relates to the formula I compound or pharmaceutically acceptable salt thereof is applied to strengthen or improve sleep quality and prevention or the sleep disordered and somnopathy of treatment Mammals.Especially, the invention provides a kind of holding time and improve or improve the method for sleep quality by increase Sleep efficiency and increase sleep.In addition, the invention provides the method for the sleep disordered and somnopathy of a kind of prevention or treatment Mammals, this method comprises to using the formula I compound or pharmaceutically acceptable salt thereof.The present invention can be used for treating sleep disordered, comprise sleeping and keep sleep disease (insomnia) (" DIMS "), described disease can come from physiological reason, as psychosis (particularly relevant) with anxiety, come from use or Drug abuse and alcohol (particularly in the withdrawal stage), childhood outbreak DIMS, nocturnal myoclonus and how moving leg and in the elderly common non-special REM obstacle.

In the subject, following advantage provided by the present invention may be with to improve sleep quality relevant: subject length of one's sleep is divided by subject's value increase of the desired length of one's sleep; Sleep latent period (needing the sleeping time) reduces; Number of times awake in the sleep descends; Begin the sleeping awake minimizing of taking time in back; Total amount of sleep increases; REM amount of sleep and percentage ratio increase; REM time and increasing; Slow wave (slow-wave) (promptly 3 or 4 sections) amount and percentage ratio increase; 2 sections amount of sleep and percentage ratio increase; Awake (particularly morning) number of times reduces; The increase of holding time that alertness improved and slept daytime.An advantage more provided by the present invention comprises that cognitive function improves and hypermnesia.

The present invention can be further used for prevention or treat sleep disordered and somnopathy, comprise with insomnia, hypersomnia, sleep apnea, hypnolepsy, nocturnal myoclonus, the REM sleep is interrupted, high-speed flight causes circadian rhythm destructions, break tour workman somnopathy, dysoemia, palpitation with fear at night, with melancholy or with the disorderly relevant insomnia of mood or emotion, with sleep (parasomnia) and the dysfunction of sleep-walking and enuresis blood vessel, and follow old age sleep disordered.Sleep disordered and general feature somnopathy is sleeping and keeps sleep or obtain peace and quiet or sufficient dyskoimesis.

In addition, as side effect, some drugs also can cause the REM sleep to reduce, and it is sleep disordered that the present invention also can be used for proofreading and correct this class.The present invention also is being useful in treatment aspect the syndromes, as by with sleep period between the fibromyalgia that shows of the relevant non-restorative sleep of dyspnoea and myalgia or sleep apnea.For those skilled in the art should be very clear, and the present invention is not limited to sleep disordered and somnopathy, also can be applicable to by the caused various diseases of sleep quality that reduces.

The formula I compound can use separately or can mix use to other medicament that changes circadian rhythm or increase Sleep efficiency with known.For example, the formula I compound can be used in combination with other compound that is used to suppress or stimulates melatonin to produce well known in the art, can medicament, norepinephrine energy and contain serotonin reuptake retarding agent, α-1-norepinephrine energy agonist, oxidase inhibitor, beta-adrenergic blocking agent and benzodiazepine class (as atenolol USP 23) as melatonin; Or be used in combination with other compound that is used to stimulate melatonin to produce known in this field, comprise tricyclic antidepressants and α-2-1 adrenergic antagonists; Or be used in combination with melatonin precursors, as tryptophane, 5-hydroxyryptophan, thrombotonin and N-ethanoyl thrombotonin; And be used in combination with melatonin analogue, melatonin agonists and melatonin antagonist.In addition, the formula I compound can be used to improve sleep disordered and other compound somnopathy of sleep quality and prevention and treatment and is used in combination with known in this field, comprise as tranquilizer, soporific, antianxiety agent, neuroleptics, a small amount of tranquilizer, melatonin agonists and antagonist, melatonin, melatonin energy medicament, benzodiazepine class, barbiturate, 5HT-2 antagonists etc. are as adinazolam, allobarbital, spiral is piperazine ketone how, ALprazolanic, amitriptyline, Amobarbital, chlorine piperazine oxygen , bentazepam, the peace of heaving a deep sigh, brotizolam, Wellbutrin, buspirone, neo-barb, tetrallobarbital, 2-second-3-first valeryl urea, chloralurethane, somnalclor, Chloral Hydrate, zeisin, chlorimipramine, cloperidone, chlorine nitrogen , chlorethate, leoponex, W-3623, desmethylimipramine, dexclamol, stable, bonadorm, the Lip river, ground, diphenhydramine, P-3693A, triazole nitrogen , ethclorvynol, etomidate, fenobam, funitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, rigenox, halazepam, hydroxyzine, imipramine, Wypax, lormetazepam, maprotiline, meclogaulone, melatonin, promind, peaceful, turzolon, midaflur, midazolam, nefazodone, nisobamate, surem, nortriptyline, oxazepan, paraldehyde, paroxetine, Sodital, perlapine, trilafon, Phenelzine, phenylethyl barbituric acid, W-4020, promethazine, propofol, protriptyline, quazepam, reclazepam, Luo Laimite, but speed acetone, Sertraline, suproclone, temazepam, thioridazine, bent benzyl azoles ester, Tranylcypromine, Trazodone, triazole benzene phenodiazine , trepipam, tricetamide, trichloroethyl phosphate, trifluoperazine, trimetozine, trimeproprimine, Uldazepam, valproate, literary composition daraf(reciprocal of farad) star, zoleplon, zolazepam, azoles pyrrole dawn and salt and binding substances etc.

The formula I compound can carry out administration with Physiotherapy method bonded form, described Physiotherapy method such as phototherapy or electricity irritation.Especially, the formula I compound can expose or is exposed to dim light or dark (or even sleep) bonded mode is carried out administration with the administration of time series Mingguang City, regular tenacity light.In one embodiment of the invention, in order to obtain to treat additional dark other effect, the formula I compound makes the pill taker put under the condition of black or red safety glasses to carry out administration in the time of can being administration.In another embodiment of the present invention,, can make the pill taker outside the time with the formula I compound of giving, put on the black safety glasses for fear of there being the outside zeitgeber that changes with respect to the time that causes by the formula I compound.Similarly, Mingguang City exposes and can use with formula I compound bonded form.

Thus, the scope of the invention provides the formula I compound to be used in combination separately or with other medicament further, thereby changes 24 hours rhythm, or prevents or treat mammiferous sleep disease and sleep disordered.

Just as used herein, term " Mammals " comprises the animal with Economic Importance, and as ox, sheep and pig, particularly those can produce the animal of meat, and comprises domestic animal, motion animal, zoo animal and the mankind, and the latter is preferred.

People should be appreciated that when use described here any in conjunction with the time, formula I compound and other active agents should reasonably carry out administration to the patient in the time interval.This compound can mix with identical pharmaceutically acceptable carrier, carries out the while administration.They can be pharmaceutically acceptable carrier separately, and as conventional oral dosage form, they can carry out the while administration.Term " combination " also is meant the situation that compound and order administration are provided with the form of separating.Therefore, as an example, a kind of activeconstituents is with the tablet form administration, then in rational timed interval, gives with oral dosage form (as tablet) or with the fast dissolving orally dosage form and to use second activeconstituents.Term " fast dissolving orally formulation " is meant from being placed on the patient's tongue and begins that oral administration dissolved in about 10 minutes.

" the reasonably timed interval " is meant and is no more than about 1 hour timed interval.That is to say that if supply with first kind of activeconstituents with tablet form, second kind of activeconstituents should carry out administration with identical dosage form or the another kind of dosage form that can provide medicine effectively to transmit in 1 hour time so.

The good pharmaceutical property of The compounds of this invention provides chance for it is used for the treatment of with low dosage, thereby has reduced need not the danger of side effect.

In treatment and tachykinin over-drastic disease, appropriate dosage is about 0.001 to 50mg/kg/ day, particularly about 0.01 to about 25mg/kg/ day, and as about 0.05 to about 10mg/kg/ day.

For example, relate in the disease of nerve transmission of pain in treatment, appropriate dosage is about 0.001 to 25mg/kg/ day, preferably approximately 0.005 to 10mg/kg/ day, particularly about 0.005 to 5mg/kg/ day.Compound can 1 to 4 time rule administration every day, and be administered once or twice preferred every day.

Utilizing injection formulations to vomit in the treatment, appropriate dosage is about 0.001 to 10mg/kg/ day, preferably approximately 0.005 to 5mg/kg/ day, particularly 0.01 to 1mg/kg/ day.Compound can 1 to 4 time rule administration every day, and be administered once or twice preferred every day.

People should be appreciated that, the formula I compound amount that is used for any treatment is not only along with selected specific compound or composition change, and along with the disease character of administration route, required treatment and patient's age and present situation change, this farthest depends on clinician's judgement.

According to general method (A.1), wherein the non-existent formula I compound of being represented by intermittent line of two keys can represent that the corresponding formula I compound of two keys makes by reducing wherein intermittent line, and described corresponding formula I compound hereinafter is meant formula (II A),

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁹, R ¹⁰With the definition in X definition as the relevant formula I.

Suitable reductive condition comprises: utilize metal catalyst to carry out hydrogenation catalysis, described metal catalyst such as palladium, platinum or its oxyhydroxide or oxide compound; Preferably in appropriate solvent, carry out, described solvent such as alcohols, as methyl alcohol or ethanol, or the ester class, as ethyl acetate, or organic acid, as acetate, or its mixture; Perhaps utilize trifluoroacetic acid or three silicoethanes to carry out reducing.

Similarly, according to general method (A.2), wherein two keys of being represented by intermittent line do not exist and X is that the formula I compound of two hydrogen atoms can make by utilizing reductive condition reduction-type (II B) compound of describing in the aforesaid method (A.1),

According to another kind of general method (B), wherein intermittent line represents that the formula I compound (being above-mentioned formula (II A) compound) of two keys can pass through the formula III compound

Each R wherein ⁴⁵Be C _1-4Alkyl, preferable methyl or normal-butyl make with the reaction of formula IV compound,

R wherein ⁵⁰Be leavings group, as three fluoro sulfonate (OSO ₂CF ₃) or halogen atom, as chlorine, bromine or iodine, especially particularly three fluoro sulfonates, bromine or iodine.

Reaction can be carried out in the presence of lithium chloride and transition-metal catalyst (as triphenylphosphine palladium (O)) easily.The appropriate solvent that is used to react comprises aromatic hydrocarbons, as toluene; Polar aprotic solvent is as dimethyl formamide; Or ethers, as diox.Being reflected at 80 ℃ carries out between the solvent refluxing temperature.

According to another kind of general method (C), the formula I compound can pass through wherein R ⁶Be the corresponding formula I compound (hereinafter being meant formula (V)) of H,

Carry out interconversion reaction with the formula VI compound and make,

LG-R ^6a (Ⅵ)

R wherein ^6aBe the formula R relevant with formula I ⁶Group (except H) or its precursor, LG are leavings group, as alkyl-or aryl-sulfonyl oxygen (as mesylate or tosylate) or halogen atom (as bromine, chlorine or iodine); And if R ^6aBe precursor group, can be converted into radicals R ⁶(in the method, any active group can be protected, and then if necessary, can carry out deprotection).

This reaction can ordinary method be carried out, and for example in the presence of acid acceptor (as salt of wormwood), carries out in organic solvent (as dimethyl formamide).

For example in International Patent Application WO 95/18124, disclose and be used to introduce radicals R ⁶Suitable another kind of method.

According to another kind of general method (D), wherein R ¹Be C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _2-6Alkenyloxy, C _3-7Cycloalkyloxy, C _3-7Cycloalkyl C _1-4The formula I compound of alkoxyl group or benzyloxy can pass through under the alkali existence condition, wherein R ¹Be the formula I compound (hereinafter being meant formula (VII)) of hydroxyl,

With suitable alkyl-, fluoro-alkyl-, alkenyl-, cycloalkyl-, cycloalkylalkyl-or aralkyl-halogenide (particularly iodide) carry out interconversion reaction and make.

Suitable alkali is included in the alkalimetal hydride (as sodium hydride) in the appropriate solvent (as dimethyl formamide).Reaction can approximately carried out under the room temperature easily.

According to another kind of general method (E), the formula I compound can be by utilizing suitable dewatering agent, as methylsulfonyl chloride in pyridine or triethylamine or benzene sulfonyl chloride, and cyclisation formula (VIII) compound and making:

This reaction can utilize suitable organic solvent such as methylene dichloride (if necessary), carries out easily under 0 ℃ to 100 ℃ temperature, preferred room temperature to 80 ℃.

Formula (VIII) intermediate can particularly preferably be used to control the stereochemistry of formula I compound 3-position.

According to further general method (F), wherein intermittent line represents that the formula I compound (being above-mentioned formula (II A) compound) of two keys can be by utilizing acid, as trifluoroacetic acid, makes the dehydration of formula (I X) compound and makes:

This reaction can utilize suitable organic solvent such as methylene dichloride, carries out easily to the temperature of room temperature at 0 ℃.

According to another kind of general method (G), wherein the non-existent formula I compound of being represented by intermittent line of two keys can contain as three-o-tolylphosphine, dimethyl formamide and Tributylamine by utilization, or the palladium catalyst of TBAC tetrabutylammonium chloride and dimethyl formamide (as acid chloride) and reductive agent (preferable formic acid or its salt, as potassium formiate) carry out reductibility Heck reaction, by formula (X) compound

Make with the formula IV compound, wherein the Hal in the formula IV compound is chlorine, bromine or preferred iodine.

According to another kind of general method (H), the formula I compound can be by formula (XX) compound,

React in tetrahydrofuran (THF) with the naphthyl lithium and to make.This reaction is preferably carried out at low temperatures, as approximately-78 ℃.

The further details of proper method will provide among the embodiment hereinafter.

If the X in formula (IX) compound is two hydrogen atoms, formula (II B) compound can utilize above-mentioned general method (F) preparation so.

Intermediate (V) can make according to the mode that is similar to above-mentioned general method (B), and this method preferably contains the amido protecting group on the piperidines nitrogen-atoms of formula III compound.Suitable amido protecting group comprises alkoxy carbonyl, as tert-butoxycarbonyl and trichlorine ethoxy carbonyl, and aromatic alkoxy carbonyl, as benzyloxycarbonyl, perhaps aralkyl is as benzyl.Blocking group can be removed by conventional method, and for example tert-butoxycarbonyl can be removed as trifluoroacetic acid by utilizing under acidic conditions; The tert-butoxycarbonyl that contains benzyloxycarbonyl and benzyl also can be removed by hydrolysis under the condition that has catalyzer (as palladium); The trichlorine ethoxy carbonyl can utilize zinc powder to remove.

But formula III compound through type (XII) compound,

R wherein ⁵⁰Definition (being preferably trifluoromethanesulfonic acid root or bromine or iodine atom) as mentioned is with formula (R ⁴⁵) ₃Sn-Sn (R ⁴⁵) ₃(as hexa methyl ditin alkane) reaction makes.Reaction can be carried out under the condition that has alkali (as Quilonum Retard) and catalyzer (as triphenylphosphine (O) palladium) easily.The appropriate solvent that is used to react comprises ethers, as tetrahydrofuran (THF); Reaction can be carried out under room temperature to 100 ℃ temperature, for example carries out under about 60 ℃.

Wherein X is that formula (XII) compound of two hydrogen atoms can make by following method: exist under alkali (as the hexamethyldisilane sodium amide) condition, making formula (X III) compound ketone enolization,

Then make the reagent of leavings group (for example work as R with can introducing ⁵⁰For-OSO ₂CF ₃The time, use 2-[N, two (trifluoromethyl sulfonyl) amino of N-]-5-chloropyridine or trifluoromethanesulfonic acid acid anhydrides) reaction.Reaction can be carried out under low temperature (as-80 ℃) in appropriate solvent (for example ethers, as tetrahydrofuran (THF)) easily.

Formula (X III) compound can (condition be R by following reactions steps (flow process A or flow process B) or by similar method ⁹And R ¹⁰Be not the oxygen base), make by formula (X IV) compound:

Flow process A

Flow process B

In the preferred embodiment of aforesaid method, R ⁶Be benzyl.The above-mentioned reduction reaction that is used to prepare the method (A) of formula I compound can utilize hydrogen atom to substitute benzyl easily.Be appreciated that wherein R by above-mentioned discussion ⁶For the formula I compound of hydrogen atom is the particularly preferred precursor of other formula I compound.

In another approach, wherein X be two hydrogen atoms the formula III compound can (condition be R by following reactions steps (flow process C) or by similar method ⁹And R ¹⁰Be not the oxygen base) make:

Flow process C

In another preferred embodiment of aforesaid method, R ⁶Can be substituted by amido protecting group (particularly tertbutyloxycarbonyl condition), described blocking group can be removed before easily in reduction 7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene structure (general method (A)).

Formula (VII) compound can be made by suitable phenol precursor (or benzyloxy derivatives protection) by utilizing method (A), (B) or (C).

Wherein X is that formula (VIII) compound of two hydrogen atoms can be by utilizing as hydroborate (as lithium borohydride or lithium triethylborohydride) in tetrahydrofuran (THF) or utilize hydride (as lithium aluminum hydride or hydrogenation diisobutyl lithium), and the X wherein of reducing is that the formula I compound of Sauerstoffatom makes.

Wherein X be Sauerstoffatom the formula I compound can by under high temperature (as about 80 ℃) in appropriate solvent (as dimethyl formamide), utilize as acid chloride and potassium formiate, perhaps preferably appropriate solvent (for example pure, as methyl alcohol, or ester, as ethyl acetate, or organic acid, as acetate, or its mixture) in, utilization has the catalytic hydrogenation of palladium hydroxide/carbon or platinic hydroxide/carbon, perhaps utilizes sodium borohydride and nickelous chloride, and the X wherein of reducing is that formula (II A) compound of Sauerstoffatom makes.

In another approach, formula (VIII) compound can make by following method: with formula (X IV) compound and the reaction of formula (X V) Grignard reagent,

R wherein ⁶⁰Be suitable hydroxy-protective group, preferred benzyl, Hal is a halogen atom, preferred chlorine; Then remove blocking group R ⁶⁰In order to control the 3-position stereochemistry in the formula I compound, suitable especially use formula (X V) chiral intermediate.

Formula (X V) compound can make by ordinary method well known in the art or by the method in the embodiments described herein.

In further another kind of method, formula (VIII) compound can be by preferably (for example pure at appropriate solvent, as methyl alcohol, ester is as ethyl acetate, or organic acid, as acetate, or its mixture) in, in the presence of metal catalyst (as palladium hydroxide or platinic hydroxide or its oxide compound), utilize and make as catalytic hydrogenation reduction-type (X VI) compound

Formula (X VI) compound can be by under the reduction Heck condition of describing in general method (G) as mentioned, formula (X VII) compound and formula IV compound is reacted make.

Formula (X VII) compound can be by utilizing ordinary method, by formula (X IV) compound and as by the Grignard reagent reaction that O-trimethyl silyl propargyl alcohol makes, then remove hydroxy-protective group and make.

According to another kind of method, formula (VIII) compound can make by following method: in tetrahydrofuran (THF), and with formula (X VIII) compound,

With the borine reaction, then utilize and carry out oxidative work-up as hydrogen peroxide and sodium hydroxide.

Formula (X VIII) compound can make by formula (X IV) compound with by the Grignard reagent that the 2-aryl-3-bromo-1-propylene makes by utilizing ordinary method.

Formula (IX) compound can preferably utilize magnesium and formula IV bromide, is made by formula (X III) compound and the Grignard reagent reaction that is made by the formula IV compound.Coupled reaction can be easily by utilizing appropriate solvent (for example ether, as ether), under low temperature (as about 0 ℃), carry out.

Formula (X) compound can by as following method make: in appropriate solvent (as methylene dichloride), under low temperature (as approximately-78 ℃),, the formula III stannane is transformed into corresponding iodide by utilizing iodinate; Under high temperature (as about 100 ℃), in appropriate solvent (as toluene), utilize α '-azepine-isopropyl cyanide and tributyltin hydride processing, thereby replace iodine and obtain formula (X) compound as α.

In addition, formula (X) compound also can make by following method: in appropriate solvent (as tetrahydrofuran (THF)), utilize the dehydration conditions of above-mentioned general method (E) description or utilize triphenylphosphine and diethyl azepine dicarboxylic ester, and cyclisation formula (X IX) compound,

Formula (X IX) compound can make by partial reduction formula (X VII) acetylide.This reaction can be carried out by utilizing the reduction of metal catalyst (as palladium/lime carbonate) catalytic hydrogenation in the presence of lead poisoning gas (as the Lindlar catalyzer) easily.To those skilled in the art, other suitable method also is conspicuous.

Formula (XX) but the reaction of compound through type (VII) compound and (1-iodo-ring third-1-yl) phenyl sulfide make.

Should be appreciated that wherein R ⁶Contain=O or=the formula I compound of S can be present in the tautomeric forms.All these class tautomeric forms and composition thereof include within the scope of the present invention.The most suitably, R ⁶In=O or=the S substituting group can be=the O substituting group.

When they can not be commercial, above-mentioned formula IV intermediate can be by the method for utilizing the embodiment of the invention to describe, by as corresponding amphyl make; Perhaps by well known to a person skilled in the art that other method makes.

In above-mentioned all synthesis steps, be necessary and/or any related molecule that needs protection in sensitivity or active group.This can obtain by the method for GPF (General Protection False group, the method of in following document, describing for example: Protective Groups in Organic Chemistry, J.F.W.McOmie edits, Plenum Press, 1973 and T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley ﹠amp; Sons, 1991.Utilize method well known in the art, can in the sequential steps of routine, remove blocking group.

By the method for the 36th to 39 page of proposition of International Application No. WO 93/01165 specification sheets, can test the compound of institute of the present invention illustration.In described test method, compound is to NK ₁The IC of acceptor ₅₀Active in 100nM.The compounds of this invention particularly preferred 3 (R) group epimer generally is higher than 2 to 5 times of corresponding 3 (S) epimer to the avidity of nk 1 receptor.

For fear of query, the name relevant in full with specification sheets of the present invention is based on descending array structure:

Following indefiniteness embodiment is used to illustrate the preparation of The compounds of this invention.

Illustrative examples 1

(2S)-1-tert-butoxycarbonyl-2-Phenylpiperidine-3-ketone

Will ((13.95ml, 20.30g be in methylene dichloride 160mmol) (350ml) cooling (70 ℃) solution 29.3mmol) to be added drop-wise to oxalyl chloride for 20.80ml, 22.90g in the dimethyl sulfoxide (DMSO) in the methylene dichloride (75ml).This mixture stirred 15 minutes down at-70 ℃, drip then in methylene dichloride (150ml) (2S, 3S)-1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine (method of being described by European patent specification 0528495-A makes, 36.91g, 133mmol).Mixture stirred 20 minutes down at-70 ℃, was warmed to-30 ℃ then.Mixture is cooled to-50 ℃, slowly add triethylamine (55.95ml, 40.45g, 400mmol).Mixture is warmed to 0 ℃, utilizes ice-cold methylene dichloride (250ml) dilution.Utilize ice-cold aqueous citric acid solution (5%, 2 * 300ml) and water (300ml) purging compound, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is yellow oil (42.3g), and this oily matter can not be further purified down use immediately. ¹H NMR (250MHz, CDCl ₃) δ 7.5-7.3 (and 5H, m), 5.8 (1H, br s), 4.2 (1H, brs), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m) and 1.54 (9H, s).

Illustrative examples 2

(2S, 3R)-1-tert-butoxycarbonyl-3-hydroxyl-3-(2-methylene radical-3-phenoxy propyl)-2-Phenylpiperidine

THF solution (0.91M with 3-(chlorine magnesium)-2-(phenoxymethyl)-1-propylene, 3ml) (people such as Louw, Tetrahedron, 48,6087-6104,1992, make by 2.74mmol 3-chloro-2-(phenoxymethyl)-1-propylene) slowly join in THF (3ml) solution of (2S)-1-tert-butoxycarbonyl-2-Phenylpiperidine-3-ketone (illustrative examples 1).Mixture at room temperature stirred 1 hour, added ammonium chloride saturated solution (20ml) then, utilized ethyl acetate (20ml) extraction mixture.Utilize salt water washing organic phase, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 80: 20 at 100: 0) wash-out by silica gel chromatography, obtains title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.48 (2H, d, J6.9Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, J13.7Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J14.0Hz), 1.95 (2H, m), 1.79 (2H, m) and 1.36 (9H, s) .m/z (ES ⁺) 424 (M+1).

Illustrative examples 3

(5R, 6S)-3-methylene radical-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

To (2S, 3R)-1-tert-butoxycarbonyl-3-hydroxyl-3-(2-methylene radical-3-phenoxy propyl)-2-Phenylpiperidine (illustrative examples 2,1.53g, 3.62mmol) THF (20ml) cooling (80 ℃) solution in add n-Butyl Lithium (2.5M hexane solution, 1.45ml, 3.62mmol), after use ZnCl ₂(0.5MTHF, 7.24ml, 3.62mmmol) solution-treated.Solution is warmed to room temperature, and adding tetrakis triphenylphosphine palladium (O) (0.23g, 0.2mmol).Make the mixture degassing, reflux 16 hours by being blown into nitrogen.Cooling mixture, solvent evaporated under reduced pressure.Residue is distributed between ethyl acetate and the 2M NaOH.Utilize salt water washing organic phase, dry (MgSO ₄), by silica gel chromatography (utilization contains ratio by the 0% hexane wash-out that increases to 5% ethyl acetate), the evaporation fraction, obtain (5R, 6S)-3-methylene radical-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane. ¹H NMR (360MHz, CDCl ₃) δ 7.58 (2H, d, J8.4Hz), 7.32-7.21 (3H, m), 5.23 (1H, s), 5.06 (1H, m), 4.97 (1H, m), 4.39 (2H, AB d, J13.3Hz), 3.99 (1H, dd, J13.3,4.48Hz), (2.83 1H, ABd J15.5Hz), 2.7 (1H, tdJ12.5,3.93Hz), 2.5 (1H, ABd, J15.4Hz), 2.15 (2H, td, J12., .4Hz), 1.69 (2H, m) and 1.46 (9H, s).m/z(ES ⁺)329(M+2H- ^tBuOCO)。

Illustrative examples 4

(5R, 6S)-3-ketone group-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

By (5R, 6S)-(illustrative examples 3, methylene dichloride 0.665g) (5ml) and methyl alcohol (5ml) cooling (80 ℃) solution are blown into the mixture 45 minutes of ozone and oxygen to 3-methylene radical-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.After utilizing nitrogen purge solution, add methyl-sulfide (0.5ml), at room temperature stirred 16 hours down then in nitrogen atmosphere.Vacuum evaporating solvent, residue are distributed between ethyl acetate and the water.Dry (MgSO ₄) organic phase, evaporation, residue evaporates fraction by silica gel chromatography (utilization contains ratio by the 0% hexane wash-out that increases to 10% ethyl acetate), obtains title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.58 (2H, d, J6.2Hz), 7.37-7.26 (3H, m), 5.3 (1H, s), 4.15 and 4.09 (2H, AB d, J17.4Hz), 3.97 (1H, m), 2.80 (1H, td, J12.9,4.0Hz), 2.74 and 2.48 (2H, ABd, J18.1Hz), 2.29 (2H, m), 1.88-1.63 (2H, m) and 1.44 (9H, s).m/z(ES ⁺)332(M+1)。

Illustrative examples 5

(5R, 6S)-3-trifluoromethyl sulfonyloxy-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

To the THF of 1M hexamethyldisilane sodium amide cooling (80 ℃) solution (0.38ml, 0.38mmol) join (5R, 6S)-(illustrative examples 4,0.105mg is in THF 0.319mmol) (3ml) solution for 3-ketone group-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Solution stirred 1 hour down at-80 ℃, added 2-[N then, two (trifluoromethyl sulfonyloxy) amino of N-]-5-chloropyridine (0.163g, THF 0.415mmol) (3ml) solution.Solution stirred 30 minutes down at-80 ℃, at room temperature stirred then 30 minutes, added saturated ammonium chloride solution and ethyl acetate afterwards, and reaction is stopped.Dry (MgSO ₄) organic phase by silica gel chromatography (utilization contains ratio by the 0% hexane wash-out that increases to 5% ethyl acetate), the evaporation fraction obtains title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.4 (2H, d, J7.3Hz), 7.3-7.22 (3H, m), 6.01 (1H, t, J2.13Hz), 5.13 (1H, s), 4.56 and 4.26 (2H, ABdd, J12.4,1.97Hz), 4.10 (1H, dt, J12.6,4.22Hz), 3.00 (1H, m), 2.28-2.04 (2H, m), 1.88-1.76 (2H, m) and 1.37 (9H, s).m/z(ES ⁺)464(M+1)。

Illustrative examples 6

(5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

To (5R, 6S)-3-trifluoromethyl sulfonyloxy-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 5,0.482g, 1.04mmol), lithium chloride (0.264g, 6.25mmol), (0.96g adds triphenylphosphine palladium (O) (0.06g) in THF 2.9mmol) (10ml) de-gassed solution for Quilonum Retard (0.076g) and hexa methyl ditin alkane.The solution degassing was heated 5 hours down in 60 ℃ under nitrogen atmosphere then.Add entry (20ml) and ethyl acetate (20ml), the exsiccant organic phase is by silica gel chromatography (utilization contains ratio by the 0% hexane wash-out that increases to 5% ethyl acetate), and the evaporation fraction obtains title compound, is crystalline solid. ¹H NMR (360MHz, CDCl ₃) δ 7.25 (2H, d, J7.3Hz), 7.1-7.0 (3H, m), 5.83 (1H, t, J2.5Hz), 4.78 (1H, s), 4.48 and 4.02 (2H, dd, J12.9,2.3Hz), 3.96 (1H, dd, J6.16,13.4Hz), 2.95 (1H, td, J13.3,4.5Hz), 1.84 (1H, m), 1.68 (1H, m), 1.60 (2H, m), 1.19 (9H, s) and 0.0 (6H, s).

Illustrative examples 7

(2S.3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-Phenylpiperidine-3-alcohol

((tetrahydrofuran solution of 1M, 160ml is 160mmol) in cooling (10 ℃) solution 160ml) slowly to join ethyl-magnesium-bromide for 24.51ml, 20.47g with 0-trimethyl silyl propargyl alcohol.Mixture stirred 20 minutes down at 0 ℃, at room temperature stirred then 2 hours.Mixture is cooled to-10 ℃, in 30 minutes, drips (2S)-1-tert-butoxycarbonyl-2-Phenylpiperidine-3-ketone (illustrative examples 1, tetrahydrofuran solution 42.3g) (200ml) (internal temperature is lower than-5 ℃).Mixture at room temperature stirred 14 hours, was injected in water (300ml) and the saturated aqueous ammonium chloride (300ml), utilized ethyl acetate (2 * 300ml) extractions.The organic phase of utilizing salt solution (300ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue is dissolved in the ethyl acetate (500ml), and the dropping tetrabutylammonium (tetrahydrofuran solution of 1M, 160ml, 160mmol).Mixture at room temperature stirred 30 minutes, added entry (300ml), and layering utilizes ethyl acetate (2 * 300ml) aqueous layer extracted, the organic fraction that utilizes the washing of water (300ml) and salt solution (300ml) to merge, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is orange oily matter (45g).This roughage utilizes hexane/EtOAc (increasing to 25: 75 at 90: 10) wash-out by quick silica gel chromatography, obtains title compound, is amber oily thing (32.2g). ¹H NMR (CDCl ₃) δ 7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 (1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m), 3.25 (1H, brs), 2.77-2.81 (1H, m), 2.77 (1H, brs), 2.12-2.20 (1H, m), 1.91-1.99 (2H, m), 1.77-1.83 (1H, m) and 1.39 (9H, s).

Illustrative examples 8

(5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

Will be thick (2S, 3R)-(illustrative examples 7 45g) is dissolved in the toluene (750ml) 1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-Phenylpiperidine-3-alcohol, utilizes the nitrogen degassing.Be incorporated in tetrakis triphenylphosphine palladium (O) in the toluene (600ml) (2.30g, 2.0mmol), the mixture degassing.In 15 minutes, and dropping tributyltin hydride under stirring and cooling (internal temperature is lower than 25 ℃) (35.78ml, 38.71g, 133mmol).Mixture at room temperature stirred 1 hour, then solvent evaporated under reduced pressure.Residue is dissolved in the tetrahydrofuran (THF) (600ml), and the adding triphenylphosphine (34.88g, 133mmol).Stir and cooling conditions under dropping azo and diethyl carbonate (20.94ml, 23.16g, tetrahydrofuran (THF) 133mmol) (150ml) solution, mixture at room temperature stirred 1 hour.Solvent evaporated under reduced pressure adds acetonitrile (600ml), and (8 * 150ml) extraction mixtures merge the hexane fraction, solvent evaporated under reduced pressure to utilize hexane.Residue is by quick silica gel chromatography, utilize dichloromethane/ethyl acetate (increasing to 99: 1 at 100: 0) wash-out, obtain title compound, be yellow oil (53.64g, from (2S, 3S)-obtain 67% in 1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine). ¹H NMR (CDCl ₃) δ 7.38-7.40 (2H, m), 7.15-7.25 (3H, m), 5.96 (1H, t, J 2.3Hz), 4.93 (1H, s), 4.63 (1H, dd, J2.23,12.9Hz), 4.22 (1H, dd, J2.23,12.9Hz), 4.09-4.14 (1H, m), and 3.09-3.17 (1H, m), 1.95-1.99 (1H, m), 1.83-1.86 (1H, m), and 1.72-1.76 (2H, m), 1.40-1.51 (6H, m), 1.38 (9H, s), 1.25-1.32 (6H, m), and 0.86-0.99 (15H, m).

Illustrative examples 9

3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl) propynoic acid (2S, 3R)-ethyl ester

((0.370ml is in tetrahydrofuran (THF) 3.64mmol) (10ml) cooling (78 ℃) solution 3.64mmol) slowly to join ethyl propiolate for 2.28ml, 1.6M hexane solution with n-Butyl Lithium.After reinforced the finishing, solution stirred 10 minutes down at-78 ℃, and (3.64mmol), temperature maintenance is lower than-75 ℃ for illustrative examples 1,1.0g to be incorporated in (2S)-1-tert-butoxycarbonyl-2-Phenylpiperidine-3-ketone in the tetrahydrofuran (THF) (10ml) then.Mixture further stirred 10 minutes, was warmed to-60 ℃, added Glacial acetic acid (1ml).Mixture is warmed to room temperature, is injected in the saturated sodium bicarbonate aqueous solution (20ml).Separate organic phase, utilize ethyl acetate (20ml) aqueous phase extracted.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (90: 10) wash-out by quick silica gel chromatography, obtains title compound, is jelly (801mg, 59%). ¹H NMR (250MHz, CDCl ₃) δ 7.50 (and 2H, m), 7.35 (3H, m), 5.49 (1H, s), 4.25 (2H, q, J7.12Hz), 4.15 (1H, m), 3.02 (1H, m), 2.23 (2H, m), 2.00 (2H, m), 1.78 (1H, m), 1.37 (9H, s) and 1.29 (3H, t, J7.12Hz).m/z(ES ⁺)374(M+1)。

Illustrative examples 10

(5R.6S)-7-tert-butoxycarbonyl-6-phenyl-3-tributyl stannyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-2-ketone

Utilize nitrogen with 3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl) propynoic acid (2S, 3R)-ethyl ester (illustrative examples 9,524mg, 1.4mmol) and tetrakis triphenylphosphine palladium (O) toluene (10ml) mixture (50mg) outgased 30 minutes.(0.405mM, 1.5mmol), the gained mixture stirred 2 hours under 23# to drip tributyltin hydride.Solvent evaporated under reduced pressure, residue are collected in the ethyl acetate (50ml).Utilize saturated sodium bicarbonate aqueous solution (50ml) purging compound, dry (Na ₂SO ₄), solvent evaporated under reduced pressure.Residue obtains title compound by quick silica gel chromatography, is jelly (538mg, 0.87mmol, 62%). ¹H NMR (250MHz, CDCl ₃) δ 7.63 (and 1H, s), 7.30 (5H, m), 5.11 (1H, s), 4.17 (1H, m), 3.10 (1H, m), 2.19 (1H, m), 1.80 (3H, m), 1.30-1.50 (12H, m), 1.40 (9H, s), 1.02 (6H, m) and 0.88 (9H, t, J7.22Hz).m/z(ES ⁺)619(M+1)

Illustrative examples 11

2-bromo-4-(trifluoromethoxy) phenol

To 4-trifluoro-methoxy-phenol (35.6g, dripping bromine (32g, chloroform 0.2mol) (50ml) solution in chloroform 0.2mol) (280ml) cooling (0 ℃) solution.Solution stirred 1 hour down at 0 ℃, at room temperature stirred 2 hours.Add methylene dichloride (200ml) and water (400ml), utilize water (400ml), salt solution (200ml) further to wash organic phase, dry (MgSO ₄).Remove and desolvate, residue obtains title compound by the underpressure distillation purifying. ¹H NMR (250MHz, CDCl ₃) δ 7.38 (and 1H, d, J2.1Hz), 7.13 (1H, dd, J9.1,2.1Hz), 7.03 (1H, d, J9.1Hz) and 5.53 (1H, s).

Illustrative examples 12

2-bromo-4-(trifluoromethoxy) phenyl ether

To 2-bromo-4-(trifluoromethoxy) phenol (illustrative examples 11,7.2g) and salt of wormwood (11.6g, add in dimethyl formamide 0.084mol) (60ml) solution methyl-iodide (14.94ml, 0.24mol).Solution in stirring at room 15 hours, adds entry (400ml) and ether (200ml) simultaneously under nitrogen atmosphere, utilize water (4 * 200ml), saturated sodium bicarbonate (2 * 200ml), salt solution (200ml) washing organic phase, solvent removed in vacuo.Residue utilizes the eluent ethyl acetate that contains hexane (0-2%) by the silica gel chromatography purifying, obtains title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.45 (and 1H, d, J2.8Hz), 7.16 (1H, dd, J9.0,2.8Hz), 6.88 (1H, d, J9.0Hz) and 3.90 (3H, s).

Illustrative examples 13

2-bromo-4-trifluoromethoxy isopropoxy benzene

To 2-bromo-4-trifluoro-methoxy-phenol (illustrative examples 11,1g, 3.9mmol) and salt of wormwood (1.1g, add in dimethyl formamide 7.8mmol) (15ml) solution 2-N-PROPYLE BROMIDE (0.55ml, 5.9mmol).Solution under nitrogen atmosphere in stirring at room 14 hours, in solution, add entry (200ml) and ethyl acetate (3 * 70ml), utilize water (100ml), salt solution (100ml) washing organic phase, dry (MgSO ₄), solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing 5% ethyl acetate/hexane wash-out). ¹H NMR (250MHz, CDCl ₃) δ 1.38 (and 6H, d, J6.1Hz), 4.53 (1H, m), 6.88 (1H, d, J, 9Hz), 7.12 (1H, dd, J8.8,2.6Hz) and 7.43 (1H, d, J2.8Hz).

Illustrative examples 14

2-bromo-4-trifluoromethoxy-allyloxy benzene

To 2-bromo-4-trifluoro-methoxy-phenol (illustrative examples 11,8g, 0.03mol) and salt of wormwood (8.6g, add in dimethyl formamide 0.06mol) (100ml) solution allyl bromide 98 (4ml, 0.045mol).Solution under nitrogen atmosphere in stirring at room 4 hours, add simultaneously entry (400ml) and ethyl acetate (3 * 100ml), the organic phase of utilizing water (200ml), saturated brine (200ml) washing to merge, dry (MgSO ₄), solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing 5% ethyl acetate/hexane wash-out), is yellow oil. ¹H NMR (250MHz, CDCl ₃) δ 4.60 (and 2H, dt, J5,1.6Hz), 5.33 (1H, dq, J10.5,1.4Hz), 5.48 (1H, dq, J17.3,1.6Hz), 6.04 (1H, m), 6.86 (1H, d, J9Hz), 7.13 (1H, dd, J8.4,2.7Hz) and 7.45 (1H, d, J2.8Hz).

Illustrative examples 15

2-bromo-6-(third-2-thiazolinyl)-4-trifluoro-methoxy-phenol

With 2-bromo-4-trifluoromethoxy allyloxy benzene (illustrative examples 14,8.6g) heated 7 hours down at 200 ℃, the refrigerative residue obtains 2-bromo-6-(third-2-thiazolinyl)-4-trifluoro-methoxy-phenol by silica gel chromatography purifying (utilizing 1% ethyl acetate/hexane wash-out), is yellow oil. ¹H NMR (250MHz, CDCl ₃) δ 3.43 (and 2H, d, J6.6Hz), 5.13 (2H, m), 5.60 (1H, s), 5.98 (1H, m), 6.98 (1H, d, J2.4Hz) and 7.24 (1H, d, 2.4Hz).

Illustrative examples 16

2-bromo-6-(2-hydroxyethyl)-4-trifluoro-methoxy-phenol

(illustrative examples 15,5.9g, methylene dichloride 0.02mol) (30ml) and methyl alcohol (30ml) cooling (78 ℃) solution were blown into ozone and oxygen mixture 4 hours by 2-bromo-6-(third-2-thiazolinyl)-4-trifluoro-methoxy-phenol.Utilize nitrogen purge solution after 1 hour, add sodium borohydride (0.755g), at room temperature stirred then 15 hours.Solvent removed in vacuo is distributed in ethyl acetate with residue and contains between the water of 2M HCl (20ml) and utilizes saturated brine washing organic phase, dry (MgSO ₄), solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing 20% ethyl acetate/hexane wash-out). ¹H NMR (250MHz, CDCl ₃) δ 2.93 (and 2H, t, J5.6Hz), 3.98 (2H, t, J5.4Hz), 6.96 (1H, d, J2.5Hz) and 7.3 (1H, d, J2.4Hz).

Illustrative examples 17

7-bromo-5-trifluoromethoxy-2, the 3-Dihydrobenzofuranes

To the triphenylphosphine in tetrahydrofuran (THF) (40ml) (6.11g, add in 0.0234mol) the azoethane dicarboxylic acid esters (3.7ml, 0.0234mol).Solution stirring 30 minutes, (illustrative examples 16,5.4g, tetrahydrofuran solution 0.018mol), solution at room temperature stirred 15 hours, solvent removed in vacuo to add 2-bromo-6-(2-hydroxyethyl)-4-trifluoro-methoxy-phenol simultaneously.Residue is dissolved in the ethyl acetate, utilizes water, saturated brine washing soln, dry (MgSO ₄).After solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing 10% ethyl acetate/hexane wash-out), is pink oily matter. ¹H NMR (250MHz, CDCl ₃) δ 2.93 (and 2H, t, J5.6Hz), 3.98 (2H, t, J5.4Hz), 6.96 (1H, d, J2.5Hz) and 7.30 (1H, d, J2.4Hz).

Illustrative examples 18

1-benzyloxy-4-(2,2, the 2-trifluoro ethoxy) benzene

To 4-benzyloxy phenol (5g) and 2,2, add in dimethyl formamide (50ml) solution of 2-trifluoro ethoxy-p-toluenesulfonic esters (5g) sodium hydride (60% oil suspension, 2.3g), solution be heated to 110 ℃ 16 hours.Cooling mixture utilizes the water dilution, utilizes the ethyl acetate extraction product.Utilize water, salt water washing organic phase, dry (MgSO ₄).Solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing 10% ethyl acetate/hexane wash-out), is solid.m.p.72-74℃。

Illustrative examples 19

4-(2,2, the 2-trifluoro ethoxy) phenol

With 1-benzyloxy-4-(2,2, the 2-trifluoro ethoxy) benzene (illustrative examples 18,5g) and palladium (10% carbon, methyl alcohol 0.1g) (50ml) solution hydrogenation 12 hours under 50psi.Filtering solution, solvent removed in vacuo obtains title compound, is colorless solid.m.p.60-64℃。

Illustrative examples 20

2-bromo-4-(2,2, the 2-trifluoro ethoxy) phenol

Chloroform (5ml) solution that in cooling (0 ℃) solution of the acetate of 4-(2,2, the 2-trifluoro ethoxy) phenol (illustrative examples 19) and chloroform mixture (20ml, 1: 1), adds bromine (0.83g).Stirred the mixture 10 minutes, and utilized the chloroform dilution, utilize water (2 * 50ml) washings, dry (MgSO then ₄) and evaporation, obtain title compound, be oily matter. ¹H NMR (250MHz, CDCl ₃) δ 4.33 (and 2H, q, J8Hz), 6.83 (1H, dd, J2.8,8.8Hz), 6.97 (1H, d, J8.8Hz) and 7.10 (1H, d, J2.8Hz).

Illustrative examples 21

2-bromo-4-(2,2,2-three-fluorine oxyethyl group) phenyl ether

(illustrative examples 20 adds salt of wormwood (1g) and methyl-iodide (1ml) in acetone soln 0.6g) to 2-bromo-4-(2,2, the 2-trifluoro ethoxy) phenol.Reflux solution 1 hour, vacuum-evaporation then.Residue is distributed between ethyl acetate and the water, utilizes water and saturated brine further to wash organic phase.Dry (MgSO ₄) final vacuum removes and to desolvate, and obtains title compound, is yellow oil. ¹H NMR (250MHz, CDCl ₃) δ 3.87 (and 3H, s), 4.30 (2H, q, J8Hz), 6.82-6.92 (2H, m) and 7.20 (1H, d, J3Hz).

Illustrative examples 22

2, two (2,2, the 2-trifluoro ethoxy) bromobenzenes of 5-

To 2-bromo-4-(2,2, the 2-trifluoro ethoxy) phenol (illustrative examples 20,0.83g, 3.06mmol) and sodium hydride (60% oil, 0.367g add 2 in dimethyl formamide 9.18mmol) (10ml) solution, 2, and 2-trifluoro ethoxy-p-toluenesulfonic esters (1.17g, 4.6mmol).Mixture heated 10 hours down at 100 ℃, and cooling utilizes the dilution of ethyl acetate and water.Utilize water, saturated brine washing organic phase, dry (MgSO ₄), vacuum-evaporation, residue obtains title compound by silica gel chromatography purifying (utilizing 2% ethyl acetate/hexane wash-out), is oily matter. ¹H NMR (250MHz, CDCl ₃) δ 4.32 (and 4H, m), 6.89 (2H, m) and 7.20 (1H, d, J4.1Hz)

Illustrative examples 23

2-bromo-1-(difluoro-methoxy)-4-(trifluoromethoxy) benzene

(illustrative examples 11 slowly adds sodium hydride (0.96g, 60% oil) in dimethyl formamide solution 5.14g) to 2-bromo-4-(trifluoromethoxy) phenol.Stir after 20 minutes, slowly fed chlorodifluoromethane steam 10 minutes by solution.Mixture heated 2 hours down at 60 ℃, and cooling utilizes the water dilution, utilizes ether (2 * 100ml) extraction solutions.Merge organic phase, utilize water, saturated brine washing, dry (MgSO ₄) and vacuum-evaporation.Residue obtains title compound by silica gel chromatography purifying (utilizing the hexane wash-out), is solid. ¹H NMR (250MHz, CDCl ₃) δ 6.53 (and 1H, t, J7.2Hz), 7.17-7.29 (2H, m) and 7.51 (1H, d, J2.5Hz).

