CN1370167A - Bispidine compounds useful in treatment of cardiac arrhythmias - Google Patents

Bispidine compounds useful in treatment of cardiac arrhythmias Download PDF

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CN1370167A
CN1370167A CN00811696A CN00811696A CN1370167A CN 1370167 A CN1370167 A CN 1370167A CN 00811696 A CN00811696 A CN 00811696A CN 00811696 A CN00811696 A CN 00811696A CN 1370167 A CN1370167 A CN 1370167A
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CN1144805C (en
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C·阿尔斯特马克
K·安德松
A·比约雷
M·比约斯尼
E·L·林斯特德特阿尔斯特马克
G·尼尔松
M·波拉
G·斯特兰伦德
Y·厄滕格伦
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

There is provided compounds of formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<41>, R<42>, R<43>, R<44>, R<45>, R<46>, R<47>, A and B have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Description

New bridge joint bipiperidine compound for treating arrhythmia cordis
Invention field
The present invention relates to new medicinal compound, in particular for treating the compound of arrhythmia cordis.
Background and prior art
Arrhythmia cordis may be defined as the speed, regular or starting point exception or the conductive impairment for causing activation sequence exception of heartbeat.Clinically arrhythmia cordis can presumptive starting point (i.e. supraventricular, to include the arrhythmia cordis of the arrhythmia cordis and ventricle of atrium and chamber) and/or speed (i.e. bradyarrhythmia (slow type) and tachy-arrhythmia (Quick-type)) classify.
In the treatment of arrhythmia cordis, it is main by slowing down " tradition " antiarrhythmic drug (I classes antiarrhymic) that conduction of velocity works clinical test negative findings (referring to, such as New England Journal of Medicine, 321, Arrhythmia Suppression Trial (CAST) result of report in 406 (1989)) promote for selectivity delay cardiac repolarisation, therefore the drug development of the compound at extension QT intervals.Group III antiarrhymic may be defined as extension transmembrane action potential duration (by blocking outside K+Flow or increase inside ion stream and produce) and refractoriness, but the medicine of cardiac conduction is not influenceed.
The known drug (Group III or other medicines) worked before this by delayed repolarization it is main have the disadvantage it is known they can all show to be referred to as unique preceding arrhythmia cordis form of Torsade de points (torsades depointes), it is sometimes fatal.For the angle of security, the minimum of this phenomenon (being also due to that non-cardiac medicine is administered, such as the phenomenon that phenothiazines, tricyclic antidepressant, antihistamine and antibiotic are shown) is to provide effective antiarrhythmic drug key issue to be solved.
To bridge bipiperidine (bispidine) class (3,7- diazabicyclos [3.3.1] nonane) based on antiarrhythmic drug known to be especially recorded in international patent application WO 91/07405, european patent application 306871,308843 and 655228, with United States Patent (USP) 3962449,4556662,4550112,4459301 and 5468858, and journal of writings, especially include J.Med.Chem., 39,2559 (1996)；Pharmacol.Res., 24,149 (1991)；Circulation, 90,2032 (1994) and Anal.Sci.9,429 (1993).The known antiarrhythmic compounds based on bridging bipiperidine include the Bisaramil (α of 3- methyl -7- ethyls -9, 4 '-(Cl- benzoyloxys) -3, 7- diazabicyclos [3.3.1] nonane), Tedisamil (3 ', 7 '-two (Cvclopropvlmethvl) spiral shell (pentamethylene -1, 9 ') -3, 7- diazabicyclos [3.3.1] nonane), SAZ-VII-22 (3- (4- chlorobenzene formacyls) -7- isopropyls -3, 7- diazabicyclos [3.3.1] nonane), SAZ-VII-23 (3- benzoyl -7- isopropyls -3, 7- diazabicyclos [3.3.1] nonane), GLG-V-13 (3- [4- (1H- imidazoles -1- bases) benzoyl] -7- isopropyls -3, 7- diazabicyclos [3.3.1] nonane), KMC-IV-84 (7- [4 '-(1H- imidazoles -1- bases) benzenesulfonyl] -3- isopropyls -3, 7- diazabicyclos [3.3.1] nonane dihydro perchlorate and Ambasilide (3- (4- amino benzoyls) -7- benzyls -3, 7- diazabicyclos [3.3.1] nonane).