Illustrative examples 24

2-bromo-1-(2,2, the 2-trifluoro ethoxy)-4-(trifluoromethoxy) benzene

(illustrative examples 11 2g) with 2,2, slowly adds sodium hydride (2g, 60% oil) in the dimethyl formamide of 2-trifluoroethyl-p-toluenesulfonic esters (30ml) solution, mixture heated 12 hours down at 110 ℃ to 2-bromo-4-trifluoro-methoxy-phenol.Cooling mixture utilizes water (300ml) dilution, utilizes ethyl acetate (2 * 50ml) extractions.Utilize water, saturated brine washing organic phase, dry (MgSO ₄).Solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing ether/hexane wash-out (1: 10)), is colorless oil. ¹H NMR (250MHz, CDCl ₃) δ 4.40 (2H, q, J8Hz), 6.95 (1H, d, J9Hz), 7.15-7.20 (1H, m), and 7.48-7.49 (1H, m).

Illustrative examples 25

2-bromo-4-fluoro-(2,2, the 2-trifluoro ethoxy) benzene

To 2-bromo-4-fluorine phenol (4g) and 2,2, slowly add sodium hydride (1g, 60% oil) in the dimethyl formamide (40ml) of 2-trifluoro ethoxy-p-toluenesulfonic esters (5g), mixture heated 12 hours down at 110 ℃.Cooling solution utilizes water (500ml) dilution, utilizes ethyl acetate (2 * 150ml) extractions.Utilize saturated sodium bicarbonate, water, saturated brine washing organic phase, dry (MgSO ₄).Solvent removed in vacuo, residue obtains title compound by silica gel chromatography purifying (utilizing ether/hexane (1: 5) wash-out), is colorless oil. ¹H NMR (250MHz, CDCl ₃) δ 4.36 (and 2H, q, J8Hz), 6.91-7.05 (2H, m) and 7.33 (1H, dd, J8,3Hz).

Illustrative examples 26

4-(methylsulfonyl) phenol

Will (65.8g 0.108mol) joins 4-(methyl mercapto) phenol (5g, 36mmol) methyl alcohol (290ml) cooling (ice bath) solution in the oxone in the water (290ml).Gained solution stirred 48 hours at ambient temperature, then vacuum concentration.Utilize water (100ml) dilution residue, utilize methylene dichloride (10 * 100ml) extractions.The dry organic layer that merges on sodium sulfate, solvent removed in vacuo obtains title compound, is limpid oily matter (5.66g, 92%). ¹H NMR (250MHz, CDCl ₃) δ 7.80-7.75 (and 2H, d, J11.7Hz), 7.28 (1H, br s), 7.01-6.96 (2H, d, J11.7Hz) and 3.08 (3H, s).

Illustrative examples 27

2-bromo-4-(methylsulfonyl) phenol

(0.9ml, Glacial acetic acid 17.45mmol) (10ml) drips of solution is added to 4-(methylsulfonyl) phenol, and (illustrative examples 26,3g is in stirred solution 17.45mmol) with bromine.Gained solution at room temperature stirred 16 hours.Glacial acetic acid (5ml) solution of dripping bromine (0.45ml), solution stirring 2 hours.Vacuum is removed excessive acetate and bromine, utilizes the methylbenzene azeotropic residue, obtains required compound, is white solid (3.54g, 81%). ¹H NMR (250MHz, CDCl ₃) δ 8.06-8.05 (and 1H, d, J2.3Hz), 7.73-7.69 (1H, dd, J8.6,2.3Hz), 7.06-7.02 (1H, d, J8.6Hz) and 3.06 (3H, s).

Illustrative examples 28

2-bromo-4-(methylsulfonyl) phenyl ether

(2.31g, (illustrative examples 27,3.5g is in dimethyl formamide 14mmol) (50ml) solution 16.8mmol) to join 2-bromo-4-(methylsulfonyl) phenol with salt of wormwood.Stirred gained solution 30 minutes, and the adding methyl-iodide (1.04ml, 16.8mmol).Stir after 1 hour, solution is injected in the water (200ml), utilize ethyl acetate (2 * 100ml) extractions.The organic phase of utilizing water washing to merge, dry on sodium sulfate.Solvent removed in vacuo obtains white solid, obtains title compound (2.02g) by the ether crystallization. ¹H NMR (250MHz, CDCl ₃) δ 8.12-8.11 (and 1H, d, J2.2Hz), 7.90-7.86 (1H, dd, J8.7,2.2Hz), 7.04-7.00 (1H, d, J8.7Hz), 3.99 (3H, s) and 3.05 (3H, s).

Illustrative examples 29

3-bromo-4-(cyclobutoxy group) trifluorophenyl ether

(5.83mmol) (3.0g 17.5mmol) is dissolved in the dimethyl formamide (10ml) with the cyclobutyl bromine for illustrative examples 11,1.5g with 2-bromo-4-(trifluoromethoxy) phenol.(4.85g 35mmol), stirred 16 hours down at 50 ℃ to add salt of wormwood.Cooling solution is injected in 10% citric acid solution (50ml) to envrionment temperature, utilizes ethyl acetate (2 * 100ml) extractions.The organic layer that utilizes water washing to merge, dry on sodium sulfate.Solvent removed in vacuo obtains oily matter, and this oily matter obtains title compound by silica gel chromatography purifying (10% ethyl acetate/hexane wash-out), is oily matter (1.65g, 91%). ¹H NMR (250MHz, CDCl ₃) δ 7.44-7.42 (1H, m), 7.12-7.07 (1H, m), 6.73-6.70 (1H, d, J9.0Hz), 4.71-4.60 (1H, m), 2.52-2.41 (2H, m), 2.30-2.18 (2H, m), and 1.92-1.55 (2H, m).

Illustrative examples 30

2-(2-hydroxyl-oxethyl)-5-(trifluoromethoxy) bromobenzene

According to the method for illustrative examples 16, by illustrative examples 14 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 2.20 (and 1H, t, J6.3Hz), 4.0 (2H, q, J5.6Hz), 4.13 (2H, q, J4.2Hz), 6.91 (1H, d, J9Hz), 7.15 (1H, m) and 7.45 (1H, d, J2.3Hz).

Illustrative examples 31

2-(2-fluorine oxyethyl group)-5-(trifluoromethoxy) bromobenzene

To 2-(2-hydroxyl-oxethyl)-5-(trifluoromethoxy) bromobenzene (illustrative examples 30,8.9g, add in methylene dichloride 30mmol) (80ml) cooling (78 ℃) suspension trifluoro diethylamino sulphur (3.88ml, 31.5mmol).Solution stirred 2 hours at ambient temperature, then by adding entry (100ml) quenching.Separate organic layer, utilize salt solution (100ml) washing, dry (MgSO ₄), vacuum-evaporation.Purifying on silica gel utilizes 15%-20% ethyl acetate/hexane wash-out, obtains title compound, is limpid oily matter (1.9g, 15%). ¹H NMR (360MHz, CDCl ₃) δ 4.23 (and 1H, m), 4.31 (1H, m), 4.37 (1H, m), 4.86 (1H, m), 6.90 (1H, m), 7.15 (1H, m) and 7.47 (1H, t, J0.7Hz).

Illustrative examples 32

Trifluoromethanesulfonic acid 2-bromo-4-(trifluoromethoxy) phenylester

((7.2ml, 44mmol), reaction was stirred 2 hours at ambient temperature 40mmol) to add trifluoromethanesulfanhydride anhydride in cooling (0 ℃) pyridine (20ml) solution for illustrative examples 11,10g to 2-bromo-4-(trifluoromethoxy) phenol.Utilize (80ml) diluting reaction of copper/saturated copper sulphate (II), utilize ethyl acetate (3 * 60ml) extractions.The organic fraction that utilizes water (80ml), saturated brine (80ml) washing to merge, dry (MgSO ₄), vacuum-evaporation.Purifying on silica gel utilizes the hexane wash-out, obtains title compound, is limpid oily matter (13.1g, 85%). ¹H NMR (250MHz, CDCl ₃) δ 7.28 (and 1H, m), 7.40 (1H, d, J9.1Hz) and 7.58 (1H, d, J2.8Hz).

Illustrative examples 33

2-(ethene-1-yl)-5-(trifluoromethoxy) bromobenzene

With trifluoromethanesulfonic acid 2-bromo-4-(trifluoromethoxy) phenylester (illustrative examples 32,1.8g, 4.6mmol), vinyl tributyl tin (1.61g, 5.1mmol) and lithium chloride (1.18g, 27.6mmol) N, dinethylformamide (20ml) mixture outgases, and adds two (triphenylphosphine) palladiums (II) of two chloro-afterwards.After further outgasing, reaction mixture heated 14 hours down at 110 ℃.Solution is distributed in water (70ml) and ethyl acetate (between 3 * 50ml).The organic fraction that utilizes salt solution (50ml) washing to merge, dry (MgSO ₄), vacuum-evaporation.Purifying on silica gel utilizes the hexane wash-out, obtains title compound, is limpid oily matter (780mg, 64%). ¹H NMR (250MHz, CDCl ₃) 65.40 (and 1H, dd, J9.1Hz, J1.8Hz), 5.70 (1H, dd, J10.5Hz, J0.5Hz), 7.0 (1H, m), 7.16 (1H, m), 7.44 (1H, d, J1.4Hz) and 7.56 (1H, d, J8.7Hz).

Illustrative examples 34

2-benzyloxy-5-(trifluoromethoxy) bromobenzene

(illustrative examples 11,5g 20mmol) are dissolved in N, and in the dinethylformamide (60ml), (5.4g, 40mmol), (3.5ml, 30mmol), reaction was stirred 15 hours at ambient temperature then to add bromotoluene to add salt of wormwood with 2-bromo-4-trifluoro-methoxy-phenol.Utilize water (150ml) diluting reaction, utilize ethyl acetate (3 * 60ml) extractions.The organic fraction that utilizes water (100ml), salt solution (100ml) washing to merge, dry (MgSO ₄), vacuum-evaporation.Purifying on silica gel utilizes 2% and 5% ethyl acetate/hexane wash-out, obtains title compound, is limpid oily matter (6.7g, 96%). ¹H NMR (250MHz, CDCl ₃) δ 5.47 (and 2H, s), 7.23 (1H, d, J9Hz), 7.43 (1H, dd J8.2,2.9Hz) and 7.75 (6H, m).

Illustrative examples 35

2-bromo-4-(trifluoromethyl) phenol

According to the method for illustrative examples 11, prepare title compound by 4-(trifluoromethyl) phenol. ¹H NMR (250MHz, CDCl ₃) δ 7.06 (and 1H, dd, J8.5,0.5Hz), 7.4 (1H, dd, J6.5,2.0Hz), 7.7 (1H, d, J1.7Hz) and 8.93 (1H, s).

Illustrative examples 36

1-benzyloxy-2-bromo-4-(trifluoromethyl) benzene

With 2-bromo-4-(trifluoromethyl) phenol (illustrative examples 35,3.85g) and bromotoluene (2.36ml) be dissolved in the dimethyl formamide, add salt of wormwood (6.8g).Mixture stirred 3 hours down at 60 ℃, utilized water (200ml) diluting reaction, utilized ethyl acetate extraction.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure, residue utilizes hexane/ethyl acetate (increasing to 95: 5 at 99: 1) wash-out by silica gel chromatography, obtains title compound. ¹H NMR (360MHz, CDCl ₃) δ 5.21 (and 2H, s), 6.98 (1H, d, J8.65Hz), 7.31-7.51 (6H, m) and 7.82 (1H, d, J1.7Hz).

Illustrative examples 37

(3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alcohol

Under nitrogen atmosphere, with 2-bromo-4-Trifluoromethoxyphen-l ether (illustrative examples 12,417mg, 1.54mmol) be added drop-wise to magnesium in ether (1ml) (41mg, 1.7mmol) in, mixture carries out brief reflux each after reinforced.In a single day reinforced finishing, mixture reflux 30 minutes, most of therebetween magnesium is dissolved.Solution is cooled to room temperature, it is added drop-wise to (5R, 6S)-(illustrative examples 4,212mg is in ether 0.64mmol) (10ml) cooling (0 ℃) solution for 3-ketone group-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Mixture stirred 10 minutes down at 0 ℃, at room temperature stirred and spent the night.Add saturated aqueous ammonium chloride (40ml), utilize ethyl acetate (2 * 40ml) extraction mixtures.With salt solution (20m1) washing organic fraction, dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure, residue utilizes ethyl acetate/hexane (1: 5) wash-out by silica gel chromatography, obtains title compound, is grey foam (240mg, 72%). ¹H NMR (360MHz, CDCl ₃) δ 1.47 (9H, s), 1.52-1.71 (3H, m), 2.17-2.22 (1H, m), 2.42 (1H, d, J13.5Hz), 2.56 (1H, d, J13.5Hz), 2.77-2.84 (1H, m), 3.89 (3H, s), 3.96-4.00 (1H, m), 4.20 (1H, d, J9.5Hz), 4.29 (1H, d, J9.5Hz), 5.78 (1H, s), 6.90 (1H, d, J8.9Hz), 7.13-7.16 (1H, m), 7.21-7.25 (1H, m), 7.30-7.35 (1H, m) and 7.62 (2H, d, J7.7Hz).m/z(ES ⁺)524(M+1)。

Illustrative examples 38

Z-(2S, 3R)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-(2-p-methoxy-phenyl) third-2-alkene-1-alcohol

At room temperature, with formic acid (138ml, 3.77mmol) join (2S, 3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-Phenylpiperidine-3-alcohol (illustrative examples 7,473mg, 1.43mmol), acid chloride (II) (33mg, 0.14mmol), three-o-tolylphosphine (85mg, 0.28mmol), Tributylamine (1.12ml, 4.87mmol) and 2-iodophenyl ether (446ml, 3.44mmol) N, dinethylformamide (3ml) stirs in the de-gassed solution, the gained mixture is 70 ℃ of heating 5 hours down.Cooling mixture filters, and utilizes ethyl acetate (50ml) dilution, utilize water (100ml), hydrochloric acid (2M, 50ml) and saturated sodium-chloride water solution (50ml) washing, drying (MgSO ₄), solvent evaporated under reduced pressure, residue utilizes hexane/ethyl acetate (60: 40) wash-out by the silica gel chromatography purifying, obtains title compound, is yellow glass shape thing (220mg, 35%). ¹H NMR (360MHz, CDCl ₃) δ 7.41 (2H, d, J7.6Hz), 7.22-7.34 (4H, m), 7.12 (1H, dd, J1.7,7.4Hz), 6.94 (1H, t, J7.5Hz), 6.89 (1H, d, J8.2Hz), 5.84 (1H, s), 5.00 (1H, s), 4.40 (1H, d, J12.7Hz), 4.15 (1H, dd, J6.0,13.1Hz), 4.05 (1H, d, J12.5Hz), 3.86 (3H, s), 3.44 (1H, dt, J5.6,12.3Hz), 2.04-2.18 (1H, m), 1.80-1.96 (3H, m), 1.28 (9H, s), and 1.64-1.84 (3H, m).m/z(ES ⁺)440(M+1)。

Illustrative examples 39

(2S, 3R, 2 ' R)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-(2-p-methoxy-phenyl) third-1-pure and mild (2S, 3R, 2 ' S)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-(2-p-methoxy-phenyl) third-1-alcohol

With palladium hydroxide (II)/carbon (20%, 78mg) join Z-(2S, 3R)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-(2-p-methoxy-phenyl) third-2-alkene-1-alcohol (illustrative examples 38,78mg, 0.18mmol) and methyl alcohol (10ml) solution of acetate (2ml) in, mixture is hydrogenation 5 hours under 50psi under agitation condition.Filtering mixt, solvent evaporated under reduced pressure is utilized ethyl acetate (20ml) dilution residue, utilizes saturated sodium carbonate solution (10ml) dilution, dry (MgSO ₄), solvent evaporated under reduced pressure, residue utilizes hexane/ethyl acetate (80: 20) wash-out by the preparation of silica gel chromatogram purification, obtains title compound, is 2 ' R and 2 ' S epimer mixture 1: 3 (22mg, 28%). ¹H NMR (360MHz, CDCl ₃) δ 7.45-7.61 (2H, m, 3R and 3S isomer), 7.1 6-7.37 (5H, m, 3R and 3S isomer), 6.85-6.98 (2H, m, 3R and 3S isomer), 5.17 (1H, s, 3R isomer), (5.04 1H, s, 3S isomer), 3.96-4.04 (1H, m, 3R and 3S isomer), 3.83 (3H, s, the 3R isomer), 3.82 (3H, s, 3S isomer), (3.46-3.84 3H, m, 3R and 3S isomer), 3.04-3.20 (1H, m, 3R and 3S isomer), 1.64-2.40 (8H, m, 3R and 3S isomer), 1.32 (9H, s, 3S isomer), with 1.27 (9H, s, 3R isomer).m/z(ES ⁺)442(M+1)。

Illustrative examples 40

2-bromo-4-nitrophenols

Bromine (27ml) is added drop-wise in 4-nitrophenols (50g) Glacial acetic acid (400ml) stirred solution, and mixture at room temperature stirred 18 hours.Solvent evaporated under reduced pressure, residue are by methylene dichloride: the hexane crystallization, obtain title compound, and be colorless solid (67g). ¹H NMR (250MHz, CDCl ₃) δ 8.44 (and 1H, d, J2.6Hz), 8.16 (1H, dd, J2.6,8.9Hz) and 7.13 (1H, d, J9.0Hz).

Illustrative examples 41

2-isopropoxy-5-nitro bromobenzene

Reflux 2-bromo-4-nitrophenols (illustrative examples 40,2.5g), acetone (30ml) mixture of 2-iodopropane (2.2g) and salt of wormwood (5g) 18 hours.Solvent evaporated under reduced pressure adds entry, utilizes the ethyl acetate extraction mixture.Utilize water and salt water washing organic layer, dry (MgSO ₄), solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (90: 10) wash-out by quick silica gel chromatography, obtains title compound (2.8 grams, 94%). ¹H NMR (250MHz, CDCl ₃) δ 8.46 (and 1H, s), 8.20 (1H, m), 6.93 (1H, m), 4.75 (1H, m) and 1.42 (6H, d, J7.5Hz).

Illustrative examples 42

2-(difluoro-methoxy)-5-nitro bromobenzene

According to the method for illustrative examples 23, by illustrative examples 40 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 8.54 (and 1H, d, J2.6Hz), 8.22 (1H, dd, J9.0,2.6Hz), 7.38 (1H, d, J9.0Hz) and 6.68 (1H, t, J71.7Hz).

Illustrative examples 43

3-bromo-4-anisidine

Reflux 3-bromo-4-methoxy nitrobenzene (15g, 64.6mmol) and iron powder (27.3g, water 0.49mol) (100ml) and Glacial acetic acid (25ml) mixture 2 hours.Cooling mixture passes through Hyflo ^TMPad filters, and utilizes the washing of 25% acetic acid/water.Utilize ethyl acetate (2 * 250ml) extraction filtrates, dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (60: 40) wash-out by quick silica gel chromatography, obtains title compound, is brown solid (10.32g, 79%).m/z(ES ⁺)202(M+1)。

Illustrative examples 44

3-bromo-4-isopropoxy aniline

According to the method for illustrative examples 43, by illustrative examples 41 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 6.91 (and 1H, d, J2.7Hz), 6.78 (1H, d, J8.6Hz), 6.57 (1H, dd, J2.9,8.8Hz), 4.33 (1H, m) and 1.32 (3H, d, J5.6Hz).

Illustrative examples 45

3-bromo-4-(difluoro-methoxy) aniline

According to the method for illustrative examples 43, by illustrative examples 42 compound title compounds.

Illustrative examples 46

3-bromo-4-(trifluoromethoxy) aniline

Under agitation condition, 4-trifluoromethoxy oil of mirbane (4.1g) is suspended in the water (16ml) and the vitriol oil (16ml), be warmed to 80 ℃.Added potassium bromate (3.7g) in 3 hours, mixture further heated 2 hours down at 80 ℃ in batches.Mixture is cooled to room temperature, is injected in the ice (100g).Utilize the ethyl acetate extraction mixture, dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure, residue is dissolved in acetate (2.5ml) and the water (10ml), adding iron powder (2.0g).Reflux mixture 2 hours is cooled to room temperature, passes through Celite ^TMFilter.Utilize ethyl acetate extraction filtrate, dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (3: 1) wash-out by quick silica gel chromatography, obtains title compound, is yellow solid. ³H?NMR(CDCl ₃)δ6.57(1H,dd),6.9(1H,d),7.06(1H,dd)。

Illustrative examples 47

N-(3-bromo-4-p-methoxy-phenyl) trifluoroacetamide

With trifluoroacetic anhydride (3.5ml, 24.7mmol) slowly join 3-bromo-4-anisidine (illustrative examples 43,5g, 24.7mmol) and triethylamine (3.44ml, methylene dichloride 24.7mmol) (50ml) stir in cooling (0 ℃) solution.Mixture at room temperature stirred 2 hours, utilized methylene dichloride (200ml) dilution, utilized water (2 * 200ml) washings.Dry (Na ₂SO ₄) organic layer, solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (increasing to 75: 25 at 85: 15) wash-out by quick silica gel chromatography, obtains title compound, is colorless solid (4.4g, 60%). ¹H NMR (250MHz, CDCl ₃) δ 7.79 (and 1H, d, J2.6Hz), 7.58 (1H, dd, J2.6,8.9Hz), 6.90 (1H, d, J8.9Hz) and 3.90 (3H, s).

Illustrative examples 48

N-(3-bromo-4-isopropyl phenyl) trifluoroacetamide

According to the method for illustrative examples 43, by illustrative examples 44 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.79 (1H, br s), 7.76 (1H, d, J2.7Hz), 7.48 (1H, dd, J8.9,2.7Hz), 6.92 (1H, d, J8.9Hz), 4.55 (1H, sept, J6.1Hz) and 1.38 (6H, d, J6.1Hz).

Illustrative examples 49

N-[3-bromo-4-(difluoro-methoxy) phenyl] trifluoroacetamide

According to the method for illustrative examples 43, by illustrative examples 45 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 8.01 (1H, br s), 7.94 (1H, d, J2.6Hz), 7.53 (1H, dd, J8.9,2.6Hz), 7.26 (1H, d, J8.9Hz) and 6.53 (1H, t, J73.1Hz).

Illustrative examples 50

N-[3-bromo-4-(trifluoromethoxy) phenyl] trifluoroacetamide

According to the method for illustrative examples 47, by illustrative examples 46 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 8.24 (1H, br s), 7.97 (1H, d, J2.6Hz), 7.59 (1H, dd, J8.9,2.6Hz) and 7.34 (1H, d, J8.9Hz).

Illustrative examples 51

N-methyl-3-bromo-4-(trifluoromethoxy) aniline

With sodium hydride (60% mineral oil dispersion liquid, 870mg 21.7mmol) join N-[3-bromo-4-(trifluoromethoxy) phenyl] (illustrative examples 50,6.3g, DMF 18.0mmol) (50ml) stir in cooling (0 ℃) solution trifluoroacetamide.Mixture stirred 20 minutes down at 0 ℃, in 5 minutes, add methyl-iodide (1.35ml, 21.7mmol).Mixture stirred 45 minutes down at 0 ℃, at room temperature stirred 4 hours.Add entry (100ml), utilize ethyl acetate (3 * 100ml) extraction mixtures.Utilize water (3 * 100ml) and the organic fraction that merges of salt solution (100ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure, residue utilizes hexane/CH by quick silica gel chromatography ₂Cl ₂(increasing to 1: 1 at 3: 1) wash-out obtains title compound, is tawny oily matter (1.20g, 25%). ¹H NMR (250MHz, CDCl ₃) δ 7.11 (and 1H, dq, J8.9,1.2Hz), 6.86 (1H, d, J2.8Hz), 6.56 (1H, dd, J8.9,2.8Hz) and 2.83 (3H, s).

Illustrative examples 52

N-(3-bromo-4-p-methoxy-phenyl)-N-(methyl) trifluoroacetamide

((illustrative examples 43,2.98g, dimethyl formamide 10mmol) (30ml) stir in cooling (0 ℃) solution 12mmol) to join N-(3-bromo-4-p-methoxy-phenyl) trifluoroacetamide for 60% mineral oil dispersion liquid, 0.48g with sodium hydride.Mixture stirred 30 minutes down at 0 ℃, add then methyl-iodide (0.75ml, 1.70g, 12mmol).Mixture stirred 30 minutes down at 0 ℃, at room temperature stirred 3 hours.Add entry (50ml), utilize ethyl acetate (3 * 50ml) extraction mixtures.Utilize water (4 * 50ml) and the organic fraction that merges of salt solution (50ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure, residue utilizes hexane/CH by quick silica gel chromatography ₂Cl ₂(increasing to 30: 70 at 50: 50) wash-out obtains title compound, is colorless solid (2.72g, 87%). ¹H NMR (250MHz, CDCl ₃) δ 7.46 (and 1H, d, J2.4Hz), 7.18 (1H, dd, J8.7,2.4Hz), 6.91 (1H, d, J8.7Hz), 3.94 (3H, s) and 3.32 (3H, s).

Illustrative examples 53

N-(3-bromo-4-isopropyl phenyl)-N-(methyl) trifluoroacetamide

According to the method for illustrative examples 52, by illustrative examples 48 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.45 (and 1H, d, J2.5Hz), 7.13 (1H, dd, J8.8,2.5Hz), 6.90 (1H, d, J8.8Hz), 4.59 (1H, sept, J6.1Hz), 3.32 (3H, s) and 1.41 (6H, d, J6.1Hz).

Illustrative examples 54

N-[3-bromo-4-(difluoro-methoxy) phenyl]-N-(methyl) trifluoroacetamide

According to the method for illustrative examples 52, by illustrative examples 49 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 7.56 (and 1H, d, J2.5Hz), 7.26 (2H, m), 6.58 (1H, t, J72.6Hz) and 3.35 (3H, s).

Illustrative examples 55

N-[3-bromo-4-(trifluoromethoxy) phenyl]-N-(methyl) trifluoroacetamide

According to the method for illustrative examples 47, by illustrative examples 51 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.59 (and 1H, d, J2.3Hz), 7.39 (1H, br d, J9Hz), 7.27 (1H, br d, J9Hz) and 3.36 (3H, s).

Illustrative examples 56

2-methoxyl group-5-(2,2,2-trifluoroethyl amino) bromobenzene

With borine-dimethyl sulphide title complex (2M THF solution, 6.7ml, 13.4mmol) join N-(3-bromo-4-p-methoxy-phenyl) trifluoroacetamide (illustrative examples 52,2.0g, in tetrahydrofuran (THF) 6.7mmol) (20ml) solution, reflux mixture 18 hours.Cooling mixture, solvent evaporated under reduced pressure obtains title compound, is yellow oil (2.1g). ¹H NMR (360MHz, CDCl ₃) δ 6.93 (and 1H, d, J2.9Hz), 6.80 (1H, d, J 8.8Hz), 6.62 (1H, dd, J8.8,2.9Hz), 3.82 (3H, s) and 3.71 (3H, m).m/z(ES ⁺)284,286(M+1)。

Illustrative examples 57

N-(3-bromo-4-p-methoxy-phenyl)-N-(2,2, the 2-trifluoroethyl) ethanamide

(1.26ml 13.4mmol) joins 2-methoxyl group-5-(2,2 with acetic anhydride, 2-trifluoroethyl amino) bromobenzene (illustrative examples 56,2.1g) and triethylamine (1.9ml, 1.37g, 13.4mmol) methylene dichloride cooling (0 ℃) solution in, reflux mixture 18 hours.Cooling mixture, solvent evaporated under reduced pressure.Add 1,2-ethylene dichloride (20ml), reflux mixture 24 hours.Add acetic anhydride (0.6ml) and triethylamine (0.95ml) again, reflux mixture 24 hours, cooling utilizes methylene dichloride (100ml) dilution.Utilize water (3 * 50ml) and salt solution (50ml) diluted mixture thing, dry (MgSO ₄) and solvent evaporated under reduced pressure.Utilize ethyl acetate to grind residue, collect solid, vacuum-drying obtains title compound, is white solid (1.28g, 59%). ¹H NMR (360MHz, CDCl ₃) δ 7.44 (and 1H, d, J2.5Hz), 7.17 (1H, dd, J8.7,2.5Hz), 6.93 (1H, d, J8.7Hz), 4.29 (2H, q, J8.8Hz), 3.94 (3H, s) and 1.90 (3H, m).m/z(ES ⁺)326,328(M+1)。

Illustrative examples 58

2-oxyethyl group-5-(trifluoromethoxy) bromobenzene

(illustrative examples 11 1g) is dissolved in N, in the dinethylformamide (12ml), adds salt of wormwood (1.07g) with 2-bromo-4-Trifluoromethyl phenyl ether.Add iodoethane (0.78ml), mixture at room temperature stirs.Add entry (150ml) and ethyl acetate, layering.Utilize salt water washing organic layer, dry (MgSO ₄) and solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 95: 5 at 100: 0) wash-out by quick silica gel chromatography, obtains title compound, is colorless oil (1.02g). ¹H NMR (250MHz, CDCl ₃) δ 1.47 (and 3H, t, J7.0Hz), 4.09 (2H, q, J7.0Hz), 6.85 (1H, d, J9.0Hz), 7.11 (1H, m) and 7.43 (1H, m).

Illustrative examples 59

2-(trifluoromethylthio) bromobenzene

Utilize the N of nitrogen purge 2-bromo thiophenol (2g) and triethylamine (2.2ml), dinethylformamide solution 5 minutes adds methyl viologen dichloride, utilizes trifluoromethyl iodine gas saturated mixture.After 40 minutes mixture is injected in the ice, utilizes extracted with diethyl ether, dry (MgSO ₄) organic layer, solvent evaporated under reduced pressure.Residue utilizes the hexane wash-out by silica gel chromatography, obtains title compound, is colorless oil (0.8g). ¹H NMR (360MHz, CDCl ₃) δ 7.30-7.42 (and 2H, m) and 7.70-7.81 (2H, m).

Illustrative examples 60

2-bromo-1-(2,2, the 2-trifluoro ethoxy)-4-(trifluoromethyl) benzene

According to the method for illustrative examples 22, by illustrative examples 35 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 4.45 (and 2H, q, J7.9Hz), 6.97 (1H, d, J8.6Hz), 7.58 (1H, dd, J10.7,1.5Hz) and 7.85 (1H, d, J1.4Hz).

Illustrative examples 61

1-isopropoxy-2-bromo-4-(trifluoromethyl) benzene

According to the method for illustrative examples 41, by illustrative examples 35 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 1.40 (and 6H, d, J6.1Hz), 4.64 (1H, septet, J6.1Hz), 6.94 (1H, d, J8.8Hz), 7.49 (1H, dd, J8.9,2.1Hz) and 7.78 (1H, d, J1.9Hz).

Illustrative examples 62

2-benzyloxy bromobenzene

Bromotoluene (27.5ml) is joined 2-bromine phenol, and (10g, 58mmol) and in DMF (70ml) mixture of salt of wormwood (64g), mixture at room temperature stirred 72 hours.Mixture is injected in the water, utilizes ethyl acetate (2 *) washing.The organic fraction that utilizes water washing to merge, dry (Na ₂SO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (98: 2) wash-out by silica gel chromatography, obtains title compound (2.9g). ¹H NMR (250MHz, CDCl ₂) δ 7.58-7.20 (and 7H, m), 6.94 (1H, d, J7.9Hz), 6.84 (1H, t, J7.9Hz) and 5.16 (2H, s).

Illustrative examples 63

3-bromo-4-anisole carboxylic acid amides

With oxalyl chloride (1.13ml, 1.65g, 13mmol) slowly join 3-bromo-4-methoxybenzoic acid (3g, 13mmol) and the methylene dichloride (50ml) of DMF (1) stir in cooling (0 ℃) solution, mixture stirred 10 minutes down at 0 ℃, at room temperature stirred 2 hours again.Be blown into ammonia 10 minutes by mixture, add methylene dichloride, utilize the water washing mixture, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is colorless solid (2.80g, 86%). ¹H NMR (250MHz, DMSO-d ₆) δ 8.23 (and 1H, d, J2.2Hz), 8.08 (1H, br s), 8.03 (1H, dd, J8.6,2.3Hz), 7.47 (1H, br s), 7.30 (1H, d, J8.6Hz) and 4.03 (3H, s).

Illustrative examples 64

3-bromo-4-methyl hydroxybenzoate

(dense, (10.0g, in methyl alcohol 46mmol) (100ml) solution, mixture at room temperature stirred 72 hours 10ml) to join 3-bromo-4-hydroxy-benzoic acid with sulfuric acid.Solvent evaporated under reduced pressure, residue are dissolved in the ethyl acetate (250ml).Utilize saturated sodium bicarbonate aqueous solution (2 * 250ml) purging compounds, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is colorless solid (8.83g, 83%). ¹H NMR (250MHz, CDCl ₃) δ 8.19 (and 1H, d, J2.0Hz), 7.92 (1H, dd, J8.5,2.0Hz), 7.05 (1H, d, J8.5Hz), 5.91 (1H, s) and 3.90 (3H, s).

Illustrative examples 65

3-bromo-4-(difluoro-methoxy) methyl benzoate

(1.12ml 8.7mmol) joins 3-bromo-4-methyl hydroxybenzoate (illustrative examples 64,2.0g with the chlorine ethyl difluoro, 8.7mmol) and salt of wormwood (1.2g, 8.7mmol) N, in dinethylformamide (20ml) mixture, mixture is 65 ℃ of down heating 16 hours.Cooling mixture adds entry (100ml), utilizes ethyl acetate (2 * 100ml) extraction mixtures.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (95: 5) wash-out by silica gel chromatography, obtains title compound, is colorless solid (1.20g, 49%). ¹H NMR (250MHz, CDCl ₃) δ 8.31 (1H, d, J2.0Hz), 8.22 (1H, dd, J8.5,2.0Hz), 7.05 (1H, m), 6.61 (1H, t, J73, Hz) and 3.93 (3H, s).

Illustrative examples 66

3-bromo-4-(2,2, the 2-trifluoro ethoxy) methyl benzoate

(60% mineral oil dispersion liquid, 520mg 13.0mmol) join 3-bromo-4-methyl hydroxybenzoate (illustrative examples 64 with sodium hydride, 3.0g, 13.0mmol) N, N '-dimethyl formamide (100ml) stirs in cooling (0 ℃) solution, mixture stirred 15 minutes down at 0 ℃, be incorporated in N, among the N '-dimethyl formamide (50ml) 2,2,2-trifluoroethyl tosylate (6.61g, 26.0mmol), mixture stirred 16 hours down at 100 ℃.The concentrating under reduced pressure mixture is to half volume, be injected into aqueous sodium hydroxide solution (1M, 300ml) in, utilize ethyl acetate (2 * 350ml) extractions, dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc wash-out by silica gel chromatography, obtains title compound, is colorless oil (1.37g, 34%). ¹H NMR (250MHz, CDCl ₃) δ 8.27 (and 1H, d, J2.1Hz), 7.99 (1H, dd, J2.1,8.6Hz), 6.92 (1H, d, J8.6Hz), 4.42-4.52 (2H, quartet, J7.9Hz) and 3.91 (3H, s).

Illustrative examples 67

3-bromo-4-(cyclobutoxy group) methyl benzoate

With 3-bromo-4-methyl hydroxybenzoate (illustrative examples 64,2.3g, 10mmol), the bromine tetramethylene (2.0g, 15mmol) and salt of wormwood (2.42g, DMF 17.5mmol) (25ml) mixture at room temperature stirred 3 days, stirred 6 hours down at 70 ℃ then.Cooling mixture utilizes water (150ml) dilution, utilizes ethyl acetate (4 * 25ml) extractions.Utilize aqueous sodium hydroxide solution (1M, 25ml) washing organic fraction, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is jelly (1.15g). ¹H NMR (CDCl ₃) δ 1.66-1.77 (1H, m), 1.88-1.93 (1H, m), 2.22-2.31 (2H, m), 2.46-2.60 (2H, m), 3.89 (3H, s), 4.75, (1H, app.pent, J7.0Hz), 6.74 (1H, d, J8.6Hz), 7.91 (1H, dd, J8.6,2.1Hz) and 8.23 (1H, d, J2.1Hz).

Illustrative examples 68

3-bromo-4-(cyclobutoxy group) benzene carboxylic acid amides

(4M, (in methyl alcohol 4mmol) (15ml) solution, mixture at room temperature stirred 20 hours for illustrative examples 67,1.15g 4ml) to join 3-bromo-4-(cyclobutoxy group) methyl benzoate with aqueous sodium hydroxide solution.Evaporating solvent adds entry (25ml), utilizes ethyl acetate (2 * 10ml) purging compounds.Utilize hydrochloric acid (5M) acidifying water layer, utilize methylene dichloride (2 * 25ml) extraction gained suspension.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure is suspended in residue in the methylene dichloride (15ml) that contains DMF (3), adds oxalyl chloride (0.44ml).Mixture at room temperature stirred 1.5 hours, then solvent evaporated under reduced pressure.Under agitation condition, residue is dissolved among the THF (5ml), concentrate hydration ammonia (50ml).Collecting precipitation utilizes water washing, obtains title compound (0.91g). ¹HNMR (DMSO-d ₆) δ 1.60-1.88 (2H, m), 2.01-2.12 (2H, m), 2.43-2.51 (1H, m), 3.34 (3H, s), 4.83 (1H, app.pent, J7.1Hz), 7.00 (1H, d, J8.6Hz), 7.33 (1H, br s), 7.84 (1H, dd, J 8.6,2.1Hz), 8.09 (1H, br s) and 8.10 (1H, d, J2.1Hz).

Illustrative examples 69

2-bromo-4-(trifluoromethoxy) benzonitrile

Under 0 ℃, (2.76g, 40mmol) water (15ml) drips of solution is added to 2-bromo-4-(trifluoromethoxy) aniline (10.2g is in the suspension of concentrated hydrochloric acid 40mmol) (20ml) and water (50ml) mixture with Sodium Nitrite.Mixture stirred 45 minutes down at 0 ℃, then under 65 ℃, drip potassium cyanide in water (80ml) (11.4g, 176mmol) and copper sulfate (II) (6.4g, 40mmol) mixture.Mixture stirred 30 minutes down at 65 ℃, was cooled to room temperature, passed through Hyflo ^TMPad filters, and utilizes methylene dichloride (2 * 200ml) washings.Phase-splitting utilizes methylene dichloride (100ml) aqueous phase extracted.The dry organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (75: 25) wash-out by silica gel chromatography, obtains title compound, is oily matter. ¹H NMR (360MHz, CDCl ₃) δ 7.12-7.15 (and 1H, m), 7.56 (1H, s) and 7.72 (1H, d, J8.6Hz).

Illustrative examples 70

(2-bromobenzene) methyl sulfoxide

To slowly join in the ozone (9.7g) in the water (40ml) 2-bromine sulphur methyl-phenoxide (5g, 24.6mmol) and the acetone (20ml) of sodium bicarbonate (16g) stir in cooling (0 ℃) solution.Mixture at room temperature stirred 16 hours, added entry and methylene dichloride then.Layering, dry (MgSO ₄) organic phase, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 40: 60 at 80: 20) wash-out by silica gel chromatography, obtains title compound (6.1g).m/z(ES ⁺)219(M+1)。

Illustrative examples 71

(2-bromobenzene) methyl sulfone

Will be in the ozone (Oxone in the water (40ml) ^TM, 9.7g) slowly join 2-(bromophenyl) methyl sulfoxide (illustrative examples 70,24mmol) and the acetone (20ml) of sodium bicarbonate (16g) stir in cooling (0 ℃) solution.Mixture heated 2 hours down at 60 ℃, added entry and methylene dichloride then.Layering, dry (MgSO ₄) organic phase, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 70: 30 at 100: 0) wash-out by the silica gel chromatography purifying, obtains title compound (4.1g).m.p.106-107℃,m/z(ES ⁺)235,237(M+1)。

Illustrative examples 72

(3S, 5R, 6S)-3-(5-cyano group-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(trifluoroacetyl group) azepine-spiral shell [4.5] decane

According to the method for embodiment 111, by embodiment 139 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 1.71-1.81 (3H, m), 2.05-2.28 (3H, m), 2.05-2.28 (3H, m), 3.24-3.36 (1H, m), 5.55 (1H, s), 6.79-6.83 (1H, d, J12.3Hz), 7.19-7.32 (4H, m), and 7.42-7.49 (3H, m).m/z(ES ⁺)445(M+1)。

Illustrative examples 73

3-bromo-4-hydroxy phenyl methyl glycolate

Will be in the bromine (16.59g in the chloroform (25ml), 104mmol) be added drop-wise to 4-hydroxy phenyl methyl glycolate (17.25g, 104mmol) and the chloroform (140ml) of acetate (10ml) stir in cooling (0 ℃) mixture, mixture stirred 1 hour down at 0 ℃, utilize methylene dichloride (100ml) dilution, utilize water (2 * 200ml) and salt solution (200ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is colorless solid (25.43g, 100%). ¹H NMR (360MHz, CDCl ₃) δ 7.39 (and 1H, d, J2.0Hz), 7.12 (1H, dd, J8.3,2.0Hz), 6.96 (1H, d, J8.3Hz), 5.54 (1H, brs), 3.70 (3H, s) and 3.54 (2H, s).

Illustrative examples 74

3-bromo-4-p-methoxy-phenyl methyl glycolate

(2.05ml, 4.68g 33mmol) join 3-bromo-4-hydroxy phenyl methyl glycolate (illustrative examples 73 with methyl-iodide, 7.35g, 30mmol) and salt of wormwood (8.29g, in dimethyl formamide 60mmol) (30ml) mixture, mixture at room temperature stirred 16 hours.Add entry (100ml), utilize ethyl acetate (3 * 100ml) extraction mixtures.Utilize aqueous sodium hydroxide solution (1M, 2 * 100ml), water (2 * 100ml) and the organic fraction that merges of salt solution (100ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is colorless solid (7.65g, 100%). ¹H NMR (360MHz, CDCl ₃) δ 7.47 (and 1H, d, J2.1Hz), 7.18 (1H, dd, J8.4,2.1Hz), 6.85 (1H, d, J8.4Hz), 3.88 (3H, s), 3.70 (3H, s) and 3.49 (2H, s).

Illustrative examples 75

(3S, 5R, 6S)-7-(4-neoprene-2-alkynes-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

With 1,4-dichloro butine (0.2ml) joins (3S, 5R, 6S)-(2-(2 for 3-, 2,2-trifluoro ethoxy)-the 5-fluorophenyl)-(embodiment 19,100mg) and in dimethyl formamide (1ml) mixture of salt of wormwood (140mg) for 6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.Mixture at room temperature stirs and spends the night, and utilizes water (20ml) diluted mixture thing, utilizes ether (3 * 5ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 80: 20 at 95: 5) wash-out by the silica gel chromatography purifying, obtains title compound, is colorless oil (100mg).m/z(ES ⁺)m/z?506(M+1)。

Illustrative examples 76

(3S, 5R, 6S)-7-(4-azido-fourth-2-alkynes-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

(15ml) joins (3S with sodiumazide, 5R, 6S)-7-(4-neoprene-2-alkynes-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-(illustrative examples 75 is in dimethyl sulfoxide (DMSO) 100mg) (1ml) solution for 6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.Mixture at room temperature stirs and spends the night, and utilizes water (20ml) dilution, utilizes ether (3 * 5ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is colorless oil (98mg).m/z(ES ⁺)m/z?513(M+1)。

Illustrative examples 77

1-dimethylamino-4-(trifluoromethoxy) benzene

Toluene (30ml) mixture of reflux 1-bromo-4-(trifluoromethoxy) benzene (2.41g), three (dimethylamino) borine (1.43g), sodium tert-butoxide (1.34g), three (dibenzalacetones), two palladiums (18mg) and o-tolyl phosphine (12mg) 4 hours.Cooling mixture utilizes water (30ml) washing, utilizes ethyl acetate (3 * 10ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 95: 5 at 99: 1) wash-out by the silica gel chromatography purifying, obtains title compound, is oily matter (600mg). ¹H NMR (360MHz, CDCl ₃) δ 2.95 (and 6H, s), 6.66 (2H, d, J9Hz) and 7.08 (2H, d, J8.5Hz).m/z(ES ⁺)m/z206(M+1)。

Illustrative examples 78

2-dimethylamino-5-(trifluoromethoxy) bromobenzene

With bromine (0.15ml) be added drop-wise to 1-dimethylamino-4-(trifluoromethoxy) benzene (illustrative examples 77,600mg) and the chloroform (15ml) of yellow soda ash (620mg) stir in cooling (0 ℃) mixture.Stirred the mixture 1 hour, and utilized the water dilution.Utilize salt water washing organic layer, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 95: 5 at 99: 1) wash-out by the silica gel chromatography purifying, obtains title compound, is oily matter (300mg). ¹H NMR (360MHz, CDCl ₃) δ 2.79 (and 6H, s), 7.06 (1H, d, J9Hz), 7.14 (1H, dd, J6,1.5Hz) and 7.44 (1H, d, J2.0Hz).m/z(ES ⁺)m/z?270,272(M+1)。

Illustrative examples 79

(2R, 3R)-1-(phenyl methoxycarbonyl)-2-Phenylpiperidine-3-alcohol

With (2R; 3R)-(method of being described by European patent specification 0528495-A prepares 3-hydroxyl-2-Phenylpiperidine dibenzoyl tartaric acid salt; 35.6g; 0.1mol) slowly join the benzyl chloride manthanoate (21.4ml, 25.6g, 0.15mol), methylene dichloride (50ml) and hydronium(ion) oxidation sodium (1M; vigorous stirring mixture 1 dilution in mixture 500ml); further slowly be incorporated in then benzyl chloride manthanoate in the methylene dichloride (50ml) (8.0ml, 9.56g, 56mmol).The vigorous stirring mixture overnight, layering utilizes methylene dichloride (100ml) aqueous layer extracted.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Utilize hexane to grind residue, collect solid, vacuum-drying obtains title compound, is colorless oil (29.53g, 95%). ¹H NMR (250MHz, CDCl ₃) δ 7.47-7.24 (10H, m), 5.44 (1H, d, J5.7Hz), 5.14 (1H, d, J12.4Hz) .5.07 (1H, d, J12.4Hz), 4.09 (2H, m), 3.09 (1H, m), and 1.88-1.58 (6H, m).