We are surprisingly found that one group of noval chemical compound based on bridging bipiperidine shows the electrophysiologic activity of electrophysiologic activity, preferably Group III medicine, it is therefore contemplated that available for treatment arrhythmia cordis.
Disclosure of the invention
The present invention provides compound of formula I or its pharmaceutical usable derivatives,Wherein R1And R2Independently represent H, C1-4Alkyl, OR2bOr N (R2c)R2d, or be-O- (CH together2)2-O-、-(CH2)3-、-(CH2)4- or-(CH2)5-；R2b、R2cAnd R2dIndependently represent H or C1-6Alkyl；R3Represent H, C1-6Alkyl or and R4C is represented together3-6(alkylidene is optionally interrupted and/or optionally by one or more C alkylidene by O atom1-3Alkyl replaces)；R4Represent H, C1-12Alkyl, C1-6(latter two group is optionally replaced and/or terminated selected from following substituent by one or more alkoxy：- OH, halogen, cyano group, nitro, C1-4Alkyl and/or C1-4Alkoxy) ,-(CH2)q- aryl ,-(CH2)q- epoxide aryl ,-(CH2)q-Het1(rear three groups are optionally (in-(CH2)q- part and/or aryl/Het1Part) replaced by one or more selected from following substituent：- OH, halogen, cyano group, nitro ,-C (O) R10、-C(O)OR11、-N(H)S(O)2R11a、C1-6Alkyl and/or C1-6Alkoxy) ,-(CH2)qN(H)C(O)R8、-(CH2)qS(O)2R8、-(CH2)qC(O)R8、(CH2)qC(O)OR8、-(CH2)qC(O)N(R9)R8, or and R3C is represented together3-6(alkylidene is optionally interrupted and/or by one or more C alkylidene by O atom1-3Alkyl replaces)；Q represents 0,1,2,3,4,5 or 6；R8Represent H, C1-6(latter group is optionally replaced and/or terminated selected from following substituent by one or more for alkyl, aryl：- OH, halogen, cyano group, nitro ,-C (O) R10、-C(O)OR11、-N(H)S(O)2R11a、C1-6Alkyl and/or C1-6Alkoxy), or and R9C is represented together3-7Alkylidene；R9Represent H, C1-4Alkyl or and R8C is represented together3-7Alkylidene；Het1Represent to contain one or more 5-12 circle heterocycles selected from oxygen, nitrogen and/or sulphur, the heterocycle also optionally includes one or more=O substituents；R41、R42、R43、R44、R45Or R46Independently represent H or C1-3Alkyl；R5Represent H, halogen, C1-3Alkyl ,-OR12、-N(R13)R12, or and R6Expression=O together；R6Represent H, C1-4Alkyl or and R5Expression=O together；R12Represent H, C1-6Alkyl ,-S (O)2-C1-4- alkyl ,-C (O) R14、-C(O)OR14、-C(O)N(R15)R15aOr (latter group is optionally replaced and/or terminated selected from following substituent by one or more aryl：- OH, halogen, cyano group, nitro ,-C (O) R10、-C(O)OR11、-N(H)S(O)2R11a、C1-6Alkyl and/or C1-6Alkoxy)；R13Represent H or C1-4Alkyl；R14Represent H or C1-6Alkyl；R15And R15aIndependently represent H or C1-4Alkyl, or C is represented together3-6Alkylidene, the alkylidene is optionally interrupted by O atom；A represents singly-bound, a C1-6Alkylidene ,-N (R16)(CH2)r- or-O (CH2)r- (in latter two group ,-(CH2)r- base is connected with bridging the nitrogen-atoms of bipiperidine)；B represents singly-bound, a C1-4Alkylidene ,-(CH2)nN(R17)-、-(CH2)nS(O)p-、-(CH2)nO- (in rear three groups ,-(CH2)n- base is with carrying R5And R6Carbon atom be connected) ,-C (O) N (R17In)-(latter group ,-C (O)-base is with carrying R5And R6Carbon atom be connected) ,-N (R17)C(O)O(CH2)n-、-N(R17)(CH2)n- (in latter two group, N (R17) base with R5And R6Carbon atom be connected) or-(CH2)mC(H)(OH)(CH2)n- (in latter group, (CH2)m- base