Illustrative examples 80

(±)-1-(phenyl methoxycarbonyl)-2-Phenylpiperidine-3-ketone

Will ((6.9ml, 10.2g be in methylene dichloride 80.4mmol) (500ml) cooling (75 ℃) solution 128.6mmol) slowly to join oxalyl chloride for 9.1ml, 10.0g in the dimethyl sulfoxide (DMSO) in the methylene dichloride (50ml).Mixture stirred 15 minutes down at-75 ℃, slowly add then (2R, 3R)-1-(phenyl methoxycarbonyl)-2-Phenylpiperidine-3-alcohol (illustrative examples 79,20.0g, 64.3mmol).Mixture stirred 1 hour down at-75 ℃, add then triethylamine (27ml, 19.5g, 192.9mmol).Mixture stirred 1 hour down at-75 ℃, at room temperature spent the night then.Utilize aqueous citric acid solution (1M), sodium bicarbonate aqueous solution, water and salt solution purging compound, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is yellow oil (19.56g, 98%). ¹H NMR (250MHz, CDCl ₃) δ 7.39-7.20 (and 10H, m), 5.74 (1H, br s), 5.17 (2H, br s), 4.13 (1H, br s), 3.40 (1H, br m), 2.47 (2H, m) and 1.94 (2H, m).

Illustrative examples 81

(±)-(2S*, 3R*)-3-(3-hydroxypropyn-1-yl)-1-(phenyl methoxycarbonyl)-2-Phenylpiperidine-3-alcohol

According to the method for illustrative examples 7, by illustrative examples 80 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.56 (2H, d, J6.0Hz), 7.31 (8H, m), 5.66 (1H, s), 5.15 (1H, d, J12.5Hz) .5.09 (1H, d, J12.5Hz), 4.12 (2H, s), 4.08 (1H, m), (3.55 2H, br s), 3.20 (1H, m), 2.91 (1H, m), and 2.34-1.35 (3H, m).

Illustrative examples 82

(±)-(5R*, 6S*)-3-tributyl stannyl-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for illustrative examples 8, by illustrative examples 81 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.39-7.14 (10H, m), 5.91 (1H, t, J2.4Hz), 5.15 (1H, d, J12.5Hz) .5.01 (1H, d, J12.5Hz), 4.99 (1H, s), 4.60 (1H, dd, J12.8,2.4Hz), 4.22 (1H, m), 4.14 (1H, dd, J12.8,2.4Hz), 3.31 (1H, m), 2.01-1.70 (4H, m), and 1.54-0.82 (27H, m).

Illustrative examples 83

(±)-(5R*, 6S*)-3-iodo-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

Under-78 ℃, with iodine (2.08g, 8.2mmol) methylene dichloride (100ml) solution join (±)-(5R*, 6S*)-3-tributyl stannyl-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 82,5.0g, in stirred solution 7.8mmol).Stirred the mixture 1 hour, and utilized saturated sodium bisulfite solution (10ml) quenching.After being warmed to room temperature, utilize saturated nacl aqueous solution (100ml) purging compound, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue is collected in the acetonitrile (100ml), utilizes hexane (3 * 100ml) washings.Utilize acetonitrile (3 * 50ml) extraction hexane wash liquid.The acetonitrile fraction that reduction vaporization merges obtains yellow oil, utilizes hexane to grind this yellow oil, obtains title compound, is white solid (2.27g, 61%). ¹H NMR (360MHz, CDCl ₃) δ 7.40 (2H, d, J7.4Hz), 7.20-7.33 (8H, m), 6.36 (1H, t, J2.2Hz), 5.16 (1H, s), 5.12 (2H, s), 4.49 (1H, dd, J2.2 and 12.6Hz), 4.16 (1H, dd, J2.2 and 12.6Hz), 4.13-4.19 (1H, m), 3.08-3.18 (1H, m), 2.00-2.12 (1H, m), 1.70-1.84 (3H, m).m/z(ES ⁺)476(M+1)。

Illustrative examples 84

(±)-(5R*, 6S*)-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

Under 100 ℃, with (±)-(5R*, 6S*)-3-iodo-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 83,1.11g, 2.34mmol), α, α '-azo-isopropyl cyanide (38mg, 0.23mmol) and tributyltin hydride (0.75ml, 2.80mmol) toluene solution (10ml) heating 5 hours, cooling, solvent evaporated under reduced pressure.Residue is collected in the acetonitrile (50ml), utilizes hexane (3 * 50ml) washings.Utilize acetonitrile (50ml) extraction hexane wash liquid.The acetonitrile fraction that reduction vaporization merges obtains oily matter, and this oily matter of purifying utilizes 10% ethyl acetate/hexane wash-out, obtains title compound, is colorless oil (665mg, 81%). ¹H NMR (360MHz, CDCl ₃) δ 7.45 (2H, d, J7.2Hz), 7.20-7.31 (8H, m), 6.00 (1H, dt, J6.2,2.3Hz), 5.87 (1H, bd, J6.2Hz), 5.15 (1H, s), 5.15 (1H, d, J12.5Hz), 5.09 (1H, d, J12.5Hz), 4.61 (1H, dt, J13.3,1.9Hz), 4.32 (1H, dt, J13.2,2.1Hz), 4.16 (1H, dd, J13.1,5.7Hz), 3.08-3.18 (1H, m), 2.00-2.10 (1H, m), and 1.70-1.90 (3H, m).m/z(ES ⁺)350(M+1)。

Illustrative examples 85

Z-(2S, 3R)-1-tert-butoxycarbonyl-3-(3-hydroxyl third-1-alkene-1-yl)-2-Phenylpiperidine-3-alcohol

With palladium/lime carbonate, lead poisoning gas (as the Lindlar catalyzer, 2g) join (2S, 3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-Phenylpiperidine-3-alcohol (illustrative examples 7,32g, 96.6mmol) ethyl acetate (300ml) solution in, mixture stirs down at hydrogen atmosphere (1 normal atmosphere).Filtering mixt, solvent evaporated under reduced pressure obtains title compound, is oily matter (32g, 100%). ¹H NMR (360MHz, CDCl ₃) δ 7.42 (2H, d, J7.6Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, J12.3Hz), 5.68 (1H, dt, J12.3,6.0Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32 (1H, m), 3.13 (1H, s), 2.28 (1H, t, J5.9Hz), 2.02 (1H, m), 1.92-1.78 (3H, m) and 1.32 (9H, s).m/z(ES ⁺)334(M+1)。

Illustrative examples 86

(5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

Will be in the azoethane dicarboxylic ester (18.2ml among the THF (100ml), 115mmol) be added drop-wise to Z-(2S, 3R)-1-tert-butoxycarbonyl-3-(3-hydroxyl third-1-alkene-1-yl)-2-Phenylpiperidine-3-alcohol (illustrative examples 85,32g, 96mmol) and triphenylphosphine (30.2g is in THF 115mmol) (700ml) solution.Mixture stirred 30 minutes down at 0 ℃, at room temperature stirred then 1.5 hours.Solvent evaporated under reduced pressure, residue are utilized hexane/EtOAc (increasing to 80: 20 at 95: 5) wash-out by quick silica gel chromatography, obtain title compound, are colorless solid (23.4g, 77%). ¹H NMR (CDCl ₃) δ 7.45 (2H, d, J7.4Hz), 7.27 (2H, t, J7.4Hz), 7.20 (1H, t, J7.4Hz), 6.03 (1H, dt, J6.1,2.0Hz), 5.68 (1H, dt, J6.1,2.0Hz), 5.06 (1H, s), 4.61 (1H, dt, J13.1,2.0Hz), 4.32 (1H, dt, J13.1,2.0Hz), 4.08 (1H, m), 3.05 (1H, m), 2.05 (1H, m), 1.75 (3H, m) and 1.37 (9H, s).m/z(ES ⁺)316(M+1)。

Illustrative examples 87

(2S)-1-tert-butoxycarbonyl-2-(4-fluorophenyl) piperidines-3-ketone

According to the method for illustrative examples 1, by (2S, 3S)-1-tert-butoxycarbonyl-3-hydroxyl-2-(4-fluorophenyl) piperidines (method of describing according to International Application No. WO 94/19323 prepares) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.43 (and 9H, s), 1.99 (2H, m), 2.48 (2H, m) 3.31 (1H, m), 4.05 (1H, br s), 5.62 (1H, brs), 7.04 (2H, t, J7.4Hz) and 7.21 (2H, dd, J7.5,8.9Hz).

Illustrative examples 88

(2S, 3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-(4-fluorophenyl) piperidines-3-alcohol

According to the method for illustrative examples 7, by illustrative examples 87 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.40 (9H, s), 1.64 (1H, m), 2.04 (2H, m), 2.1 (1H, m), 2.75 (1H, td, J13.4,3.6Hz), 3.03 (1H, br s), 3.47 (1H, br s), 3.96 (1H, dd, J14.8,4.7Hz), 4.25 (2H, s), 5.58 (1H, s), 6.96 (2H, t, J6.7Hz) and 7.53 (2H, dd, J8.5,5.4Hz).

Illustrative examples 89

Z-(2S.3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1 base)-2-(4-fluorophenyl) piperidines-3-alcohol

According to the method for illustrative examples 85, by illustrative examples 88 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 1.34 (9H, s), 1.77 (1H, m), 1.90 (1H, m), 2.03 (1H, m), 3.19 (2H, dd, J11.3,5.9Hz), 4.06 (1H, dd, J13.7,6.04Hz), 4.18 (1H, dd, J5.73,1.2Hz), 4.30 (1H, dd, J14.0,7.4Hz), 5.10 (1H, s), 5.68 (1H, m), 5.85 (1H, dt, J12.3,1.3Hz), 7.00 (2H, t, J8.9Hz) and 7.41 (2H, dd, J8.71,5.6Hz).

Illustrative examples 90

(5R, 6S)-6-(4-fluorophenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for illustrative examples 86, by illustrative examples 89 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 1.37 (9H, s), 1.75 (3H, m), 1.99 (1H, m), 3.04 (1H, td, J11.7Hz), 4.08 (1H, dd, J13.2Hz), 4.27 (1H, dt, J12.9Hz), 4.60 (1H, dt, J13.2,1.8Hz), 5.00 (1H, s), 5.87 (1H, d, J6.16Hz), 5.99 (1H, d, J8.6Hz), 6.95 (2H, t, J8.7Hz) and 7.40 (2H, dd, J8.7,5.8Hz).

Illustrative examples 91

(3S, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alcohol

Under nitrogen atmosphere, with 2-bromo-4-(trifluoromethoxy) phenyl ether (illustrative examples 12,417mg, 1.54mmol) join in batches magnesium in ether (1ml) (41mg, 1.7mmol) in, mixture carries out brief reflux each after reinforced.In a single day reinforced finishing, mixture reflux 30 minutes, most of therebetween magnesium is dissolved.Solution is cooled to room temperature, it is added drop-wise to (5R, 6S)-(illustrative examples 4,212mg is in ether 0.64mmol) (10ml) cooling (0 ℃) solution for 3-ketone group-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Mixture stirred 10 minutes down at 0 ℃, at room temperature spent the night.Add saturated aqueous ammonium chloride (40ml), utilize ethyl acetate (2 * 40ml) extraction mixtures.Organic fraction drying (MgSO with salt solution (20ml) washing merging ₄) organic fraction that merges, solvent evaporated under reduced pressure, residue utilizes ethyl acetate/hexane (1: 5) wash-out by silica gel chromatography, obtains title compound, is grey foam (240mg, 72%). ¹H NMR (360MHz, CDCl ₃) δ 1.47 (9H, s), 1.52-1.71 (3H, m), 2.17-2.22 (1H, m), 2.42 (1H, d, J13.5Hz), 2.56 (1H, d, J13.5Hz), 2.77-2.84 (1H, m), 3.89 (3H, s), 3.96-4.00 (1H, m), 4.20 (1H, d, J9.5Hz), 4.29 (1H, d, J9.5Hz), 5.78 (1H, s), 6.90 (1H, d, J8.9Hz), 7.13-7.16 (1H, m), 7.21-7.25 (1H, m), 7.30-7.35 (1H, m) and 7.62 (2H, d, J7.7Hz).m/z(ES ⁺)524(M+1)。

Illustrative examples 92

(5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-alkene and (5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

(1ml) joins (3S with trifluoroacetic acid, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(illustrative examples 91,240mg is in methylene dichloride 0.46mmol) (10ml) cooling (0 ℃) solution for 3-alcohol.Solution stirred 10 minutes down at 0 ℃, at room temperature stirred 1 hour.Solvent evaporated under reduced pressure adds the unsaturated carbonate aqueous solutions of potassium.(2 * 40ml) extract this mixture, the organic fraction that utilizes salt solution (20ml) washing to merge, dry (MgSO to utilize ethyl acetate ₄), solvent evaporated under reduced pressure, residue passes through silica gel chromatography, utilize methylene chloride/ammonia (160: 8: 1) wash-out, obtain (5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-alkene (29mg, 16%). ¹H NMR (360MHz, CDCl ₃) δ 1.56-1.65 (2H, m), 2.05-2.12 (1H, m), 2.22-2.26 (1H, m), 2.41 (1H, dd, J14.0,1.6Hz), 2.76 (1H, dd, J14.0,1.9Hz), 2.87 (1H, dt, J12.2,2.7Hz), 3.23-3.28 (1H, m), 3.59 (1H, s), 3.79 (3H, s), 6.58 (1H, d, J2.7Hz), 6.98 (1H, d, J8.9Hz), 6.83-6.85 (1H, m), 7.13 (1H, s), 7.15-7.26 (3H, m), and 7.43-7.45 (2H, m), m/z (ES ⁺) 506 (M+1) and (5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (69mg, 37%). ¹H NMR (250MHz, CDCl ₃) δ 7.45 (2H, d, J7.2Hz), 7.30-7.2 (3H, m), 7.13-7.09 (1H, dd, J9.0Hz), 6.89 (2H, s+d), 6.64 (1H, t, J2.04Hz), 5.16 (1H, s), 4.96 and 4.56 (2H, ABdd, J12.1 and 2Hz), 4.11 (1H, m), 3.86 (3H, s), 3.08 (1H, m), 2.1 (1H, m), 1.87-1.77 (3H, m) and 1.37 (9H, s), m/z (ES ⁺) 506 (M+1).

Illustrative examples 93

3-bromo-2-phenyl third-1-alkene

With 2-phenyl third-1-alkene (14.16g, 0.12mmol), N-bromine succinimide (13.5g, 72mmol) and α, tetracol phenixin (7.5ml) mixture of α '-azo isobutyronitrile (1.5mg) is placed in 170 ℃ the pre-hot oil bath (internal temperature rises to 110 ℃).Violent stirring pulpous state liquid is 2 hours under this temperature.Be cooled to envrionment temperature then, filtering mixt utilizes the tetracol phenixin washing, solvent evaporated under reduced pressure.Residue utilizes the hexane wash-out by silica gel chromatography, obtains title compound, is oily matter (320mg). ¹H NMR (250MHz, CDCl ₃) δ (7.85-7.81 (2H, m), 7.75-7.63 (3H, m), 5.89 (1H, s), 5.82 (1H, s) and 4.72 (2H, s).

Illustrative examples 94

(2S.3R)-1-tert-butoxycarbonyl-2-phenyl-3-(2-phenyl third-1-alkene-3-yl) piperidines-3-alcohol

Because the 3-bromo-2-phenyl third-1-alkene among the THF (4ml) (illustrative examples 93,150mg, 0.76mmol) and MAGNESIUM METAL (24mg 1mmol) prepares Grignard reagent.Cooling solution adds (2S)-1-tert-butoxycarbonyl-2-Phenylpiperidine-3-ketone (illustrative examples 1,161mg, THF 0.59mmol) (1ml) solution to-30 ℃.Mixture stirred 16 hours at ambient temperature, added saturated aqueous ammonium chloride (10ml) then.Utilize ethyl acetate (2 * 20ml) extraction mixtures, dry (Na ₂SO ₄) organic fraction that merges.Solvent evaporated under reduced pressure, residue utilizes hexane/ethyl acetate (85: 15) wash-out by silica gel chromatography, obtains title compound, is oily matter (52mg). ¹H NMR (360MHz, CDCl ₃) δ 7.44-7.20 (10H, m), 5.43 (1H, s), 5.25 (1H, s), 5.12 (1H, s), 4.06-4.03 (1H, m), 3.34-3.30 (1H, m), 3.08-2.94 (3H, m), 2.47-2.43 (1H, m), 1.93-1.86 (2H, m), 1.70-1.64 (2H, m) and 1.38 (9H, s).m/z(ES ⁺)394(M+1)。

Illustrative examples 95

(2S, 3R, 2 ' R)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-phenyl third-1-alcohol

Will (2S, 3R)-(illustrative examples 94,46mg 0.12mmol) are dissolved among the THF (5ml) 1-tert-butoxycarbonyl-2-phenyl-3-(2-phenyl third-1-alkene-3-yl) piperidines-3-alcohol, are cooled to 0 ℃.(0.36mmol), the gained mixture stirred 16 hours at ambient temperature for 1.0M THF solution, 0.36ml to add borine-tetrahydrofuran (THF) title complex in 5 minutes.Add aqueous sodium hydroxide solution (4M, 0.5ml) and aqueous hydrogen peroxide solution (30%, 0.5ml), mixture stirred 1 hour at ambient temperature.Utilize water (10ml) diluted mixture thing, utilize ethyl acetate (15ml) extraction.Dry (Na ₂SO ₄) organic layer, solvent evaporated under reduced pressure.Residue utilizes hexane/ethyl acetate (75: 25) wash-out by preparation property silica gel thin-layer chromatography purifying, obtains title compound, is oily matter (13mg). ¹H NMR (250MHz, CDCl ₃) δ 7.51-7.48 (2H, m), 7.34-7.19 (8H, m), 5.29 (1H, s), 4.03-3.98 (1H, m), 3.83-3.70 (2H, m), 3.29-3.19 (1H, m), 3.15-3.03 (1H, m), 2.41-2.30 (3H, m), 2.12-1.95 (2H, m), 1.78-1.73 (2H, m), 1.45-1.41 (1H, m) and 1.31 (9H, s).m/z(ES ⁺)412(M+1)。

Illustrative examples 96

(4S)-and 4-benzyl-3-(2-p-methoxy-phenyl) ethanoyl-1,3-oxazolidine-2-ketone

Sulfuryl chloride (6.91ml) is slowly joined 2-anisole guanidine-acetic acid, and (13.77g, 0.083mol) and in the toluene (50ml) of dimethyl formamide (0.1ml) warm (50 ℃) solution, mixture stirred 2 hours down at 50 ℃.Solvent evaporated under reduced pressure is dissolved in residue in the tetrahydrofuran (THF) (50ml).(14.7g, (1.6M, 52ml 83mmol) cool off (20 ℃) solution, and mixture is warmed to 0 ℃ slowly to add n-Butyl Lithium in tetrahydrofuran (THF) 83mmol) (80ml) to (4S)-4-Bian Ji oxazolidine-2-ketone.In 20 minutes, in this solution, slowly add above-mentioned acyl chlorides tetrahydrofuran solution.Mixture is warmed to room temperature, stirred 72 hours.Add saturated aqueous ammonium chloride, utilize the ethyl acetate extraction mixture.The organic fraction that utilizes water and salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 50: 50 at 90: 10) wash-out by the silica gel chromatography purifying, obtains title compound (12.8g). ¹H NMR (360MHz, CDCl ₃) δ 7.37-7.15 (and 7H, m), 6.92 (2H, m), 4.71 (1H, m), 4.30 (1H, d, J17.6Hz), 4.26-4.17 (4H, m), 3.82 (3H, s), 3.29 (1H, dd, J13.4,3.1Hz) and 2.81 (1H, dd, J13.39.4Hz).

Illustrative examples 97

(2 ' R, 4S)-4-benzyl-3-[3-benzyloxy-2-(2-p-methoxy-phenyl)] propionyl-1,3-oxazolidine-2-ketone

Titanium tetrachloride (1M that will be in methylene dichloride; 37.2ml) join (4S)-4-benzyl-3-(2-p-methoxy-phenyl) ethanoyl-1,3-oxazolidine-2-ketone (illustrative examples 96,12.1g; 37.2mmol) methylene dichloride (100ml) cooling (80 ℃) solution in, mixture is warmed to room temperature.Extremely-80 ℃ of cooling mixtures, and the adding diisopropylethylamine (7.0ml, 39.4mmol).Mixture be warmed to 0 ℃ 1 hour, (10.3ml, 74.4mmol), mixture at room temperature stirred 16 hours to add benzyloxymethyl chlorine.Mixture is injected in saturated aqueous ammonium chloride and the ethyl acetate, utilizes water and salt water washing organic phase, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue obtains title compound (9.14g) by the ethyl acetate/hexane recrystallization. ¹H NMR (360MHz, CDCl ₃) δ 7.36-7.21 (14H, m), 6.9-6.85 (2H, m), (5.80 1H, dd J9.33Hz and 4.45Hz), 4.69 (1H, m), 4.63 (2H, s), 4.16-4.06 (3H, m), 3.85 (3H, s), (3.74 1H, dd J9.3Hz and 4.5Hz), 3.30 (1H, dd J13.5Hz and 3.14Hz) and 2.83 (1H, dd J13.5Hz and 9.2Hz).

Illustrative examples 98

(2S)-3-benzyloxy-2-(2-p-methoxy-phenyl) third-1-alcohol

With lithium borohydride (0.366g; 16.8mmol) join (2 ' R; 4S)-and 4-benzyl-3-[3-benzyloxy-2-(2-p-methoxy-phenyl)] propionyl-1; 3-oxazolidine-2-ketone (illustrative examples 97; 6.8g; 15.3mmol) tetrahydrofuran (THF) (100ml) and water (0.3ml) solution in, mixture at room temperature stirred 2 hours.Add aqueous sodium hydroxide solution (1M, 100ml) and ethyl acetate (200ml), layering.Utilize water and salt water washing organic phase, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 80: 20 at 90: 10) wash-out by the silica gel chromatography purifying, obtains title compound, is oily matter (3.4g). ¹HNMR (250MHz, CDCl ₃) δ 7.38-7.13 (5H, m), 6.94-6.85 (2H, m), 4.56 (2H, s), 4.06-3.98 (1H, dd J10.7Hz and 7.03Hz), and 3.90-3.52 (7H, m).

Illustrative examples 99

(2R)-3-benzyloxy-1-chloro-2-(2-p-methoxy-phenyl) propane

With (2S)-3-benzyloxy-2-(2-p-methoxy-phenyl) third-1-alcohol (illustrative examples 98,2 gram, 7.4mmol) and triphenylphosphine (2.12g, tetracol phenixin 8.1mmol) (10ml) solution heated 5 hours in 100 ℃ of oil baths.The careful methyl alcohol (1ml) that adds, mixture is cooled to room temperature and stirred 16 hours.Solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (increasing to 95: 5 at 100: 0) wash-out by the silica gel chromatography purifying, obtains title compound (1.5g). ¹H NMR (250MHz, CDCl ₃) δ 7.37-7.2 (7H, m), 6.96-6.86 (2H, m), 4.54 (2H, s), 3.92 (2H, m), and 3.81-3.73 (7H, m).

Illustrative examples 100

(2S, 3R, 2 ' R)-1-tert-butoxycarbonyl-3-hydroxyl-3-[3-benzyloxy-2-(2-p-methoxy-phenyl) propyl group]-the 2-Phenylpiperidine

Under 60 ℃, utilize (2R)-3-benzyloxy-1-chloro-2-(2-p-methoxy-phenyl) propane (illustrative examples 99,0.45g, tetrahydrofuran (THF) 1.55mmol) (1ml) solution-treated magnesium (0.1g, tetrahydrofuran (THF) 4.2mmol) (1ml) suspension 3 hours.Cooling mixture is incorporated in (the 2S)-1-tert-butoxycarbonyl-2-Phenylpiperidine-2-ketone (illustrative examples 1) in the tetrahydrofuran (THF) (1ml).Mixture at room temperature stirred 1 hour, was distributed between ethyl acetate and the saturated ammonium chloride solution, utilized water and saturated brine washing organic phase, dry (MgSO ₄).Solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (95: 5) wash-out by the silica gel chromatography purifying, obtains title compound (0.115g). ¹H NMR (360MHz, CDCl ₃) δ 7.48 (2H, d J6.8Hz), 7.36 (1H, d J4.5Hz), 7.30-7.16 (9H, m), (6.88 1H, t J7.4Hz), 6.84 (1H, d J8.0Hz), 5.17 (1H, s), 4.53 (2H, s), 4.00 (1H, dd), 3.83-3.68 (5H, m), 3.67 (2H, m), 3.27 (1H, s), 3.02 (1H, td J3.0Hz and 12.0Hz), (2.35 1H, dd J14.7Hz and 6.12Hz), 2.20 (1H, dd J14.6Hz and 6.2Hz), 2.04 (1H, m), 1.76 (2H, m) and 1.28 (9H, s).m/z(ES ⁺)532(M+1)。

Illustrative examples 101

(2S, 3R, 2 ' R)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-(2-p-methoxy-phenyl) third-1-alcohol

In the presence of 10% palladium hydroxide/carbon (50mg), with (2S, 3R, 2 ' R)-1-tert-butoxycarbonyl-3-hydroxyl-3-[3-benzyloxy-2-(2-p-methoxy-phenyl) propyl group]-(illustrative examples 100, ethyl acetate 0.115g) (10ml) and methyl alcohol (10ml) the solution hydrogenation 1 hour under 50psi of 2-Phenylpiperidine.Filtering mixt, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 75: 25 at 95: 5) wash-out by the silica gel chromatography purifying, obtains title compound (0.073g). ¹H NMR (360MHz, CDCl ₃) δ 7.48 (2H, d J7.2Hz), and 7.30-7.16 (5H, m), 6.91 (1H, t J7.5Hz), 6.86 (1H, d J7.9Hz), 5.19 (1H, s), (4.00 1H, dd J13.0Hz and 4.7Hz), 3.82 (3H, s), 3.79-3.62 (3H, m), 3.09 (1H, m), 2.69 (2H, vbs), (2.33 1H, dd J14.7Hz and 5.6Hz), 2.08 (1H, dd J14.9Hz and 6.4Hz), 1.98 (1H, m), 1.73 (3H, m), 1.27 (9H, s).m/z(ES ⁺)442(M+1)。

Illustrative examples 102

2-benzyloxy-5-(trifluoromethoxy) benzene

With bromotoluene (66.17ml, 95.35g, 0.56mol) join 4-(trifluoromethoxy) phenol (90.26g, 0.51mol) and salt of wormwood (140.97g, in dimethyl formamide 1.2mol) (160ml) mixture, mixture at room temperature stirred 72 hours.Mixture is injected in the water (1.51), utilize ethyl acetate (3 * 500ml) extractions, utilize aqueous sodium carbonate (saturated, the 500ml) organic fraction that merges of washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is colorless solid (133.5g, 99%). ¹H NMR (360MHz, CDCl ₃) δ 7.39 (and 5H, m), 7.14 (2H, d, J9.0Hz), 6.95 (2H, d, J9.0Hz) and 5.05 (2H, s).

Illustrative examples 103

2-benzyloxy-5-(trifluoromethoxy) iodobenzene

Iodine (71.96g that will be in chloroform, 0.28mol) join 2-benzyloxy-5-(trifluoromethoxy) benzene (illustrative examples 102,73.06g, 0.27mol) and trifluoroacetic acid silver (71.57g, 0.32mol) dichloromethane mixture in, mixture at room temperature stirred 18 hours.By the diatomite filtration mixture, utilize sodium thiosulfate solution (5%, 2 * 21) washing, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc wash-out by quick silica gel chromatography, obtains title compound, is colorless oil (108.03g), contains 11% unreacted 2-benzyloxy-5-(trifluoromethoxy) iodobenzene. ¹H NMR (360MHz, CDCl ₃) δ 7.67 (and 1H, d, J2.8Hz), 7.40 (5H, m), 7.16 (1H, dd, J8.9,2.8Hz), 6.82 (1H, d, J8.9Hz) and 5.14 (2H, s).

Illustrative examples 104

1-benzyloxy-4-(difluoro-methoxy) benzene

With the chlorine ethyl difluoro (25ml, 0.20mol) join 4-(benzyloxy) phenol in dimethyl formamide (200ml) (20.10g, 0.10mol) and salt of wormwood (41.90g, 0.30mol) in.Mixture stirred 18 hours down at 80 ℃.Add other chlorine ethyl difluoro (12.7ml, 0.10mol) and salt of wormwood (27.74g, 0.20mol), mixture stirred 6 hours down at 80 ℃.Add again other chlorine ethyl difluoro (12.7ml, 0.10mol) and salt of wormwood (27.74g, 0.20mol), mixture stirred 15 hours down at 120 ℃.Cooling mixture is injected in the water (1000ml), utilizes ethyl acetate (500ml) extraction.Utilize saturated sodium hydroxide (1M, 500ml) and salt solution (500ml) washing organic fraction, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/CH by silica gel chromatography ₂Cl ₂(90: 10) wash-out obtains title compound, is colorless solid (6.67g, 27%). ¹H NMR (360MHz, CDCl ₃) δ 5.05 (2H, s), 6.42 (1H, t, J74Hz), 6.94 (2H, m), 7.06 (2H, m), and 7.31-7.44 (5H, m).

Illustrative examples 105

2-benzyloxy-5-(difluoro-methoxy) iodobenzene

According to the method for illustrative examples 103, by illustrative examples 104 compound title compounds. ¹H?NMR(360MHz,CDCl ₃)δ5.13(2H,s),6.40(1H,t,J74Hz),6.80(1H,d,J8.9Hz),7.07(1H,dd,J8.9,2.8Hz),7.33(1H,m),7.40(2H,m),7.48(2H,m),7.60(1H,d,J2.8Hz)。

Illustrative examples 106

5-fluoro-2-hydroxy-iodobenzene

With chloramine-T trihydrate (50g, 178mmol) join the 4-fluorophenol (20g, 178mmol) and sodium iodide (26.7g is in dimethyl formamide 178mmol) (250ml) cooling (0 ℃) solution, mixture stirred 1 hour down at 0 ℃, was injected in the water (1000ml).Utilize hydrochloric acid (1M) acidifying mixture, utilize ether (4 * 200ml) extractions.Utilize sodium thiosulfate solution (5%, 3 * 100ml), water (2 * 50ml) and the organic fraction that merges of salt solution (50ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/CH by quick silica gel chromatography ₂Cl ₂Wash-out obtains title compound, is white solid (7.8g, 18%). ¹H NMR (360MHz, CDCl ₃) δ 5.08 (and 1H, s), 6.90-7.01 (2H, m) and 7.37 (1H, dd, J7.6,2.9Hz).

Illustrative examples 107

2-benzyloxy-5-fluorine iodobenzene

According to the method for illustrative examples 36, by illustrative examples 106 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 5.10 (2H, s), 6.78 (1H, dd, J9.0,4.6Hz), 6.94-7.01 (1H, m), and 7.30-7.56 (6H, m).

Illustrative examples 108

5-benzyloxy-2-isopropoxy oil of mirbane

(4.51ml, 5.90g 48mmol) join 4-benzyloxy-2-nitrophenols (J.Biol.Chem., 1985 with the 2-N-PROPYLE BROMIDE, 260,3440,2.94g, 12mmol) and salt of wormwood (9.95g, in dimethyl formamide 72mmol) (20ml) mixture, mixture stirred 22 hours down at 50 ℃.Cooling mixture utilizes water (100ml) dilution, utilizes ethyl acetate (3 * 100ml) extractions.Utilize aqueous sodium hydroxide solution (1M, 4 * 100ml) and the organic fraction that merges of salt solution (100ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is orange oily matter (3.40g, 99%). ¹H NMR (360MHz, CDCl ₃) δ 7.41-7.33 (and 6H, m), 7.12 (1H, dd, J9.1,3.1Hz), 7.02 (1H, d, J9.1Hz), 5.05 (2H, s), 4.52 (1H, hept, J6.1Hz) and 1.35 (6H, d, J6.1Hz).

Illustrative examples 109

5-benzyloxy-2-isopropoxy aniline

(10% solution in 20-30% hydrochloric acid, (in acetate 9.7mmol) (50ml) solution, mixture at room temperature stirred 18 hours for illustrative examples 108,2.78g 50ml) to join 5-benzyloxy-2-isopropoxy oil of mirbane with titanous chloride.With mixture be injected into ice-cold aqueous sodium hydroxide solution (4M, 400ml) in, utilize methylene dichloride (8 * 100ml) extraction mixtures.Utilize saturated sodium bicarbonate aqueous solution (organic fraction that 2 * 200ml) washings merge, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is dark oil thing (1.74g, 71%). ¹H NMR (360MHz, CDCl ₃) δ 7.42-7.25 (and 5H, m), 6.71 (1H, d, J8.7Hz), 6.41 (1H, d, J2.9Hz), 6.30 (1H, dd, J8.7,2.9Hz), 4.97 (2H, s), 4.38 (1H, hept, J6.0Hz), 3.6 (2H, brs) and 1.32 (6H, d, J6.0Hz).

Illustrative examples 110

5-benzyloxy-2-isopropoxy iodobenzene

Will be in the Sodium Nitrite (589mg in the water (2.5ml), 8.5mmol) be added drop-wise to 5-benzyloxy-2-isopropoxy aniline (illustrative examples 109,2.05g, 8.4mmol) sulfuric acid (2M, 14ml) stir cooling (0 ℃) suspension, mixture stirred 30 minutes down at 0 ℃, and (2.50g is in stirring cooling (0 ℃) water (10ml) solution 15.1mmol) to be added drop-wise to potassiumiodide then.Mixture at room temperature stirred 90 minutes, added entry (50ml) then.Utilize ethyl acetate (3 * 50ml) extraction mixtures.Utilize hydration Sulfothiorine (10%, 2 * 50ml), hydrochloric acid (2M, 2 * 50ml), saturated sodium bicarbonate aqueous solution (2 * 50ml) and the organic fraction that merges of salt water washing, dry (MgSO ₄) and solvent evaporated under reduced pressure.Residue utilizes hexane/CH by quick silica gel chromatography ₂Cl ₂(80: 20) wash-out obtains title compound, is paste solid (1.49g, 48%). ¹H NMR (360MHz, CDCl ₃) δ 7.42-7.30 (and 6H, m), 6.90 (1H, dd, J9.0,2.9Hz), 6.77 (1H, d, J9.0Hz), 4.98 (2H, s), 4.41 (1H, hept, J6.1Hz) and 1.35 (6H, d, J6.1Hz).

Illustrative examples 111

(3S, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Will (3S, 5R, 6S)-(embodiment 212 for 3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 290mg, 0.59mmol) be dissolved in the toluene (5ml), add a silver carbonate (179mg, 0.65mmol).At room temperature in 1 minute, add (1-iodine ring third-1-yl) phenyl sulphur (Cohen T. and MatzJ.R., J.Am.Chem.Soc.1980,102,6902) (180mg, 0.65mmol).Mixture stirred 4 hours down at 55 ℃, add then another part silver carbonate (179mg, 0.65mmol) and (1-iodine ring third-1-yl) phenyl sulphur (180mg, 0.65mmol).Stirred the mixture under 55 ℃ 3 hours, cooling is filtered and solvent evaporated under reduced pressure again.Residue utilizes hexane/ethyl acetate (increasing to 80: 20 at 90: 10) wash-out by silica gel chromatography, obtains title compound, is colorless oil (120mg, 32%). ¹H NMR (250MHz, CDCl ₃) δ 7.55-7.44 (4H, m), 7.36-7.23 (7H, m), 7.13-7.02 (2H, m), 5.16 (1H, br s), 4.09 (1H, t, J6Hz), and 4.03-3.92 (1H, m), 3.67-3.49 (2H, m), 2.94-2.79 (1H, m), 2.26 (1H, dd, J7.9,12.9Hz), 2.15-2.01 (2H, m), 1.76-1.59 (3H, m), 1.53-1.45 (4H, m) and 1.36 (9H, s).m/z(ES ⁺)642(M+1)。

Illustrative examples 112

(3R, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 111, by (3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 212) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.57 (2H, app.d, J7.6Hz), 7.45 (2H, app.d, J7.7Hz), 7.36-7.19 (7H, m), and 7.16-7.06 (2H, m), 5.28 (1H, br s), 4.13 (1H, app.t, J7.8Hz), 3.96 (1H, br.d, J13Hz), 3.80-3.60 (2H, m), 2.79 (1H, br.t, J13Hz), 2.50 (1H, dd, J13,7.9Hz), 2.17 (1H, dt, J13,4.6Hz), 1.80 (1H, dd, J12,9.8Hz), 1.75-1.38 (7H, m) and 1.44 (9H, s).m/z(ES ⁺)642(M+1)。

Illustrative examples 113

(3S, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 111, by (3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 216) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.53-7.22 (13H, m), 5.13 (1H, s), 4.11 (1H, m), 3.97 (1H, m), 3.59 (2H, m), 2.89 (1H, m), 2.28 (1H, dd, J12.7,7.6Hz), 2.08 (2H, m), 1.68 (3H, m), 1.75-1.48 (4H, m) and 1.34 (9H, s).m/z(ES ⁺)626(M+1)。

Illustrative examples 114

(3R, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 111, by embodiment 225 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.57 (2H, d, J7.6Hz), 7.46 (2H, d, J7.2Hz), 7.35-7.20 (7H, m), 7.03 (2H, m), 6.44 (1H, t, J74.3Hz), 5.27 (1H, s), 4.12 (1H, m), 3.96 (1H, m), 3.70 (2H, m), 2.80 (1H, m), 2.49 (1H, m), 2.18 (1H, m), 1.82 (1H, m), 1.75-1.26 (7H, m) and 1.44 (9H, s).m/z(ES ⁺)624(M+1)。

Illustrative examples 115

(3R, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethoxy) phenyl]-6-(4-fluorophenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 111, by embodiment 223 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.42 (9H, s), 1.43-1.65 (5H, m), 1.80 (1H, dd, J12.5,9.6Hz), 2.12 (1H, m), 2.47 (1H, dd, J7.8,12.8Hz), 2.77 (1H, td, J13.2,9.5Hz), 3.65 (1H, qn, J8.6Hz), 3.73 (1H, t, J8.3Hz), 3.95 (1H, dd, J9.67Hz), 4.10 (1H, m), 5.23 (1H, s), 7.00 (2H, t, J8.76Hz), 7.10 (2H, s), 7.29 (6H, m), 7.47 (2H, d, J8.5Hz) and 7.53 (2H, dd, J8.9,5.8Hz).

Illustrative examples 116

Fourth Ring propyl group tin

To be added drop-wise in the Cyclopropyl Bromide (3.3ml) in the tetrahydrofuran (THF) (18ml) in the magnesium (1.1g) in tetrahydrofuran (THF) (2ml), heated mixt is until the beginning that refluxes of controlling oneself.Mixture stirred 1 hour down at 65 ℃, was cooled to room temperature, dripped tin chloride (IV) (2.4ml).Mixture is 65 ℃ of down heating 16 hours, cooling, utilize aqueous ammonium chloride solution (saturated, 30ml) dilution.Utilize ether (3 * 20ml) extraction mixtures, the organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄) and solvent evaporated under reduced pressure.Residue utilizes the hexane wash-out by quick silica gel chromatography, obtains title compound, is colorless oil. ¹H NMR (360MHz, CDCl ₃) δ-0.38 (and 4H, m), 0.37 (8H, m) and 0.57 (8H, m).

Illustrative examples 117

3-iodo-4-(4-methoxyl group benzyloxy base) cyanobenzene

With iodine (21g, 84mmol) join the 4-cyanophenol (10.0g, 84mmol) and sodium bicarbonate (7.06g, in water 84mmol) (100ml) solution, mixture at room temperature stirred 24 hours.Collect solid, utilize water washing, vacuum-drying.Solid is dissolved in the tetrahydrofuran (THF) (100ml), add triphenylphosphine (14.4g, 55mmol) and 4-methoxybenzyl methyl alcohol (8.3g, 60mmol).(8.5ml, 55mmol), mixture at room temperature stirred 16 hours slowly to add azo-dicarboxylate.With mixture be injected into sodium hydrogen carbonate solution (saturated, 200ml) in, utilize ethyl acetate (2 * 200ml) extraction.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue obtains title compound (3.38g) by quick silica gel chromatography. ¹H NMR (250MHz, CDCl ₃) δ 8.05 (and 1H, d, J2.0Hz), 7.57 (1H, dd, J2.0,8.5Hz), 7.38 (2H, d, J6.8Hz), 6.79-6.96 (3H, m), 5.14 (2H, s) and 3.82 (3H, s).

Illustrative examples 118

(3R, 5R, 6S)-3-[5-cyano group-2-(4-methoxyl group benzyloxy base) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 219, by illustrative examples 117 compounds and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86) preparation title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.48-7.57 (4H, m), 7.20-7.34 (5H, m), 6.89-7.01 (3H, m), 5.29 (1H, s), 5.07 (1H, s), 4.22-4.32 (1H, m), 3.90-3.99 (1H, m), 3.81 (3H, s), 2.76 (1H, dt, J12.0,4.3Hz), 2.50-2.57 (1H, m), 1.91-2.23 (2H, m), 1.60-1.66 (5H, m) and 1.42 (9H, s).

Illustrative examples 119

(3R, 5R, 6S)-3-[5-cyano group-2-(tert-butoxycarbonyl) oxygen base phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With two (tertiary butyl) two carbonic ether (698mg, 3.2mmol) join (3R, 5R, 6S)-3-(5-cyano-2-hydroxy-phenyl)-6-phenyl-1-oxa--(embodiment 274 for 7-azepine-spiral shell [4.5] decane, 533mg, 1.6mmol) and diisopropylethylamine (0.556ml, in methylene dichloride 3.2mmol) (50ml) solution, mixture at room temperature stirred 16 hours.Utilize sodium hydrogen carbonate solution (saturated, 50ml) purging compound, MgSO ₄Drying, solvent evaporated under reduced pressure.Residue obtains title compound by the fast silica gel chromatogram purifying, is colorless solid (465mg). ¹H NMR (250MHz, CDCl ₃) δ 7.72 (1H, d, J1.9Hz), 7.54-7.60 (3H, m), 7.22-7.36 (4H, m), 5.33 (1H, m), 4.26 (1H, dd, 7.2,8.7Hz), 3.94-3.98 (1H, m), and 3.81-3.88 (1H, m), 3.69-3.75 (1H, m), 2.77 (1H, dt, J3.5,12.6Hz), 2.64 (1H, dd, J8.3,13.0Hz), 2.25 (1H, dt, J8.1,13.1Hz), 1.89 (1H, dd, J8.6,13.0Hz), 1.71-1.77 (3H, m), 1.56 (9H, s) and 1.46 (9H, s).

Illustrative examples 120

(3R, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 111, by (3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 216) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.44 (9H, s), 1.40-1.72 (7H, m), 1.84 (1H, m), 2.16 (1H, m), 2.51 (1H, m), 2.80 (1H, m), 3.71 (2H, m), 3.97 (1H, m), 4.15 (1H, m), 5.29 (1H, s), and 7.22-7.59 (13H, m).m/z(ES ⁺)570(M+1-C ₄H ₈)。

Illustrative examples 121

6-fluoro-2-methoxyl group iodobenzene

((5.0g, THF 40mmol) (150ml) stir in cooling (78 ℃) solution, and mixture stirred 2.5 hours down at-78 ℃ 42mmol) to join 3-fluorophenyl ether for 1.6M hexane solution, 26ml with n-Butyl Lithium.(11.1g, 43mmol), mixture is warmed to room temperature to drip iodine in THF (50ml).Add entry (200ml), saturated aqueous sodium thiosulfate (100ml) and ether (300ml), layering utilizes ether (200ml) aqueous layer extracted, dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (99: 1) wash-out by quick silica gel chromatography, obtains title compound, is light yellow oil (7.65g, 77%). ¹H NMR (360MHz, CDCl ₃) δ 7.27 (and 1H, dt, Jd6.6Hz, Jt8.2Hz), 6.71 (1H, t, J8.2Hz), 6.62 (1H, d, J8.2Hz) and 3.90 (3H, s).

Embodiment 1

(5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

Will be in toluene (25ml) (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 6; 3.07g, 6.43mmol), lithium chloride (0.163g), 2-bromo-4-trifluoromethoxy methyl-phenoxide (illustrative examples 12; 2.07g, 7.7mmol) outgas, add triphenylphosphine palladium (O) then (0.37g).Solution is thoroughly outgased, be heated to then 110 ℃ 14 hours.Solution is distributed between water and the ethyl acetate, and the dry organic phase of crossing is carried out silica gel chromatography column purification (utilization contains the hexane solution wash-out of ethyl acetate, and the ratio of described ethyl acetate increases to 4% by 0%), obtains title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.45 (2H, d, J7.2Hz), 7.30-7.2 (3H, m), 7.13-7.09 (1H, dd, J9.0Hz), 6.89 (2H, s+d), 6.64 (1H, t, J2.04Hz), 5.16 (1H, s), 4.96 and 4.56 (2H, ABdd, J12.1,2Hz), 4.11 (1H, m), 3.86 (3H, s), 3.08 (1H, m), 2.1 (1H, m), 1.87-1.1.77 (3H, m) and 1.37 (9H, s).m/z(ES ⁺)506(M+1)。

Embodiment 2

(5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

Will (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 1 for 3-alkene; 2.7g) be dissolved in the methylene dichloride (25ml), in 10 minutes, add anhydrous trifluoroacetic acid (25ml), be evaporated to dried then, (utilization contains the dichloromethane solution wash-out that methanol is closed ammonia (25: 1) to carry out silica gel chromatography, the ratio that described methanol is closed ammonia increases to 5% by 0%), obtain title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.35 (2H, dd, J8.4,1.58Hz), 7.20-7.10 (3H, m), 7.00 (1H, dd, J8.89,1.89Hz), 6.77 (1H, d, J8.97Hz), 6.64 (1H, d, J2.58Hz), 6.12 (1H, t, J2.11Hz), 4.85 and 4.26 (2H, ABdd, J11.91,2.0Hz), 3.75 (4H, s), 3.26 (1H, bd), 2.83 (1H, td, J12.1,2.75Hz), and 2.06-1.63 (4H, m).m/z(ES ⁺)406(M+1)。

The sample of this material with the acetate form by the ether crystallization .p.278-286 ℃.

Embodiment 3

(3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

Will be in the methyl alcohol that contains acetate (9ml) (90ml) (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 2 for 3-alkene; 1.4g), the hydrogenation 16 hours under 50psi of 10% palladium hydroxide/carbon (0.25g) mixture.Filter and evaporating solns, residue obtains title compound by hexane crystallization twice, m.p.91-104 ℃. ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.54 (2H, m), 7.33-7.36 (3H, m)), 6.90 (1H, dd, J8.9,2.07Hz), 6.68 (1H, d, J8.9Hz), 6.17 (1H, d, J2.7Hz), 4.08 (1H, t, J7.8Hz), 3.75 (1H, m), 3.69 (4H, s+d), 3.24 (1H, bd), 3.12 (1H, dd, J10.3,8.03Hz), 2.82 (1H, td, J12.4,2.6Hz), 2.16-1.80 (6H, m), and 1.55-1.64 (2H, m).m/z(ES ⁺)408(M+1)。

Embodiment 4

(±)-(3S*, 5R*, 6S*)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to embodiment 1,2 and 3 similar methods, utilize racemize (5R*, 6S*)-and 3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (3.07g, 0.149mmol) as starting raw material, the preparation title compound; Described starting raw material can be that starting raw material prepares with (±)-1-tert-butoxycarbonyl-2-Phenylpiperidine-3-ketone (illustrative examples 1) according to the described method of illustrative examples 2-6. ¹H NMR (250Mz) δ 1.55-1.64 (2H, m), 1.85 (2H, d, J9.9Hz), 2.10-2.14 (2H, m), 2.80 (1H, m), 3.10-3.28 (2H, m), 3.69 (1H, s), 3.76-3.86 (2H, m), 4.11 (1H, m), 6.17 (1H, d, J2.7Hz), 6.68 (1H, d, J8.9Hz), 6.89-6.94 (1H, m), 7.33-7.36 (3H, m), and 7.50-7.54 (2H, m).m/z(ES ⁺)408(M+1)。

Embodiment 5

(3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-7-(1,2,4-triazolyl-3-methylene radical)-1-oxa--7-azepine-spiral shell [4.5] decane

Will (3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane (embodiment 3,0.15g, 0.369mmol) and K ₂CO ₃(0.254g, dimethyl carboxylic acid amides (2ml) solution 1.84mmol) join N-formyl radical-2-chloro-amidrazone, and (0.055g is in dimethyl carboxylic acid amides (0.5ml) solution 0.405mmol).Solution at room temperature stirred 2 hours, and solution heated 2 hours in 140 ℃ of oil baths.With the mixture of refrigerative solution injection ethyl acetate and water, utilize saturated brine washing organic phase and dry (MgSO ₄).Solvent removed in vacuo, (utilization contains the methyl alcohol of 1-5% to residue: ammonia (SG0.88) (96: 4) methylene dichloride wash-out), obtain title compound containing purifying on the post of silica gel. ¹H NMR (360MHz, CDCl ₃) δ 7.91 (1H, s), 7.55 (2H, bs), 7.34-7.33 (3H, m), 6.92 (1H, d, J8.8Hz), 6.69 (1H, d, J8.9Hz), 6.13 (1H, s), 4.09 (1H, t, 7.89Hz), 3.84 (1H, s), 3.77 (1H, t, J9.15Hz), 3.71 (3H, s), 3.48-3.39 (2H, m), 3.10-3.01 (2H, m), 2.36 (1H, t J12.0Hz), 2.17-2.06 (3H, m), 1.86 (2H, m) and 1.62 (2H, m).m/z(ES ⁺)489(M+1)。

Embodiment 6

(5R, 6S)-3-(2-isopropoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1 and 2, by illustrative examples 13 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.25 (3H, d, J2.6Hz), 1.27 (3H, d, J2.6Hz), 1.66 (1H, m), 1.78 (1H, dd, J13.5,4.5Hz), 1.96 (1H, m), 2.08 (1H, m), 2.83 (1H, dt, J12.6,2.8Hz), 3.30 (1H, d, J10.4Hz), 3.79 (1H, s), 4.33 (1H, dd, J12,2.1Hz), 4.45 (1H, m), 4.86 (1H, dd, J12,2Hz), 6.10 (1H, t, 2.1Hz), 6.69 (1H, d, J2.5Hz), 6.73 (1H, d, J9.1Hz), 6.96 (1H, d, J8.6Hz), 7.17 (3H, m) and 7.37 (2H, d, 6.4Hz).m/z(ES ⁺)434(M+1)。

Embodiment 7

(5R, 6S)-3-(2-allyloxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-pinene hyhrochloride

According to the method for embodiment 1 and 2, by illustrative examples 14 compounds with (5R 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene, can prepare title compound, m.p.234-245 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 1.73 (1H, d, J12.4Hz), 1.81 (1H, m), 1.92 (1H, dt, J13,3.9Hz), 2.03 (1H, m), 2.43 (1H, dd, J16.3,5.9Hz), 2.60 (1H, dd, J16.6,5.3Hz), 3.02 (1H, m), 3.26 (1H, m), 3.89 (1H, d, J13.4Hz), 4.34 (1H, d, J12.4Hz), 4.43 (1H, m), 4.57 (1H, dd, J17,1.6Hz), 4.80 (1H, d, J10.1Hz), 5.34 (1H, m), 5.42 (1H, s), 7.36 (5H, m), 8.99 (1H, bs) and 9.68 (1H, bs).

Embodiment 8

(5R, 6S)-3-(5-trifluoromethoxy-2,3-Dihydrobenzofuranes-7-yl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1 and 2, by illustrative examples 17 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 1.68 (1H, m), 1.80 (1H, dd, J13.3,4.33Hz), 1.95 (1H, m), 2.11 (1H, m), 2.80 (1H, td, J12.5,2.7Hz), 3.17 (2H, t, J8.8Hz), 3.28 (1H, m), 3.80 (1H, s), 4.32 (1H, dd, J2.2,12Hz), 4.63 (2H, t, J8.8Hz), 4.80 (1H, dd, J12,2.1Hz), 6.23 (1H, t, J2.1Hz), 6.41 (1H, d, J1.61Hz), 6.88 (1H, d, 1.2Hz), 7.17 (3H, m) and 7.37 (2H, m).m/z(ES ⁺)418(M+1)。

Embodiment 9

(5R, 6S)-3-(2-methoxyl group-5-(2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1 and 2, by illustrative examples 21 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, DMSO-d ₆) δ 1.64 (1H, m), 1.79 (1H, dt, J13.4,4.2Hz), 2.00 (2H, m), 2.82 (1H, dt, J12.4,2.8Hz), 3.26 (1H, m), 3.70 (3H, s), 3.75 (1H, s), 4.21 (2H, dq, J8.3,2.5Hz), 4.3 (1H, dd, J11.9,2.2Hz), 4.84 (1H, dd, J11.9,2.1Hz), 6.12 (1H, t, J2.1Hz), 6.41 (1H, t, J1.7Hz), 6.72 (2H, d, J1.7Hz), 7.15 (3H, m) and 7.35 (2H, m).m/z(ES ⁺)420(M+1)。

Embodiment 10

(5R, 6S)-3-(2,5-two (2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1 and 2, by illustrative examples 22 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 1.60 (1H, m), 1.80 (1H, dt, J13.5 and 4.3Hz), 1.97 (1H, m), 2.02 (1H, m), 2.83 (1H, dt, J12.4 and 2.7Hz), 3.28 (1H, m), 3.78 (1H, s), 4.08 (2H, m), 4.22 (2H, q, J8Hz), (4.36 1H, dd, J11.9 and 2.2Hz), 4.84 (1H, dd, J11.9 and 1.9Hz), 6.16 (1H, t, J2.1Hz), 6.45 (1H, t, 1.7Hz), 6.72 (2H, d, J1.7Hz), 7.15 (3H, m) and 7.36 (2H, m).m/z(ES ⁺)488(M+1)。

Embodiment 11

(5R, 6S)-3-(2-difluoro-methoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1 and 2, by illustrative examples 23 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, DMSO-d ₆) δ 1.8-1.9 (1H, m), 1.9-2.1 (1H, m), 3.04-3.12 (1H, m), and 3.26-3.36 (1h, m), 4.33 (1H, d, J12Hz), 4.60 (1H, s), 4.91 (1H, d, J12Hz), 6.41 (1H, s), 7.08 (1H, d, J3Hz), 7.16 (1H, t, J7.3Hz), 7.25-7.4 (5H, m), and 7.45-7.47 (2H, m).m/z(ES ⁺)442(M+1)。

Embodiment 12

(5R, 6S)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-pinene hyhrochloride

According to the method for embodiment 1 and 2, by illustrative examples 24 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound.m/z(ES ⁺)474(M+1)。

Embodiment 13

(3S, 5R, 6S)-3-(2-isopropoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 6 compound title compounds, m.p.85-88 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 1.23 (6H, t, J6.4Hz), 1.65 (1H, t, J12.3Hz), 1.80 (2H, d, J11.7Hz), 2.04 (3H, m), 3.06 (2H, q, J9Hz), 3.30 (1H, m), 3.79 (1H, m), 4.15 (1H, t, J7.8Hz), 4.49 (1H, s), 4.55 (1H, m), 6.12 (1H, s), 6.99 (1H, d, 9Hz), 7.06 (1H, m), 7.46 (3H, m), 7.56 (2H, m), 9.0 (1H, bs) and 9.65 (1H, bs).m/z(ES ⁺)436(M+1)。

Embodiment 14

(3S, 5R, 6S)-3-(5-trifluoromethoxy-2,3-Dihydrobenzofuranes-7-yl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 8 compound title compounds, m.p.303-305 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 1.81 (3H, m), 2.0 (3H, m), 3.09 (3H, t, J8.9Hz), 3.22 (2H, m), 3.57 (1H, m), 4.06 (1H, t, J7.9Hz), 4.35 (2H, dt, J8.9,4Hz), 4.46 (1H, s), 6.17 (1H, s), 7.03 (1H, s), 7.47 (3H, m) and 7.54 (2H, m).m/z(ES ⁺)420(M+1)。

Embodiment 15

(3S, 5R, 6S)-3-(2-methoxyl group-5-(2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 9 compound title compounds, m.p.126-128 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 1.77 (and 3H, m), 1.99 (3H, m), 3.17 (1H, t, J10.2Hz), 3.59 (3H, s), 4.09 (1H, t, J7.7Hz), 4.47 (1H, q, J8.9Hz), 6.05 (1H, s), 6.82 (2H, s), 7.47 (3H, m) and 7.57 (2H, m).m/z(ES ⁺)422(M+1)。

Embodiment 16

(3S, 5R, 6S)-3-(2, two (2,2, the 2-trifluoro ethoxy) phenyl of 5-)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 10 compound title compounds, m.p.210-212 ℃. ¹H NMR (250MHz, DMSO-d ₆) δ 1.88 (1H, t, J11.7Hz), 2.04 (2H, m), 2.27 (3H, m), 3.35 (2H, t, J9.9Hz), 3.48 (1H, m), 3.96 (1H, m), 4.37 (1H, t, J7.9Hz), 4.73 (3H, q, J2.9Hz), 7.09 (1H, dd, J9.0,2.9Hz), 7.23 (1H, d, 9.1Hz), 7.67 (3H, m) and 7.77 (2H, m).m/z(ES ⁺)490(M+1)。

Embodiment 17

(3S, 5R, 6S)-3-(2-difluoro-methoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 11 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 1.67 (1H, t, J12Hz), 1.74-1.84 (2H, m), 2.00-2.18 (3H, m), 3.07 (1H, m), 3.14 (1H, t, J8Hz), 3.3 (1H, m), 3.81 (1H, qn, J9Hz), 4.1 5 (1H, t, J8Hz), 4.51 (1H, s), 6.10 (1H, s), 7.16 (1H, t, J7.3 Hz), 7.23 (2H, s), 7.40-7.54 (3H, m), and 7.58-7.60 (2H, m).m/z(ES ⁺)444(M+1)。

Embodiment 18

(3S, 5R, 6S)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 12 compound title compounds, m.p.209-211 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 1.63-1.69 (1H, m), 1.70-1.88 (2H, m), 2.0-2.14 (3H, m), and 3.06-3.12 (2H, m), 3.24-3.32 (1H, m), 3.77 (1H, m), 4.16 (1H, t, J8Hz), 4.51 (1H, s), 4.74-4.78 (2H, m), 6.19 (1H, s), 7.11-7.20 (2H, m), 7.44-7.48 (3H, m), and 7.56-7.58 (2H, m).m/z(ES ⁺)476(M+1)。

Embodiment 19

(3S, 5R, 6S)-3-(2-(2,2,2-trifluoro ethoxy-5-trifluorophenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 1,2 and 3, by illustrative examples 25 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.69 (1H, m), 1.81 (1H, dd, J8.5,8Hz), 1.92-2.07 (2H, m), 2.74 (1H, dt, J12,2.7Hz), 3.11 (1H, t), 3.15 (1H, m), 3.58 (1H, s), 3.73 (1H, qn, J8Hz), 4.02 (1H, t, J8Hz), 4.16 (2H, q, J8Hz), 5.95 (1H, dd, J9.6,3Hz), 6.56-6.69 (2H, m), 7.18-7.27 (3H, m), and 7.39-7.41 (2H, m).m/z(ES ⁺)410(M+1)。

Embodiment 20

(5R, 6S)-3-(5-methylsulfonyl-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 28 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250Mz, CDCl ₃) δ 7.86-7.83 (1H, dd, J8.8,2.4Hz), 7.59-7.58 (1H, d, J2.4Hz), 7.49-7.43 (2H, m), and 7.31-7.20 (3H, m), 7.05-7.02 (1H, d, 8.8Hz), 6.69-6.68 (1H, m), 5.17 (1H, s), 5.00-4.94 (1H, dd, J12.1,2.06Hz), 4.68-4.62 (1H, dd, J12.1,2.06Hz), 4.15-4.11 (1H, m), 3.95 (3H, s), 3.18-3.01 (1H, m), 3.03 (3H, s), 2.13-2.06 (1H, m), 1.92-1.79 (3H, m) and 1.37 (9H, s).m/z(ES ⁺)500(M+1)。

Embodiment 21

(5R, 6S)-3-(5-methylsulfonyl-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 20 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 10.33 (1H, br s), and 7.78-7.73 (1H, dd, J8.7,2.4Hz), 7.55-7.45 (2H, m), 7.32-7.31 (1H, d, J2.4Hz), 7.28-7.21 (3H, m), and 6.92-6.89 (1H, d, J8.7Hz), 6.05-6.03 (1H, m), 5.34 (1H, s), 4.91-4.86 (1H, m), 4.46-4.41 (1H, m), 4.16-4.12 (1H, m), 3.82 (3H, s), 3.53-3.49 (1H, m), 2.97 (3H, s), 2.56-2.50 (1H, m), and 2.1-1.95 (3H, m).m/z(ES ⁺)400(M+1)。

Embodiment 22

(3S, 5R, 6S)-3-(5-methylsulfonyl-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 21 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.72-7.67 (1H, dd, J8.7,2.3Hz), 7.54-7.50 (2H, m), 7.39-7.29 (3H, m), 7.06-7.05 (1H, d, J2.3Hz), 6.85-6.82 (1H, d, J8.7Hz), 4.13-4.07 (1H, m), 3.86-3.74 (1H, m), 3.74 (3H, s), 3.70 (1H, s), 3.27-3.22 (1H, m), 3.19-3.11 (1H, m), 2.87 (3H, m), 2.88-2.78 (1H, m), and 2.14-1.56 (6H, m).m/z(ES ⁺)402(M+1)。

Embodiment 23

(5R, 6S)-3-[2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by 2-(trifluoromethoxy) iodobenzene and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.56-7.43 (3H, m), 7.34-7.17 (6H, m), 6.51-6.49 (1H, m), 5.14 (1H, s), 4.95-4.89 (1H, dd, J12.2,2.0Hz), 4.61-4.55 (1H, dd, J12.2,2.0Hz), 4.18-4.11 (1H, m), and 3.20-3.15 (1H, m), 2.12-2.08 (1H, m), and 1.90-1.78 (3H, m) and 1.35 (9H).m/z(ES ⁺)420(M+1-C4H8)。

Embodiment 24

(5R, 6S)-3-[2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 23 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.39-7.35 (2H, m), 7.25-7.06 (6H, m), 6.90-6.87 (1H, m), and 6.04-6.03 (1H, m), 4.87-4.82 (1H, dd, J12.0,2.0Hz), 4.38-4.33 (1H, dd, J12.0,2.0Hz), 3.79 (1H, s), 3.31-3.25 (1H, m), (3.05-2.95 1H, br s), and 2.85-2.75 (1H, m), 2.14-1.94 (2H, m), and 1.85-1.64 (2H, m).m/z(ES ⁺)376(M+1)。

Embodiment 25

(3S, 5R, 6S)-3-[2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 24 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 9.76 (1H, br s), 9.04 (1H, br s), 7.62-7.51 (5H, m), and 7.27-7.25 (2H, m), 7.12-7.07 (1H, m), 6.23-6.21 (1H, d, J7.5Hz), 4.52 (1H, s), 4.15-4.11 (1H, m), 3.80-3.74 (1H, m), 3.39-3.26 (1H, m), and 3.22-3.17 (1H, m), 3.10-3.04 (1H, m), 2.14-2.08 (3H, m), and 1.83-1.67 (3H, m).m/z(ES ⁺)378(M+1)。

Embodiment 26

(5R, 6S)-3-[2-cyclobutoxy group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 29 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.47-7.45 (2H, m), 7.28-7.20 (3H, m), 7.06-7.02 (1H, m), 6.96-6.94 (1H, m), 6.70-6.67 (1H, d, J8.9Hz), 6.64-6.63 (1H, m), 5.15 (1H, s), 5.00-4.94 (1H, m), and 4.66-4.59 (2H, m), 4.15-4.11 (2H, m), 3.10-3.08 (1H, m), 2.48-2.44 (2H, m), 2.20-2.10 (3H, m), 1.88-1.67 (4H, m) and 1.36 (9H, s).

Embodiment 27

(5R, 6S)-3-[2-cyclobutoxy group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 26 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.38-7.34 (2H, m), 7.23-7.10 (3H, m), 6.97-6.92 (1H, m), 6.68-6.67 (1H, d, J2.3Hz), 6.60-6.56 (1H, d, J9.0Hz), 6.16-6.14 (1H, m), 4.90-4.85 (1H, dd, J12.0,2.1Hz), 4.60-4.49 (1H, m), 4.33-4.27 (1H, dd, J12.0,2.1Hz), 3.76 (1H, s), 3.31-3.24 (1H, m), 2.87-2.76 (1H, m), 2.48-2.36 (2H, m), and 2.19-1.62 (8H, m).m/z(ES ⁺)446(M+1)。

Embodiment 28

(3S, 5R, 6S)-3-[2-cyclobutoxy group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 27 compound title compounds. ¹H NMR (360MHz, DMSO-d ₆) δ 9.69 (1H, br s), and 9.00 (1H, br s) 7.58-7.57 (2H, m), 7.48-7.43 (3H, m), and 7.07-7.05 (1H, m), 6.81-6.79 (1H, d, J9.0Hz), 6.13 (1H, s), 4.67-4.63 (1H, m), 4.51-4.48 (1H, m), and 4.19-4.15 (1H, m), 3.82-3.78 (1H, m), 3.41-3.36 (1H, m), 3.09-3.04 (2H, m), 2.40-2.36 (2H, m), 2.12-1.96 (5H, m), and 1.80-1.60 (5H, m).m/z(ES ⁺)448(M+1)。

Embodiment 29

(5R, 6S)-3-(2-(2-fluoro oxyethyl group)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 31 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.36 (9H, s), 1.84 (3H, m), 2.09 (1H, m), 3.12 (1H, dt, J12Hz, J 5.1Hz), 4.11 (1H, m), 4.18 (1H, q, J4.6Hz), 4.27 (1H, q, J4.7Hz), 4.60 (1H, dd, J12.2Hz, J2.1Hz), 4.69 (1H, m), 4.82 (1H, m), 4.95 (1H, dd, J12.3Hz, J2.1Hz), 5.14 (1H, s), 6.65 (1H, t, J2.1Hz), 6.85 (1H, d, J9Hz), 6.95 (1H, d, J2.4Hz), 7.09 (1H, d, J8.1Hz), 7.24 (3H, m) and 7.45 (2H, d, J7.5Hz).

Embodiment 30

(5R, 6S)-3-(2-(2-fluoro oxyethyl group)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-pinene hyhrochloride

In 1N methyl alcohol HCl, stirred embodiment 29 compounds 15 hours at ambient temperature.Vacuum evaporating solvent is distributed in unsaturated carbonate aqueous solutions of potassium (50ml) with residue and ethyl acetate (between 3 * 50ml), is utilized the organic fraction of salt solution (50ml) washing merging, dry (MgSO ₄) and vacuum-evaporation.Purifying on silica gel is used in 10% methanol-eluted fractions in the methylene dichloride, obtains title compound, is white solid (180mg, 68%). ¹H NMR (360MHz, CDCl ₃) δ 1.86 (2H, m), 2.02 (2H, m), 3.14 (1H, m), 3.40 (1H, m), 4.21 (1H, m), 4.28 (1H, m), 4.33 (1H, d, J12.5Hz), 4.58 (1H, d, J11.7Hz), 4.71 (1H, m), 4.84 (1H, m), 4.94 (1H, d, J12.4Hz), 6.44 (1H, s), 6.94 (1H, d, J2.5Hz), 7.08 (1H, d, J9.1Hz), 7.30 (3H, m), 7.45 (2H, d, J6.6Hz), 9.07 (1H, broad peaks) and 9.70 (1H, broad peaks).m/z(ES ⁺)438(M+1)。

Embodiment 31

(3S, 5R, 6S)-3-(2-(2-fluoro oxyethyl group)-5-(trifluoromethoxy)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 30 compound title compounds. ¹H NMR (500MHz, DMSO-d ₆300K) δ 1.70 (1H, m), 1.80 (2H, m), 1.95 (1H, m), 2.09 (2H, m), 3.07 (2H, m), 3.73 (1H, d, J12.8Hz), 3.82 (1H, m), 4.17 (1H, m), 4.22 (1H, m), 4.33 (1H, d, J11.3Hz), 4.51 (1H, d, J11.6Hz), 4.65 (1H, m), 4.75 (1H, m), 7.01 (1H, d, J9Hz), 7.12 (1H, d, J10.8Hz), 7.18 (2H, m), 7.39 (1H, m), 7.46 (2H, m), 7.55 (1H, d, J7.4Hz), 8.93 (1H, m) and 9.53 (1H, m).m/z(ES ⁺)440(M+1)。

Embodiment 32

(5R, 6S)-3-(2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 33 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 1.36 (9H, s), 1.86 (2H, m), 2.12 (1H, m), 3.22 (1H, m), 4.12 (1H, q, J7.1Hz), 4.18 (1H, m), 4.37 (1H, dd, J12.6Hz, J2.2Hz), 4.7 (1H, dd, J12.6Hz, J2.0Hz), 5.1 (1H, s), 5.28 (1H, d, J11.1Hz), 5.61 (1H, d, J17.4Hz), 6.03 (1H, t, J2.1Hz), 6.66 (1H, m), 6.85 (1H, m), 7.11 (1H, m), 7.28 (3H, m), 7.46 (2H, m) and 7.50 (1H, d, J8.6Hz).

Embodiment 33

(5R, 6S)-3-(2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 30, by embodiment 32 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 1.67 (1H, m), 1.81 (2H, m), 2.83 (1H, dt, J3Hz, J12.3Hz), 3.26 (1H, m), 3.74 (1H, s), 4.28 (1H, dd, J2.4Hz, J12.6Hz), 4.68 (1H, dd, J2.2Hz, J12.4Hz), 5.06 (1H, dd, J1.2Hz, J11Hz), 5.47 (1H, dd, J1.1Hz, J17.3Hz), 5.57 (1H, t, J2.2Hz), 5.92 (1H, m), 6.60 (1H, s), 7.01 (1H, d, J8.6Hz), 7.28 (4H, m) and 7.40 (2H, m).

Embodiment 34

(3S, 5R, 6S)-3-(2-ethyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 33 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 1.12 (3H, t, J7.5Hz), 1.61 (2H, m), 1.90 (2H, m), 2.12 (2H, m), 2.58 (2H, q, J7.6Hz), 2.77 (1H, dt, J2.5Hz, J12.2Hz), 3.16 (1H, m), 3.27 (1H, m), 3.61 (1H, m), 3.73 (1H, s), 4.05 (1H, t, J8.1Hz), 4.56 (1H, broad peaks), 5.88 (1H, d, J1.63Hz), 6.85 (1H, dd, J1.2Hz, J8.3Hz), 7.03 (1H, d, J8.4Hz), 7.36 (3H, m) and 7.54 (2H, m).m/z(ES ⁺)406(M+1)。

Embodiment 35

(5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 34 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H?NMR(360MHz,CDCl ₃)δ1.33(9H,s),1.65(1H,m),1.76(2H,m),2.08(1H,m),3.11(1H,m),4.08(1H,m),4.60(1H,dd,J12.2?Hz,J2Hz),4.92(1H,dd,J12.1Hz,J1.8Hz),5.08(1H,s),5.1(2H,q,J11.5Hz),6.65(1H,s),6.94(2H,d,J8.9Hz),7.08(1H,d,J9Hz),7.18(2H,t,J8.1Hz),7.25(3H,m),7.38(5H,m)。

Embodiment 36

(5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 30, by embodiment 35 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 1.70 (2H, m), 1.94 (1H, m), 2.05 (1H, m), 2.77 (1H, td, J12.5Hz, J2.8Hz), 2.93 (1H, broad peaks), 3.25 (1H, m), 3.70 (1H, s), 4.34 (1H, dd, J14.5Hz, J2Hz), 4.99 (1H, s), 6.14 (1H, t, J2Hz), 6.67 (1H, d, J2.7Hz), 6.80 (1H, d, J9Hz), 6.98 (1H, dd, J9Hz, J2Hz), 7.17 (3H, m), and 7.26-7.47 (7H, m).m/z(ES ⁺)482(M+1)。

Embodiment 37

(3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 36 compound title compounds. ¹H NMR (360MHz, DMSO-d ₆) δ 1.67 (1H, t, J12.1Hz), 1.80 (2H, d, J11.5Hz), 2.05 (3H, m), 3.06 (2H, t, J8.1Hz), 3.30 (1H, m), 3.77 (1H, m), 4.13 (1H, t, J7.8Hz), 4.48 (1H, m), 6.03 (1H, d), 6.80 (1H, d, J8.8Hz), 6.92 (1H, dd, J8.9Hz), 7.45 (3H, m) and 7.56 (2H, m).m/z(ES ⁺)394(M+1)。

Embodiment 38

(3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

To (3S, 5R, 6S)-(embodiment 37, and 290mg adds the yellow soda ash solid in water 0.7mmol) (3ml) solution, be 10 until pH for 3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride.Add methylene dichloride (2ml) in this solution, (170mg, 0.8mmol), reaction was stirred 16 hours at ambient temperature then to add di-t-butyl carbonic acid hydrogen ester.Utilize water (40ml) diluted reaction mixture, separate organic layer.Utilize salt solution (50ml) washing organic layer, dry (MgSO ₄), vacuum-evaporation obtains title compound, is white solid (320mg, 96%). ¹H NMR (360MHz, CDCl ₃) δ 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m), 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J7.2Hz), 3.92 (1H, m), 3.98 (1H, d, J13.2Hz), 4.23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J8.5Hz), 6.94 (2H, m), 7.25 (1H, m), 7.31 (2H, m) and 7.55 (2H, d, J7.8Hz).

Embodiment 39

(3S, 5R, 6S)-3-(2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 33, prepare title compound by embodiment 144 compounds and vinyl tributyl tin. ¹H NMR (250MHz, CDCl ₃) δ 1.76 (2H, m), 2.10 (2H, m), 2.43 (1H, m), 2.90 (1H, m), 3.69 (2H, m), 4.0 (1H, d, J13.5Hz), 4.12 (1H, d, J7.1Hz), 4.22 (1H, m), 5.18 (1H, s), 5.38 (1H, dd, J10.9Hz, J1.2Hz), 5.59 (1H, dd, J17.2Hz, J1.2Hz), 6.96 (1H, m), 7.04 (1H, m), 7.15 (1H, m), 7.32 (3H, m), 7.45 (1H, d, J8.2Hz) and 7.56 (2H, m).

Embodiment 40

(3S, 5R, 6S)-3-(2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 2, by embodiment 39 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 1.62 (2H, d, J11.1Hz), 1.88 (2H, d, J9.5Hz), 2.10 (2H, m), 2.78 (1H, dt, J12.2Hz, J2.5Hz), 3.17 (1H, m), 3.25 (1H, dt, J9.9Hz, J2.1Hz), 3.66 (1H, m), 3.72 (1H, s), 4.06 (1H, d, J8Hz), 5.29 (1H, dd, J10.9Hz, J1.3Hz), 5.49 (1H, dd, J17.2Hz, J1.3Hz), 6.04 (1H, d, J1.5Hz), 6.83 (1H, m), 6.92 (1H, d, J7.6Hz), 7.36 (4H, m) and 7.50 (2H, m).m/z(ES ⁺)404(M+1)。

Embodiment 41

(5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by 2-methoxyl group chlorobenzene and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.27 (9H, s), 1.75-1.90 (3H, m), 2.09-2.12 (1H, m), 3.07-3.14 (1H, m), 3.86 (3H, s), 4.11-4.15 (1H, m), (4.61 1H, dd, J12.0 and 2.1Hz), 4.97 (1H, dd, J12.0 and 2.1Hz), 5.16 (1H, s), 6.19 (1H, s), 6.88-6.92 (2H, m), 7.04 (1H, d, J8.1Hz), 7.16-7.27 (4H, m) and 7.46 (2H, d, J7.4Hz).

Embodiment 42

(5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 41 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 2.02-2.23 (4H, m), 3.27 (1H, t, J12.7Hz), 3.57-3.60 (1H, m), 3.77 (3H, s), 4.49 (1H, s), 4.51 (1H, d, J12.3Hz), 4.93 (1H, d, J12.3Hz), 6.31 (1H, s), 6.89 (2H, d, J4.4Hz), 6.99 (1H, d, J8.3Hz), 7.26-7.38 (4H, m) and 7.46 (2H, d, 7.4Hz).

Embodiment 43

(3S, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 42 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 1.87-1.95 (3H, m), 2.07-2.20 (3H, m), 3.23 (1H, t, J12.6Hz), and 3.33-3.38 (1H, m), 3.49-3.53 (1H.m), 3.67 (3H, s), 4.14 (1H, t, J7.8Hz), 4.42 (1H, s), 6.49 (1H, d, J7.7Hz), 6.79 (1H, t, J7.4Hz), 6.95 (1H, d, J7.4Hz), 7.19 (1H, t, J8.7Hz), and 7.48-7.54 (5H, m).

Embodiment 44

Will (5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 35,3.88g) are dissolved in ethyl acetate (15ml) and the methyl alcohol (15ml) for 3-alkene.Add palladium hydroxide/carbon (1.00g), suspension stirred 72 hours down at hydrogen atmosphere (50psi).Filtering mixt, solvent evaporated under reduced pressure.Residue is by middle hydraulic fluid phase silica gel chromatography purifying, utilize hexane/ethyl acetate (75: 25) wash-out, obtain (3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (191mg) ¹H NMR (250MHz, CDCl ₃) δ 7.70 (2H, d, J7.3Hz), 7.33 (2H, t, J7.3Hz), 7.26 (1H, d, J7.3Hz), 7.05 (1H, br s), 6.96 (2H, m), 6.82 (1H, d, J9.4Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m); With 1.50 (9H, s). and (3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (2.3g), ¹H NMR (360MHz, CDCl ₃) δ 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m), 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J7.2Hz), 3.92 (1H, m), 3.98 (1H, d, J13.2Hz), 4.23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J8.5Hz), 6.94 (2H, m), 7.25 (1H, m), 7.31 (2H, m) and 7.55 (2H, d, J7.8Hz).

Embodiment 45

(5R, 6S)-3-(2-benzyloxy-5-(trifluoromethyl) phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 36 compounds and (5R, 6S)-3-tri-tert stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.33 (9H, s), 1.72-1.83 (3H, m), 2.03-2.11 (1H, m), 3.06-3.15 (1H, m), and 4.07-4.11 (1H, m), 4.64 (1H, dd, J11.5,15.5Hz), 4.96 (1H, dd, J2,12Hz), 5.09 (1H, s), 5.16 (2H, dd, J11.5,15.5Hz), 6.66 (1H, t, J2Hz), 7.02 (1H, d, 8.5Hz), 7.16-7.27 (3H, m), 7.32 (1H, d, J2Hz), and 7.34-7.49 (8H, m).m/z(ES ⁺)566(M+1)。

Embodiment 46

(3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 44, from embodiment 45 compounds, the preparation title compound.(3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, ¹H NMR (250MHz, CDCl ₃) δ 1.51 (9H, s), 1.58-1.75 (2H, m), 1.82-1.88 (2H, m), 2.33 (1H, dt, J4,13Hz), 2.70 (1H, dd, J8.6,13Hz), 2.79 (1H, dt, J3,13Hz), 3.84 (1H, qn), 3.93-3.97 (2H, m), 4.31 (1H, t, J9Hz), 5.44 (1H, s), 6.89 (1H, d, J9Hz), 7.23-7.35 (5H, m), and 7.58-7.60 (2H, m).m/z(ES ⁺)478(M+1)。(3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, ¹H NMR (360MHz, CDCl ₃) δ 1.34 (9H, s), 1.72-1.82 (3H, m), 2.10-2.21 (2H, m), 2.53 (1H, dd, J9,13Hz), 2.79-2.88 (1H, m), 3.65 (1H, qn, J8.6Hz), 3.94-3.98 (2H, m), 4.24 (1H, dd, J7,9Hz), 5.33 (1H, s), 6.83 (1H, d, J9Hz), 7.01 (1H, s), 7.23-7.34 (5H, m) and 7.55 (2H, d, J7.5Hz).m/z(ES ⁺)478(M+1)。

Embodiment 47

(1ml) joins (3S with trifluoroacetic acid, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(illustrative examples 37,240mg is in methylene dichloride 0.46mmol) (10ml) cooling (0 ℃) solution for the 3-alkanol.Solution stirred 10 minutes down at 0 ℃, at room temperature stirred 1 hour.Solvent evaporated under reduced pressure adds the unsaturated carbonate aqueous solutions of potassium.Utilize ethyl acetate (2 * 40ml) extraction mixtures, the organic fraction that utilizes salt solution (20ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes methylene chloride/ammonia (160: 8: 1) wash-out by the silica gel chromatography column purification, obtain (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-alkene (29mg, 16%), ¹H NMR (360MHz, CDCl ₃) δ 1.56-1.65 (2H, m), 2.05-2.12 (1H, m), 2.22-2.26 (1H, m), 2.41 (1H, dd, J14.0,1.6Hz), 2.76 (1H, dd, J14.0,1.9Hz), 2.87 (1H, dt, J12.2,2.7Hz), 3.23-3.28 (1H, m), 3.59 (1H, s), 3.79 (3H, s), 6.58 (1H, d, J2.7Hz), 6.98 (1H, d, J8.9Hz), 6.83-6.85 (1H, m), 7.13 (1H, s), 7.15-7.26 (3H, m), and 7.43-7.45 (2H, m), m/z (ES ⁺) 506 (M+1) and (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (69mg, 37%), ¹H NMR (250MHz, CDCl ₃) δ 7.45 (2H, d, J7.2Hz), 7.30-7.2 (3H, m), 7.13-7.09 (1H, dd, J9.0Hz), 6.89 (2H, s+d), 6.64 (1H, t, J2.04Hz), 5.16 (1H, s), 4.96 and 4.56 (2H, ABdd, J12.1 and 2Hz), 4.11 (1H, m), 3.86 (3H, s), 3.08 (1H, m), 2.1 (1H, m), 1.87-1.77 (3H, m) and 1.37 (9H, s), m/z (ES ⁺) 506 (M+1).

Embodiment 48

(5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene and (3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

With three silicoethanes (100 (1,0.6mmol) join (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 47 for 2-alkene, 14mg, 0.03mmol) trifluoroacetic acid (1ml) solution in, mixture at room temperature stirred 2 hours.(100 (1,0.6mmol), mixture at room temperature stirred 15 hours to add three other silicoethanes.Solvent evaporated under reduced pressure, residue and toluene (2 * 10ml) azeotropic.Add saturated aqueous sodium carbonate, utilize methylene dichloride (3 * 10ml) extraction mixtures, the organic fraction that utilizes salt solution (20ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes methylene chloride/ammonia (120: 8: 1) wash-out by preparation property silica gel thin-layer chromatography purifying, obtains jelly (6mg).The HPLC of this jelly analyzes [HIPRB post (250 * 4.6mm); In 25mM KH ₂PO ₄In 40%MeCN, 0.2% triethylamine, pH3.1,210nm] show that it contains (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene, (3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane and (3R, 5R, 6S)-mixture (ratio is 1.5: 2.5: 1) of 3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

Embodiment 49

With three silicoethanes (252 (1,1.6mmol) join (5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 47 for 3-alkene, 32mg, 0.08mmol) trifluoroacetic acid (2ml) solution in, mixture stirred 16 hours down at 50 ℃.Solvent evaporated under reduced pressure, residue and toluene (2 * 10ml) azeotropic.Add saturated aqueous sodium carbonate, utilize methylene dichloride (4 * 20ml) extraction mixtures, the organic fraction that utilizes salt solution (20ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes methylene chloride/ammonia (120: 8: 1) wash-out by preparation property silica gel thin-layer chromatography purifying, obtains jelly (6mg).The HPLC of this jelly analyzes [HIPRB post (250 * 4.6mm); In 25mM KH ₂PO ₄In 40%MeCN, 0.2% triethylamine, pH3.1,210nm] show that it contains (3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane and (3R, 5R, 6S)-mixture (ratio is 2: 1) of 3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

Embodiment 50

(3S, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Under 0 ℃, (10ml, (42ml, 0.3mmol) (19mg is in methylene dichloride 0.043mmol) (2ml) with illustrative examples 39 0.14mmol) to join the triethylamine that is stirring with methylsulfonyl chloride.Mixture is warmed to room temperature, stirred 18 hours, utilize methylene dichloride (20ml) dilution, utilize hydrochloric acid (2M, 10ml) and saturated aqueous sodium carbonate (10ml) washing, drying (MgSO ₄), solvent evaporated under reduced pressure.Residue is collected in the tetrahydrofuran (THF) (3ml), utilize sodium hydride (60% oily dispersion liquid, 100mg) reflux is 18 hours, the cooling, be injected into hydrochloric acid soln (2M, 20ml) in, utilize ethyl acetate (2 * 20ml) extraction.The organic fraction that utilizes saturated sodium-chloride water solution (10ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/ethyl acetate (80: 20) wash-out by the silica gel chromatography purifying, obtains title compound, is 1: 33R and 3S epimer mixture (8mg, 44%). ¹H NMR (360MHz, CDCl ₃) δ 7.61 (2H, d, J7.6Hz, 3R isomer), (7.57 2H, d, J7.5Hz, 3S isomer), (7.05-7.34 5H, m, 3R and 3S isomer), 6.80-6.98 (2H, m, 3R and 3S isomer), 5.37 (1H, s, the 3R isomer), 5.25 (1H, s, 3S isomer), (4.31 1H, t, J7.4Hz, 3R isomer), (4.21 1H, t, J7.2Hz, 3S isomer), (3.95-4.04 1H, m, 3R and 3S isomer), 3.82 (3H, s, the 3R isomer), 3.81 (3H, s, the 3S isomer), 3.64-3.81 (2H, m, 3R and 3S isomer), (2.85 1H, dt, J5.9 and 12.1Hz, 3S isomer), 2.67 (1H, dt, J4.9,12.7Hz, the 3R isomer), 2.59 (1H, dd, J7.3 and 12.7Hz, the 3R isomer), 2.37 (1H, dd, J8.0 and 12.6Hz, the 3S isomer), 2.21 (1H, dd, J9.1,12.6Hz, the 3S isomer), 2.08-2.23 (1H, m, 3R and 3S isomer), 1.93 (1H, dd, J10.4,12.4Hz, the 3R isomer), 1.64-1.78 (3H, m, 3R and 3S isomer), 1.47 (9H, s, 3R isomer), with 1.38 (9H, s, 3S isomer).m/z(ES ⁺)424(M+1)。

Embodiment 51

(3S, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

Method according to embodiment 2, by embodiment 50 compound title compounds, be (3S, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane and (3R, 5R, 6S)-mixture of 3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane. ¹H NMR (360MHz, CDCl ₃) δ 7.51-7.59 (2H, m, 3R and 3S isomer), 7.32-7.45 (3H, m, 3R and 3S isomer), 7.05-7.13 (1H, m, 3R and 3S isomer), 6.97 (1H, d, J7.6Hz, 3R isomer), 6.81 (1H, t, J7.5Hz, the 3R isomer), 6.71-6.82 (1H, m, 3R and 3S isomer), (6.69 1H, t, J7.5Hz, 3S isomer), 6.43 (1H, d, J7.6Hz, 3S isomer), 4.09 (1H, t, J7.8Hz, the 3S isomer), 3.94 (1H, t, J7.6Hz, the 3R isomer), 3.67-3.87 (1H, m, 3R and 3S isomer), 3.68 (4H, s, the 3S isomer), 3.63 (3H, s, 3R isomer), (3.53 1H, s, 3R isomer), 3.17-3.25 (1H, m, 3R and 3S isomer), 2.75-2.84 (1H, m, 3R and 3S isomer), and 1.55-2.37 (8H, m, 3R and 3S isomer).m/z(ES ⁺)324(M+1)。

Embodiment 52

(5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-2-ketone

Under 60 ℃, utilize that nitrogen will be in toluene (10ml) (5R, 6S)-7-tert-butoxycarbonyl-6-phenyl-3-tributyl stannyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-2-ketone (illustrative examples 10; 538mg, 0.87mmol), 2-bromo-4-trifluoromethoxy methyl-phenoxide (illustrative examples 12,244mg, 0.90mmol) and lithium chloride (230mg, 5.4mmol) mixture outgased 30 minutes.Add tetrakis triphenylphosphine palladium (O) (100mg), mixture heated 16 hours under nitrogen.Cooling mixture filters solvent evaporated under reduced pressure.Residue is dissolved in the acetonitrile (50ml), and (4 * 20ml) washings utilize 10% methyl alcohol potassium fluoride solution to handle then to utilize hexane.Stirred the mixture 30 minutes, and filtered and solvent evaporated under reduced pressure.Residue is distributed between saturated sodium bicarbonate aqueous solution (50ml) and the ethyl acetate (50ml) dry (Na ₂SO ₄) organic phase, solvent evaporated under reduced pressure.Residue is carried out the silica gel chromatography purifying, obtain title compound, be jelly (200mg, 0.39mmol, 44%). ¹H NMR (250MHz, CDCl ₃) δ 8.60 (and 1H, s), 8.02 (1H, d), 7.40 (2H, m), 7.26 (4H, m), 6.93 (1H, d, J9.11Hz), 5.28 (1H, s), 4.20 (1H, m), 3.91 (3H, s), 3.18 (1H, m), 2.32 (1H, m), 1.89 (3H, m) and 1.39 (9H, s).

Embodiment 53

(3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone

Utilize the nitrogen will be in N, (5R in N '-dimethyl carboxylic acid amides (1ml), 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 52 for 3-alkene-2-ketone, 100mg, 0.19mmol) and acid chloride (10mg) mixture outgased 30 minutes.(42mg, 0.50mmol), mixture heated 16 hours down at 80 ℃ to add potassium formiate.Mixture is injected in the water (10ml), utilizes ethyl acetate (2 * 10ml) extractions.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue is carried out the silica gel chromatography purifying, obtain title compound, be colorless solid (44mg, 0.08mmol, 44%). ¹H NMR shows that it is 1: 1 (3S, 5R, 6S)-and (3R, 5R, 6S)-mixture of steric isomer, by utilizing being prepared property of KR60 post liquid chromatography purifies and separates, utilization contains the 5% ethanol/hexane wash-out of 0.1%DEA, obtains (3R, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.14 (1H, dd, J2.59,8.96Hz), 7.02 (1H, d, J2.59Hz), 6.88 (1H, d, J8.96Hz), 5.35 (1H, s), 4.00-4.05 (1H, m), 3.85 (3H, s), 3.70 (1H, t, J11.02Hz), 2.70-2.97 (2H, m), and 2.38-2.50 (1H, m), 2.22 (1H, dd, J11.32,12.97Hz), 1.72-1.92 (3H, m) and 1.46 (9H, s); And title compound (3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone, ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.13 (1H, dd, J2.91,8.97Hz), 6.90 (1H, d, J2.91Hz), 6.83 (1H, d, J8.97Hz), 5.31 (1H, br s), 4.02-4.10 (1H, m), 3.92 (1H, t, J10.56Hz), 3.64 (3H, s), 2.91-3.02 (1H, m), 2.67 (1H, dd, J10.04,12.98Hz), 2.29-2.52 (2H, m), 1.80-1.87 (3H, m) and 1.36 (9H, s).

Embodiment 54

(3S, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-keto hydrochloride

According to the method for embodiment 2, by embodiment 53 compound title compounds, m.p.248-250 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 9.90 (1H, br s), 9.30 (1H, br s), 7.42-7.60 (5H, m), 7.19 (1H, d, J7.17Hz), 6.93 (1H, d, J7.17Hz), (4.70 1H, br s), and 4.42-4.48 (1H, m), 3.30-3.33 (1H, m), 3.11-3.15 (1H, m), 2.29-2.36 (1H, m), and 1.94-2.03 (5H, m).m/z(ES ⁺)422(M+1)。Measured value: C, 55.94; H, 5.06; N, 3.06.C ₂₂H ₂₂F ₃NO ₄.HCl.H ₂O theoretical value: C, 55.53; H, 5.30; N, 2.94%.