is with carrying R5And R6Carbon atom be connected)；M represents 1,2 or 3；N and r independently represent 0,1,2,3 or 4；P represents 0,1 or 2；R16And R17Independently represent H or C1-4Alkyl；R7Represent C1-6Alkyl, aryl or Het2, how properly all these groups optionally replaced selected from following substituent and/or terminated () by one or more：- OH, cyano group, halogen, amino, nitro, Het3、-C(O)R10、-C(O)OR11、C1-6Alkyl, C1-6Alkoxy ,-N (H) S (O)2R18、-S(O)2R19、-OS(O)2R20、-N(H)C(O)N(H)R21、-C(O)N(H)R22And/or aryl (latter group is optionally replaced by one or more cyano group)；Het2And Het3Independently represent to contain one or more heteroatomic 5-12 circle heterocycles selected from oxygen, nitrogen and/or sulphur, and they also optionally include one or more=O substituents；R18、R19And R20Independently represent C1-6Alkyl；R21And R22Independently represent independently to represent H or C1-6Alkyl (is optionally terminated) by cyano group；And in all cases, R10And R11Independently represent H or C1-6Alkyl.In all cases, R11aRepresent C1-6Alkyl；Condition is：(a) when A and B are singly-bound and R7When being optionally substituted aryl, R5And R6Not all it is H；(b) when A represents a singly-bound, R5And R6Expression=O not together；Work as R (c)5Expression-OR12Or-N (R13)R12When, then：(i) A does not indicate that-N (R16)(CH2)r- or-O (CH2)r-；And/or (ii) represents-(CH as B2)nN(R17)-、-(CH2)nS(O)p- or-(CH2)nDuring O-, n not tables
Show 0,
Hereinafter referred to as these compounds are " the compounds of this invention ".
The aryl that can be mentioned that includes C6-10Aryl, such as phenyl, naphthyl.The epoxide aryl that can be mentioned that includes C6-10Epoxide aryl, such as phenyl (phenoxy group), epoxide naphthyl (naphthoxy).When substituted, aryl and aryloxy group are preferably replaced by 1-3 substituent.
The Het that can be mentioned that1、Het2And Het3It is the heterocycle of 5-12 that group, which is included containing 1-4 hetero atom (being selected from oxygen, nitrogen and/or sulphur) and wherein annular atom sum,.Het(Het1、Het2And Het3) group can be whole/partial aromatic in nature or bicyclic.The heterocyclic radical that can be mentioned that includes morpholinyl, thiazolyl, oxazolyl, isoxazolyl, cinnolines base, quinazolyl, phthalazinyl, purine radicals, benzimidazolyl, pyrimidine radicals, piperazinyl, pyrazinyl, piperidyl, pyridine radicals, triazolyl, imidazole radicals, quinolyl, isoquinolyl, alkyl dioxin, benzodioxan base, benzodioxole base, benzo Dioxepane base, benzo morpholinyl, indyl, pyrazolyl, pyrrole radicals, benzothienyl, thienyl, chromanyl, thiochroman base, benzofuranyl, pyranose, THP trtrahydropyranyl, tetrahydrofuran base, furyl etc..The Het that can be mentioned that1Being worth (Value) includes THP trtrahydropyranyl, isoxazolyls, benzodioxole base, benzo Dioxepane base and thienyl.The Het that can be mentioned that2Value includes quinolyl, isoquinolyl, benzo morpholinyl, benzodioxan base, piperazinyl, indyl and pyrazolyl.The Het that can be mentioned that3Including imidazole radicals.If appropriate, Het (Het1、Het2And Het3) on substituent can be located at any atom of ring system, including on hetero atom.Het(Het1、Het2And Het3) binding site can by any atom on ring, (if appropriate) include hetero atom.Het(Het1、Het2And Het3) group can also be N- or S- oxidised forms.
Pharmaceutical usable derivatives include salt and solvate.The salt that can be mentioned that includes acid-addition salts.Pharmaceutical usable derivatives are additionally included in the C on bridge joint bipiperidine nitrogen-atoms1-4Alkyl quaternary ammonium salts and N- oxides, condition are in the presence of N- oxides：(a)Het(Het1、Het2、Het3) group do not contain unoxidized S- atoms；And/or (b) represents-(CH as B2)nS(O)p- when, p does not represent 0.
The compound of the present invention can show tautomerism.All these tautomeric forms of the invention and their mixture are included within the scope of the present invention.
The compound of the present invention can also include one or more asymmetric carbon atoms, therefore can show optically-active and/or diastereo-isomerism.Diastereoisomer can use routine techniques, such as chromatogram or the separation of fractional crystallization method.Various stereoisomers can use routine techniques, and the racemic modification or other mixtures of such as fractional crystallization or HPLC technologies separation compound are obtained.Or, required optical isomer can be prepared as follows：The reaction by suitable optically active raw material under conditions of racemization or epimerization is not caused, or pass through derivatization, for example using homochirality acid, the ester of diastereomer form is then separated by conventional meanses (such as HPLC, silica gel chromatograph).All stereoisomers are included in the scope of the invention.
R1、R2、R2b、R2c、R2d、R3、R4、R5、R6、R7、R8、R9、R10、R11、R11a、R12、R13、R14、R15、R15a、R16、R17、R18、R19、R20、R21、R22、R41、R42、R43、R44、R45And R46Denotable, R12It is may include and may replace R3、R4、R7、R8And R12Alkyl and R4It is denotable, may replace R4、R7、R8And R12Alkoxy can be straight chain；Or when there is sufficient amount of (that is, three) carbon atom, they can also be side chain or annular form.In addition, when there is sufficient amount of (that is, four) carbon atom, this kind of alkyl and alkoxy can also be part cyclic/non-annularity forms.This kind of alkyl and alkoxy can also be saturations；Or when there is sufficient amount of (that is, two) carbon atom, they can be undersaturated and/or by oxygen interval.
R3And R4、R8And R9、R15And R15a, A and the denotable alkylidenes of B, and A, B and R4May include-(CH2)m-、-(CH2)n-、-(CH2)q- and-(CH2)r- chain (if appropriate) can be straight chain；Or can be branched form when there is sufficient amount of (that is, two) carbon atom.This kind of alkylidene and include-(CH2)-chain can be saturation；Or when there is sufficient amount of (that is, two) carbon atom, they can be undersaturated and/or by oxygen interval.
R5It is denotable and may replace R4、R7、R8And R12Halogen include fluorine, chlorine, bromine and iodine.
To avoid producing query, R illustrated herein10、R11And R11aEach group and others R10、R11And R11aGroup is independently from each other.For example, working as R4And R7All represent by-C (O) R10During substituted aryl, two-C (O) R10Substituent is independently from each other, and not necessarily identical (although being not excluded for this possibility).
Abbreviation is arranged at the end of this specification.