Embodiment 55

(5R, 6S)-N-{4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl } trifluoroacetamide

According to the method for embodiment 1, by illustrative examples 47 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.83 (1H, br s), 7.53 (1H, dd, J8.9,2.7Hz), 7.47 (2H, m), 7.23 (3H, m), 7.13 (1H, d, J2.7Hz), 6.97 (1H, d, J8.9Hz), 6.67 (1H, t, J2.1Hz), 5.15 (1H, s), 4.94 (1H, dd, J12,2.1Hz), 4.58 (1H, dd, J12,2.1Hz), 4.12 (1H, m), 3.87 (3H, s), 3.11 (1H, m), 2.11 (1H, m), 1.88-1.82 (3H, m) and 1.36 (9H, s).m/z(ES ⁺)533(M+1)。

Embodiment 56

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] trifluoroacetamide

According to the method for embodiment 2, by embodiment 55 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.94 (1H, br s), 7.41 (1H, dd, J8.9,2.7Hz), 7.36 (2H, m), 6.91 (1H, d, J2.7Hz), 6.80 (1H, d, J 8.9Hz), 6.18 (1H, t, J2.0Hz), 4.83 (1H, dd, J11.8,2.0Hz), 4.32 (1H, dd, J11.8,2.0Hz), 3.78 (3H, s), 3.77 (1H, m), 3.27 (1H, m), 2.81 (1H, m), 2.20-1.95 (2H, m), 1.88-1.79 (2H, m) and 1.69 (1H, m).m/z(ES ⁺)433(M+1)。

Embodiment 57

(3S, 5R, 6S)-and N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] trifluoroacetamide

According to the method for embodiment 3, by embodiment 56 compound title compounds. ¹H NMR (360MHz, DMSO-d ₆) δ 7.44 (2H, m), 7.32 (1H, dd, J8.8,2.5Hz), 7.27-7.16 (5H, m), 6.87 (1H, d, J8.8Hz), 6.78 (1H, d, J2.5Hz), 3.97 (1H, t, J7.5Hz), 3.64 (3H, s), 3.63 (1H, m), 3.01 (1H, m), 2.93 (1H, m), 1.89-1.73 (3H, m), and 1.59-1.48 (2H, m).m/z(ES ⁺)435(M+1)。

Embodiment 58

(5R, 6S)-3-(5-amino-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 43 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.46 (2H, m), 7.23 (3H, m), 6.79 (1H, d, J8.7Hz), 6.64 (2H, m), 6.43 (1H, d, J2.8Hz), 5.13 (1H, s), 4.92 (1H, dd, J12.0,2.0Hz), 4.56 (1H, dd, J12.0,2.0Hz), 4.12 (1H, m), 3.78 (3H, s), 3.12 (1H, m), 1.87-1.81 (4H, m) and 1.36 (9H, s).m/z(ES ⁺)437(M+1)。

Embodiment 59

(3S, 5R, 6S)-3-(5-amino-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 58 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 7.52 (2H, m), 7.27 (3H, m), 6.68 (1H, d, J8.4Hz), 6.55 (1H, d, J2.7Hz), 6.52 (1H, dd, J8.4,2.7), 5.25 (1H, s), 4.18 (1H, m), 4.00 (1H, m), 3.77 (1H, m), 3.74 (3H, s), 3.67 (1H, m), 2.91 (1H, m), 2.35 (1H, m), 2.38-2.32 (2H, m), 2.20-2.09 (3H, m) and 1.38 (9H, s).m/z(ES ⁺)439(M+1)。

Embodiment 60

N-{4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl } carboxylamine (3S, 5R, 6S)-methyl ester

With salt of wormwood (200mg, 1.4mmol) and Methyl Chloroformate (70 μ L, 86mg, 0.9mmol) join (3S, 5R, 6S)-3-(5-amino-2-p-methoxy-phenyl)-6-phenyl-(embodiment 59,100mg for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 0.23mmol) acetone (4ml) solution in, mixture at room temperature stirs and spends the night.Solvent evaporated under reduced pressure adds entry (50ml).Utilize the ethyl acetate extraction mixture, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (80: 20) wash-out by quick silica gel chromatography, obtains title compound, is solid (80mg, 70%). ¹H NMR (250MHz, CDCl ₃) δ 7.56 (2H, m), 7.35-7.21 (4H, m), 7.01 (1H, d, J2.5Hz), 6.79 (1H, d, J8.8Hz), 6.60 (1H, br s), 5.27 (1H, s), 4.22 (1H, m), 4.00 (1H, m), 3.79 (3H, s), 3.74 (3H, s), 3.81-3.66 (2H, m), 2.89 (1H, m), 2.39-2.06 (3H, m), 1,37 (3H, m) and 1.38 (9H, s).m/z(ES ⁺)497(M+1)。

Embodiment 61

N-{4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl }-N-(methyl) carboxylamine (3S, 5R, 6S)-methyl ester

With sodium hydride (60% mineral oil dispersion liquid, 16mg, 0.4mmol) join N-{4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl } carboxylamine (3S, 5R, 6S)-(embodiment 60 for methyl ester, 80mg, 0.16mmol) DMF (8ml) solution in, mixture at room temperature stirred 30 minutes, added methyl iodide (50 μ L, 114mg 0.8mmol) stirred the mixture 3 hours.Add entry (100ml), utilize the ethyl acetate extraction mixture.The organic fraction that utilizes water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (70: 30) wash-out by quick silica gel chromatography, obtains title compound, is colourless foam shape thing (67mg, 83%). ¹H NMR (360MHz, CDCl ₃) δ 7.56 (2H, m), 7.32-7.21 (4H, m), 7.02 (1H, br s), 6.81 (1H, d, J9.2Hz), 5.02 (1H, s), 4.20 (1H, m), 4.00 (1H, m), 3.81 (3H, s), 3.77-3.67 (2H, m), 3.62 (3H, br s), 3.2 (3H, s), 2.87 (1H, m), 2.35 (1H, m), 2.22-2.08 (2H, m), 1.74 (3H, m) and 1.36 (9H, s).m/z(ES ⁺)511(M+1)。

Embodiment 62

N-[4-methoxyl group-3-[6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) carboxylamine (3S, 5R, 6S)-methyl ester

According to the method for embodiment 2, prepare title compound by embodiment 61 mixtures. ¹HNMR(360MHz,CDCl ₃)δ7.49(2H,m),7.33-7.26(3H,m),6.91(1H,br?s),6.69(1H,d,J8.7Hz),6.1?5(1H,m),4.09(1H,m),3.79(1H,m),3.69(3H,s),3.68(1H,s),3.64(3H,brs),3.25-3.15(2H,m),3.08(3H,s),2.28(1H,m),2.15-2.02(2H,m),1.90-1.83(2H,m),1.62-1.55(2H,m),1.26(1H,m).)。m/z(ES ⁺)411(M+1)。

Embodiment 63

(5R, 6S)-N-{4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl }-N-(methyl) trifluoroacetamide

According to the method for embodiment 1, by illustrative examples 52 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.49-7.20 (5H, m), 7.12 (1H, dd, J8.7,2.0Hz), 6.91 (1H, d, J8.7Hz), 6.89 (1H, d, J2.0Hz), 6.63 (1H, s), 5.16 (1H, s), 4.93 (1H, d, J12.0Hz), 4.57 (1H, d, J12.0Hz), 4.12 (1H, m), 3.89 (3H, s), 3.31 (3H, s), 3.11 (1H, m), 2.13 (1H, m), 1.82 (3H, m) and 1.36 (9H, s).m/z(ES ⁺)547(M+1)。

Embodiment 64

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(methyl) trifluoroacetyl amine hydrochlorate

According to the method for embodiment 2, by embodiment 63 compound title compounds. ¹H NMR (250MHz, CD ₃OD) δ 7.47 (2H, d, J7.5Hz), 7.34 (3H, m), 7.19 (1H, dd, J8.9,2.0Hz), 6.99 (1H, d, J8.9Hz), 6.85 (1H, d, J2.0Hz), 6.26 (1H, t, J1.9Hz), 4.95 (1H, dd, J12.3,1.9Hz), 4.51 (1H, dd, J12.3,1.9Hz), 4.47 (1H, s), 3.82 (3H, s), 3.44 (1H, m), 3.24 (3H, s), 3.23 (1H, m), and 2.34-1.95 (4H, m).m/z(ES ⁺)447(M+1)。Measured value: C, 59.47; H, 5.43; N, 5.80.C ₂₄H ₂₅F ₃N ₂O ₃.HCl theoretical value: C, 59.69; H, 5.43; N, 5.80%.

Embodiment 65

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) trifluoroacetyl amine hydrochlorate

According to the method for embodiment 3, by embodiment 64 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 1.80-2.00 (3H, m), 2.10-2.20 (3H, m), 3.17 (3H, s), 3.22-3.33 (2H, m), 3.48-3.60 (1H, m), 3.75 (3H, s), 3.97 (1H, t, J9.2Hz), 4.15 (1H, t, J8.3Hz), 4.41 (1H, s), 5.79 (1H, m), 6.96 (1H, d, J8.8Hz), 7.15 (1H, dd, J8.8,2.4Hz), and 7.50-7.56 (5H, m).m/z(ES ⁺)449(M+1)。

Embodiment 66

(5R, 6S)-N-{4-isopropoxy-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl }-N-(methyl) trifluoroacetamide

According to the method for embodiment 1, by illustrative examples 53 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.46 (2H, d, J7.4Hz), 7.24 (3H, m), 7.08 (1H, dd, J8.8,2.5Hz), 6.95 (1H, d, J2.5Hz), 6.88 (1H, d, J8.8Hz), 6.60 (1H, s), 5.15 (1H, s), 4.94 (1H, d, J12.3Hz), 4.61 (2H, m), 4.12 (1H, m), 3.31 (3H, s), 3.12 (1H, m), 2.10 (1H, m), 1.84 (3H, m) and 1.36 (15H, m).m/z(ES ⁺)575(M+1)。

Embodiment 67

(5R, 6s)-N-[4-isopropoxy-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(methyl) trifluoroacetamide

According to the method for embodiment 2, by embodiment 66 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 7.36 (2H, d, J6.6Hz), 7.17 (3H, m), 6.97 (1H, dd, J8.8,2.6Hz), 6.77 (1H, d, J8.8Hz), 6.66 (1H, d, J2.6Hz), 6.11 (1H, t, J2.1Hz), 4.86 (1H, dd, J12.0,2.1Hz), 4.51 (1H, sept, J6.0Hz), 4.30 (1H, dd, J12.0,2.1Hz), 3.77 (1H, s), 3.31 (1H, m), 3.25 (3H, s), 2.83 (1H, m), 2.14-1.64 (5H, m) and 1.31 (6H, d, J6.0Hz).m/z(ES ⁺)475(M+1)。

Embodiment 68

(3S, 5R, 6S)-N-[4-isopropoxy-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) trifluoroacetyl amine hydrochlorate

According to the method for embodiment 3, by embodiment 67 compound title compounds. ¹H NMR (360MHz, CD ₃OD) δ 7.63-7.44 (5H, m), 7.05 (1H, dd, J8.8,2.5Hz), 6.93 (1H, d, J8.8Hz), 5.98 (1H, d, J2.5Hz), (4.89 2H, br s), 4.59 (1H, sept, J5.8Hz), 4.43 (1H, s), 4.23 (1H, m), 3.98 (1H, m), 3.44 (1H, m), 3.21 (2H, m), 3.15 (3H, s), 2.32-1.76 (6H, m), 1.30 (3H, d, J5.8Hz) and 1.29 (3H, d, J5.8Hz).m/z(ES ⁺)477(M+1)。Measured value: C, 60.61; H, 6.14; N, 5.46.C ₂₆H ₃₁F ₃N ₂O ₃.HCl theoretical value: C, 60.87; H, 6.29; N, 5.46%.

Embodiment 69

(5R, 6S)-N-{4-(difluoro-methoxy)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl } N-(methyl) trifluoroacetamide

According to the method for embodiment 1, by illustrative examples 54 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.45 (2H, d, J7.4Hz), 7.29-7.17 (5H, m), 7.03 (1H, s), 6.59 (1H, s), 6.52 (1H, t, J73.0Hz), 5.15 (1H, s), 4.91 (1H, d, J12.2Hz), 4.56 (1H, d, J12.2Hz), 4.12 (1H, m), 3.33 (3H, s), 2.12 (1H, m), 1.84 (3H, m) and 1.36 (9H, s).m/z(ES ⁺)583(M+1)。

Embodiment 70

(5R, 6S)-N-[4-(difluoro-methoxy)-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(methyl) trifluoroacetamide

According to the method for embodiment 2, by embodiment 69 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.65-1.69 (1H, m), 1.80-2.05 (4H, m), 2.80-2.87 (1H, m), 3.27 (3H, s), 3.41 (1H, s), 4.29-4.32 (1H, m), 4.81-4.85 (1H, m), 6.14 (1H, s), 6.23 (1H, t, J73Hz), 6.74 (1H, s), 7.08 (2H, s), 7.15-7.22 (3H, m) and 7.37 (2H, d, J6.5Hz).m/z(ES ⁺)483(M+1)。

Embodiment 71

(3S, 5R, 6S)-N-[4-(difluoro-methoxy)-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) trifluoroacetyl amine hydrochlorate

According to the method for embodiment 3, by embodiment 70 compound title compounds. ¹HNMR (360MHz, D ₂O) δ δ 1.83-1.96 (3H, m), 2.14-2.30 (3H, m), 3.18 (3H, s), and 3.23-3.35 (2H, m), 3.50-3.54 (1H, m), 4.00 (1H, quin, J9.3Hz), 4.19 (1H, t, J8.5Hz), 4.42 (1H, s), 5.70 (1H, s), 6.75 (1H, t, J73Hz), 7.19 (2H, s), and 7.50-7.57 (5H, m).m/z(ES ⁺)485(M+1)。

Embodiment 72

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(2,2, the 2-trifluoroethyl) ethanamide

According to the method for embodiment 1, by illustrative examples 57 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.47 (2H, d, J7.5Hz), 7.24 (3H, m), 7.12 (1H, dd, J8.7,2.6Hz), 6.93 (1H, d, J8.7Hz), 6.87 (1H, d, J2.6Hz), 6.64 (1H, t, J2.0Hz), 5.17 (1H, s), 4.94 (1H, dd, J12.0,2.0Hz), 4.58 (1H, d, J12.0,2.0Hz), 4.29 (2H, m), 4.13 (1H, m), 3.90 (3H, s), 3.10 (1H, m), 2.12 (1H, m), 1.87 (3H, s), 1.82 (3H, m) and 1.37 (9H, s).m/z(ES ⁺)561(M+1)。

Embodiment 73

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(2,2, the 2-trifluoroethyl) ethanamide

According to the method for embodiment 2, by embodiment 72 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.37 (2H, d, J6.8Hz), 7.16 (3H, m), 7.01 (1H, dd, J8.7,2.6Hz), 6.81 (1H, d, J8.7Hz), 6.60 (1H, d, J2.6Hz), 6.08 (1H, t, J2.1Hz), 4.85 (1H, dd, J12.0,2.1Hz), 4.23 (3H, m), 4.29 (2H, m), 3.80 (3H, s), 3.77 (1H, s), 3.29 (1H, m), 2.83 (1H, m), 2.06-1.65 (5H, m) and 1.79 (3H, s).m/z(ES ⁺)461(M+1)。

Embodiment 74

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(2,2, the 2-trifluoroethyl) ethanamide

According to the method for embodiment 3, by embodiment 73 compound title compounds. ¹HNMR (360MHz, CD ₃OD) δ 7.64 (2H, m), 7.52 (3H, m), 7.12 (1H, dd, J8.8,2.5Hz), 6.98 (1H, d, J8.8Hz), 6.24 (1H, d, J2.5Hz), 4.88 (2H, br s), 4.47 (1H, s), 4.36-4.22 (3H, m), 4.02 (1H, m), 3.78 (3H, s), 3.47 (1H, m), 3.39 (1H, m), 3.23 (1H, m), 2.35-1.86 (6H, m) and 1.70 (3H, s).m/z(ES ⁺)463(M+1)。Measured value: C, 60.39; H, 5.99; N, 5.63.C ₂₅H ₂₉F ₃N ₂O ₃.HCl theoretical value: C, 60.18; H, 6.06; N, 5.61%.

Embodiment 75

(3S, 5R, 6S)-and N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] benzamide

With Benzoyl chloride (40 μ L, 0.34mmol) join (3S that is stirring, 5R, 6S)-3-(5-amino-2-p-methoxy-phenyl)-6-phenyl-(embodiment 59 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 98mg, 0.22mmol) and pyridine (200 μ L are in methylene dichloride 2.47mmol) (3ml) cooling solution.Mixture stirred 15 minutes, added entry (20ml) and ether (30ml) then.Layering, water layer utilize ether (10ml) extraction.Utilize copper sulfate (II) aqueous solution (0.5M, 2 * 20ml) and the organic fraction that merges of saturated sodium bicarbonate aqueous solution (20ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (75: 25) wash-out by silica gel chromatography, obtains title compound, is flint glass shape thing (102mg, 84%). ¹H NMR (250MHz, CDCl ₃) δ 8.07 (1H, br s), and 8.0-7.85 (2H, m), 7.65-7.18 (10H, m), 6.84 (1H, d, J8.8Hz), 5.43 (1H, br s), 4.28 (1H, t, J7.8Hz), 4.03-3.68 (3H, m), 3.82 (3H, s), 2.94-2.79 (1H, m), 2.30-2.05 (2H, m), 1.80-1.60 (4H, m) and 1.38 (9H, s).m/z(ES ⁺)543(M+1)。

Embodiment 76

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) benzamide

With (3S, 5R, 6S)-and N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] (embodiment 75 for benzamide, 100mg, 0.18mmol) join sodium hydride (60% mineral oil dispersion liquid, 22mg is in DMF 0.55mmol) (3ml) cooling (0 ℃) suspension.(79mg, 0.55mmol), mixture at room temperature stirred 1 hour to add methyl-iodide then.Add entry (10ml), utilize ethyl acetate (3 * 10ml) extraction mixtures.Utilize water (3 * 10ml) and the organic fraction that merges of salt solution (10ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (2: 1) wash-out by silica gel chromatography, obtains title compound, is flint glass shape thing (95mg, 93%). ¹H NMR (250MHz, CDCl ₃) δ 7.59-7.50 (2H, m), 7.38-7.05 (8H, m), 6.90-6.75 (2H, m), 6.64 (1H, d, J9.6Hz), 5.15 (1H, br s), 4.07-3.92 (2H, m), 3.75 (3H, s), 3.75-3.60 (1H, m), 3.41 (3H, s), and 3.40-3.25 (1H, m), 2.98-2.82 (1H, m), 2.27 (1H, dd, J13,9Hz), 2.11-1.96 (1H, m), 1.78-1.60 (4H, m) and 1.38 (9H, s).m/z(ES ⁺)557(M+1)。

Embodiment 77

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) benzamide hydrochloride salt

According to the method for embodiment 2, by embodiment 76 compound title compounds.m.p.275-280℃。 ¹H NMR (360MHz, CD ₃OD) δ 7.62-7.52 (5H, m), 7.28-7.02 (5H, m), 6.91 (1H, br d, J8.6Hz), 6.74 (1H, d, J8.6Hz), 5.98 (1H, br s), 4.40 (1H, s), 4.01 (1H, t, J8.0Hz), 3.82 (1H, app.quin, J9.8Hz), 3.64 (3H, s), 3.41 (1H, dd, J12,4.2Hz), 3.28 (3H, s), 3.19 (1H, dt, J13,3.2Hz), 3.13-3.05 (1H, m), 2.30-2.08 (2H, m), and 1.96-1.65 (4H, m).m/z(ES ⁺)457(M+1)。Measured value: C, 69.80; H, 6.75; N, 5.45.C ₂₉H ₃₂N ₂O ₃.HCl theoretical value: C, 70.60; H, 6.75; N, 5.68%.

Embodiment 78

(5R, 6S)-3-[5-methylamino--2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 51 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.40 (2H, m), 7.31-7.20 (3H, m), 7.09 (1H, dq, J8.8,1.5Hz), 6.55 (1H, dd, J8.8,2.9Hz), 6.44 (1H, t, J2.1Hz), 6.38 (1H, d, J2.9Hz), 5.13 (1H, br s), 4.88 (1H, dd, J12,2.1Hz), 4.55 (1H, dd, J12,2.2Hz), 4.17-4.08 (1H, m), 3.20-3.05 (1H, m), 2.83 (3H, s), 1.90-1.50 (5H, m) and 1.35 (9H, s).

Embodiment 79

(5R, 6S)-3-[5-methylamino--2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-oxa--spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 78 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.42-7.30 (2H, m), 7.25-7.13 (3H, m), 6.98 (1H, dq, J8.8,1.4Hz), 6.38 (1H, dd, J8.8,2.9Hz), 5.99-5.97 (2H, m), 4.80 (1H, dd, J13,2.1Hz), 4.31 (1H, dd, J13,2.3Hz), 3.78 (1H, s), 3.68 (1H, br.s), 3.33-3.20 (1H, m), 2.82 (1H, dd, J12,3.0Hz), 2.75 (3H, s), 2.15-1.60 and (5H, m).m/z(ES ⁺)405(M+1)。

Embodiment 80

(3S, 5R, 6S)-3-[5-methylamino--2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 79 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.60-7.50 (2H, m), 7.40-7.35 (3H, m), 6.91 (1H, br d, J7.5Hz), 6.30 (1H, dd, J8.8,2.8Hz), 5.28 (1H, d, J2.9Hz), 4.10 (1H, t, J8.0Hz), 3.98 (1H, s), 3.82-3.72 (1H, m), 3.40-2.85 (5H, m), 2.57 (3H, s), and 2.30-1.55 (6H, m).m/z(ES ⁺)407(M+1)。

Embodiment 81

(5R, 6S)-N-methyl-N-{3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl]-4-(trifluoromethoxy) phenyl } trifluoroacetamide

According to the method for embodiment 1, by illustrative examples 55 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.40 (2H, m), 7.35-7.15 (5H, m), 7.06 (1H, br s), 6.54 (1H, t, J2Hz), 5.16 (1H, br s), 4.90 (1H, br.d, J12Hz), 4.55 (1H, br d, J12Hz), 4.18-4.08 (1H, m), 3.35 (3H, s), and 3.20-3.04 (1H, m), 2.20-2.05 (1H, m), 1.95-1.70 (3H, m) and 1.35 (9H, s).

Embodiment 82

(5R, 6S)-N-methyl-N-[3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl)-4-(Trifluoromethoxyphen-l)] trifluoroacetamide

According to the method for embodiment 2, by embodiment 81 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.40-7.30 (2H, m), 7.25-7.05 (5H, m), 6.73 (1H, br s), 6.08 (1H, t, J2.1Hz), 4.81 (1H, dd, J2.0,12Hz), 4.30 (1H, dd, J12,2.0Hz), 3.80 (1H, s), 3.28 (3H, s), 2.83 (1H, dt, J12,2.9Hz), and 2.25-1.60 (6H, m).m/z(ES ⁺)501(M+1)。

Embodiment 83

(3S, 5R, 6S)-and N-methyl-N-[3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl)-4-(trifluoromethoxy) phenyl] the trifluoroacetyl amine hydrochlorate

According to the method for embodiment 3, by embodiment 82 compound title compounds. ¹H NMR (250MHz, CD ₃OD) δ 7.65-7.40 (5H, m), 7.28 (1H, dd, J6.1,1.0Hz), 7.22 (1H, br d, J6.1Hz), 5.89 (1H, br s), 4.44 (1H, s), 4.22 (1H, t, J5.8Hz), 3.93 (1H, app.quin, J6.5Hz), 3.42 (1H, dd, J8.8,2.7Hz), 3.35 (1H, t, J6.2Hz), 3.22 (1H, dd, J9.0,2.2Hz), 3.16 (3H, s), 2.26-2.15 (3H, m), and 1.95-1.75 (3H, m).m/z(ES ⁺)503(M+1)。Measured value: C, 53.10; H, 4.69; N, 5.06.C ₂₄H ₂₄F ₆N ₂O ₃.HCl theoretical value: C, 53.50; H, 4.68; N, 5.20%.

Embodiment 84

(5R, 6S)-3-[2-oxyethyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 58 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 1.36 (9H, s), 1.45 (3H, t, J7.0Hz), 1.73-1.93 (3H, m), 2.06-2.16 (1H, m), 3.05-3.18 (1H, m), 3.98-4.19 (3H, m), 4.61 (1H, dd, J12.2,2.2Hz), 4.97 (1H, dd, J12.2,2.2Hz), 5.15 (1H, s), 6.64 (1H, t, J2.1Hz), 6.84 (1H, d, J9.0Hz), 6.93 (1H, d, J2.7Hz), 7.07 (1H, bd, J8.15Hz), 7.18-7.32 (3H, m), and 7.44-7.51 (2H, m).m/z(ES ⁺)520(M+1)。

Embodiment 85

(5R, 6S)-3-[2-oxyethyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 84 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.39 (3H, t, J7.0Hz), 1.67 (1H, bd, J15.3Hz), 1.78 (1H, td, J13.4,4.3Hz), 1.93-2.16 (2H, m), 2.83 (1H, td, J12.6,2.9Hz), 3.27 (1H, bd, J12.4Hz), 3.83 (1H, s), 3.94 (2H, q, J7.0Hz), 4.34 (1H, dd, J12.0,2.2Hz), 4.89 (1H, dd, J12.0,2.2Hz), 6.12 (1H, t, J2.1Hz), 6.67 (1H, d, J3.0Hz), 6.73 (1H, d, J9.0Hz), 6.98 (1H, d, J8.8Hz), 7.10-7.23 (3H, m), and 7.32-7.39 (2H, m).m/z(ES ⁺)420(M+1)。

Embodiment 86

(3S, 5R, 6S)-3-[2-oxyethyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 85 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 1.27 (3H, t, J7.0Hz), 1.66-1.84 (3H, m), 2.01-2.10 (3H, m), and 3.03-3.12 (2H, m), 3.24-3.32 (1H, m), 3.79 (1H, q), 3.96 (2H, q, J7.0Hz), 4.14 (1H, t, J8.0Hz), 4.48 (1H, br s), 6.17 (1H, br s), 6.95 (1H, d, J9.0Hz), 7.08 (1H, br d, J9.0Hz), 7.41-7.49 (3H, m), and 7.54-7.59 (2H, m).m/z(ES ₊)422(M+1)。

Embodiment 87

(5R, 6S)-3-[2-(trifluoromethylthio) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 59 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound.m/z(ES ⁺)492(M+1)。

Embodiment 88

(5R, 6S)-3-[2-(trifluoromethylthio) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 87 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.66 (1H, m), 1.76-1.86 (1H, m), 1.96-2.11 (2H, m), 2.82 (1H, td, J12,3Hz), 3.26 (1H, br d, J10.3Hz), 3.75 (1H, s), 4.30 (1H, dd, J12.3,2.2Hz), 4.81 (1H, dd, J12.3,2.2Hz), 5.66 (1H, t, J2.0Hz), 6.70 (1H, dd, J7.3,1.8Hz), 7.18-7.32 (4H, m), 7.39 (1H, dd, J5.8,1.5Hz) and 7.58 (1H, d, J7.4Hz).m/z(ES ⁺)392(M+1)。

Embodiment 89

(3S, 5R, 6S)-3-[2-(trifluoromethylthio) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 88 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 1.54-1.64 (2H, m), 1.81-2.21 (5H, m), 2.81 (1H, td, J12.2,2.5Hz), 3.21-3.32 (2H, m), 3.66 (1H, s), 4.07 (1H, t, J8.2Hz), 4.20-4.32 (1H, m), 6.20 (1H, dd, J7.6,2.0Hz), 7.08-7.18 (2H, m), 7.30-7.43 (3H, m), and 7.48-7.62 (3H, m).m/z(ES ⁺)394(M+1)。

Embodiment 90

(5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 60 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 1.36 (9H, s), 1.86 (3H, m), 2.10 (1H, m), 3.18 (1H, m), 4.11 (1H, m), 4.43 (2H, dq, J7.8,3.9Hz), 4.64 (1H, dd, J12.2,2.2Hz), 4.96 (1H, dd, J12.2,2.0Hz), 5.15 (1H, s), 6.67 (1H, t, J2.1Hz), 6.90 (1H, d, J8.6Hz), 7.27 (4H, m), 7.36 (1H, d, J2.1Hz), 7.45 (1H, d, J7.3Hz) and 7.55 (1H, d, J8.8Hz)

Embodiment 91

(5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 90 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 1.79 (2H, m), 1.90 (1H, m), 2.24 (1H, m), 2.83 (1H, td, J12.6,2.6Hz), 3.47 (1H, d, J10.7Hz), 3.93 (1H, s), 4.33 (2H, q, J7.9Hz), 4.40 (1H, dd, J12.2,2.2Hz), 4.90 (1H, dd, J12.2,2.0Hz), 6.16 (1H, t, J2.0Hz), 6.81 (1H, d, J8.6Hz), 7.01 (1H, d, J2.0Hz), 7.18 (3H, m) and 7.74 (3H, m).m/z(ES ⁺)458(M+1)。

Embodiment 92

(3S, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 91 compound title compounds. ¹H NMR (250MHz, DMSO-d ₆) δ 1.72 (3H, m), 2.10 (3H, m), 3.11 (1H, t, J8.4Hz), 3.80 (1H, m), 4.15 (1H, t, J8.0Hz), 4.49 (1H, s), 4.83 (2H, dq, J8.8,4.9Hz), 6.58 (1H, s), 7.21 (1H, d, J8.7Hz), 7.44 (3H, m) and 7.56 (4H, m).m/z(ES ⁺)460(M+1)。

Embodiment 93

(5R, 6S)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 61 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 0.93 (2H, m), 1.31 (15H, m), 1.83 (2H, m), 2.30 (1H, m), 3.14 (1H, m), 4.61 (2H, m), 4.98 (1H, dd, J12.3,2.0Hz), 5.15 (1H, s), 6.78 (1H, d, J2.1Hz), 7.22 (1H, d, J8.4Hz), 7.44 (2H, m) and 7.55 (5H, m).

Embodiment 94

(5R, 6S)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-pinene hyhrochloride

According to the method for embodiment 2, by embodiment 93 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 1.25 (6H, dd, J8.8Hz), 1.85 (2H, m), 2.01 (2H, m), 3.12 (1H, m), 3.33 (1H, m), 4.37 (1H, d, J14.2Hz), 4.60 (1H, s), 4.72 (1H, septet, J6.0Hz), 4.94 (1H, d, J12.3Hz), 6.41 (1H, t), 7.17 (2H, m), 7.30 (3H, m), 7.47 (2H, d, J6.4Hz) and 7.53 (1H, d, J8.5Hz).

Embodiment 95

(3S, 5R, 6S)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 94 compound title compounds. ¹H NMR (360MHz, DMSO-d ₆) δ 1.23 (6H, dd, J8.8,5.9Hz), 1.79 (2H, m), 2.06 (2H, m), 3.07 (2H, t, J10.2Hz), 3.81 (1H, qn), 4.14 (1H, t, J7.9Hz), 4.46 (1H, s), 4.66 (1H, septet, J6.0Hz), 6.52 (1H, s), 7.09 (1H, d, J8.6Hz), 7.44 (5H, m) and 7.56 (2H, d, J6.5Hz).

Embodiment 96

(3S, 5R, 6S)-3-[2-cyclopropyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(128mg) places dry flask with the magnesium smear metal, with the tetrahydrofuran (THF) covering of minimum.Add ethylene dibromide (0.1ml) and reacting by heating.When observing foam, drip tetrahydrofuran (THF) (10ml) solution of Cyclopropyl Bromide (0.4ml), keep stable the backflow.Be reflected at 65 ℃ then and heated 1 hour down, mixture is cooled to room temperature, add tetrahydrofuran (THF) (5ml) solution of zinc bromide (1.6g), form white precipitate.Reaction was at room temperature stirred 2 hours.Add [1, two (diphenylphosphino) ferrocene of 1-] dichloro palladium (11) (50mg), stirring reaction 5 minutes.Add (3S, 5R, 6S)-(5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl)-the 6-phenyl-(embodiment 144,300mg) for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane for 3-, solution at room temperature stirred 16 hours, stirred 1 hour down at 65 ℃ then.Cooling mixture utilizes saturated ammonia chloride water solution (20ml) dilution, utilizes methylene dichloride (3 * 20ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (80: 20) wash-out by middle hydraulic fluid phase silica gel chromatography purifying, obtains title compound, is oily matter (121mg). ¹H NMR (250MHz, CDCl ₃) δ 0.64 (2H, m), 0.97 (2H, dt, J8.1,1.4Hz), 1.36 (9H, s), 1.78 (1H, m), 1.92 (1H, m), 2.16 (1H, m), 2.48 (1H, m), 3.66 (1H, t, J8.6Hz), 4.07 (3H, m), 4.22 (1H, t, J6.9Hz), 5.22 (1H, s), 6.99 (3H, m), 7.30 (3H, m) and 7.56 (2H, d, J7.5Hz).

Embodiment 97

(3S, 5R, 6S)-3-[2-cyclopropyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 2, by embodiment 96 compound title compounds. ¹H NMR (360MHz, DMSO-d ₆) δ 0.56 (2H, m), 0.88 (2H, d, J8.1Hz), 1.72 (1H, m), 1.80 (2H, m), 1.94 (1H, m), 2.14 (3H, m), 3.15 (2H, t, J8.2Hz), 4.18 (2H, m), 4.51 (1H, s), 5.92 (1H, s), 7.02 (2H, m), 7.51 (3H, m) and 7.60 (2H, d, J6.3Hz).

Embodiment 98

(5R, 6S)-3-(2-benzyloxy phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 62 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.43-6.90 (14H, m), 6.65 (1H, t, J2.1Hz), 5.15 (1H, d, J11.5Hz), 5.09 (1H, d, J11.5Hz), 5.07 (1H, s), 4.95 (1H, dd, J12.0,2.1Hz), 4.648 (1H, dd, J12.0,2.1Hz), 4.10 (1H, m), 3.13 (1H, m), 2.04 (1H, m), 1.76 (3H, m) and 1.32 (9H, s).m/z(ES ⁺)498(M+1)。

Embodiment 99

(3S, 5R, 6S)-3-(2-hydroxy phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 98 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.58 (2H, d, J7.5Hz), 7.32 (2H, t, J7.5Hz), 7.24 (1H, t, J7.5Hz), 7.13 (1H, d, J7.7Hz), 7.08 (1H, t, J7.7Hz), 6.85 (1H, t, J7.7Hz), 6.76 (1H, d, J7.7Hz), 5.79 (1H, s), 5.36 (1H, s), 4.24 (1H, dd, J8.9,7.1Hz), 3.96 (1H, m), 3.92 (1H, dd, J8.9,7.2Hz), 3.68 (1H, m), 2.83 (1H, m), 2.47 (1H, m), 2.22 (1H, m), 2.09 (1H, m), 1.75 (3H, m) and 1.36 (9H, s).m/z(ES ⁺)410(M+1)。

Embodiment 100

(3S, 5R, 6S)-3-(5-bromo-2-hydroxy phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

In 10 minutes, high bromination tetrabutylammonium (118mg) is joined (3S, 5R, 6S)-3-(2-hydroxy phenyl)-6-phenyl-(embodiment 99 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 100mg is in methylene dichloride 0.24mmol) (3ml)/methyl alcohol (2ml) solution.Mixture at room temperature stirred 10 minutes.Residue is injected in the water, utilizes ethyl acetate extraction.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (80: 20) wash-out by the fast silica gel chromatogram purifying, obtains title compound, is foam (76mg, 64%). ¹H NMR (360MHz, CDCl ₃) δ 7.56 (2H, d, J7.5Hz), 7.33 (2H, t, J7.5Hz), 7.26 (1H, t, J7.5Hz), 7.21 (1H, d, J2.4Hz), 7.17 (1H, dd, J8.4,2.4Hz), 6.66 (1H, d, J8.4Hz), 6.20 (1H, br s), 5.33 (1H, s), 4.21 (1H, dd, J9.1,7.1Hz), 3.98 (1H, m), 3.91 (1H, dd, J9.1,6.6Hz), 3.59 (1H, m), 2.84 (1H, m), 2.48 (1H, m), 2.14 (2H, m), 1.74 (3H, m) and 1.36 (9H, s).m/z(ES ⁺)488,490(M+1)。

Embodiment 101

(3S, 5R, 6S)-3-(5-bromo-2-isopropyl phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

2-N-PROPYLE BROMIDE (0.053ml) is joined (3S in DMF (5ml), 5R, 6S)-(embodiment 100, and 69mg is 0.14mmol) and in the mixture of salt of wormwood (157mg) for 3-(5-bromo-2-hydroxy phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Mixture stirred 3 days down at 50 ℃.Cooling mixture is injected in the water, with ethyl acetate (2x) extraction, washes the organic fraction of this merging with water, dry (Na ₂SO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (85: 15) wash-out by the fast silica gel chromatogram purifying, obtains title compound, is oily matter (68mg, 91%). ¹H NMR (360MHz, CDCl ₃) δ 7.56 (2H, d, J7.4Hz), 7.34-7.23 (5H, m), 6.72 (1H, d, J8.5Hz), 5.20 (1H, s), 4.50 (1H, hept, J6.2Hz), 4.23 (1H, t, J8.2Hz), 4.00 (1H, m), 3.73 (1H, m), 3.63 (1H, t, J8.2Hz), 2.89 (1H, m), 2.38 (1H, m), 2.15 (2H, m), 1.74 (3H, m), 1.40 (9H, s), 1.34 (3H, d, J6.2Hz) and 1.32 (3H, d, J6.2Hz).m/z(ES ⁺)530,532(M+1)。

Embodiment 102

(3S, 5R, 6S)-3-(5-bromo-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 2, prepare title compound by embodiment 101 mixtures. ¹HNMR (360MHz, CDCl ₃) δ 7.49-7.47 (2H, m), 7.37-7.31 (3H, m), 7.12-7.09 (1H, dd, J8.6,2.4Hz), 6.62-6.60 (1H, d, J8.6Hz), 6.35-6.34 (1H, d, J2.4Hz), 4.42-4.36 (1H, m), 4.09-4.04 (1H, t, J7.9Hz), 3.84-3.73 (1H, m), 3.65 (1H, s), 3.24-3.21 (1H, m), and 3.10-3.06 (1H, m), 2.85-2.78 (1H, m), and 2.14-1.96 (2H, m), 1.87-1.76 (3H, m), 1.63-1.55 (2H, m), and 1.28-1.24 (6H, m).m/z(ES ⁺)430,432(M+1)。

Embodiment 103

(3S, 5R, 6S)-3-(5-cyano group-2-isopropyl phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Under reflux temperature, with (3S, 5R, 6S)-3-(5-bromo-2-isopropyl phenyl)-the 6-phenyl-(embodiment 101 for 1-oxa--7-(uncle-butoxy carbonyl) azepine-spiral shell [4.5] decane, 226mg, 0.43mmol) and cupric cyanide (I) (227mg, DMF 2.54mmol) (4ml) solution heating 17 hours.Cooling mixture, be injected into ethylenediamine solution (10%, 50ml) in, utilize ethyl acetate (2 * 50ml) extraction.Utilize quadrol (10%, 50ml) and salt solution (50ml) washing organic fraction, merge dry (MgSO ₄), solvent evaporated under reduced pressure.Residue is dissolved in the methylene dichloride (4ml), and (110mg 0.50mmol) handles, and mixture at room temperature stirs and spends the night to utilize two dimethyl dicarbonate butyl esters.Solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (increasing to 70: 30 at 80: 20) wash-out by the fast silica gel chromatogram purifying, obtains title compound (92mg, 45%).m/z(ES ⁺)477(M+1)。

Embodiment 104

(3S, 5R, 6S)-3-(5-cyano group-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 3, by embodiment 103 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 1.27 (6H, m), 1.73-1.97 (3H, m), 2.19 (3H, m), 3.23 (1H, m), 3.39 (1H, m), 3.53 (1H, m), 3.76 (1H, m), 4.17 (1H, t, J8.1Hz), 4.39 (1H, s), 4.61 (1H, p, J6.0Hz), 6.49 (1H, s), 6.88 (1H, d, J8.7Hz), 7.32 (1H, m) and 7.47 (5H, m); M/z (ES ⁺) 377 (M+1).Measured value: C, 66.59; H, 6.80; N, 6.51.C ₂₄H ₂₈N ₂O ₂.HCl.H ₂O theoretical value: C, 66.89; H, 7.25; N, 6.50%.

Embodiment 105

4-(difluoro-methoxy)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] and phenylformic acid (5R, 6S)-methyl ester

According to the method for embodiment 1, by illustrative examples 65 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.98 (1H, dd, J2.1,8.6Hz), 7.85 (1H, d, J2.1Hz), 7.47 (2H, m), 7.25 (4H, m), 6.62 (1H, t, J2.1Hz), 6.55 (1H, t, J73Hz), 5.16 (1H, s), 4.97 (1H, dd, J2., 12.3Hz), 4.62 (1H, dd, J2.1,12.3Hz), 4.13 (1H, m), 3.92 (3H, s), 3.18 (1H, m), 2.12 (1H, m), 1.85 (3H, m) and 1.37 (9H, s).

Embodiment 106

3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl]-4-(2,2, the 2-trifluoro ethoxy) phenylformic acid (5R, 6S)-methyl ester

According to the method for embodiment 1, by illustrative examples 66 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.97 (1H, dd, J8.67,2.14Hz), 7.80 (1H, d, J2.1Hz), 7.44 (2H, m), 7.17-7.30 (3H, m), 6.85 (1H, d, J8.7Hz), 6.67 (1H, t, J2.1Hz), 5.15 (1H, s), 4.98 (1H, dd, J2.0,12.2Hz), 4.67 (1H, dd, J2., 12.2Hz), 4.36-4.51 (2H, m), 4.13 (1H, m), 3.90 (3H, s), 3.14 (1H, m), 2.08 (1H, m), 1.79-1.89 (3H, m) and 1.36 (9H, s)

Embodiment 107

4-(difluoro-methoxy)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] and phenylformic acid (3S, 5R, 6S)-methyl ester

According to the method for embodiment 3, by embodiment 105 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.96 (2H, m), 7.56 (2H, m), 7.30 (3H, m), 7.13 (1H, d, J5.9Hz), 6.59 (1H, t, J73Hz), 5.22 (1H, s), 4.23 (1H, m), 3.98 (1H, m), 3.89 (3H, s), 3.77 (2H, m), 2.89 (1H, m), 2.47 (1H, m), 2.19 (2H, m), 1.75 (3H, m) and 1.37 (9H, s).

Embodiment 108

3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl]-4-(2.2.2-trifluoro ethoxy) phenylformic acid (3S, 5R, 6S)-methyl ester

According to the method for embodiment 3, by embodiment 106 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.96 (1H, m), 7.83 (2H, m), 7.22-7.36 (4H, m), 6.82 (1H, d, J8.4Hz), 5.22 (1H, s), 4.38-4.52 (2H, m), 3.94 (1H, m), 3.88 (3H, s), 3.74 (1H, m), 2.85-2.93 (1H, m), and 2.46-2.54 (1H, m), 2.10-2.22 (1H, m), 1.76-1.81 (3H, m) and 1.38 (9H, s).

Embodiment 109

(3S, 5R, 6S)-4-(difluoro-methoxy)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] and phenyl } carboxylic acid amides

Utilize the saturated 4-of ammonia (difluoro-methoxy)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenylformic acid (3S, 5R, 6S)-(embodiment 107 for methyl ester, 730mg, 1.41mmol) methyl alcohol (100ml) cooling (0 ℃) solution, solution in sealed tube with 80 ℃ of heating 16 hours down.Cooling mixture, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (50: 50) wash-out by silica gel chromatography, obtains title compound, is colorless solid (410mg, 58%). ¹H NMR (250MHz, CDCl ₃) δ 8.25 (1H, br s), 8.00 (1H, dd, J2.1,8.6Hz), 7.64 (2H, m), 7.30 (3H, m), 7.15 (1H, d, J8.6Hz), 6.57 (1H, t, J73Hz), 5.78 (1H, br s), (5.53 1H, br s), 4.34 (1H, t, J8.8Hz), 4.10 (2H, m), 3.68 (1H, t, J8.8Hz), 2.75 (1H, m), 2.30 (3H, m), 1.65 (3H, m) and 1.47 (9H, s).

Embodiment 110

(3S, 5R, 6S)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl]-4-(2,2, the 2-trifluoro ethoxy) phenyl } carboxylic acid amides

According to the method for embodiment 109, by embodiment 108 compound title compounds.m/z(ES ⁺)535(M+1)。

Embodiment 111

(3S, 5R, 6S)-3-[5-cyano group-2-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With trifluoroacetic acid acid anhydrides (252 μ l, 1.8mmol) be added drop-wise to (3S, 5R, 6S)-4-(difluoro-methoxy)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl } (embodiment 109 for carboxylic acid amides, 410mg, 0.82mmol) and pyridine (332 μ l, 4.1mmol) 1, in 4-diox (20ml) solution, mixture at room temperature stirred 1 hour.Mixture is injected in the saturated sodium bicarbonate aqueous solution (50ml), utilizes ethyl acetate (2 * 50ml) extractions.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (75: 25) wash-out by silica gel chromatography, obtains title compound, is jelly (347mg, 87%). ¹H NMR (250MHz, CDCl ₃) δ 7.50 (4H, m), 7.25 (4H, m), 7.15 (1H, d, J8.6Hz), 6.60 (1H, t, J73Hz), (5.13 1H, br s), 4.16 (1H, m), 4.03 (1H, m), 3.67 (2H, m), 2.94 (1H, m), 2.42 (1H, m), 2.13 (2H, m), 1.75 (3H, m) and 1.47 (9H, s).

Embodiment 112

(3S, 5R, 6S)-3-[5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 111, by embodiment 110 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.48-7.56 (4H, m), 7.22-7.36 (3H, m), 6.84 (1H, d, J8.5Hz), 5.14 (1H, s), 4.42 (2H, q, J7.8Hz), 4.25 (1H, m), 4.00 (1H, m), and 3.67-3.84 (2H, m), 2.84-3.00 (1H, m), 2.40-2.56 (1H, m), 2.02-2.18 (2H, m), 1.64-1.75 (3H, m) and 1.37 (9H, s).

Embodiment 113

(3S, 5R, 6S)-3-[5-cyano group-2-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 2, by embodiment 111 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 9.78 (1H, br s), 9.05 (1H, br s), 7.70 (1H, dd, J2.0,8.5Hz), 7.50 (5H, m), 7.31 (1H, t, J73Hz), 7.20 (1H, d, J8.5Hz), 6,58 (1H, d, J2.0Hz), 4.51 (1H, brs), 4.14 (1H, t, J8.1Hz), 3.78 (1H, m), 3.28 (1H, m), 3.07 (1H, m), 2.09 (3H, m) and 1.70 (3H, m).m/z(ES ⁺)385(M+1)。

Embodiment 114

(3S, 5R, 6S)-3-[5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 2, by embodiment 112 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 9.60 (1H, br s), 8.96 (1H, br s), 7.66 (1H, dd, J6.7,1.9Hz), 7.44-7.54 (5H, m), 7.18 (1H, d, J8.7Hz), 6.66 (1H, d, J1.9Hz), 4.81-4.88 (2H, m), 4.50 (1H, m), 4.16 (1H, t, J8.0Hz), 3.72 (1H, m), 3.26 (2H, m), 3.06 (1H, brm), 1.99-2.17 (3H, m), and 1.60-1.81 (3H, m).m/z(ES ⁺)417(M+1)。

Embodiment 115

(5R, 6S)-4-(cyclobutoxy group)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl } carboxylic acid amides

According to the method for embodiment 1, by illustrative examples 68 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (CDCl ₃) δ 1.37 (9H, s), 1.70-1.93 (4H, m), 2.14-2.21 (3H, m), 2.42-2.34 (3H, m), and 3.07-3.20 (1H, m), 4.09-4.18 (1H, m), 4.66-4.75 (2H, m), 5.00 (1H, dd, J12.3,2.0Hz), 5.16 (1H, br.s), 6.20 (2H, br.s), 6.67 (1H, br.s), 6.74 (2H, d, J8.5Hz), 7.20-7.29 (3H, m), 7.47 (2H, d, J8.0Hz), 7.60 (1H, d, J2.2Hz) and 7.64 (1H, dd, J8.5,2.2Hz).

Embodiment 116

(3S, 5R, 6S)-4-(cyclobutoxy group)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] and phenyl } carboxylic acid amides

(0.5ml) joins (5R with trifluoroacetic acid, 6S)-4-(cyclobutoxy group)-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl } (embodiment 115 for carboxylic acid amides, 0.5g) methylene dichloride (15ml) solution in, mixture at room temperature stirs and spends the night.Solvent evaporated under reduced pressure, residue utilizes methylene chloride/ammonia (90: 10: 1) wash-out by silica gel chromatography.Residue is dissolved in the mixture of methyl alcohol (25ml) and acetate (0.5ml), adds palladium/carbon (50mg), mixture stirred two days under the 50psi hydrogen atmosphere.Filtering mixt further adds part palladium hydroxide/carbon (50mg), and mixture stirred 24 hours under the 50psi hydrogen atmosphere.Filtering mixt, solvent evaporated under reduced pressure.Residue is dissolved in the methylene dichloride (15ml), adds triethylamine (0.14ml) and two dimethyl dicarbonate butyl esters (130mg), mixture at room temperature stirs and spends the night.Solvent evaporated under reduced pressure.Residue utilizes the ethyl acetate/hexane wash-out by silica gel chromatography, obtains title compound, is jelly (210mg). ¹H NMR (CDCl ₃) δ (CDCl ₃) δ 1.46 (9H, s), 1.64-1.93 (5H, m), 2.08-2.27 (4H, m), and 2.39-2.48 (3H, m), 2.74-2.80 (1H, m), 3.64 (1H, app.t, J9.0Hz), 3.93 (1H, br d, J12.7Hz), 3.98-4.09 (1H, m), 4.35 (1H, app.t, J8.6Hz), 4.69 (1H, app.pent, J7.0Hz), 5.68 (1H, br s), 6.73 (1H, d, J8.6Hz), 7.21-7.25 (1H, m), 7.30-7.34 (2H, m), 7.62 (2H, d, J7.7Hz), 7.90 (1H, d, J8.5Hz) and 8.06 (1H, br s).