On the other hand, the present invention provides compound of formula I as defined above, but further condition is：(a) when A represents-N (R16)(CH2)r- or-O (CH2)r- when, r does not indicate that 0 or 1；Work as R (b)5Expression-OH or-N (R13)R12When, then B does not indicate that-N (R17)C(O)O(CH2)n- or-N (R17)(CH2)n-。
Preferred compounds of the invention includes following compounds：Wherein R1Represent H；R2Represent H；R3Represent
H；
C1-2Alkyl；Or
With R4C is represented together4-5Alkylidene, the group replaces optionally by O atom interval and/or optionally by one or more methyl；R4Represent
H；
Straight or branched and/or saturated or unsaturated and/or ring-type, acyclic and/or part cyclic/acyclic C1-8Alkyl (alkyl is optionally replaced and/or by O atom interval by one or more cyano group or halogen group)；
C1-6Alkoxy；
-(CH2)qS(O)2R8、-(CH2)qC(O)OR8、-(CH2)qN(H)C(O)R8、-(CH2)qC(O)R8(in rear four groups, q represents 0,1 or 2 and R8Represent straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-4Alkyl, or (phenyl is optionally by one or more cyano group and/or C for phenyl1-3Alkyl replaces))；
-(CH2)qC(O)N(R9)R8(in latter group, q represents 0,1 or 2 and R8And R9Independently represent H, straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-4Alkyl, or C is represented together4-6Alkylidene)；
-(CH2)q- phenyl ,-(CH2)q- phenyl or-(CH2)q-Het1(in rear three groups, q represents 0,1,2 or 3 ,-(CH2)q- part is optionally replaced by cyano group, and phenyl or Het1Part is optionally replaced by one or more selected from following substituent：Cyano group, nitro, the C of straight or branched1-4The C of alkyl, straight or branched1-4Alkoxy and N (H) S (O)2R11a)；Or
With R3C is represented together4-5Alkylidene, the group replaces optionally by O atom interval and/or optionally by one or more methyl；R5Represent
H；
Fluorine；
OR12(wherein R12Represent H, phenyl (optionally by one or more methoxy substitutions) or C (O) N (H) R15a(wherein R15aRepresent the C of straight or branched1-4Alkyl))；
-N(R13)(R12) (wherein R12Represent H, C1-2Alkyl ,-S (O)2-C1-2Alkyl ,-C (O) R14(wherein R14Represent C1-2Alkyl) ,-C (O) OR14(wherein R14Represent the C of straight or branched1-5Alkyl) or-C (O) N (R15)(R15a) (wherein R15And R15aIndependently represent the C of H or straight or branched1-3Alkyl represents C together4-5Alkylidene, the alkylidene is optionally by O atom interval) and R13Represent H or C1-2Alkyl)；Or
With R6Together, expression=O is (especially in R7Represent alkyl or Het2In the case of)；R6Represent H or C1-2Alkyl or and R5Expression=O is (especially in R together7Represent alkyl or Het2In the case of)；A represents a singly-bound, the C of straight or branched1-4Alkylidene (group is also optionally by O intervals) ,-N (H) (CH2)r- or-O (CH2)r- (in latter two group, r is 1 or 2)；B represents singly-bound, a C1-4Alkylidene ,-(CH2)nO-、-(CH2)nS(O)2-、-(CH2)nN (H)-or-N (H) (CH2)n- (in the latter cases, n is 0,1,2 or 3)；R7Represent
Straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-6Alkyl (is optionally replaced and/or terminated by OH)；
Het2(optionally replaced by one or more selected from following substituent：Cyano group, C1-3Alkyl, phenyl (latter group is optionally replaced by one or more cyano group) ,=O, C (O) R10(wherein R10It is the C of straight or branched1-3Alkyl) or S (O)2R19(wherein R19It is C1-2Alkyl))；Or
Phenyl (is optionally replaced by one or more selected from following substituent：Cyano group, nitro, the C of straight or branched1-3The C of alkyl, straight or branched1-3Alkoxy, fluorine, chlorine, C (O) N (H) R22(wherein R22Represent straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-4Alkyl, the alkyl is optionally terminated by cyano group), N (H) S (O)2R18(wherein R18Represent C1-2Alkyl) or Het3)；R41、R42、R43、R44、R45And R46All represent H.The preferred compound of the present invention includes those compounds, wherein R3Represent H；R5Represent H, OH or-N (H) C (O) N (R15)(R15a)；R6Represent H；A represents-CH2- or-(CH2)2-；B represents singly-bound ,-a CH2N (H)-or-CH2O- (herein for avoid produce query ,-CH2- partly with R5And R6Carbon atom be connected)；R7Represent phenyl (by a cyano group (preferably relative to 4 of B) and one or more optional C (O) N (H) R22Substituent replaces).