Embodiment 117

(3S, 5R, 6S)-3-[5-cyano group-2-(cyclobutoxy group) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 111, by embodiment 116 compound title compounds. ¹H NMR (CDCl ₃) δ 1.38 (9H, s), 1.67-1.81 (4H, m), 1.86-1.95 (1H, m), and 2.09-2.22 (4H, m), 2.41 (1H, dd, J12.9,8.3Hz), 2.44-2.54 (2H, m), 2.87-2.95 (1H, m), 3.65 (1H, app.t, J8.4Hz), 3.68-3.76 (1H, m), 4.01 (1H br.d, J13.1Hz), 4.26 (1H, app.t, J8.4Hz), 4.68 (1H, app.pent, J7.1Hz), 5.16 (1H, br s), 6.71 (2H, d, J8.5Hz), 7.23-7.27 (1H, m), 7.33 (2H, app.t, J7.1Hz), 7.42 (1H, d, J1.9Hz), 7.45 (1H, dd, J8.4,1.9Hz) and 7.54 (2H, d, J7.7Hz).m/z(ES ⁺)489(M+1)。

Embodiment 118

(3S, 5R, 6S)-3-[5-cyano group-2-(cyclobutoxy group) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 2, by embodiment 117 compound title compounds, 252-254 ℃ of m.p. (MeOH/ tertiary butyl methyl ester). ¹H NMR (D ₂O) δ 1.59-1.82 (3H, m), 1.87-1.96 (3H, m), 2.04-2.23 (3H, m), 2.26-2.41 (2H, m), and 3.11-3.24 (1H, m), 3.24-3.37 (2H, m), 3.47 (1H, br d, J10.3Hz), 3.74 (1H, app.pent, J8.6Hz), 4.14 (1H, app.t, J8.2Hz), 4.34 (1H, s), 4.60 (1H, app.pent, J7.1Hz), 6.40 (1H, d, J1.9Hz), 6.66 (1H, d, J8.7Hz), 7.27 (1H, dd, J8.6,1.9Hz), and 7.35-7.52 (5H, m).m/z(ES ⁺)389(M+1)。Measured value: C, 66.82; H, 7.01; N, 6.38.C ₂₅H ₂₅N ₂O ₂.HCl.1.25H ₂O theoretical value: C, 67.10; H, 7.10; N, 6.26%.

Embodiment 119

(5R, 6S)-3-[2-cyano group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by illustrative examples 69 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.34 (9H, s), 1.82-1.94 (3H, m), 2.12-2.16 (1H, m), and 3.18-3.24 (1H, m), 4.13-4.16 (1H, m), 4.48 (1H, d, J11.7Hz), 4.91 (1H, d, J11.7Hz), 5.13 (1H, s), 6.85 (1H, s), 6.89 (1H, s), 7.20-7.29 (4H, m), 7.43 (2H, d, J7.2Hz) and 7.74 (1H, d, J8.6Hz).

Embodiment 120

(5R, 6S)-3-[2-cyano group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-oxa--spiral shell [4.5] last of the ten Heavenly stems-3-pinene hyhrochloride

According to the method for embodiment 2, by embodiment 119 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 1.96-2.18 (3H, m), 3.19-3.29 (1H, m), 3.49-3.56 (1H, m), 4.49 (1H, d, J12.5Hz), 4.91 (1H, d, J12.5Hz), 6.44,1H, s), 6.81 (1H, s), 7.17-7.19 (1H, m), and 7.33-7.38 (4H, m), 7.42-7.45 (2H, m) and 7.61 (1H, d, J8.7Hz).

Embodiment 121

(3S, 5R, 6S)-3-[2-(cyclo propyl methoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With cyclopropyl monobromomethane (0.078ml, 0.8mmol) join (3S, 5R, 6S)-3-[2-hydroxyl-5-(trifluoromethoxy) phenyl]-the 6-phenyl-(embodiment 44 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 330mg, 0.67mmol) and salt of wormwood (103mg is in DMF 0.75mmol) (5ml) mixture.Mixture at room temperature stirred 48 hours.Add entry (20ml), utilize ethyl acetate (2 * 20ml) extraction mixtures.The dry organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (90: 10) wash-out by quick silica gel chromatography, obtains title compound (150mg). ¹H NMR (360MHz, CDCl ₃) δ 0.31-0.35 (2H, m), 0.61-0.65 (2H, m), 1.20-1.29 (1H, m), 1.37 (9H, s), 1.72-1.84 (3H, m), 2.09-2.18 (2H, m), 2.41-2.47 (1H, m), 2.83-2.91 (1H, m), (3.39 1H, br s), and 3.62-3.68 (1H, m), 3.77-3.84 (2H, m), 3.98-4.02 (1H, m), 4.27-4.32 (1H, m), 5.21 (1H, s), 6.74-6.77 (1H, m), 6.99-7.04 (2H, m), and 7.21-7.33 (3H, m), with 7.56 (1H, d, J 7.5Hz).

Embodiment 122

(3S, 5R, 6S)-3-[2-(cyclo propyl methoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 2, by embodiment 121 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 0.29-0.28 (2H, m), 0.56-0.58 (2H, m), 1.14-1.18 (1H, m), and 1.78-2.02 (2H, m), 2.16-2.26 (3H, m), 3.18-3.28 (2H, m), 3.48-3.55 (1H, m), 3.74-3.79 (2H, m), 4.18-4.22 (1H, m), 4.40 (1H, s), 6.20 (1H, s), 6.92 (1H, d, J 9.0Hz), 7.02-7.06 (1H, m), and 7.45-7.53 (6H, m).

Embodiment 123

(3S, 5R, 6S)-3-[2-methoxyl group-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With sodium hydride (60% mineral oil dispersion liquid, 10mg) join (3S, 5R, 6S)-(embodiment 46, in DMF 100mg) (2ml) solution for 3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Mixture at room temperature stirs, and until producing foam, adds methyl-iodide (0.4ml), and mixture at room temperature stirred 1 hour.Add entry (10ml), utilize ethyl acetate (3 * 10ml) extraction mixtures.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is yellow oil (102mg).m/z(ES ⁺)492(M+1)。

Embodiment 124

(3S, 5R, 6S)-3-[2-methoxyl group-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 2, by embodiment 123 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 1.18 (2H, s), 1.54 (2H, d, J11.1Hz), 1.87 (1H, d, J12.2Hz), 2.04 (2H, d, J12.0Hz), 2.73 (1H, t, J12.4Hz), 3.10 (1H, dd, J8.0,10.4Hz), 3.18 (1H, d, J11.7Hz), 3.65 (3H, s), 4.02 (1H, t, J7.6Hz), 6.52 (1H, d, J2.1Hz), 6.69 (1H, d, J8.6Hz), 7.25 (4H, m) and 7.43 (3H, m).

Embodiment 125

(3S, 5R, 6S)-3-[2-methoxyl group-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(1,2,4-triazolyl-3-methyl)-7-azepine-spiral shell [4.5] decane

According to the method for embodiment 5, by embodiment 124 compound title compounds. ¹HNMR (500MHz, CDCl ₃) δ 0.9 (2H, t, J7.3Hz), 1.29 (2H, s), 1.35 (1H, q, J7.35Hz), 1.54 (1H, dt, J9.8,4Hz), 1.62 (2H, m), 2.00 (2H, m), 2.15 (1H, d, J12.3Hz), 3.11 (1H, m), 3.74 (3H, s), 3.82 (1H, m), 4.08 (1H, t, J8.0Hz), 6.52 (1H, s), 6.77 (1H, d, J8.6Hz), 7.25 (1H, s), 7.35 (4H, m), 7.58 (1H, m) and 8.13 (1H, s).

Embodiment 126

(5R, 6S)-3-(2-methylsulfonyl phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 71 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 8.14 (1H, dd, J7.7,1.34Hz), 7.61-7.47 (4H, m), 7.36-7.26 (3H, m), 7.10 (1H, dd, J7.33,1.51Hz), 6.16 (1H, t, J2.15Hz), 5.19 (1H, s), 4.90 (1H, dd, J12.5,2.1Hz), 4.56 (1H, dd, J12.5,2.2Hz), 4.11 (1H, dt, J12.3Hz), 3.20 (1H, m), 3.07 (3H, s), 2.17 (1H, m), 1.90 (3H, m) and 1.35 (9H, s).m/z(ES ⁺)470(M+1)。

Embodiment 127

(5R.6S)-3-(2-methylsulfonyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 126 compound title compounds. ¹HNMR (250MHz, CD ₃OD) δ 7.89 (1H, m), 7.50-7.22 (8H, m), 6.33 (1H, m), 5.71 (1H, t, J2.1Hz), 4.87 (1H, dd, J12.5,2.2Hz), 4.76 (5H, br s), 4.39 (1H, dd, J12.5,2.2Hz), 4.28 (1H, s), 3.38 (1H, broad peak d, J11.7Hz), 3.13 (1H, td, J10.2,2.5Hz), 2.71 (3H, s), and 2.27-1.87 (4H, m).m/z(ES ⁺)370(M+1)。

Embodiment 128

(3S, 5R, 6S)-3-(2-methylsulfonyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 127 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 7.9 (1H, dd, J7.7,1.99Hz), 7.55 (2H, br d), 7.38 (3H, m), 7.21 (2H, m), 6.16 (1H, d, J7.3Hz), 5.01 (2H, br s), 4.39 (1H, q, J8.9Hz), 4.17 (1H, t, J8.3Hz), 3.88 (1H, s), 3.47 (1H, m), 3.33 (1H, dm, J13.2Hz), 3.04 (3H, s), 2.88 (1H, td, J12.61Hz), 2.17 (3H, m), 1.86 (1H, dd, J12.7,10.3Hz) and 1.60 (2H, m).m/z(ES ⁺)372(M+1)。

Embodiment 129

4-hydroxyl-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl } oxyacetic acid (5R, 6S)-methyl esters

According to the method for embodiment 1, by illustrative examples 73 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.53 (2H, m), 7.18-7.32 (3H, m), 7.05 (1H, dd, J2.27,8.31Hz), 6.86 (1H, d, J2.27Hz), 6.82 (1H, d, J8.31Hz), 6.51 (1H, t, J2.06Hz), 6.33 (1H, br s), (5.24 1H, br s), 4.98 (1H, dd, J2.01,12.44Hz), 4.62 (1H, dd, J2.01,12.44Hz), 4.03-4.10 (1H, m), 3.68 (3H, s), 3.51 (2H, s), 3.02-3.10 (1H, m), 2.11-2.18 (1H, m), 1.75-1.88 (3H, m) and 1.42 (9H, s).

Embodiment 130

[4-hydroxyl-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] oxyacetic acid (5R, 6S)-methyl esters

According to the method for embodiment 2, by embodiment 129 compound title compounds. ¹HNMR (250MHz, CDCl ₃) δ 7.37-, 7.42 (2H, m), 7.16-7.30 (3H, m), 6.96 (1H, dd, J2.18,8.40Hz), 6.70 (1H, d, J2.18Hz), 6.68 (1H, d, J8.40Hz), 5.87 (1H, t, J2.18Hz), 4.82 (1H, dd, J2.06,12.54Hz), 4.30 (1H, dd, J2.06,12.54Hz), 3.78 (1H, s), 3.65 (3H, s), 3.44 (2H, s), 3.25-3.36 (1H, m), 2.82 (1H, dt, J2.83,12.39Hz), 1.97-2.09 (2H, m), and 1.65-1.84 (2H, m).

Embodiment 131

[4-hydroxyl-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] oxyacetic acid (3S, 5R, 6S)-methyl esters

According to the method for embodiment 3, by embodiment 130 compound title compounds. ¹HNMR (250MHz, DMSO-d ₆) δ 9.33 (1H, br s), and 7.50-7.54 (2H, m), 7.35-7.44 (3H, m), 6.80 (1H, dd, J2.11,8.18Hz), 6.65 (1H, d, J8.18Hz), 5.99 (1H, d, J2.11Hz), 3.89-4.04 (2H, m), 3.64-3.72 (1H, m), 3.60 (3H, s), 3.30 (2H, s), 3.11-3.16 (1H, m), 2.94 (1H, dd, J7.84,10.36Hz), 2.78-2.87 (1H, m), and 1.62-2.06 (6H, m)

Embodiment 132

4-hydroxyl-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl } oxyacetic acid (3S, 5R, 6S)-methyl esters

With N-ethyl diisopropylamine (0.324ml, 1.9mmol) join [4-hydroxyl-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] oxyacetic acid (3S, 5R, 6S)-(embodiment 131 for methyl esters, 309mg, 0.81mmol) and two dimethyl dicarbonate butyl esters (400mg, in tetrahydrofuran (THF) 1.83mmol) (100ml) mixture, mixture at room temperature stirred 4 hours.(0.324ml, 1.9mmol), mixture at room temperature stirred 16 hours, was injected in the saturated sodium bicarbonate aqueous solution (100ml), utilized ethyl acetate (2 * 100ml) extractions further to add N-ethyl Isopropylamine.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue obtains title compound by the silica gel chromatography purifying, is colorless solid (259mg, 66%). ¹H NMR (250MHz, CDCl ₃) δ 7.55-7.58 (2H, m), 7.24-7.35 (3H, m), 6.98-7.01 (2H, m), 6.71 (1H, d, J8.75Hz), 5.99 (1H, br s), 5.35 (1H, br s), 4.22 (1H, dd, J7.13,8.95Hz), 3.90-3.98 (2H, m), 3.66 (3H, s), 3.51 (2H, s), 2.84-2.88 (1H, m), 2.48 (1H, dd, J8.84,12.87Hz), 2.05-2.24 (3H, m), 1.72-1.82 (3H, m) and 1.35 (9H, s).

Embodiment 133

4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl } oxyacetic acid (3S, 5R, 6S)-methyl esters

With methyl iodide (0.051ml, 0.81mmol) join 4-hydroxyl-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] phenyl oxyacetic acid (3S, 5R, 6S)-(embodiment 132 for methyl esters, 259mg, 0.54mmol) and salt of wormwood (149mg, in acetone 1.08mmol) (10ml) mixture, reflux mixture 16 hours.Cooling mixture filters solvent evaporated under reduced pressure.Add saturated sodium bicarbonate aqueous solution (20ml), utilize ethyl acetate (2 * 20ml) extractions.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue obtains title compound, jelly (179mg, 67%) by the silica gel chromatography purifying. ¹H NMR (250MHz, CDCl ₃) δ 7.55-7.58 (2H, m), 7.20-7.35 (3H, m), 7.10 (1H, dd, J2.25,8.28Hz), 7.04 (1H, d, J2.25Hz), 6.80 (1H, d, J8.28Hz), (5.21 1H, br s), and 4.16-4.20 (1H, m), 3.96-4.02 (1H, m), 3.80 (3H, s), 3.69-3.72 (2H, m), 3.64 (3H, s), 3.52 (2H, s), 2.82-2.94 (1H, m), 2.34-2.42 (1H, m), 2.08-2.24 (2H, m, 1.72-1.78 (3H, m) and 1.37 (9H, s).

Embodiment 134

(3S, 5R, 6S)-4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl] and phenyl } ethanamide

According to the method for embodiment 109, by embodiment 133 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.54-7.57 (2H, m), 7.23-7.34 (4H, m), 7.13 (1H, dd, J8.27,2.24Hz), 6.81 (1H, d J8.27Hz), 5.31 (1H, br s), 5.17 (1H, br s), 4.25 (1H, dd, J6.84,14.75Hz), 3.93-4.00 (1H, m), 3.81 (3H, s), 3.47 (2H, s), 3.00 (1H, t, J7.07Hz), 2.80-2.84 (1H, m), 2.27-2.31 (2H, m), 2.12-2.16 (1H, m), 1.66-1.73 (3H, m) and 1.39 (9H, s).

Embodiment 135

(3S, 5R, 6S)-3-[5-(cyano methyl)-2-p-methoxy-phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 111, by embodiment 134 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.54-7.57 (2H, m), 7.24-7.36 (3H, m), 7.17 (1H, dd, J2.34,8.36Hz), 7.05 (1H, d, J2.34Hz), 6.83 (1H, d, J8.36Hz), 5.21 (1H, br s), 4.20 (1H, t, J6.84Hz), 3.96-4.02 (1H, m), 3.82 (3H, s), 3.68-3.79 (2H, m), 3.63 (2H, s), 2.84-2.96 (1H, m), 2.32-2.41 (1H, m), 2.06-2.23 (2H, m), 1.73-1.78 (3H, m) and 1.37 (9H, s)

Embodiment 136

(3S, 5R, 6S)-3-[5-(cyano methyl)-2-p-methoxy-phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 111, by embodiment 135 compound title compounds. ¹H NMR (360MHz, DMSO-d ₆) δ 9.56 (1H, br d), 8.84 (1H, br d), 7.55-7.58 (2H, m), 7.48-7.51 (3H, m), 7.09 (1H, d, J8.52Hz), 6.87 (1H, d, J8.52Hz), 6.34 (1H, s), 4.47-4.50 (1H, m), 4.09 (1H, t, J7.63Hz), 3.72 (2H, s), 3.59 (3H, s), 3.08-3.30 (4H, m), 1.96-2.07 (3H, m), and 1.77-1.85 (3H, m).m/z(ES+)363(M+1)。

Embodiment 137

(5R, 6S)-(4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] phenyl) carboxylic acid amides

According to the method for embodiment 1, by illustrative examples 63 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (250MHz, CDCl ₃) δ 1.36 (9H, s), 1.81-2.11 (4H, m), 3.02-3.16 (1H, m), 3.86 (3H, s), 4.10-4.16 (1H, m), 4.62-4.67 (1H, dd, J2,12Hz), 4.95-5.01 (1H, dd, J2,12Hz), 5.16 (1H, s), 6.66 (1H, m), 6.91-6.95 (2H, m), 7.19-7.58 (5H, m) and 7.59 (1H, d, J2.2Hz).m/z(ES ⁺)465(M+1)。

Embodiment 138

(5R, 6S)-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] carboxylic acid amides

According to the method for embodiment 2, by embodiment 137 compound title compounds. ¹HNMR (250MHz, DMSO-d ₆) δ 1.51-1.63 (1H, m), 1.86-1.96 (3H, m), 2.58-2.72 (1H, m), 3.10-3.15 (1H, m), 3.81 (1H, s), 3.87 (3H, s), 4.20-4.25 (1H, dd, J2,12Hz), and 4.77-4.83 (1H, dd, J2,12Hz), 6.43 (1H, s), 7.04-7.39 (7H, m), and 7.77-7.81 (1H, dd, J2,8.6Hz).

Embodiment 139

(3S, 5R, 6S)-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] carboxylic acid amides

According to the method for embodiment 3, by embodiment 138 compound title compounds. ¹HNMR (360MHz, DMSO-d ₆) δ 1.78-1.85 (3H, m), 1.97-2.08 (3H, m), 3.00-3.08 (1H, m), 3.21-3.31 (2H, m), 3.61 (3H, s), 3.63-3.88 (1H, m), 4.11-4.15 (1H, m), 4.47-4.51 (1H, m), 6.90 (1H, d, J8.60Hz), 7.08 (1H, s), 7.21 (1H, d, J2.04Hz), 7.41-7.48 (3H, m), 7.54-7.56 (2H, m), 7.66-7.69 (2H, m), 8.93 (1H, brs) and 9.55 (1H, br s).m/z(ES ⁺)367(M+1)。

Embodiment 140

(3S, 5R, 6S)-3-(5-cyano group-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

(250mg) joins (3S with salt of wormwood; 5R; 6S)-and 3-(5-cyano group-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(trifluoroacetyl group) azepine-spiral shell [4.5] decane (illustrative examples 72, in methyl alcohol 160mg) (10ml) and water (1ml) solution, reflux mixture 2 hours.Cooling mixture also utilizes the water dilution.Utilize the ethyl acetate extraction mixture.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes CH by the silica gel chromatography purifying ₂Cl ₂/ MeOH (increasing to 92.5: 7.5 at 97.5: 2.5) obtains title compound. ¹H NMR (250MHz, DMSO-d ₆) δ 1.72-1.79 (3H, m), 2.01-2.09 (3H, m), 3.06-3.12 (1H, m), 3.23-3.28 (2H, m), 3.66, (3H, s), 3.71-3.76 (1H, m), and 4.08-4.12 (1H, m), 4.47-4.50 (1H, m), 6.67 (1H, d, J2.0Hz), 6.99 (1H, J8.7Hz), and 7.47-7.63 (5H, m).m/z(ES ⁺)349(M+1)。

Embodiment 141

4-methoxyl group-3-[6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl] and phenyl } oxyacetic acid (5R.6S)-methyl esters

According to the method for embodiment 1, by illustrative examples 74 compounds and (5R, 6S)-3-tributyl stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.47 (2H, d, J7.3Hz), 7.26 (2H, t, J7.3Hz), 7.19 (1H, t, J7.3Hz), 7.16 (1H, dd, J8.4,2.3Hz), 6.94 (1H, d, J2.3Hz), 6.86 (1H, d, J8.4Hz), 6.61 (1H, t, J2.1Hz), 5.15 (1H, s), 4.96 (1H, dd, J12.0,2.1Hz), 4.63 (1H, dd, J12.0,2.1Hz), 4.14 (1H, m), 3.84 (3H, s), 3.68 (3H, s), 3.54 (2H, s), 3.11 (1H, m), 2.10 (1H, m), 1.95-1.74 (3H, m) and 1.37 (9H, s).

Embodiment 142

[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] oxyacetic acid (5R, 6S)-methyl esters

According to the method for embodiment 2, by embodiment 141 compound title compounds. ¹HNMR (360MHz, CDCl ₃) δ 7.37 (2H, d, J6.9Hz), 7.16 (3H, m), 7.07 (1H, dd, J8.4,2.2Hz), 6.76 (1H, d, J8.4Hz), 6.70 (1H, d, J2.2Hz), 6.10 (1H, t, J2.1Hz), 4.86 (1H, dd, J11.9,2.1Hz), 4.33 (1H, dd, J11.9,2.1Hz), 3.76 (1H, s), 3.74 (3H, s), 3.66 (3H, s), 3.46 (2H, s), 3.27 (1H, m), 2.81 (1H, m), and 2.10-1.61 (5H, m).m/z(ES ⁺)394(M+1)。

Embodiment 143

[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] oxyacetic acid (3S, 5R, 6S)-methyl esters

According to the method for embodiment 3, by embodiment 142 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 7.52 (5H, m), 7.01 (1H, dd, J8.4,2.1Hz), 6.87 (1H, d, J8.4Hz), 6.03 (1H, d, J2.1Hz), 4.74 (2H, brs), 4.39 (1H, s), 4.10 (1H, m), 3.87 (1H, m), 3.69 (3H, s), 3.68 (3H, s), 3.51 (1H, m), 3.42 (2H, s), 3.34-3.18 (2H, m), and 2.21-1.80 (6H, m).m/z(ES ⁺)396(M+1)。

Embodiment 144

(3S, 5R, 6S)-3-(5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl)-6-phenyl-1-oxa--7-(tert.-butoxy) azepine-spiral shell [4.5] decane

To (3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-the 6-phenyl-(embodiment 38 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 320mg, 0.65mmol) pyridine (2ml) cooling (0 ℃) solution in add trifluoromethanesulfanhydride anhydride (0.12ml, 0.71mmol), mixture stirred 2 hours at ambient temperature.Utilize (80ml) washing reaction of copper/saturated copper sulphate (II), utilize ethyl acetate (3 * 60ml) extractions.The organic fraction that utilizes water (80ml), salt solution (80ml) washing to merge, dry (MgSO ₄), vacuum-evaporation.Purifying on silica gel utilizes 25% ethyl acetate/hexane wash-out, obtains title compound, is yellow oil (160mg). ¹H NMR (250MHz, CDCl ₃) δ 1.36 (9H, s), 1.75 (3H, m), 2.11 (2H, m), 2.53 (1H, m), 2.95 (1H, m), 3.66 (1H, q, J7.9Hz), 3.72 (1H, m), 4.0 (1H, m), 4.23 (1H, t, J6.5Hz), 5.18 (1H, s), 7.16 (2H, m), 7.30 (4H, m) and 7.53 (2H, d, J7.1Hz).

Embodiment 145

(3S, 5R, 6S)-3-(5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 2, by embodiment 144 compound title compounds. ¹HNMR (360MHz, D ₂O) δ 1.78-2.00 (3H, m), 2.07-2.36 (3H, m), 3.42-3.50 (2H, m), 3.77-3.89 (1H, m), 4.16-4.24 (1H, m), 4.441H, s), 6.09 (1H, s), 7.16-7.20 (1H, m), 7.36 (1H, d, J9.2Hz), and 7.50-7.55 (6H, m).

Embodiment 146

(3S, 5R, 6S)-and 7-{5-(dimethylamino methyl)-1H-[1,2,3] triazole-4-yl] methyl }-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

Dimethylamine is blown into (3S, 5R, 6S)-7-(4-azido-fourth-2-alkynes-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-(illustrative examples 76,98mg) De diox (3ml) solution is 10 minutes for 6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.In airtight test tube with mixture in 80 ℃ of following heated overnight, cooling mixture, solvent evaporated under reduced pressure.Utilize water (20ml) diluted mixture thing, utilize ethyl acetate (3 * 5ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes CH by the silica gel chromatography purifying ₂Cl ₂/ MeOH/NH ₃(hydration) (increasing to 90: 10: 1 at 98: 2: 0) wash-out..Residue is dissolved in the ether, utilizes excessive ether to close the salt acid treatment.Solvent evaporated under reduced pressure, residue is by ethanol/re-crystallizing in ethyl acetate.Collect solid and vacuum-drying, obtain title compound, be colorless solid. ¹H NMR (360MHz, DMSO-d ₆) δ 1.24 (6H, t, J6.2Hz), 1.62 (1H, m), 1.68-1.92 (2H, m), 2.04-2.26 (3H, m), 2.68 (6H, s), 3.07 (1H, m), 3.36 (1H, m), 3.58-3.72 (1H, m), 3.74-3.96 (2H, m), 4.10-4.39 (4H, m), 4.66 (1H, q, J6.0Hz), (4.6 1H, br s), 6.45 (1H, s), 7.09 (1H, d, J8.6Hz), 7.36-7.68 (5H, m), and 8.00-8.10 (1H, m).m/z(ES ⁺)m/z558(M+1)。

Embodiment 147

(3S, 5R, 6S)-3-[5-fluoro-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(1,2,4-triazolyl-3-methyl)-7-azepine-spiral shell [4.5] decane

According to the method for embodiment 5, by embodiment 19 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.54 (1H, dt, J13,4Hz), 1.58-1.64 (1H, m), 1.77 (1H, t, J12Hz), 1.94 (1H, dd, J12,12Hz), 2.00-2.22 (2H, m), 2.37 (1H, m), and 3.00-3.10 (1H, m), 3.13 (1H, t, J8Hz), and 3.38-3.52 (2H, m), 3.74-3.92 (2H, m), 4.11 (1H, t, J8Hz), 4.22 (2H, q, J8Hz), 5.95 (1H, dd, J9,3Hz), 6.66 (1H, dd, J9,4.5Hz), 6.76 (1H, dt, J9,3Hz), 7.30-7.37 (3H, m), 7.56 (2H, br s, ArH) and 7.92 (1H, s).m/z(ES ⁺)m/z491(M+1)。Measured value: C, 60.76; H, 5.28; N, 11.15, C ₂₅H ₂₆F ₄N ₄O ₂Theoretical value: C, 61.22; H, 5.34; N, 11.42%.

Embodiment 148

(5R, 6S)-3-[2-dimethylamino-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 1, by illustrative examples 78 compounds and (5R, 6S)-3-trimethylammonium stannyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene prepares title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.47 (2H, d, J7.4Hz), 7.29-6.94 (6H, m), 6.36 (1H, t, J2.1Hz), 5.12 (1H, s), 4.92 (1H, dd, J12.6,2.1Hz), 4.61 (1H, dd, J12.6,2.1Hz), 4.13 (1H, m), 3.14 (1H, m), 2.57 (6H, s), 2.05 (1H, m), 1.85 (3H, m) and 1.35 (9H, s).

Embodiment 149

(5R, 6S)-3-[2-dimethylamino-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene

According to the method for embodiment 2, by embodiment 148 compound title compounds.

Embodiment 150

(3S, 5R, 6S)-3-[2-dimethylamino-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 3, by embodiment 149 compound title compounds.m/z(ES ⁺)m/z?421(M+1)。

Embodiment 151

(±)-(3R*, 5R*, 6S*)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] decane

At room temperature, with formic acid (35ml, 0.95mmol) join (±)-(5R*, 6S*)-6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 84,125mg, 0.36mmol) acid chloride (II) (8.3mg, 0.036mmol), three-o-tolylphosphine (21mg, 0.071mmol), Tributylamine (282ml, 1.23mmol) and 2-iodanisol (112ml, 0.87mmol) N, dinethylformamide (2ml) stirs in the de-gassed solution, the gained mixture is 100 ℃ of heating 2 hours down.Add the second equivalent acid chloride (II), three-o-tolylphosphine, Tributylamine and 2-iodanisol, mixture stirred 18 hours down at 90 ℃.Cooling mixture filters, and utilizes ether (15ml) dilution, utilize water (5ml), hydrochloric acid (2M, 10ml) and saturated sodium-chloride water solution (10ml) washing, drying (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/ethyl acetate (80: 20) washing by the silica gel chromatography purifying, obtains title compound, is yellow oil (28mg, 17%). ¹HNMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J7.8Hz), 7.18-7.32 (10H, m), 6.92 (1H, t, J7.5Hz), 6.85 (1H, d, J8.7Hz), 5.42 (1H, s), 5.19 (1H, d, J12.4Hz), 5.16 (1H, d, J12.6Hz), 4.31 (1H, t, J6.6Hz), 4.02-4.10 (1H, m), 3.80-3.90 (2H, m), 3.79 (3H, s), 2.87 (1H, dt, J4.4,12.7Hz), 2.54 (1H, dd, J7.2,12.7Hz), 2.23 (1H, dt, J5.5,12.5Hz), 1.95 (1H, dd, J10.4,12.6Hz), and 1.64-1.84 (3H, m).m/z(ES ⁺)458(M+1)。

Embodiment 152

(±)-(3R*, 5R*, 6S*)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

With palladium/carbon (10%, 10mg) join (±)-(3R*, 5R*, 6S*)-3-(2-p-methoxy-phenyl)-(embodiment 151 for 6-phenyl-1-oxa--7-(phenyl methoxycarbonyl) azepine-spiral shell [4.5] decane, 17mg, 0.037mmol) and ethanol (10ml) stirred solution of tetrahydrobenzene (2ml) in, reflux gained suspension 5 hours.Cooling mixture filters solvent evaporated under reduced pressure.Residue utilizes methylene chloride/ammonia (95: 5: 1) wash-out by the preparative chromatography purifying, obtains title compound, is orange oily matter (4mg, 33%). ¹H NMR (360MHz, CDCl ₃) δ 7.47 (2H, dd, J1.9,7.9Hz), 7.27-7.35 (3H, m), 7.10 (1H, dt, J1.7,7.8Hz), 6.97 (1H, d, J7.6Hz), 6.81 (1H, t, J7.5Hz), 6.72 (1H, d, J8.2Hz), 3.94 (1H, t, J7.6Hz), 3.68 (1H, dd, J7.9,10.6Hz), 3.63 (3H, s), 3.53 (3H, s), 3.16-3.26 (1H, m), 2.78 (1H, dt, J2.7,12.3Hz), 2.28-2.38 (1H, m), 2.15 (1H, dd, J8.0,12.4Hz), 1.92-2.10 (2H, m), and 1.56-1.70 (4H, m).m/z(ES ⁺)324(M+1)。

Embodiment 153

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

With three silicoethane (0.1ml, 0.6mmol) join (5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-alkene (illustrative examples 92,14mg, 0.03mmol) trifluoroacetic acid (1ml) solution in, mixture at room temperature stirred 2 hours.(0.1ml, 0.6mmol), mixture at room temperature stirred 15 hours to add three other silicoethanes.Solvent evaporated under reduced pressure, residue and toluene (2 * 10ml) azeotropic.Add saturated aqueous sodium carbonate, utilize methylene dichloride (3 * 10ml) extraction mixtures.The organic fraction that utilizes salt solution (20ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure, residue utilizes methylene chloride/ammonia (120: 8: 1) wash-out by the preparation of silica gel chromatogram purification, obtains jelly (6mg).The HPLC of this jelly analyzes [HIPRB post (250 * 4.6mm); In 25mM KH ₂PO ₄In 40%MeCN, 0.2% triethylamine, pH3.1,210nm] show that it contains (5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene, (3S, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane and (3R, 5R, 6S)-mixture (ratio is 1.5: 2.5: 1) of 3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

Embodiment 154

With three silicoethane (0.25ml, 1.6mmol) join (5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 92 for 3-alkene, 32mg, 0.08mmol) trifluoroacetic acid (2ml) solution in, mixture stirred 16 hours down at 50 ℃.Solvent evaporated under reduced pressure, residue and toluene (2 * 10ml) azeotropic.Add saturated aqueous sodium carbonate, utilize methylene dichloride (4 * 20ml) extraction mixtures, the organic fraction that utilizes salt solution (20ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes methylene chloride/ammonia (120: 8: 1) wash-out by preparation property silica gel thin-layer chromatography purifying, obtains jelly (6mg).The HPLC of this jelly analyzes [HIPRB post (250 * 4.6mm); In 25mM KH ₂PO ₄In 40%MeCN, 0.2% triethylamine, pH3.1,210nm] show that it contains (3S, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane and (3R, 5R, 6S)-mixture (ratio is 2: 1) of 3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

Embodiment 155

(3R, 5R, 6S)-3, two (phenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane of 6-

With ((illustrative examples 95,13mg 0.03mm0l) are dissolved in the methylene dichloride (1ml) 2 ' R)-3-(1-tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-phenylpropyl alcohol-1-alcohol for 2S, 3R.(0.038ml, 0.045mmol), (3.2ml, 0.039mmol), mixture stirred 72 hours at ambient temperature then to add methylsulfonyl chloride to add pyridine.Add methylene dichloride (10ml), utilize water (10ml) purging compound, dry (Na ₂SO ₄) and solvent evaporated under reduced pressure.Residue utilizes ethyl acetate/hexane (25: 75) wash-out by preparation property silica gel thin-layer chromatography purifying, obtains title compound, is oily matter (6.4mg). ¹H NMR (360MHz, CDCl ₃) δ 7.61-7.59 (2H, m), 7.35-7.30 (4H, m), 7.27-7.22 (4H, m), 5.34 (1H, s), 4.31 (1H, t, J8.1Hz), 4.00-3.96 (1H, m), 3.89 (1H, t, J8.9Hz), 3.62-3.54 (1H, m), and 2.80-2.72 (1H, m), 2.70-2.65 (1H, m), 2.29-2.21 (1H, m), 1.92-1.85 (1H, m), 1.81-1.78 (1H, m), 1.70-1.54 (3H, m) and 1.47 (9H, s).m/z(ES ⁺)394(M+1)。

Embodiment 156

(3R, 5R, 6S)-3, two (the phenyl)-1-oxa-s of 6--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 155 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.51-7.48 (2H, m), 7.35-7.33 (3H, m), 7.21-7.13 (3H, m), and 6.91-6.88 (2H, m), 4.04-3.99 (1H, t, J7.9Hz), 3.66 (1H, s), 3.66-3.60 (1H, m), 3.26-3.22 (1H, m), 2.85-2.79 (1H, m), (2.75 1H, br s), and 2.24-2.11 (2H, m), 2.03-1.94 (2H, m), and 1.73-1.61 (3H, m).m/z(ES ⁺)294(M+1)。

Embodiment 157

(3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Under 0 ℃, (10ml, (42ml, 0.3mmol) (19mg is in methylene dichloride 0.043mmol) (2ml) solution with illustrative examples 39 products 0.14mmol) to join triethylamine with methylsulfonyl chloride.Mixture is warmed to room temperature, stirred 18 hours, utilize methylene dichloride (20ml) dilution, utilize hydrochloric acid (2M, 10ml) and saturated aqueous sodium carbonate (10ml) washing, drying (MgSO ₄) and solvent evaporated under reduced pressure.Residue is collected in the tetrahydrofuran (THF) (3ml), utilize sodium hydride (60% oily dispersion liquid, 100ml) reflux is 18 hours, the cooling, be injected into hydrochloric acid soln (2M, 20ml) in, utilize ethyl acetate (2 * 20ml) extraction.The organic fraction that utilizes saturated sodium-chloride water solution (10ml) washing to merge, dry (MgSO ₄) and solvent evaporated under reduced pressure.Residue is by the silica gel chromatography purifying, utilize hexane/ethyl acetate (80: 20) wash-out, obtain (3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane and (3S, 5R, 6S)-1: 3 mixture (8mg, 44%) of 3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane. ¹H NMR (360MHz, CDCl ₃) δ 7.61 (2H, d, J7.6Hz, 3R isomer), (7.57 2H, d, J7.5Hz, 3S isomer), (7.05-7.34 5H, m, 3R and 3S isomer), 6.80-6.98 (2H, m, 3R and 3S isomer), 5.37 (1H, s, the 3R isomer), 5.25 (1H, s, 3S isomer), (4.31 1H, t, J7.4Hz, 3R isomer), (4.21 1H, t, J7.2Hz, 3S isomer), (3.95-4.04 1H, m, 3R and 3S isomer), 3.82 (3H, s, the 3R isomer), 3.81 (3H, s, the 3S isomer), 3.64-3.81 (2H, m, 3R and 3S isomer), (2.85 1H, dt, J5.9 and 12.1Hz, 3S isomer), 2.67 (1H, dt, J4.9,12.7Hz, the 3R isomer), 2.59 (1H, dd, J7.3 and 12.7Hz, the 3R isomer), 2.37 (1H, dd, J8.0 and 12.6Hz, the 3S isomer), 2.21 (1H, dd, J9.1,12.6Hz, the 3S isomer), 2.08-2.23 (1H, m, 3R and 3S isomer), 1.93 (1H, dd, J10.4,12.4Hz, the 3R isomer), 1.64-1.78 (3H, m, 3R and 3S isomer), 1.47 (9H, s, 3R isomer), with 1.38 (9H, s, 3S isomer).m/z(ES ⁺)424(M+1)。

Embodiment 158

(3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

Method according to embodiment 181, by embodiment 157 compound (3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane and (3S, 5R, 6S)-mixture of 3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane. ¹H NMR (360MHz, CDCl ₃) δ 7.51-7.59 (2H, m, 3R and 3S isomer), 7.32-7.45 (3H, m, 3R and 3S isomer), 7.05-7.13 (1H, m, 3R and 3S isomer), 6.97 (1H, d, J7.6Hz, 3R isomer), 6.81 (1H, t, J7.5Hz, the 3R isomer), 6.71-6.82 (1H, m, 3R and 3S isomer), (6.69 1H, t, J7.5Hz, 3S isomer), 6.43 (1H, d, J7.6Hz, 3S isomer), 4.09 (1H, t, J7.8Hz, the 3S isomer), 3.94 (1H, t, J7.6Hz, the 3R isomer), 3.67-3.87 (1H, m, 3R and 3S isomer), 3.68 (4H, s, the 3S isomer), 3.63 (3H, s, 3R isomer), (3.53 1H, s, 3R isomer), 3.17-3.25 (1H, m, 3R and 3S isomer), 2.75-2.84 (1H, m, 3R and 3S isomer), and 1.55-2.37 (8H, m, 3R and 3S isomer).m/z(ES ⁺)324(M+1)。

Embodiment 159

To (2S, 3R, 2 ' R)-3-(1 tert-butoxycarbonyl-3-hydroxyl-2-Phenylpiperidine-3-yl)-2-(2-p-methoxy-phenyl) third-1-alcohol (illustrative examples 101,0.073g, 0.166mmol) methylene dichloride (1ml) and anhydrous pyridine (0.067ml) solution in add methylsulfonyl chloride (0.015ml, 0.2mmol).Solution at room temperature stirred 16 hours, added pyridine (1ml) then, and solution further heated 2 hours in 80 ℃ of oil baths.Solvent evaporated under reduced pressure is dissolved in residue in the depleted copper sulfate aqueous solution and the ethyl acetate.Utilize water and salt water washing organic phase, dry (MgSO ₄) and solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (95: 5) wash-out by the silica gel chromatography purifying, obtains title compound (0.55mg). ¹H NMR (360MHz, CDCl ₃) δ 7.56 (2H, dJ 7.9Hz), 7.25 (2H, t J7.2Hz), 7.20-7.17 (1H, m), 6.88 (1H, td J7.5Hz and 1Hz), (6.79 1H, d J7.8Hz), 5.30 (1H, s), (4.24 1H, t J7.4Hz), 3.90-3.79 (3H, m), 3.75 (3H, s), (2.67 1H, td J12.0Hz and 4.5Hz), 2.53 (1H, dd J12.6Hz and 7.2Hz), 2.14 (1H, td, J12.5Hz and 5.7Hz), 1.85 (1H, dd J12.4Hz and 10.4Hz), (1.65 1H, broad peak d J12.8Hz), 1.63-1.47 (2H, m) and 1.40 (9H, s).m/z(ES ⁺)424(M+1)。

Embodiment 160

(3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-l-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 188, by embodiment 159 compound title compounds. ¹H NMR (360MHz, CD ₃OD) δ 7.57 (2H, m), 7.53 (3H, m), 7.11 (1H, t J8.1Hz), 6.95 (1H, d H7.7Hz), 6.80 (2H, m), 4.27 (1H, s), 4.02 (1H, t J7.64), 3.77 (1H, dd J10.5Hz and 8.3Hz), 3.63 (3H, s), 3.40 (1H, broad peak d), (3.18 1H, broad t), and 2.34-2.21 (3H, m), 2.07 (1H, m), and 1.96-1.83 (3H, m).

Embodiment 161

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone

Utilize nitrogen with (5R, 6S)-3-(2-methoxyl group-5-trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 52 for 3-alkene-2-ketone, 100mg, 0.19mmol) and the N of acid chloride (10mg), N-' dimethyl formamide (1ml) mixture degassing 30 minutes.(42mg, 0.50mmol), mixture heated 16 hours down at 80 ℃ to add potassium formiate.Mixture is injected in the water (10ml), utilizes ethyl acetate (2 * 10ml) extractions.Dry (Na ₂SO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue obtains title compound by the silica gel chromatography purifying, is colorless solid (44mg, 0.08mmol, 44%). ¹H NMR shows that it is 1: 1 (3S, 5R, 6S)-and (3R, 5R, 6S)-mixture of steric isomer, by utilizing being prepared property of KR60 post liquid chromatography purifies and separates, utilization contains the 5% ethanol/hexane wash-out of 0.1%DEA, obtains (3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.14 (1H, dd, J2.59,8.96Hz), 7.02 (1H, d, J2.59Hz), 6.88 (1H, d, J8.96Hz), 5.35 (1H, s), 4.00-4.05 (1H, m), 3.85 (3H, s), 3.70 (1H, t, J11.02Hz), 2.70-2.97 (2H, m), and 2.38-2.50 (1H, m), 2.22 (1H, dd, J11.32,12.97Hz), 1.72-1.92 (3H, m) and 1.46 (9H, s); (3S, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone, ¹H NMR (250MHz, CDCl ₃) δ 7.50-7.53 (2H, m), 7.26-7.39 (3H, m), 7.13 (1H, dd, J2.9l, 8.97Hz), 6.90 (1H, d, J2.9lHz), 6.83 (1H, d, J8.97Hz), 5.31 (1H, br s), 4.02-4.10 (1H, m), 3.92 (1H, t, J10.56Hz), 3.64 (3H, s), 2.91-3.02 (1H, m), 2.67 (1H, dd, J10.04,12.98Hz), 2.29-2.52 (2H, m), 1.80-1.87 (3H, m) and 1.36 (9H, s).

Embodiment 162

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-keto hydrochloride

According to the method for embodiment 181, by embodiment 161 compound title compounds, m.p.244-245 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 10.20 (1H, br s), 9.40 (1H, br s), 7.60-7.62 (2H, m), 7.52-7.54 (3H, m), 7.23 (1H, dd, J2.61,9.03Hz), 7.04 (1H, d, J9.03Hz), 6.88 (1H, d, J2.61Hz), 4.67 (1H, br s), 3.73 (3H, s), 3.34-3.38 (1H, m), 3.10-3.12 (1H, m), 2.61 (1H, dd, J9.78,12.65Hz), and 1.93-2.20 (6H, m).m/z(ES ⁺)422(M+1)。

Embodiment 163

(3R, 5R, 6S)-and (3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Will (5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-(embodiment 35,3.88g) are dissolved in ethyl acetate (15ml) and the methyl alcohol (15ml) for 3-alkene.Add palladium hydroxide/carbon (1.00g), suspension vibrates 72 hours down at hydrogen atmosphere (50psi).Filtering mixt, solvent evaporated under reduced pressure.Residue is by the silica gel medium pressure chromatogram purification, utilize hexane/ethyl acetate (75: 25) wash-out, obtain (3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (191mg) ¹H NMR (250MHz, CDCl ₃) δ 7.70 (2H, d, J7.3Hz), 7.33 (2H, t, J7.3Hz), 7.26 (1H, d, J7.3Hz), 7.05 (1H, br s), 6.96 (2H, m), 6.82 (1H, d, J9.4Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m); With 1.50 (9H, s). and (3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, ¹H NMR (360MHz, CDCl ₃) δ 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m), 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J7.2Hz), 3.92 (1H, m), 3.98 (1H, d, J13.2Hz), 4.23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J8.5Hz), 6.94 (2H, m), 7.25 (1H, m), 7.31 (2H, m) and 7.55 (2H, d, J7.8Hz).

Embodiment 164

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With (3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-the 6-phenyl-(embodiment 163 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 180mg) be dissolved in the dimethyl formamide (2ml), add sodium hydride (60% mineral oil dispersion liquid, 23mg) stop bubbling after, add methyl-iodide (0.1ml), mixture at room temperature stirred 3 hours.Drip entry (5ml) in reaction soln, dilute this mixture, utilize ethyl acetate (3 * 10ml) extractions with (20ml) water.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure obtains title compound, is oily matter (235mg). ¹H NMR (250MHz, CDCl ₃) δ 7.61 (2H, d, J7.9Hz), 7.36-7.24 (3H, m), 7.09 (2H, m), 6.82 (1H, d, J8.7Hz), 5.35 (1H, s), 4.30 (1H, m), 3.98 (1H, m), 3.89-3.78 (2H, m), 3.83 (3H, s), 2.77 (1H, m), 2.59 (1H, m), 2.22 (1H, m), 1.90-1.66 (4H, m) and 1.47 (9H, s).

Embodiment 165

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 164 compound title compounds. ¹H NMR (500MHz, CD ₃OD) δ 1.88 (1H, dd, J12.6,10.9Hz), 1.99 (2H, m), 2.13 (1H, d, J15.4Hz), 2.34 (2H, m), 2.39 (1H, m), 3.25 (1H, dt, J15.8,3.3Hz), 3.45 (1H, m), 3.72 (3H, s), 3.79 (1H, dd, J8.3,1.2Hz), 4.09 (1H, t, J7.5Hz), 4.48 (1H, s), 6.94 (2H, m), 7.10 (1H, d, J8.9Hz), 7.58 (3H, t, J2.6Hz) and 7.64 (2H, t, J3.6Hz).

Embodiment 166

(3R, 5R, 6S)-7-benzyl-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

Will (3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride (embodiment 165,100mg, 0.2mmol) and salt of wormwood (38mg) be dissolved in the dimethyl formamide (0.5ml).Add bromotoluene (0.3ml), mixture stirred 3 hours down at 60 ℃ then in stirred overnight at room temperature.Cooling mixture utilizes water (10ml) dilution, utilizes ether (3 * 10ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue is dissolved in the ethyl acetate (5ml), add ether close hydrogenchloride (1M, 1ml).Collect solid, vacuum-drying obtains title compound, is crystalline solid (19mg). ¹H NMR (360MHz, d ₆-DMSO) δ 1.75 (3H, m), 2.01 (2H, m), 2.22 (2H, m), 2.96 (1H, m), 3.63 (3H, s), 3.67 (1H, m), 3.92 (1H, m), 4.01 (1H, m), 4.41 (1H, d, J9.74Hz), 6.92 (1H, d, J8.9Hz), 7.05 (1H, s), 7.13 (1H, d, J8.65Hz), 7.31 (2H, d, J6.53Hz), 7.42 (3H, m), 7.60 (4H, m) and 7.91 (1H, m).

Embodiment 167

(3R, 5R, 6S)-and (3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 163, by embodiment 45 compound title compounds.(3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, ¹H NMR (250MHz, CDCl ₃) δ 1.51 (9H, s), 1.58-1.75 (2H, m), 1.82-1.88 (2H, m), 2.33 (1H, dt, J4,13Hz), 2.70 (1H, dd, J8.6,13Hz), 2.79 (1H, dt, J3,13Hz), 3.84 (1H, qn), 3.93-3.97 (2H, m), 4.31 (1H, t, J9Hz), 5.44 (1H, s), 6.89 (1H, d, J9Hz), 7.23-7.35 (5H, m), and 7.58-7.60 (2H, m).m/z(ES ⁺)478(M+1)。(3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, ¹H NMR (360MHz, CDCl ₃) δ 1.34 (9H, s), 1.72-1.82 (3H, m), 2.10-2.21 (2H, m), 2.53 (1H, dd, J9,13Hz), 2.79-2.88 (1H, m), 3.65 (1H, qn, J8.6Hz), 3.94-3.98 (2H, m), 4.24 (1H, dd, J7,9Hz), 5.33 (1H, s), 6.83 (1H, d, J9Hz), 7.01 (1H, s), 7.23-7.34 (5H, m) and 7.55 (2H, d, J7.5Hz).m/z(ES ⁺)478(M+1)。

Embodiment 168

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 164, by (3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 167) preparation title compound.m/z(ES ⁺)492(M+1)。

Embodiment 169

(3R, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethyl) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 168 compound title compounds. ¹H NMR (500MHz, CDCl ₃+ CD ₃OD) δ 1.71-1.78 (3H, m), 1.94-1.98 (1H, m), 2.13-2.24 (3H, m), 3.00 (1H, dt, J3,12Hz), 3.42 (1H, dd, J4,12Hz), 3.61 (3H, s), 3.67 (1H, dd, J8,14Hz), 3.96-4.01 (2H, m), 6.71 (1H, d, J8Hz), 7.04 (1H, d, J2Hz), 7.32 (1H, dd, J2,8Hz), 7.38-7.36 (3H, m), and 7.42-7.44 (2H, m).m/z(ES ⁺)392(M+1)。

Embodiment 170

(3R, 5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize refractory pebbles valve (5 *), with 2-benzyloxy-5-(trifluoromethoxy) iodobenzene (illustrative examples 103,21.8g, 55.2mmol), (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86,7.0g, 22.1mmol), chlorination tetra-n-butyl ammonium (6.18g, 22.2mmol), lithium chloride (9.35g, 0.22mol) and potassium formiate (5.64g, dimethyl formamide 67.0mmol) (100ml) mixture outgases.(491mg 2.2mmol), utilizes refractory pebbles (5 *) to outgas to add acid chloride.Mixture stirred 15 hours down at 60 ℃, further add then 2-benzyloxy-5-(trifluoromethoxy) iodobenzene (illustrative examples 103,4.32g, 11.0mmol), potassium formiate (2.78g, 33.5mmol) and acid chloride (260mg, 1.1mmol).Mixture stirred 22 hours down at 60 ℃, and cooling is also filtered.Solvent evaporated under reduced pressure adds entry (600ml), utilizes ethyl acetate (2 * 300ml) extraction mixtures.The organic fraction that utilizes salt solution (300ml) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/CH earlier by quick silica gel chromatography ₂Cl ₂(increasing to 0: 100 at 75: 25) wash-out utilizes CH again ₂Cl ₂/ EtOAc (95: 5) wash-out obtains title compound (9.42g, 73%). ¹H NMR (360MHz, CDCl ₃) δ 7.56 (2H, d, J7.7Hz), 7.40-7.20 (8H, m), 7.14 (1H, d, J2.0Hz), 7.00 (1H, dd, J8.9,2.0Hz), 6.88 (1H, d, J8.9Hz), 5.30 (1H, s), 5.08 (2H, s), 4.27 (1H, m), 3.97 (1H, m), 3.87 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.15 (1H, m), 1.96 (1H, m), 1.67 (3H, m) and 1.42 (9H, s).

Embodiment 171

(3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With palladium/carbon (10%, 0.59g) join (3R, 5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-the 6-phenyl-(embodiment 170 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 6.10g, 10.5mmol) methanol-water (99: 1,200ml) in the solution, mixture stirred 72 hours down at hydrogen atmosphere (50psi).Filtering mixt utilizes washing with alcohol, solvent evaporated under reduced pressure.Residue utilizes CH by the fast silica gel chromatogram column purification ₂Cl ₂/ EtOAc (increasing to 90: 10 at 99: 1) wash-out obtains title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.70 (2H, d, J7.3Hz), 7.33 (2H, t, J7.3Hz), 7.26 (1H, d, J7.3Hz), 7.05 (1H, br s), 6.96 (2H, m), 6.82 (1H, d, J9.4Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m) and 1.50 (9H, s).

Embodiment 172

(3R, 5R, 6S)-3-[2-hydroxyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 171 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.83-2.35 (7H, m), 3.20 (1H, m), 3.50 (1H, m), 3.73 (1H, m), 4.05 (1H, t, J8.0Hz), 4.29 (1H, s), 6.79 (1H, d, J9.4Hz), 7.02 (2H, m) and 7.54 (5H, br s).m/z(ES ⁺)394(M+1)。

Embodiment 173

(3R, 5R, 6S)-3-(2-benzyloxy-5-(trifluoromethyl) phenyl)-6-(4-fluorophenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by illustrative examples 103 compounds and (5R, 6S)-6-(4-fluorophenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 90) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.54-6.80 (and 12H, m), 5.25 (1H, s), 5.08 (2H, s), 4.26 (1H, m), 3.97 (1H, m), 3.86 (2H, m), 2.76 (1H, m), 2.53 (1H, m), 2.10 (1H, m), 1.97 (1H, m), 1.66 (3H, m) and 1.42 (9H, s).m/z(ES ⁺)546(M+1-C ₄H ₈)。

Embodiment 174

(3R, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-(4-fluorophenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 171, by embodiment 173 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.49 (9H, s), 1.72 (1H, m), 1.83 (3H, m), 2.25 (1H, td, J12.5,4.8Hz), 2.69 (2H, m), 3.72 (1H, qn), 3.98 (1H, m), 4.01 (1H, dd, J9.4,5.4Hz), 4.25 (1H, dd, J9.3,7.4Hz), 5.39 (1H, s), 6.81 (1H, d, J9.4Hz), 6.98 (4H, m) and 7.57 (2H, dd, J8.7,5.6Hz).

Embodiment 175

(3R, 5R.6S)-3-[2-benzyloxy-5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by illustrative examples 105 compounds and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 80) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.42 (9H, s), 1.65 (3H, m), 1.98 (1H, m), 2.15 (1H, m), 3.85 (2H, m), 3.97 (1H, m), 4.28 (1H, m), 5.07 (2H, m), 5.30 (1H, s), 6.42 (1H, t, J74Hz), 6.85 (1H, d, J8.8Hz), 6.95 (1H, dd, J8.8,2.8Hz), 7.07 (1H, d, J2.8Hz), 7.22-7.39 (8H, m) and 7.56 (2H, m).m/z(ES ⁺)566(M+1)。

Embodiment 176

(3R, 5R, 6S)-3-[5-(difluoro-methoxy)-2-hydroxy phenyl]-6-phenyl-1-oxa--7-(tertbutyloxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 171, by embodiment 175 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.50 (9H, s), 1.64 (1H, m), 1.70 (1H, m), 1.83 (2H, m), 2.33 (1H, dt, J4.8,13.0Hz), 2.72 (2H, m), 3.71 (1H, m), 3.94 (1H, m), 4.02 (1H, dd, J9.4,5.3Hz), 4.27 (1H, dd, J9.4,7.4Hz), 5.43 (1H, s), 6.40 (1H, t, J74Hz), 6.80 (1H, m), 6.89 (2H, m), 7.27 (1H, m), 7.33 (2H, m) and 7.60 (2H, m).m/z(ES ⁺)476(M+1)。

Embodiment 177

(3R, 5R, 6S)-3-(2-benzyloxy-5-fluorophenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by illustrative examples 107 compounds and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86) preparation title compound.7.56 (2H, d, J7.4Hz), 7.39-7.21 (8H, m), 7.01 (1H, dd, J9.4,2.7Hz), 6.84 (2H, m), 5.30 (1H, s), 5.05 (2H, s), 4.27 (1H, m), 3.97 (1H, m), 3.84 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.17 (1H, m), 1.95 (1H, m), 1.66 (3H, m) and 1.42 (9H, s).m/z(ES ⁺)518(M+1)。

Embodiment 178

(3R, 5R, 6S)-3-(5-fluoro-2-hydroxy phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 171, by embodiment 177 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.49 (9H, s), 1.59-1.69 (2H, m), 1.80-1.86 (2H, m), 2.31 (1H, dt, J13.0,4.9Hz), 2.67-2.79 (2H, m), 3.70-3.74 (1H, m), 3.93-4.01 (2H, m), and 4.24-4.29 (1H, m), 5.42 (1H, s), and 6.73-6.85 (3H, m), 7.23-7.35 (3H, m) and 7.60 (2H, d, J 7.5Hz).m/z(ES ⁺)428(M+1)。

Embodiment 179

(3R, 5R, 6S)-3-(5-benzyloxy-2-isopropyl phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by illustrative examples 110 compounds and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J7.9Hz), 7.53-7.21 (8H, m), 6.91 (1H, d, J1.9Hz), 6.78 (2H, m), 5.32 (1H, s), 5.01 (2H, s), 4.43 (1H, hept, J6.0Hz), 4.29 (1H, m), 3.97 (1H, m), 3.82 (2H, m), 2.78 (1H, m), 2.54 (1H, m), 2.20 (1H, m), 1.90 (1H, m), 1.77-1.65 (3H, m), 1.45 (9H, s) and 1.31 (6H, d, J6.0 Hz).m/z(ES ⁺)558(M+1)。

Embodiment 180

(3R, 5R, 6S)-3-(5-hydroxyl-2-isopropyl phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 171, by embodiment 179 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J7.5Hz), 7.32 (2H, t, J7.5Hz), 7.24 (1H, t, J7.5Hz), 6.76 (1H, d, J3.0Hz), 6.73 (1H, d, J8.7Hz), 6.63 (1H, dd, J8.7,3.0Hz), 5.32 (1H, s), 4.77 (1H, s), 4.41 (1H, hept, J6.0Hz), 4.28 (1H, m), 3.98 (1H, m), 3.82 (2H, m), 2.78 (1H, m), 2.55 (1H, m), 2.21 (1H, m), 1.91 (1H, m), and 1.79-1.62 (3H, m), 1.45 (9H, s) and 1.36 (6H, d, J6.0Hz).m/z(ES ⁺)468(M+1)。

Embodiment 181

(3R, 5R, 6S)-and 3-(5-hydroxyl-2-isopropyl phenyl)-6-phenyl-1-oxa--7-chlorine is assorted-spiral shell [4.5] decane hydrochloride

Ethanolic soln (5M with hydrogenchloride, 4ml) join (3R, 5R, 6S)-3-(5-hydroxyl-2-isopropyl phenyl)-6-phenyl-(embodiment 180 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 43mg, 0.09mmol) ethanol (2ml) stir in cooling (0 ℃) solution, mixture at room temperature stirred 3 hours.Solvent evaporated under reduced pressure is by ether-alcohol crystal residue.Collect solid, vacuum-drying obtains title compound, is colorless solid (34mg, 92%).m.p.175-178℃。 ¹H NMR (360MHz, CD ₃OD) δ 7.63 (2H, m), 7.56 (3H, m), 6.70 (1H, d, J8.6Hz), 6.57 (1H, dd, J8.6,2.9Hz), 6.52 (1H, d, J2.9Hz), 4.88 (2H, br s), 4.60 (1H, s), 4.32 (1H, s), 4.27 (1H, hept, J6.0Hz), 4.11 (1H, m), 3.71 (1H, m), 3.44 (1H, m), 3.22 (1H, m), 2.50 (1H, m), 2.29 (2H, m), 2.14 (1H, m), 2.02-1.84 (3H, m), 1.14 (3H, d, J6.0Hz) and 1.36 (3H, d, J6.0Hz).m/z(ES ⁺)368(M+1)。Measured value: C, 67.24; H, 7.59; N, 3.43.C ₂₃H ₂₉NO ₃.HCl.0.4H ₂O theoretical value: C, 67.19; H, 7.55; N, 3.41%.

Embodiment 182

(3R, 5R, 6S)-and 3-[2, two (methoxyl group) phenyl of 4-]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by 2,4-(dimethoxy) iodobenzene and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J8Hz), 7.36-7.20 (3H, m), 7.14 (1H, d, J9Hz), 6.50-6.42 (2H, m), 5.35 (1H, s), 4.32-4.24 (1H, m), 3.97 (1H, br d, J12Hz), 3.85-3.75 (2H, m), 3.80 (6H, s), 2.73 (1H, dt, J12,4.5Hz), 2.55 (1H, dd, J12,6.5Hz), 2.20 (1H, dt, J12,5.6Hz), 1.94-1.84 (1H, m), 1.80-1.60 (3H, m) and 1.47 (9H, s).m/z(ES ⁺)454(M+1)。

Embodiment 183

(3R, 5R, 6S)-two (methoxyl group) phenyl of 3-[2.4-]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 182 compound title compounds. ¹H NMR (360MHz, CD ₃OD) δ 7.60-7.40 (5H, m), 6.84 (1H, br d, J9Hz), 6.40-6.32 (2H, m), 4.26 (1H, s), 3.98 (1H, t, J7.7Hz), 3.78-3.70 (1H, m), 3.70 (3H, s), 3.61 (3H, s), 3.40 (1H, dd, J12,4Hz), 3.17 (1H, dt, J11,3Hz), 2.40-2.15 (3H, m), 2.07 (1H, br d, J13Hz), and 1.96-1.78 (3H, m).m/z(ES ⁺)354(M+1)。

Embodiment 184

(3R, 5R, 6S)-3-[2-difluoro-methoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(0.86ml) is added drop-wise to (3R with the chlorine ethyl difluoro, 5R, 6S)-(embodiment 171,1.5g) and in dimethyl formamide (10ml) stirring heating (110 ℃) mixture of salt of wormwood (1.4g) for 3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Can be observed gas and discharged at leisure, mixture heated 2 hours down at 110 ℃, stopped to discharge until gas.Cooling mixture utilizes water (150ml) dilution.Utilize ether (3 * 20ml) extraction mixtures, the organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (90: 10) wash-out by silica gel MPLC purifying, obtains title compound, is colorless oil (800mg). ¹H NMR (250MHz, CDCl ₃) δ 1.46 (9H, s), 1.63-1.72 (4H, m), 2.26 (1H, dt, J12.5,5.0Hz), 2.63-2.82 (2H, m), 3.81-4.04 (3H, m), 4.23-4.36 (1H, m), 5.34 (1H, s), 6.53 (1H, t, J73Hz), 7.12-7.36 (6H, m), and 7.58-7.61 (2H, m).m/z(ES ⁺)544(M+1)。

Embodiment 185

(3R, 5R, 6S)-3-[2-difluoro-methoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 184 compound title compounds. ¹H NMR (500MHz, CDCl ₃) δ 1.58-1.71 (3H, m), 1.93-2.00 (1H, m), 2.12-2.19 (2H, m), 2.35-2.43 (1H, m), 2.80 (1H, m), 3.34-3.37 (1H, m), 3.55 (1H, t, J9Hz), 3.82 (1H, t, J10Hz), 3.96 (1H, t, J7.5Hz), 6.10 (1H, t, J7.3Hz), 6.83 (1H, s), 6.90-6.95 (2H, m), 7.25-7.35 (3H, m), (7.53 2H, br s), 9.18 (1H, br s) and 10.16 (1H, br s).m/z(ES ⁺)444(M+1)。

Embodiment 186

(3R, 5R, 6S)-3-[2-isopropoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 108, by embodiment 171 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.33-1.35 (6H, m), 1.45 (9H, s), 1.87-1.93 (1H, m), 2.17-2.33 (4H, m), 2.5-2.59 (1H, m), 2.74-2.82 (1H, m), 3.80-3.83 (2H, m), 3.96-4.00 (1H, m), 4.30 (1H, m), 4.50-4.57 (1H, m), 5.35 (5.33 (1H, s), 6.81 (1H, d, J 8.9Hz), 6.95-7.02 (1H, m), 7.09 (1H, m), 7.22-7.26 (1H, m), 7.30-7.34 (2H, m) and 7.60 (2H, d, J7.9Hz).m/z(ES ⁺)434(M+1-CO ₂ ^tBu)。

Embodiment 187

(3R, 5R, 6S)-3-[2-isopropoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 186 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.01 (3H, d, J6.0Hz), 1.07 (3H, d, J6.0Hz), 1.78 (1H, m), 2.00-2.10 (3H, m), 2.20-2.40 (3H, m), 3.30-3.40 (1H, m), 3.50-3.58 (1H, m), 3.62-3.68 (1H, m), 4.02-4.10 (1H, m), 4.10-4.18 (1H, m), 4.39 (1H, s), 6.61 (1H, d, J9.2Hz), 6.86-6.89 (1H, m), 6.93 (1H, s), 7.56-7.58 (3H, m) and 7.66 (2H, m).m/z(ES ⁺)436(M+1)。

Embodiment 188

(3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(0.68ml) is added drop-wise to (3R with trifluoromethanesulfanhydride anhydride, 5R, 6S)-(embodiment 171, and pyridine 1g) (4ml) stirs in cooling (0 ℃) mixture for 3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane.Mixture is warmed to room temperature, stirs 16 hours.Further add trifluoromethanesulfanhydride anhydride (0.34ml), mixture at room temperature stirred 2 hours.Add copper sulfate (II) aqueous solution, utilize ethyl acetate (3 * 50ml) extraction mixtures.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (80: 20) wash-out by silica gel MPLC purifying, obtains title compound, is colorless oil. ¹H NMR (360MHz, CDCl ₃) δ 1.43 (9H, s), 1.78 (3H, m), 2.25 (2H, m), 2.78 (2H, m), 3.85 (2H, m), 4.02 (1H, dd, J13.7Hz), 4.27 (1H, dd, J8.7,6.9Hz), 5.30 (1H, s), 7.27 (1H, m), 7.31 (5H, m) and 7.57 (2H, d, J7.6Hz).

Embodiment 189

(3R, 5R, 6S)-3-[2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize fire-resistant valve (* 5), with (3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 188,200mg), vinyl tributyl tin (0.11ml), lithium chloride (80mg) and tetrakis triphenylphosphine palladium (O) (50mg) De diox (5ml) mixture outgas.Mixture heated 2 hours down at 110 ℃, and cooling is filtered.Solvent evaporated under reduced pressure, residue is dissolved in the acetonitrile.Utilize hexane (30ml) purging compound, utilize ethyl acetate (3 * 30ml) extraction mixtures, the organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (85: 15) wash-out by silica gel MPLC purifying, obtains title compound, is oily matter. ¹H NMR (360MHz, CDCl ₃) δ 1.47 (9H, s), 1.62 (3H, m), 1.83 (1H, m), 2.25 (1H, td), 2.63 (1H, dd, J7.5Hz), 2.76 (1H, td), 3.82 (1H, qn), 3.90 (1H, t, J8.3Hz), 3.98 (1H, dd), 4.24 (1H, t, J7.3Hz), 5.36 (2H, m), 5.57 (1H, d, J16.7Hz), 6.97 (1H, dd, J11.0,16.9Hz), 7.15 (1H, d), 7.25 (1H, s), 7.33 (1H, m), 7.35 (2H, m), 7.76 (1H, d, J8.5Hz) and 7.60 (2H, d, J7.6Hz).

Embodiment 190

(3R, 5R, 6S)-3-[2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 189 compound title compounds. ¹H NMR (360MHz, CD ₃OD) δ 0.53 (1H, t, J15.1Hz), 0.72 (1H, t, J11.9Hz), 0.90 (1H, m), 1.09 (3H, m), 1.95 (1H, td, J12.4Hz), 2.16 (1H, dd, J12.8Hz), 2.52 (1H, t, J9.7Hz), 2.78 (1H, t, J7.9Hz), 3.08 (1H, s), 3.92 (1H, d, J11.04Hz), 4.18 (1H, d, J17.2Hz), 4.83 (1H, dd, J17.2,10.9Hz), 5.83 (2H, m), 6.16 (1H, d, J8.5Hz) and 6.37 (5H, m).

Embodiment 191

(3R, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 201, by embodiment 167 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.44 (9H, s), 1.64-1.80 (3H, m), 1.96 (1H, dd, J13.0,8.3Hz), 2.21 (1H, dt, J13.0,5.4Hz), 2.62 (1H, dd, J12.2,7.0Hz), 2.88 (1H, dt, J13.3,4.0Hz), 3.82-3.90 (2H, m), and 3.98-4.05 (1H, m), 4.29-4.31 (1H, m), 4.42 (2H, q, J7.9Hz), 5.32 (1H, s), 6.88 (1H, d, J8.6Hz), 7.22-7.36 (3H, m), 7.51 (1H, d, J8.6Hz), and 7.54-7.63 (3H, m).m/z(ES ⁺)560(M+1)。

Embodiment 192

(3R, 5R, 6S)-3-[2-(2.2.2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 191 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.60-1.74 (3H, m), 1.96-2.02 (1H, m), 2.12 (1H, dt, J13.0,4.3Hz), 2.20-2.38 (3H, m), 2.77 (1H, dt, J12.4,3.0Hz), 3.24 (1H, dt, J12.4,4.0Hz), 3.62 (1H, dd, J9.7,8.3Hz), 4.07 (1H, t, J7.2Hz), 6.72 (1H, t, J7.3Hz), 7.24-7.34 (4H, m), 7.39 (lH, d, J8.6Hz), and 7.42-7.48 (2H, m).m/z(ES ⁺)460(M+1)。

Embodiment 193

(3R, 5R, 6S)-and 3-[2, two (difluoroethoxy) phenyl of 5-]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 184, by embodiment 176 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J7.5Hz), 7.33 (2H, t, J7.5Hz), 7.25 (1H, t, J7.5Hz), 7.15 (1H, d, J2.8Hz), 7.12 (1H, d, J8.8Hz), 7.00 (1H, dd, J8.8,2.8Hz), 6.50 (1H, t, J73.3Hz), 6.48 (1H, t, J73.5Hz), 5.34 (1H, s), 4.28 (1H, m), 3.97 (1H, m), 3.84 (2H, m), 2.77 (1H, m), 2.66 (1H, m), 2.26 (1H, m), 1.84-1.65 (4H, m) and 1.46 (9H, s).m/z(ES ⁺)526(M+1)。

Embodiment 194

(3R, 5R, 6S)-two (difluoroethoxy) phenyl of 3-[2.5-]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 193 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.83 (1H, m), 1.98 (2H, m), 2.08-2.36 (4H, m), 3.20 (1H, m), 3.52 (1H, m), 3.70 (1H, m), 4.05 (1H, m), 4.30 (1H, s), 6.46 (1H, t, J73Hz), 6.73 (1H, t, J74Hz), 7.05 (3H, m, ArH) and 7.55 (5H, br s).m/z(ES ⁺)426(M+1)。Measured value: C, 56.8; H, 5.0; N, 3.3.C ₂₂H ₂₃F ₄NO ₃.HCl theoretical value: C, 57.2; H, 5.2; N, 3.0%.

Embodiment 195

(3R, 5R, 6S)-3-[5-fluoro-2-(difluoroethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 184, by embodiment 178 compound title compounds. ¹H?NMR(360MHz,CDCl ₃)δ1.45(9H,s),1.64-1.83(4H,m),2.26(1H,dd,J12.8,7.6Hz),2.63-2.80(2H,m),3.81-3.89(2H,m),3.96-4.00(1H,m),4.26-4.29(1H,m),5.33(1H,s),6.47(1H,t,73.4Hz),6.89-6.94(1H,m),7.07-7.11(1H,m),7.22-7.27(1H,m),7.32(2H,m),7.59(2H,d,J?7.9Hz)。m/z(ES ⁺)478(M+1)。

Embodiment 196

(3R, 5R, 6S)-3-[5-fluoro-2-(difluoroethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 195 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.42-2.00 (7H, m), 2.82-2.93 (1H, m), 3.16-3.26 (1H, m), 3.32-3.39 (1H, m), 3.68-3.75 (1H, m), 3.97 (1H, s), 6.11 (1H, t, J73.3Hz), 6.58-6.74 (3H, m), and 7.58-7.61 (5H, s).m/z(ES ⁺)378(M+1)。

Embodiment 197

(3R, 5R, 6S)-3-[5-fluoro-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 201, by embodiment 178 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.45 (9H, s), 1.57-1.76 (4H, m), 1.86-1.95 (1H, m), 2.18-2.23 (1H, m), 2.56-2.65 (1H, m), 2.72-2.85 (1H, m), 3.81-3.88 (1H, m), 3.94-4.03 (1H, m), 4.24-4.38 (3H, m), 5.30 (1H, s), 6.74-6.79 (1H, m), 6.89 (1H, dt, J12.9,4.4Hz), 7.05 (1H, dd, J13.6,74.3Hz), 7.25-7.35 (3H, m) and 7.59 (2H, d, J10.9Hz).m/z(ES ⁺)454(M+1-C ₄H ₈)。

Embodiment 198

(3R, 5R, 6S)-3-[5-fluoro-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 197 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.88-1.97 (3H, m), 2.08-2.13 (1H, m), 2.26-2.37 (3H, m), and 3.15-3.21 (1H, m), 3.38-3.41 (1H, m), 3.70 (1H, dd, J10.3,8.3Hz), 4.13 (1H, t, J7.5Hz), 4.29-4.47 (3H, m), 6.83-6.89 (3H, m), 7.48-7.50 (3H, m) and 6.29 (2H, m).m/z(ES ⁺)410(M+1)。

Embodiment 199

(3R, 5R, 6S)-3-(5-fluoro-2-isopropyl phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 108, by embodiment 178 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.30-1.33 (6H, m), 1.45 (9H, s), 1.63-1.78 (2H, m), and 1.86-1.89 (1H, m), 2.18-2.27 (1H, m), 2.54-2.60 (1H, m), 2.77 (1H, dt, J12.5,4.0Hz), 3.77-3.87 (2H, m), 3.96-4.01 (1H, m), 4.29 (1H, t, J7.2Hz), and 4.43-4.51 (1H, m), 5.33 (1H, s), and 6.76-6.80 (1H, m), 6.82-6.88 (1H, m), 6.96 (1H, dd, J9.6,3.0Hz), 7.22-7.25 (1H, m), 7.32 (2H, m) and 7.60 (2H, d, J7.9Hz).m/z(ES ⁺)470(M+1)。

Embodiment 200

(3R, 5R, 6S)-3-(5-fluoro-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 199 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.00 (3H, d, J6.0Hz), 1.04 (3H, d, J6.0Hz), 1.81 (1H, t, J12.6Hz), 1.96-2.00 (2H, m), 2.10-2.14 (2H, m), and 2.26-2.32 (1H, m), 2.40-2.43 (1H, m), 3.18-3.23 (1H, m), and 3.47-3.53 (1H, m), 3.64 (1H, dd, J10.8,8.3Hz), 4.09 (1H, t, J8.0Hz), 4.24-4.28 (2H, m), 6.90-6.99 (3H, m) and 7.56 (1H, s).m/z(ES ⁺)370(M+1)。

Embodiment 201

(3R, 5R, 6S)-3-[2-isopropoxy-5-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With trichlorine methylsulfonic acid 2,2,2-trifluoro ethyl ester (127mg, 0.45mmol) join (3R, 5R, 6S)-3-(5-hydroxyl-2-isopropyl phenyl)-6-phenyl-(embodiment 180 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 140mg, 0.3mmol) and salt of wormwood (104mg is in DMF 0.75mmol) (3ml) mixture, mixture is 60 ℃ of heating down, add other trichlorine methylsulfonic acid 2,2,2-trifluoro ethyl ester (338mg after 4 hours and 22 hours, 1.2mmol) and salt of wormwood (166mg, 1.2mmol).46 hours postcooling mixtures, (10%, 20ml), (3 * 20ml) extract to utilize ethyl acetate to be injected into aqueous citric acid solution.Utilize aqueous citric acid solution (10%, 2 * 20ml) and the organic fraction that merges of salt solution (20ml) washing, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes CH by quick silica gel chromatography ₂Cl ₂/ EtOAc (increasing to 80: 20 at 85: 15) wash-out obtains title compound (138mg, 84%). ¹H NMR (250MHz, CDCl ₃) δ 1.31 (6H, d, J6.0Hz), 1.45 (9H, s), 1.60-1.80 (3H, m), and 1.87-1.92 (1H, m), 2.18-2.24 (1H, m), 2.52-2.59 (1H, m), and 2.71-2.81 (1H, m), 3.77-4.00 (3H, m), 4.25-4.35 (3H, m), 4.42-4.49 (1H, m), 5.38 (1H, s), 6.70-6.82 (2H, m), 6.90 (1H, d, J2.9Hz), 7.24-7.35 (3H, m) and 7.61 (2H, d, J7.6Hz).m/z(ES ⁺)550(M+1)。

Embodiment 202

(3R, 5R, 6S)-3-[2-isopropoxy-5-(2.2.2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 201 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 0.99 (3H, d, J6.0Hz), 1.04 (3H, d, J6.0Hz), 1.77-1.84 (1H, m), 1.98-2.05 (3H, m), 2.20-2.32 (2H, m), 2.38-2.48 (1H, m), 3.20-3.32 (1H, m), 3.50-3.63 (2H, m), and 4.02-4.10 (1H, m), 4.12-4.20 (1H, m), 4.32 (1H, s), 4.43 (2H, dd, J16.8,8.4Hz), 6.74-6.80 (3H, m), and 7.58-7.61 (5H, m).m/z(ES ⁺)450(M+1)。

Embodiment 203

(3R, 5R, 6S)-and 3-[2, two (isopropoxy) phenyl of 5-]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for illustrative examples 108, by embodiment 180 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J7.7Hz), 7.32 (2H, t, J7.7Hz), 7.23 (1H, t, J7.7Hz), 6.82 (1H, d, J2.9Hz), 6.77 (1H, d, J8.9Hz), 6.69 (1H, dd, J8.9,2.9Hz), 5.32 (1H, s), 4.43 (1H, hept, J6.0Hz), 4.29 (1H, m), 3.98 (1H, m), 3.83 (2H, m), 2.78 (1H, m), 2.55 (1H, m), 2.21 (1H, m), 1.93 (1H, m), 1.79-1.63 (3H, m), 1.45 (9H, s) and 1.30 (12H, d, J6.0Hz).m/z(ES ⁺)510(M+1)。

Embodiment 204

(3R, 5R, 6S)-and 3-[2, two (isopropoxy) phenyl of 5-]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 203 compound title compounds, m.p.233-236 ℃. ¹H NMR (360MHz, CD ₃OD) δ 7.68 (2H, m), 7.62 (3H, m), 6.82 (1H, d, J8.9Hz), 6.75 (1H, dd, J8.9,2.7Hz), 6.65 (1H, d, J2.7Hz), 4.88 (2H, br s), 4.49 (1H, hept, J6.0Hz), 4.38 (1H, hept, J6.0Hz), 4.37 (1H, s), 4.16 (1H, m), 3.77 (1H, m), 3.49 (1H, m), 3.27 (1H, m), 2.53 (1H, m), 2.34 (2H, m), 2.20 (1H, m), 2.09-1.90 (3H, m), 1.32 (6H, d, J6.0Hz), 1.21 (3H, d, J6.0Hz) and 1.15 (3H, d, J6.0Hz).m/z(ES ⁺)410(M+1)。

Embodiment 205

(3R, 5R, 6S)-3-(5-chloro-2-p-methoxy-phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by 5-chloro-2-methoxyl group iodobenzene and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 1.40 (9H, s), 1.59-1.83 (3H, s), 2.12-2.22 (1H, m), and 2.48-2.53 (1H, m), 2.64-2.72 (1H, m), and 3.71-3.83 (2H, m), 3.73 (3H, s), and 4.20-4.24 (1H, m), 5.28 (1H, s), and 6.69-6.71 (1H, d, J8.6Hz), 7.07-7.27 (5H, m), and 7.53-7.55 (2H, m).m/z(ES ⁺)458(M+1)。

Embodiment 206

(3R, 5R, 6S)-3-(5-chloro-2-p-methoxy-phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 205 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.78-2.29 (7H, m), 3.22 (1H, m), 3.51-3.57 (1H, m), 3.61 (3H, s), 3.68-3.74 (1H, m), 3.99-4.03 (1H, m), 4.29 (1H, s), 6.85-6.88 (1H, d, J8.8Hz), 7.13-7.14 (1H, d, J2.5Hz), 7.17-7.21 (1H, dd, J2.5,8.8Hz), and 7.56-7.59 (5H, m).m/z(ES ⁺)358(M+1)。

Embodiment 207

(3R, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 201, by embodiment 171 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.37 (9H, s), 1.61-1.67 (1H, s), 1.80-1.87 (1H, m), 2.09-2.13 (1H, m), 2.52-2.57 (1H, m), 2.71-2.77 (1H, m), 3.72-3.80 (2H, m), 3.89-4.00 (1H, m), 4.21 (1H, m), 4.26-4.33 (2H, q, J8Hz), 5.23 (1H, s), 6.73-6.75 (1H, d, J8.9Hz), 7.01-7.03 (1H, m), 7.11 (1H, m), 7.17-7.27 (3H, m), and 7.50-7.52 (2H, m).m/z(ES ⁺)576(M+1)。

Embodiment 208

(3R, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 207 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.83-1.89 (1H, m), 1.90-2.04 (3H, m), 2.25-2.33 (3H, m), 3.21-3.35 (1H, m), 3.58-3.68 (2H, m), 4.07-4.12 (1H, m), (4.27-4.31 2H, q, J 8.5Hz), 4.35 (1H, s), and 6.81-6.84 (1H, d, J8.9Hz), 6.99-7.05 (2H, m), and 7.54-7.61 (5H, m).m/z(ES ⁺)476(M+1)。

Embodiment 209

(3R, 5R, 6S)-3-[2-(cyclo propyl methoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(112mg) joins (3R with the cyclopropyl monobromomethane, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-the 6-phenyl-(embodiment 171 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 274mg) and in dimethyl formamide (5ml) mixture of salt of wormwood (192mg), mixture stirred 18 hours down at 60 ℃, be injected in the water (100ml), utilize ethyl acetate (2 * 25ml) extractions.The organic fraction that utilizes salt solution (2 *) and water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 90: 10 at 95: 5) wash-out by the silica gel chromatography purifying, obtains title compound, is oily matter (178mg). ¹H NMR (360MHz, CDCl ₃) δ 0.23-0.28 (2H, m), 0.54-0.59 (2H, m), 0.81 (1H, m), 1.18 (2H, m), 1.38 (9H, s), 1.63-1.72 (3H, m), 1.89-1.95 (1H, m), and 2.12-2.16 (1H, m), 2.48-2.53 (1H, m), 2.69-2.75 (1H, m), and 3.68-3.79 (3H, m), 3.89-3.93 (1H, m), 4.27 (1H, m), 5.27 (1H, s), 6.68-6.71 (1H, d, J 8.89Hz), 6.95-6.97 (1H, m), 7.03 (1H, m), and 7.52-7.54 (2H, m).m/z(ES ⁺)548(M+1)。

Embodiment 210

(3R, 5R, 6S)-3-[2-(cyclo propyl methoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 209 compound title compounds. ¹H NMR (360MHz, D ₂O) δ-0.01-0.00 (2H, m), 0.57-0.59 (2H, m), 0.94 (1H, m), 1.76 (1H, m), 1.95 (2H, m), 2.21 (2H, m), 3.19-3.23 (2H, m), 3.53 (1H, m), 3.61 (1H, m), 3.99 (1H, m), 4.35 (1H, m), 6.28-6.30 (1H, d, J9.0Hz), 6.67-6.68 (1H, m), 6.75 (1H, m), 7.46-7.52 (3H, m), and 7.61-7.63 (2H, m).m/z(ES ⁺)448(M+1)。

Embodiment 211

(3R, 5R, 6S)-3-[2-benzyloxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 170 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.83-1.91 (4H, m), 2.08-2.24 (2H, m), 3.10-3.22 (1H, m), 3.31 (3H, m), 3.42-3.48 (1H, m), 3.58-3.64 (1H, m), 4.01 (1H, m), 4.21 (1H, s), 6.86-6.89 (1H, m), 6.93 (1H, m), 7.00-7.04 (1H, m), 7.24-7.25 (2H, m), 7.32-7.34 (3H, m), and 7.44-7.46 (5H, m).m/z(ES ⁺)484(M+1)。

Embodiment 212

(3R, 5R, 6S)-3-[5-(difluoro-methoxy)-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 201, by embodiment 176 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.37 (9H, s), 1.55-1.68 (3H, m), 1.82-1.88 (1H, m), 2.09-2.16 (1H, m), 2.50-2.56 (1H, m), 2.69-2.78 (1H, m), 3.73-3.81 (2H, m), 3.89-3.93 (1H, m), 4.17-4.20 (1H, m), 4.24-4.31 (2H, q, J 8.0 Hz), 5.22 (1H, s), 6.38 (1H, t, J74Hz), 6.72 (1H, d, J8.8Hz), 6.91-6.93 (1H, dd, J2.8,8.8Hz), 7.03 (1H, d, J2.8Hz), 7.15-7.27 (3H, m), and 7.50-7.52 (2H, m).m/z(ES ⁺)558(M+1)。

Embodiment 213

(3R, 5R, 6S)-3-[5-(difluoro-methoxy)-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 212 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.89-2.32 (7H, m), 3.20 (1H, m), 3.49 (1H, m), 3.65-3.71 (1H, m), 4.08-4.12 (1H, m), 4.29 (1H, s), 4.29-4.37 (2H, q, J8.5Hz), 6.67 (1H, t, J74Hz), 6.87-7.02 (3H, m) and 7.54 (5H, s).m/z(ES ⁺)458(M+1)。

Embodiment 214

(3R, 5R, 6S)-3-[2-(2, the 2-difluoroethoxy)-5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With 2,2-difluoro monobromoethane (120mg) joins (3R, 5R, 6S)-3-[5-(difluoro-methoxy)-2-hydroxy phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl)-(embodiment 176 for azepine-spiral shell [4.5] decane, 200mg) and in dimethyl formamide (4ml) mixture of salt of wormwood (145mg), mixture stirred 2 hours down at 50 ℃, was injected in the salt solution, utilized ethyl acetate extraction.The organic fraction that utilizes water (3 *) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (increasing to 80: 20 at 90: 10) wash-out by the silica gel chromatography purifying, obtains title compound, is oily matter (178mg). ¹H NMR (360MHz, CDCl ₃) δ 1.45 (9H, s), 1.62-1.76 (3H, m), 1.86-1.93 (1H, m), and 2.18-2.23 (1H, m), 2.57-2.62 (1H, m), 2.74-2.82 (1H, m), 3.83-3.84 (1H, m), 3.96-3.99 (1H, m), 4.11-4.24 (2H, td, J8.9,12.9Hz), 4.27 (1H, m), 5.33 (1H, s), 6.12 (1H, tt, J55Hz, 4Hz), 6.43 (1H, t, J74Hz), and 6.77-6.80 (1H, d, J8.8Hz), 6.97-6.98 (1H, m), 7.07 (1H, m), 7.22-7.34 (3H, m), and 7.58-7.60 (2H, m).m/z(ES ⁺)484(M+1-C ₄H ₈)。

Embodiment 215

(3R, 5R, 6S)-3-[2-(2, the 2-difluoroethoxy)-5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 214 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.88-2.33 (7H, m), 3.18-3.22 (1H, m), 3.47-3.55 (1H, m), 3.68-3.73 (1H, m), 4.04-4.13 (3H, m), 4.29 (1H, s), 6.06 (1H, tt, J55,4Hz), 6.66 (1H, t, J74Hz), 6.67-7.03 (3H, m) and 7.55 (5H, s).m/z(ES ⁺)440(M+1)。

Embodiment 216

(3R, 5R, 6S)-3-[2-(cyclobutoxy group)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(143mg) joins (3R with the cyclobutyl bromine, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-the 6-phenyl-(embodiment 171 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 181mg) and in dimethyl formamide (10ml) mixture of salt of wormwood (126mg), mixture stirred 18 hours down at 60 ℃, be injected in the salt solution, utilize ethyl acetate (2 *) extraction.The organic fraction that utilizes water (3 *) washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (95: 5) wash-out by the silica gel chromatography purifying, obtains title compound (96mg). ¹H NMR (360MHz, CDCl ₃) δ 1.39 (9H, s), 1.58-1.87 (6H, m), 2.07-2.16 (3H, m), 2.34-2.40 (2H, m), 2.48-2.53 (1H, m), 2.66-2.75 (1H, m), 3.73-3.76 (2H, m), 3.89-3.93 (1H, m), 4.24 (1H, m), 4.52-4.56 (1H, m), 5.27 (1H, s), 6.56-6.59 (1H, d, J8.9 Hz), 6.92-6.95 (1H, m), 7.01 (1H, m), 7.1 5-7.17 (1H, m), 7.23-7.27 (2H, m), and 7.52-7.55 (2H, m).m/z(ES ⁺)548(M+1)。

Embodiment 217

(3R, 5R, 6S)-3-[2-(cyclobutoxy group)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 216 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.50-1.77 (5H, m), 1.90-1.99 (4H, m), 2.08-2.14 (1H, m), and 2.24-2.36 (3H, m), 2.68-2.74 (1H, m), 3.13-3.16 (1H, m), 3.46 (1H, s), 3.51-3.56 (1H, m), and 3.91-3.95 (1H, m), 4.35-4.39 (1H, m), (6.42-6.45 1H, d, J 8.8Hz), 6.75 (1H, m), 6.81-6.83 (1H, m), and 7.22-7.43 (5H, m) .m/z (ES ⁺) 448 (M+1).

Embodiment 218

(3R, 5R, 6S)-3-[2-(methoxy ethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(52mg) joins (3R with the 2-bromo-ethyl-methyl ether, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-the 6-phenyl-(embodiment 171 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 150mg) and in dimethyl formamide (2ml) mixture of salt of wormwood (92mg), mixture stirred 20 hours down at 60 ℃, be injected in the water, utilize ethyl acetate extraction.The organic fraction that utilizes salt solution and water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (80: 20) wash-out by the silica gel chromatography purifying, obtains title compound (105mg). ¹H NMR (360MHz, CDCl ₃) δ 1.45 (9H, s), 1.71-1.77 (3H, m), 1.94-2.00 (1H, m), 2.18-2.21 (1H, m), 2.54-2.59 (1H, m), 2.77-2.83 (1H, m), 3.42 (3H, s), 3.48-3.87 (4H, m), 3.95-3.99 (1H, m), 4.10-4.13 (2H, t, J4.90Hz), 4.29 (1H, m), 5.32 (1H, s), and 6.82-6.84 (1H, d, J8.9Hz), 7.03-7.06 (1H, m), 7.11 (1H, m), 7.24-7.34 (3H, m), and 7.58-7.60 (2H, m).m/z(ES ⁺)552(M+1)。

Embodiment 219

(3R, 5R, 6S)-3-[2-(methoxy ethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 218 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.91-2.31 (7H, m), 3.21 (1H, m), 3.43 (3H, s), and 3.49-3.53 (1H, m), 3.66-3.72 (3H, m), and 3.93-3.95 (2H, m), 4.11 (1H, m), 4.29 (1H, m), 6.88-6.91 (1H, d, J8.9Hz), 7.04 (1H, m), 7.11 (1H, m) and 7.56 (5H, s).m/z(ES ⁺)452(M+1)。

Embodiment 220

(3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 188 compound title compounds. ¹H NMR (400MHz, D ₂O) δ 7.56 (5H, br s), 7.38 (2H, d, J10.4Hz), 7.30 (1H, d, J8.8Hz), 4.34 (1H, s), 4.22 (1H, t, J7.9Hz), 3.74 (1H, t, J9.4Hz), 3.52 (1H, br d, J9.8Hz), 3.23 (1H, br t, J11.4Hz), 2.43-2.53 (2H, m), 2.17-2.28 (2H, m), and 1.95-2.02 (3H, m).m/z(ES ⁺)526(M+1)。Measured value: C, 47.19; H, 3.58; N, 2.69.C ₂₂H ₂₁F ₆NO ₅S.HCl theoretical value: C, 47.02; H, 3.95; N, 2.49%.

Embodiment 221

(3R, 5R, 6S)-3-[2-(2, the 2-difluoroethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

With 2-bromo-1,1-C2H4F2 C2H4F2 (100mg, 0.69mmol) join (3R, 5R, 6S)-and 3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 171,159mg, 0.32mmol) and salt of wormwood (110mg, 0.8mmol) DMF (5ml) mixture in, mixture stirred 72 hours down at 40 ℃.Add entry (100ml), utilize ethyl acetate (2 * 100ml) extractions.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (75: 25) wash-out by silica gel chromatography, obtains title compound (148mg, 82%). ¹H NMR (360MHz, CDCl ₃) δ 1.42 (9H, s), 1.58-1.76 (1H, m), 1.84-1.94 (2H, m), 2.10-2.26 (1H, m), 2.56-2.62 (1H, m), 2.74-2.82 (1H, m), 3.60-3.72 (2H, m), 3.78-3.92 (2H, m), 3.92-4.00 (1H, m), 4.06-4.32 (2H, m), 5.34 (1H, s), 6.14 (1H, m), 6.80 (1H, d, J8.9Hz), 7.06-7.10 (1H, m), 7.16 (1H, m), 7.20-7.36 (3H, m), and 7.56-7.62 (2H, m).m/z(ES ⁺)558(M+1)。

Embodiment 222

(3R, 5R, 6S)-3-[2-(2, the 2-difluoroethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 221 compound title compounds. ¹H NMR (360MHz, D ₂O) δ 1.89-2.42 (7H, m), 3.18-3.26 (1H, m), 3.46-3.58 (1H, m), 3.72-3.78 (1H, m), 4.10-4.20 (4H, m), 6.10 (1H, d, J9.05Hz), 7.06-7.10 (2H, m) and 7.58 (5H, s).m/z(ES ⁺)458(M+1)。

Embodiment 223

(3R, 5R, 6S)-3-[2-cyclopropyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize fire-resistant valve (3 *), with (3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-the 6-phenyl-(embodiment 188 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 200mg), Fourth Ring propyl group tin (illustrative examples 116,108mg), lithium chloride (80mg) and tetrakis triphenylphosphine palladium (O) (50mg) De diox (5ml) mixture outgas.Mixture was 110 ℃ of following heated and stirred 16 hours, and cooling mixture filters.Solvent evaporated under reduced pressure, residue are dissolved in the acetonitrile (20ml).Utilize hexane (20ml) purging compound, utilize acetonitrile (2 * 20ml) extraction hexane fractions, utilize the Potassium monofluoride methanol solution (5%, 5ml) handle the acetonitrile fraction that merges.Filtering mixt, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (85: 15) wash-out by quick silica gel chromatography, obtains title compound, is yellow oil. ¹H NMR (360MHz, CDCl ₃) δ 0.63 (2H, dm, J12.5Hz), 0.98 (2H, d, J8.5Hz), 1.45 (9H, s), 1.67 (4H, m), 1.81 (1H, dd, J12.8,9.7Hz), 2.04 (1H, m), 2.26 (1H, td, J8.4,5.1Hz), 2.70 (1H, dd, J12.7,7.8Hz), 2.78 (1H, td, J12.5Hz), 3.91 (1H, t, J8.3Hz), 3.96 (1H, dd), 4.14 (1H, qn), 4.29 (1H, t, J7.6Hz), 5.37 (1H, s), 6.99 (1H, m), 7.04 (1H, d, J8.5Hz), 7.25 (1H, d, J3.6Hz), 7.3 (1H, m), 7.33 (1H, t, J7.1Hz) and 7.61 (2H, d, J7.7Hz).m/z(ES ⁺)462(M+1-C ₄H ₈)。

Embodiment 224

(3R, 5R, 6S)-3-[2-cyclopropyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 223 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 0.3 (2H, dm, J16.8Hz), 0.57 (2H, dd, J6.6Hz), 1.10 (1H, m), 1.69 (3H, m), 2.06 (1H, m), 2.24 (1H, dd, J13.0,7.9Hz), 2.46 (1H, m), 2.62 (1H, qn), 2.87 (1H, t), 3.45 (1H, d, J7.1Hz), 3.59 (1H, t, J8.8Hz), 3.90 (1H, s), 4.09 (1H, t, J7.7Hz), 6.88 (3H, s), 7.33 (3H, m) and 7.63 (2H, br s).m/z(ES ⁺)418(M+1)。

Embodiment 225

(3R, 5R, 6S)-3-(5-cyano-2-hydroxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by illustrative examples 118 compound title compounds. ¹H NMR (250MHz, DMSO-d ₆) δ 7.15-7.47 (7H, m), 6.71 (1H, d, J8.4Hz), 3.83 (1H, t, J7.2Hz), 3.62 (1H, s), 3.46 (1H, t, J8.8Hz), 3.00-3.05 (1H, m), 2.62-2.71 (1H, m), 2.07-2.16 (2H, m), 1.83-1.96 (2H, m), and 1.49-1.68 (3H, m).

Embodiment 226

(3R, 5R, 6S)-3-(5-cyano-2-hydroxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

(50ml) joins (3R with water, 5R, 6S)-3-[5-cyano group-2-(tert-butoxycarbonyl) oxygen base phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (illustrative examples 119, in tetrahydrofuran (THF) 427mg) (50ml) solution, reflux mixture 16 hours.Cooling mixture, (saturated, 50ml), (2 * 100ml) extract mixtures to utilize ethyl acetate to add ammonium chloride solution.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure obtains title compound, is jelly (337mg). ¹H NMR (250MHz, CDCl ₃) δ 7.56-7.59 (2H, m), 7.26-7.42 (5H, m), 6.90 (1H, d, J9.0Hz), 5.43 (1H, s), 4.29 (1H, dd, J9.5,7.4Hz), 3.92-3.98 (2H, m), 3.80-3.82 (1H, m), 2.67-2.81 (2H, m), 2.31-2.37 (1H, m), 1.59-1.88 (4H, m) and 1.51 (9H, s).

Embodiment 227

(3R, 5R, 6S)-3-[5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 201, by embodiment 226 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.55-7.63 (4H, m), 7.25-7.36 (3H, m), 6.87 (1H, d, J8.5Hz), 5.32 (1H, s), 4.43 (2H, q, J7.8Hz), and 4.28-4.30 (1H, m), 3.95-3.96 (1H, m), 3.83-3.85 (2H, m), 2.79-2.81 (1H, m), 2.58-2.66 (1H, m), and 2.19-2.24 (1H, m), 1.88-1.97 (1H, m), 1.70-1,69 (3H, m) and 1.45 (9H, s).

Embodiment 228

(3R, 5R, 6S)-3-[5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 227 compound title compounds, m.p.258-260 ℃. ¹H NMR (360MHz, DMSO-d ₆) δ 9.50 (1H, br s), 8.90 (1H, br s), 7.73 (1H, dd, J2.0,8.7Hz), 7.64 (1H, d, J2.0Hz), 7.54-7.55 (2H, m), 7.44-7.46 (3H, m), 7.13 (1H, dJ8.7Hz), 4.74 (2H, q, J8.7Hz), 4.40 (1H, s), 4.01 (1H, t, J7.6Hz), 3.61 (1H, dd, J8.3,10.3Hz), 3.24-3.26 (1H, m), 3.06-3.08 (1H, m), 2.21-2.27 (1H, m), and 1.86-2.14 (6H, m).m/z(ES ⁺)417(M+1)。

Embodiment 229

(3R, 5R, 6S)-3-(5-cyano group-2-o-phenyl-isopropyl)-6-phenyl-1-oxa--7-(tertbutyloxycarbonyl) azepine-spiral shell [4,5] decane

According to the method for embodiment 108, by embodiment 226 compound title compounds. ¹H NMR (250MHz, CDCl ₃) δ 7.48-7.62 (4H, m), 7.26-7.33 (3H, m), 6.87 (1H, d, J8.4Hz), 5.35 (1H, s), 4.64 (1H, sept, J6.1Hz), and 3.95-4.00 (1H, m), 3.75-3.79 (2H, m), 2.64-2.68 (1H, m), 2.56-2.60 (1H, m), 2.23-2.27 (1H, m), and 1.90-1.94 (1H, m), 1.70-1.74 (4H, m), 1.46 (9H, s) and 1.37 (6H, d, J6.0Hz).

Embodiment 230

(3R.5R.6S)-3-(5-cyano group-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 229 compound title compounds.m.p.256-258℃。 ¹H NMR (360MHz, DMSO-d ₆) δ 7.76-7.82 (4H, m), 7.68-7.69 (3H, m), 7.24 (1H, d, J8.7Hz), 4.82 (1H, sept, J6.0Hz), 4.58 (1H, br s), 4.16 (1H, t, J7.5Hz), 3.79 (1H, dd, J8.0,10.7Hz), 3.45-3.47 (1H, m), 3.23-3.27 (1H, m), 2.41-2.46 (1H, m), 2.24-2.33 (3H, m), 1.99-2.09 (3H, m) and 1.34 (6H, dd, J6.0,10.5Hz).m/z(ES ⁺)377(M+1)。

Embodiment 231

(3R, 5R, 6S)-3-[2-(ethene-1-yl) 5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize fire-resistant valve (3 *), with (3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-the 6-phenyl-(embodiment 188 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 700mg), vinyl tributyl tin (0.4ml), lithium chloride (290mg) and tetrakis triphenylphosphine palladium (O) (50mg) De diox (10ml) mixture outgas, stirred 16 hours down at 110 ℃.Cooling mixture filters solvent evaporated under reduced pressure.Residue is dissolved in the acetonitrile (10ml), utilizes hexane (15ml) washing.Utilize acetonitrile (3 * 10ml) extraction hexane fractions, utilize the Repone K methanol solution (5%, 2ml) the hexane fraction that merges of washing.Filtering mixt, solvent evaporated under reduced pressure.Residue utilizes hexane/EtOAc (90: 10) wash-out by quick silica gel chromatography, obtains title compound, is oily matter. ¹H NMR (360MHz, CDCl ₃) δ 1.47 (9H, s), 1.77 (3H, m), 1.84 (1H, m), 2.25 (1H, td), 2.64 (1H, dd, J12.8,7.7Hz), 2.76 (1H, td), 3.79 (1H, qn), 3.90 (1H, t, J8.5Hz), 3.96 (1H, dd), 4.24 (1H, t, J8.0Hz), 5.34 (1H, s), 5.37 (1H, d, J11.1Hz), 5.59 (1H, d, J17.2Hz), 6.98 (1H, dd, J17.2,10.9Hz), 7.08 (1H, d), 7.15 (1H, s), 7.25 (1H, m), 7.33 (2H, t, J7.4Hz), 7.45 (1H, d, J8.6Hz) and 7.60 (2H, d, J7.5Hz).

Embodiment 232

(3R, 5R, 6S)-3-[2-(ethene-1-yl) 5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 231 compound title compounds. ¹H NMR (360MHz, CD ₃OD) δ 0.53 (1H, t, J15.1Hz), 0.73 (2H, m), 0.89 (1H, m), 1.09 (3H, m), 1.96 (1H, td, J12.4Hz), 2.16 (1H, dd, J12.8Hz), 2.52 (1H, t, J9.7Hz), 2.78 (1H, t, J7.1Hz), 3.08 (1H, s), 3.90 (1H, d, J11.0Hz), 4.18 (1H, d, J17.2Hz), 4.83 (1H, dd, J17.2,10.9Hz), 5.83 (2H, m), 6.17 (1H, d, J8.5Hz) and 6.34 (5H, m).m/z(ES ⁺)404(M+1)。

Embodiment 233

(3R, 5R, 6S)-3-[2-ethanoyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize fire-resistant valve (3 *), with (3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-the 6-phenyl-(embodiment 188 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 270mg), (1-vinyl ethyl ether base) tributyl tin (0.15ml), lithium chloride (108mg) and tetrakis triphenylphosphine palladium (O) (50mg) De diox (2ml) mixture outgas, stirred 16 hours down at 110 ℃.Cooling mixture filters solvent evaporated under reduced pressure.Residue is dissolved in the acetonitrile (10ml), utilizes hexane (15ml) washing.Utilize acetonitrile (3 * 10ml) extraction hexane fractions, utilize the Potassium monofluoride methanol solution (5%, 2ml) the acetonitrile fraction that merges of washing.Filtering mixt, solvent evaporated under reduced pressure.Residue is dissolved in the tetrahydrofuran (THF) (3ml), and the adding aqueous hydrochloric acid (6M, 2ml).Mixture at room temperature stirred 4 hours, utilized sodium bicarbonate aqueous solution (saturated) alkalization, utilized methylene dichloride (3 * 10ml) extractions, the organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Hydraulic fluid phase silica gel chromatography purifying in the residue utilizes hexane/EtOAc (85: 15) wash-out, obtains title compound, is oily matter. ¹H NMR (360MHz, CDCl ₃) δ 1.47 (9H, s), 1.72 (3H, m), 1.81 (1H, dd, J12.9,8.3Hz), 2.22 (1H, td), 2.58 (3H, s), 2.72 (1H, dd, J12.9,8.3Hz), 2.76 (1H, td, 12.6Hz), 3.86 (1H, dd, J8.8,6.6Hz), 4.00 (1H, dd), 4.09 (1H, qn), 4.24 (1H, dd, J8.8,7.3Hz), 5.29 (1H, s), 7.14 (1H, d, J8.6Hz), 7.25 (1H, m), 7.34 (3H, m), 7.58 (2H, d, J7.8Hz) and 7.61 (1H, d, J 8.6Hz).

Embodiment 234

(3R, 5R, 6S)-3-[2-ethanoyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 181, by embodiment 233 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.69 (3H, m), 1.99 (1H, m), 2.24 (3H, s), 2.29 (1H, dd, J13.1,8.3Hz), 2.45 (2H, m), 2.84 (1H, t), 3.39 (1H, d), 3.67 (1H, t, J8.9Hz), 3.87 (1H, s), 3.99 (1H, t, J7.6Hz), 7.05 (1H, d, J8.4Hz), 7.08 (1H, s), 7.37 (4H, m) and 7.59 (2H, d, J7.1Hz) .m/z (ES ⁺) 420 (M+1).

Embodiment 235

(3R, 5R, 6S)-3-[2-formyl radical-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize nitrogen purge (3R, 5R, 6S)-3-[2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl]-the 6-phenyl-(embodiment 231 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 420mg) and the methylene dichloride (10ml) of methyl alcohol (4ml) stir cooling (78 ℃) mixture, be blown into the ozone current stabilization 1 hour by mixture then.Utilize the oxygen washed mixture 15 minutes, utilized nitrogen purge then 15 minutes.Add methyl-sulfide (0.3ml), mixture at room temperature stirs and spends the night.Solvent evaporated under reduced pressure, residue utilizes hexane/EtOAc (85: 15) wash-out by the silica gel chromatography purifying, obtains title compound, is oily matter. ¹H NMR (360MHz, CDCl ₃) δ 1.48 (9H, s), 1.55 (2H, m), 1.72 (1H, d, J9.5Hz), 1.85 (1H, dd, J13.0,8.4Hz), 2.25 (1H, m), 2.77 (2H, m), 3.97 (2H, m), 4.27 (1H, dd, J9.0,7.2Hz), 4.53 (1H, qn, J7.2Hz), 5.36 (1H, s), 7.26 (2H, m), 7.34 (2H, m), 7.59 (1H, d, J7.6Hz), 7.87 (1H, d, J8.5Hz) and 10.26 (1H, s).m/z(ES ⁺)450(M+1-C ₄H ₈)。

Embodiment 236

(3R, 5R, 6S)-3-[2-formyl radical-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 235 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.59 (3H, m), 2.20 (3H, m), 2.25 (1H, dd, J12.7Hz), 2.80 (2H, m), 3.56 (1H, s), 3.72 (1H, t, J9.8Hz), 3.97 (1H, t, J 7.8Hz), 7.10 (2H, s), 7.38 (3H, m), 7.50 (2H, dd, J7.7,3.0Hz), 7.78 (1H, d, J9.3Hz) and 9.53 (1H, s).m/z(ES ⁺)406(M+1)。

Embodiment 237

(3R, 5R, 6S)-3-[3-fluoro-2-methoxyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

With Selectfluor ^TM(630mg) join (3R, 5R, 6S)-and 3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (embodiment 164, in acetonitrile 208mg) (15ml) solution, and reflux mixture 36 hours.Mixture is cooled and solvent evaporated under reduced pressure, and residue utilizes CH by middle hydraulic fluid phase silica gel chromatography purifying ₂Cl ₂/ MeOH (92: 8) wash-out obtains title compound, is light brown oily matter (15mg). ¹H NMR (360MHz, CDCl ₃) δ 1.46-1.56 (1H, m), 1.0-1.75 (3H, m), 1.98-2.02 (1H, m), and 2.16-2.37 (3H, m), 2.86 (1H, t, J12.6Hz), 3.20-3.24 (1H, m), 3.49 (3H, s), 3.56 (1H, s), 3.98 (1H, t, J7.6Hz), 6.64 (1H, s), 6.28 (1H, d, J11Hz), and 7.25-7.60 (5H, m).m/z(ES ⁺)426(M+1)。

Embodiment 238

(3R, 5R, 6S)-3-[2-cyano group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Utilize fire-resistant valve (* 5), with (3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-the 6-phenyl-(embodiment 188 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 230mg), zinc cyanide (26mg), three (dibenzalacetones), two palladiums (O) are (10mg) with 1,1 '-DMF (1ml) mixture of two (diphenylphosphino) ferrocene (16mg) outgases, stirred 4 hours down at 110 ℃.Cooling mixture utilizes the water dilution, utilizes ethyl acetate (3 * 5ml) extractions.The organic fraction that utilizes the salt water washing to merge, dry (MgSO ₄), solvent evaporated under reduced pressure.Hydraulic fluid phase silica gel chromatography purifying in the residue utilizes hexane/EtOAc (90: 10) wash-out, obtains title compound, is colorless oil (60mg). ¹H NMR (360MHz, CDCl ₃) δ 1.48 (9H, s), 1.56-1.68 (1H, m), 1.70-1.80 (2H, m), 1.88 (1H, dd, J13.2,8.0Hz), 2.26 (1H, dt, J13.0,5.0Hz), 2.76-2.85 (2H, m), 3.93-4.01 (3H, m), 4.28-4.35 (1H, m), 5.34 (1H, s), 7.10-7.20 (1H, m), and 7.24-7.3 (1H, m), 7.31-7.36 (3H, m), 7.57-7.60 (2H, m) and 7.68 (1H, d, J8.6Hz) .m/z (ES ⁺) 447 (M+l-C ₄H ₈).

Embodiment 239

(3R, 5R, 6S)-3-[2-cyano group-5-(trifluoromethoxy plinth) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 238 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 1.60-1.73 (2H, m), 1.86 (2H, mc), 1.98-2.07 (1H, m), and 2.36-2.54 (2H, m), 2.79 (1H, t, J12Hz), 3.19-3.25 (1H, m), 3.56 (1H, s), 3.71 (1H, t, J9.0Hz), 4.03 (1H, t, J8.0Hz), and 7.00-7.1 (2H, m), 7.30-7.40 (3H, m), 7.46-7.51 (2H, m) and 7.55 (1H, d, J8.5 Hz).m/z(ES ⁺)403(M+1)。

Embodiment 240

(3R, 5R, 6S)-3-[2-ethyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Methyl alcohol (2ml) soup compound of palladium hydroxide/carbon (100mg) is joined (3R, 5R, 6S)-3-[2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl]-the 6-phenyl-(embodiment 231 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, in ethyl acetate 200mg) (10ml) solution, mixture vibrates down at hydrogen atmosphere (50psi) and spends the night.Filtering mixt, solvent evaporated under reduced pressure obtains title compound, is oily matter. ¹H?NMR(CDCl ₃,360MHz),δ1.20(3H,t,J7.6Hz),1.46(9H,s),1.63(2H,m),1.79(2H,m),2.27(1H,td,J7.6,5.1Hz),2.67(3H,m),2.76(1H,td,J9.3,3.9Hz),3.72(1H,qn,J8.0Hz),3.89(1H,t,J8.6Hz),3.97(1H,dd,J13.1Hz),4.24(1H,t,J7.8Hz),5.35(1H,s),7.01(1H,d,J8.7Hz),7.17(2H,m),7.25(1H,m),7.33(2H,t,J7.1Hz),7.60(2H,d,J7.7Hz)。m/z(ES ⁺)450(M+1-C ₄H ₈)。

Embodiment 241

(3R, 5R, 6S)-3-[2-ethyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 240 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 0.78 (3H, t, J7.6Hz), 1.53 (1H, m), 1.34 (3H, m), 1.71 (1H, td, J12.2,4.5Hz), 2.02 (2H, q, J7.6Hz), 2.18 (2H, m), 2.80 (1H, t, J12.3Hz), 3.22 (1H, d), 3.53 (1H, s), 3.60 (1H, t, J10.3Hz), (3.91 1H, t, J 7.7Hz), 6.89 (2H, m), 6.99 (1H, d, J 8.4Hz), 7.30 (3H, m) and 7.47 (2H, m).m/z(ES ⁺)406(M+1)。

Embodiment 242

(3R, 5R, 6S)-3-(6-fluoro-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 170, by illustrative examples 121 compounds and (5R, 6S)-the 6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene (illustrative examples 86) preparation title compound. ¹H NMR (360MHz, CDCl ₃) δ 7.63 (and 2H, d, J7.8Hz), 7.32-7.11 (6H, m), 5.36 (1H, s), 4.18-3.96 (4H, m), 3.83 (3H, s), 2.80 (1H, m), 2.42 (1H, m), 2.23 (2H, m), 1.88-1.64 (3H, m) and 1.48 (9H, s).m/z(ES ⁺)442(M+1)。

Embodiment 243

(3R, 5R, 6S)-3-(6-fluoro-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 181, by embodiment 242 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.47 (2H, m), 7.34 (3H, m), 7.02 (1H, dt, J _d6.4Hz, Jt8.3Hz), 6.52 (2H, m), 3.99 (1H, m), 3.77 (1H, m), 3.63 (3H, s), 3.55 (1H, s), 3.22 (1H, m), 2.78 (1H, m), 2.70 (1H, br s), 2.06 (1H, m) and 2.12 (6H, m).m/z(ES ⁺)342(M+1)。

Embodiment 244

(3S, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Under nitrogen atmosphere, with naphthalene (120mg 0.936mm0l) is dissolved among the THF (1.5ml), add new cutting the lithium metal (7.0mg, 0.94mmol).At room temperature mixture is carried out sonication in 20 minutes then, obtain deep green naphthalene lithium.Cooling solution is to-78 ℃, in 1 minute, add (3S then, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethoxy) phenyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (illustrative examples 111) (120mg, THF 0.187mmol) (0.5ml) solution.Stirred the mixture 30 minutes, and added entry (5ml) and ether (10ml) then.Layering utilizes ether (10ml) aqueous layer extracted, dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/ethyl acetate (increasing to 80: 20 at 90: 10) wash-out by silica gel chromatography, obtains title compound, is colorless oil (58.6mg, 59%). ¹H NMR (250MHz, CDCl ₃) (7.58-7.52 (2H, m), 7.36-7.17 (4H, m), 7.10-7.01 (2H, m), 5.18 (1H, br s), 4.20 (1H, t, J6.7Hz), and 4.05-3.95 (1H, m), 3.76-3.55 (3H, m), 2.92-2.79 (1H, m), 2.37 (1H, dd, J12.9,7.8Hz), 2.18-2.06 (2H, m), 1.80-1.67 (3H, m), 1.38 (9H, s), and 0.86-0.73 (4H, m).m/z(ES ⁺)534(M+1)。

Embodiment 245

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

(2.5ml) is added drop-wise to (3R with trifluoroacetic acid, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-the 6-phenyl-(embodiment 244 for 1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane, 492mg, 0.92mmol) methylene dichloride (25ml) stir in cooling (0 ℃) solution, mixture at room temperature stirred 3 hours.Mixture is injected in the water (50ml), utilizes aqueous sodium hydroxide solution (4M) to regulate pH to 10.0, utilize methylene dichloride (3 * 50ml) extraction mixtures.Dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes CH by silica gel chromatography ₂Cl ₂/ MeOH/NH ₃(hydration) (increasing to 94: 6: 0.6 at 96: 4: 0.4) wash-out.Residue is dissolved in the ethanol (20ml), in ice, cools off, drip ether close hydrogenchloride (1M, 1.8ml, 1.8mmol).Mixture stirred 5 minutes down at 0 ℃, then solvent evaporated under reduced pressure.Residue is collected solid by ether (20ml)/ethanol (0.5ml) crystallization, and vacuum-drying obtains title compound, is colorless solid (354mg, 89%).m.p.214-216℃。 ¹H NMR (500MHz, CD ₃OD) δ 7.59 (2H, m), 7.52 (3H, m), 7.26 (1H, d, J8.9Hz), 7.03 (1H, dd, J8.9,2.2Hz), 6.20 (1H, d, J2.2Hz), 4.85 (2H, br s), 4.43 (1H, s), 4.19 (1H, t, J8.0Hz), 3.87 (1H, quin, J8.0Hz), 3.76 (1H, m), 3.44 (1H, m), 3.25 (2H, m) 2.29-1.78 (6H, m), 0.80 (2H, m) and 0.66 (2H, m).m/z(ES ⁺)434(M+1)。Measured value: C, 61.41; H, 5.51; N, 3.08.C ₂₄H ₂₈F ₃NO ₃.HCl theoretical value: C, 61.34; H, 5.79; N, 2.98%.

Embodiment 246

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

Under nitrogen atmosphere, with naphthalene (120mg 0.936mmol) is dissolved among the THF (1.5ml), add new cutting the lithium metal (7.0mg, 0.94mmol).At room temperature mixture is carried out sonication in 20 minutes then, obtain deep green naphthalene lithium.Under nitrogen atmosphere, with (3R, 5R, 6S)-3-[2-(1-phenyl sulfo-ring third-1-yl) oxygen base-5-(trifluoromethoxy) phenyl-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane (illustrative examples 112,135mg, 0.21mmol) THF (2ml) solution be cooled to-78 ℃, drip naphthalene lithium THF solution, constant until the deep green color.Stirring reaction is 1 minute then, adds entry (5ml), and mixture is warmed to room temperature.Add ether (10ml), layering.Utilize other part ether (10ml) aqueous phase extracted, dry (MgSO ₄) organic fraction that merges, solvent evaporated under reduced pressure.Residue utilizes hexane/ethyl acetate (50: 50) wash-out by silica gel chromatography, obtains title compound, is colorless oil (87mg, 78%). ¹H NMR (360MHz, CDCl ₃) δ 7.59 (2H, app.d, J7.6Hz), 7.32 (2H, app.t, J7.6Hz), 7.27-7.18 (2H, m), and 7.11-7.03 (2H, m), 5.32 (1H, br s), 4.29-4.21 (1H, m), 3.97 (1H, br.d, J13Hz), 3.83-3.68 (3H, m), 2.76 (1H, dt, J13,4.1Hz), 2.55 (1H, dd, J13,7.2Hz), 2.22 (1H, dt, J12,5.2Hz), 1.85 (1H, dd, J13,9.9Hz), 1.80-1.63 (3H, m), 1.46 (9H, s), and 0.82-0.76 (4H, m).m/z(ES ⁺)534(M+1)。

Embodiment 247

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 245, by embodiment 246 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.50-7.42 (2H, m), 7.36-7.26 (3H, m), 7.03 (1H, d, J8.9Hz), 6.95 (1H, br.d, J8.9Hz), 6.81 (1H, br s), 3.92 (1H, t, J7.4Hz), 3.62-3.53 (2H, m), 3.50 (1H, s), 3.20 (1H, dd, J12,4.2Hz), 2.77 (1H, dt, J12,2.8Hz), 2.30-1.93 (4H, m), 1.87 (1H, br s), 1.71-1.49 (3H, m), 0.76-0.65 (2H, m), and 0.65-0.54 (2H, m).m/z(ES ⁺)434(M+1)。

Embodiment 248

(3S, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 246, by illustrative examples 113 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.54 (2H, d, J7.7Hz), 7.46 (1H, d, J8.2Hz), 7.40 (1H, s), 7.33-7.24 (4H, m), 5.17 (1H, s), 4.20 (1H, t, J7.2Hz), 4.00 (1H, m), 3.78-3.60 (3H, m), 2.88 (1H, m), 2.39 (1H, dd, J12.9,7.8Hz), 2.16 (2H, m), 1.73 (3H, m), 1.36 (9H, s) and 0.82 (4H, m).

Embodiment 249

(3S, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 245, by embodiment 248 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.48-7.30 (6H, m), 7.16 (1H, d, J8.5Hz), 6.53 (1H, s), 4.05 (1H, t, J7.9Hz), 3.78-3.66 (3H, m), 3.24 (1H, m), 3.06 (1H, dd, J10.4,8.2Hz), 2.83 (1H, m), (2.6 1H, br s), 2.08 (2H, m), 1.84 (2H, m), 1.61 (2H, m) and 0.74 (4H, m).m/z(ES ⁺)418(M+1)。

Embodiment 250

(3R, 5R, 6S)-3-[2-ring propoxy--5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 246, by illustrative examples 114 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 7.60 (2H, d, J7.5Hz), 7.32 (2H, t, J7.5Hz), 7.24 (1H, t, J7.5Hz), 7.18 (1H, d, J8.7Hz), 7.02 (1H, d, J2.8Hz), 6.98 (1H, dd, J8.7,2.8Hz), 6.43 (1H, t, J74.4Hz), 5.32 (1H, s), 4.25 (1H, m), 3.97 (1H, m), 3.81-3.69 (3H, m), 2.75 (1H, m), 2.54 (1H, m), 2.22 (1H, m), 1.89-1.62 (4H, m), 1.46 (9H, s) and 0.77 (4H, m).m/z(ES ⁺)516(M+1)。

Embodiment 251

(3R, 5R, 6S)-3-[2-ring propoxy--5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 245, by embodiment 250 compound title compounds.(360MHz, D ₂O) δ 0.51 (2H, m), 0.72 (2H, m), 1.79 (1H, m), 1.90-2.28 (6H, m), 3.21 (1H, m), 3.50 (1H, m), 3.65 (2H, m), 4.00 (1H, m), 4.26 (1H, s), 6.66 (1H, t, J74Hz), 6.93 (1H, d, J2.7Hz), 7.01 (1H, dd, J8.9,2.7Hz), 7.18 (1H, d, J8.9Hz) and 7.55 (5H, m).m/z(ES ⁺)416(M+1)。Measured value: C, 62.2; H, 6.2; N, 3.1.C ₂₄H ₂₇F ₂NO ₃.HCl.0.5H ₂O theoretical value C, 62.5; H, 6.3; N, 3.0%.

Embodiment 252

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-(4-fluorophenyl)-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 246, by illustrative examples 115 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 0.79 (2H, m), 0.86 (2H, m), 1.46 (9H, s), 1.68 (3H, m), 1.87 (1H, dd, J9.9Hz), 2.14 (1H, td), 2.53 (1H, dd, J12.6Hz), 3.77 (3H, m), 3.98 (1H, dd), 4.24 (1H, s), 5.20 (1H, s), 7.00 (2H, t, J8.8Hz), 7.08 (2H, s), 7.23 (2H, d, J9.5Hz) and 7.55 (2H, dd, J8.7,5.6Hz).

Embodiment 253

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-(4-fluorophenyl)-1-oxa--7-azepine-spiral shell [4.5] decane hydrochloride

According to the method for embodiment 245, by embodiment 252 compound title compounds. ¹H NMR (400MHz, CDCl ₃) δ 0.59 (2H, s), 0.74 (2H, d, J6.28Hz), 1.68 (3H, m), 2.05 (2H, m), 2.21 (1H, m), 2.42 (1H, dd, J13.4Hz), 2.87 (1H, dd, J9.2Hz), 3.39 (1H, d, J10.2Hz), 3.59 (2H, m), 3.87 (1H, d, J10.4Hz), 4.00 (1H, t, J7.7Hz), 6.77 (1H, s), 7.03 (4H, m), 7.61 (2H, s), 9.21 (1H, s) and 10.24 (1H, s).

Embodiment 254

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(tert-butoxycarbonyl) azepine-spiral shell [4.5] decane

According to the method for embodiment 246, by illustrative examples 120 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 0.83-0.91 (4H, m), 1.46 (9H, s), 1.55-1.8 (3H, m), 1.86-1.92 (1H, m), 2.22 (1H, dt, J13.0,5.0Hz), 2.56 (1H, dd, J12.0,6.5Hz), 2.76 (1H, mc), 3.77-3.80 (3H, m), 3.97 (1H, mc), 4.27 (1H, mc), 5.33 (1H, s), 7.24-7.34 (4H, m), 7.45-7.50 (2H, m), and 7.58-7.62 (2H, m).m/z(ES ⁺)462(M+1-C ₄H ₈)。

Embodiment 255

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane

According to the method for embodiment 245, by embodiment 254 compound title compounds. ¹H NMR (360MHz, CDCl ₃) δ 0.56-0.70 (2H, m), 0.70-0.80 (2H, m), 1.62-1.72 (3H, m), and 1.96-2.04 (1H, m), 2.08-2.28 (3H, m), 2.81 (1H, t, J12.0Hz), 3.14-3.22 (1H, m), 3.58-3.68 (2H, m), 3.76 (1H, s), 4.00 (1H, t, J7.5Hz), 7.10-7.20 (2H, m), 7.26-7.42 (4H, m), and 7.42-7.54 (2H, m).m/z(ES ⁺)418(M+1)。

Claims

1. formula I compound or pharmaceutically acceptable salt thereof:

Wherein

R ²Expression hydrogen, halogen, C _1-6Alkyl or C _1-6Alkoxyl group;

Or work as R ²With R ¹When adjoining, they can connect into and contain the saturated or unsaturated ring of one or two 5-that is selected from nitrogen, oxygen or sulphur or 6-unit, and this ring can at random be selected from C _1-4Alkyl, CF ₃,=O or=substituting group of S replaces;

R ⁴Expression hydrogen, halogen, C _1-6Alkyl, C _1-6Alkoxyl group, CF ₃, OCF ₃, NO ₂, CN, SR ^a, SOR ^a, SO ₂R ^a, CO ₂R ^a, CONR ^aR ^b, C _2-6Alkenyl, C _2-6Alkynyl or by C _1-4The C that alkoxyl group replaces _1-4Alkyl, wherein R ^aAnd R ^bDefinition as mentioned;

Z is C _1-6Alkylidene group or C _3-6Cycloalkyl;

Or R ⁷, R ⁸And coupled nitrogen-atoms forms 4 to 7 yuan of heterolipid rings, and this heterolipid ring at random is selected from hydroxyl or at random by C _1-4The C that alkoxyl group or hydroxyl replace _1-4One or two group of alkoxyl group replaces, and this ring at random contains two keys, and this ring can at random contain aerobic or sulphur annular atoms, group S (O) or S (O) ₂Or can be used as NH or NR ^cSecond nitrogen-atoms of the part of part, wherein R ^cFor at random by hydroxyl or C _1-4The C that alkoxyl group replaces _1-4Alkyl;

Or R ⁷, R ⁸And coupled nitrogen-atoms forms the non-aromatics azabicyclic system that contains 6 to 12 annular atomses;

R ¹²Expression OR ^a, CONR ^aR ^bOr heteroaryl;

R ¹³Expression hydrogen or C _1-6Alkyl;

X is Sauerstoffatom or two hydrogen atoms; And

Intermittent line is represented two arbitrarily keys.

2. according to the compound of claim 1, R wherein ¹Expression hydroxyl, C _1-6Alkyl, C _2-6Alkenyl, C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _2-6Alkenyloxy, C _3-7Cycloalkyloxy, C _3-7Cycloalkyl C _1-4Alkoxyl group, cyano group, NR ^aR ^b, SR ^aOSO ₂R ^a, or R ¹With radicals R ²Form the 5-unit saturated rings that contains a Sauerstoffatom together.

3. according to the compound of claim 1 or 2, R wherein ²Be hydrogen, fluorine or chlorine atom.

4. the compound arbitrary, wherein R according to claim 1 to 3 ³Be hydrogen, halogen, fluoro C _1-6Alkyl, fluoro C _1-6Alkoxyl group, cyano group, NR ^aR ^bOr NR ^aCOR ¹⁴

5. the compound arbitrary, wherein R according to claim 1 to 4 ⁴Be hydrogen atom or fluorine atom.

6. the compound arbitrary, wherein R according to claim 1 to 5 ⁵Be hydrogen atom.

7. the compound arbitrary, wherein R according to claim 1 to 6 ⁶For hydrogen atom or as the C of the 5-unit heterocyclic substituted that contains 2 or 3 nitrogen-atoms of claim 1 definition _1-6Alkyl.

8. the compound arbitrary, wherein R according to claim 1 to 7 ⁹And R ¹⁰One of be hydrogen.

9. the compound arbitrary according to claim 1 to 8, wherein X represents two hydrogen atoms.

10. the compound arbitrary according to claim 1 to 9 wherein do not existed by two keys that intermittent line is represented.

11. formula (I is compound or pharmaceutically acceptable salt thereof a):

R wherein ¹, R ², R ³, R ⁴With intermittent line such as claim 1 definition.

12. according to the compound of claim 1, or its pharmaceutical salts, wherein

R ²The expression hydrogen or halogen;

Or work as R ²With R ¹When adjoining, they can connect into the unsaturated ring of oxygen containing 5-unit;

R ⁴The expression hydrogen or halogen;

R ⁵Expression hydrogen;

R ⁶Expression hydrogen, perhaps R ⁶Expression C _1-6Alkyl, this C _1-6Alkyl is contained the 5-unit heterocyclic substituted of 1,2 or 3 nitrogen-atoms and at random by formula ZNR ⁷R ⁸Group replace;

R ⁷Be hydrogen or C _1-4Alkyl;

R ⁸Be hydrogen or C _1-4Alkyl;

R ⁹And R ¹⁰Represent hydrogen independently of one another;

X is Sauerstoffatom or two hydrogen atoms;

Z is C _1-6Alkylidene group; And

Intermittent line is represented two arbitrarily keys.

13. compound or pharmaceutically acceptable salt thereof, described compound is selected from:

(5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-methoxyl group-5-Trifluoromethoxyphen-l)-6-phenyl-7-(1,2,4-triazolyl-3-methylene radical)-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(2-isopropoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(5R, 6S)-3-(2-allyloxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(5R, 6S)-3-(5-trifluoromethoxy-2,3-Dihydrobenzofuranes-7-yl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(5R, 6S)-3-(2-methoxyl group-5-(2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(5R, 6S)-3-(2,5-two (2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(5R, 6S)-3-(2-difluoro-methoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(5R, 6S)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-isopropoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(5-trifluoromethoxy-2,3-Dihydrobenzofuranes-7-yl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-methoxyl group-5-(2,2, the 2-trifluoro ethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2, two (2,2, the 2-trifluoro ethoxy) phenyl of 5-)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-difluoro-methoxy-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-(2,2, the 2-trifluoro ethoxy)-5-Trifluoromethoxyphen-l)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-(2,2,2-trifluoro ethoxy-5-trifluorophenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(5-methylsulfonyl-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(5-methylsulfonyl-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-cyclobutoxy group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-cyclobutoxy group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(2-(2-fluoro oxyethyl group)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-(2-fluoro oxyethyl group)-5-(trifluoromethoxy)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-ethyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(2-benzyloxy-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(2-methoxyl group-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-2-ketone;

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] trifluoroacetamide;

(3S, 5R, 6S)-and N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] trifluoroacetamide;

N-[4-methoxyl group-3-[6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) carboxylamine (3S, 5R, 6S)-methyl ester;

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(methyl) trifluoroacetamide;

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) trifluoroacetamide;

(5R, 6S)-N-[4-isopropoxy-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(methyl) trifluoroacetamide;

(3S, 5R, 6S)-N-[4-isopropoxy-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) trifluoroacetamide;

(5R, 6S)-N-[4-(difluoro-methoxy)-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(methyl) trifluoroacetamide;

(3S, 5R, 6S)-N-[4-(difluoro-methoxy)-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) trifluoroacetamide;

(5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl]-N-(2,2, the 2-trifluoroethyl) ethanamide;

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(2,2, the 2-trifluoroethyl) ethanamide;

(3S, 5R, 6S)-N-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl]-N-(methyl) benzamide;

(5R, 6S)-3-[5-methylamino--2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[5-methylamino--2-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-N-methyl-N-[3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl)-4-(trifluoromethoxy) phenyl] trifluoroacetamide;

(3S, 5R, 6S)-and N-methyl-N-[3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl)-4-(trifluoromethoxy) phenyl] trifluoroacetamide;

(5R, 6S)-3-[2-oxyethyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-oxyethyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-(trifluoromethylthio) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-(trifluoromethylthio) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[2-cyclopropyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(5-bromo-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-(5-cyano group-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[5-cyano group-2-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[5-cyano group-2-(cyclobutoxy group) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-cyano group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-(cyclo propyl methoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[2-methoxyl group-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[2-methoxyl group-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-(1,2,4-triazolyl-3-methyl)-7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-(2-methylsulfonyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-(2-methylsulfonyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

[4-hydroxyl-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] oxyacetic acid (5R, 6S)-methyl esters;

[4-hydroxyl-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] oxyacetic acid (3S, 5R, 6S)-methyl esters;

(3S, 5R, 6S)-3-[5-(cyano methyl)-2-p-methoxy-phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(5R, 6S)-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] carboxylic acid amides;

(3S, 5R, 6S)-[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] carboxylic acid amides;

(3S, 5R, 6S)-3-(5-cyano group-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene-3-yl) phenyl] oxyacetic acid (5R, 6S)-methyl esters;

[4-methoxyl group-3-(6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-yl) phenyl] oxyacetic acid (3S, 5R, 6S)-methyl esters;

(3S, 5R, 6S)-3-(5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-and 7-{[5-(dimethyl aminomethyl)-1H-[1,2,3] triazole-4-yl] methyl }-3-[2-isopropoxy-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3S, 5R, 6S)-3-[5-fluoro-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-(1,2,4-triazolyl-3-methyl)-7-azepine-spiral shell [4.5] decane;

(5R, 6S)-3-[2-dimethylamino-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] last of the ten Heavenly stems-3-alkene;

(3S, 5R, 6S)-3-[2-dimethylamino-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

14. compound or pharmaceutically acceptable salt thereof, described method is selected from:

(3R, 5R, 6S)-3-(2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4,5] decane;

(3R, 5R, 6S)-3-[2-hydroxyl-5-(trifluoromethoxy) phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(5-hydroxyl-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-and 3-[2, two (methoxyl group) phenyl of 4-]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-difluoro-methoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-isopropoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(ethene-1-yl)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-and 3-[2, two (difluoroethoxy) phenyl of 5-]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[5-fluoro-2-(difluoroethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[5-fluoro-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(5-fluoro-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-isopropoxy-5-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-and 3-[2, two (isopropoxy) phenyl of 5-]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(5-chloro-2-p-methoxy-phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(2,2, the 2-trifluoro ethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(cyclo propyl methoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-benzyloxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[5-(difluoro-methoxy)-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(2, the 2-difluoroethoxy)-5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(cyclobutoxy group)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(methoxy ethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[5-(trifluoromethoxy)-2-(trifluoromethyl sulfonyloxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(2, the 2-difluoroethoxy)-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-cyclopropyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(5-cyano-2-hydroxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(5-cyano group-2-isopropyl phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-(ethene-1-yl) 5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-ethanoyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-formyl radical-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[3-fluoro-2-methoxyl group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-cyano group-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-ethyl-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-(6-fluoro-2-p-methoxy-phenyl)-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

15. compound or pharmaceutically acceptable salt thereof, described compound is selected from:

(3S, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-ring propoxy--5-(difluoro-methoxy) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethoxy) phenyl]-6-(4-fluorophenyl)-1-oxa--7-azepine-spiral shell [4.5] decane;

(3R, 5R, 6S)-3-[2-ring propoxy--5-(trifluoromethyl) phenyl]-6-phenyl-1-oxa--7-azepine-spiral shell [4.5] decane.

16. as the compound in the above-mentioned claim is used for the treatment of.

17. a pharmaceutical composition, said composition contain arbitrary compound and pharmaceutically acceptable carrier or excipient in the claim 1 to 15.

18. the method for the physiological maladies that a treatment is excessively relevant with tachykinin, this method comprise that the patient to the needs treatment gives claim 1 compound with reduction tachykinin amount.

19., be used for the treatment of or prevent irritation or inflammation according to the method for claim 18.

20., be used for the treatment of or prevention of migraine according to the method for claim 18.

21., be used for the treatment of or prevention of emesis according to the method for claim 18.

22., be used for the treatment of or prevent postherpetic neuralgia according to the method for claim 18.

23. the application of the arbitrary compound of claim 1 to 15 in the medicine for preparing treatment or the prevention physiological maladies excessively relevant with neurodynia.

24. the application of the arbitrary compound of claim 1 to 15 in the medicine of preparation treatment or prevent irritation or inflammation.

25. the application of the arbitrary compound of claim 1 to 15 in the medicine of preparation treatment or prevention of migraine.

26. the application of the arbitrary compound of claim 1 to 15 in the medicine of preparation treatment or prevention of emesis.

27. the application of the arbitrary compound of claim 1 to 15 in the medicine of preparation treatment or prevention postherpetic neuralgia.

28. a method for preparing claim 1 compound, this method comprises:

(A.1) when two keys of being represented by intermittent line do not exist, reduction-type (II A) compound,

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁹, R ¹⁰Definition defines as claim 1 with X.Or

(A.2) do not exist and X when being two hydrogen atoms when two keys of representing by intermittent line, reduction-type (II B) compound,

Or

(B) when intermittent line is represented two key, with the formula III compound

Each R wherein ⁴⁵Be C _1-4Alkyl, with the reaction of formula IV compound,

R wherein ⁵⁰Be leavings group; Or

(C) with formula (V) compound,

With the reaction of formula VI compound,

LG-R ^6a (Ⅵ)

R wherein ^6aBe the formula R in the claim 1 ⁶Group (except H) or its precursor, LG are leavings group; And if R ^6aBe precursor group, can be converted into radicals R ⁶Or

(D) work as R ¹Be C _1-6Alkoxyl group, fluoro C _1-6Alkoxyl group, C _2-6Alkenyloxy, C _3-7Cycloalkyloxy, C _3-7Cycloalkyl C _1-4When alkoxyl group or benzyloxy, under the alkali existence condition, with formula (VII) compound,

With suitable alkyl-, fluoro-alkyl-, alkenyl-, cycloalkyl-, cycloalkylalkyl-or aralkyl-halide reaction; Or

(E) utilize dewatering agent cyclisation formula (VIII) compound,

Or

(F) when intermittent line is represented two key, utilize acid,, make the dehydration of formula (IX) compound as trifluoroacetic acid,

Or

(G) when two keys of being represented by intermittent line do not exist, under reductibility Heck reaction conditions, with formula (X) compound,

React with the formula IV compound; Or

(H) with formula (XX) compound,

React with the naphthyl lithium;

If necessary, can after each step, remove existing any blocking group; And

When the formula I compound obtains with the form of mixtures of enantiomorph or steric isomer, can at random split mixture, to obtain required enantiomorph; And/or

If necessary, gained formula I compound or its salt can be transformed into its pharmacologically acceptable salt.