Preferred compounds of the invention includes embodiment disclosed below compound.Preparation method
The present invention also provides the method for preparing compound of formula I, and this method includes：(a) for wherein R3It is H compound of formula I：For example under 0 DEG C to reflux temperature, in the presence of suitable organic solvents (such as dichloromethane)；Or by solid phase synthesis process under the conditions of well known by persons skilled in the art, by Formula II compound,
Figure A0081169600251
Wherein R1、R2、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above, reacted with formula III compound,
         R4- N=C=O III wherein R4It is as defined above；(b) for example under room temperature to reflux temperature, in the presence of suitable alkali (such as triethylamine or potassium carbonate) and suitable organic solvents (such as dichloromethane, THF, acetonitrile, toluene or its mixture), the carbonic acid derivative of Formula II compound as defined above and formula IV is reacted
        (R3)(R4)NC(O)-L1IV wherein L1Represent leaving group, such as halogen, imidazoles or R23O- (wherein R23Represent, such as C1-10Alkyl, aryl or C1-3Alkaryl, they are optionally replaced by one or more halogens or nitro) and R3And R4It is as defined above；(c) for example under room temperature to reflux temperature, in the presence of suitable alkali (such as triethylamine or potassium carbonate) and suitable organic solvents (such as dichloromethane, THF, acetonitrile, toluene or its mixture)；Or by solid phase synthesis process under the conditions of well known by persons skilled in the art, by Formula V compound,Wherein R1、R2、R5、R6、R7、R41、R42、R43、R44、R45、R46, A, B and L1It is as defined above, is reacted with Formula V A compounds,
        (R3)(R4) NH VA wherein R3And R4It is as defined above；(d) CH is represented for wherein A2And R5Expression-OH or-N (H) R12, wherein R12The compound of formula I being as defined above：For example at elevated temperature (such as 60 DEG C to reflux temperature), in the presence of suitable solvent (such as mixture of low-level chain triacontanol (such as IPA), acetonitrile or low-level chain triacontanol and water), by Formula IV compound,
Figure A0081169600262
Wherein R1、R2、R3、R4、R41、R42、R43、R44、R45And R46It is as defined above, is reacted with Formula VII compound,
Figure A0081169600271
Wherein X represents O or N (R12) and R6、R7、R12It is as defined above with B；(e) for example at elevated temperature (such as 35 DEG C to reflux temperature), in the presence of suitable alkali (such as triethylamine or potassium carbonate) and suitable organic solvents (such as acetonitrile or DMSO), Formula IV compound as defined above and Formula VIII compound are reactedWherein L2Represent leaving group (such as methanesulfonic acid base, toluenesulfonic acid base or halogen) and R5、R6、R7, A and B be as defined above；(f) for wherein R5Represent H or OH and R6Represent H compound of formula I：In the presence of the Suitable reducing agents and under suitable reaction condition, reduction-type IX compounds,
Figure A0081169600273
Wherein R1、R2、R3、R4、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above；For example, form wherein R5It is OH compound of formula I, reduction reaction can be carried out under the temperate condition that such as sodium borohydride and suitable organic solvents (such as THF) is present；For synthesis wherein R5H compound of formula I is represented, can be in Suitable reducing agents (such as sodium borohydride or sodium cyanoborohydride) and suitable organic solvents (for example, rudimentary C1-6Alkanol) in the presence of, activate correlation C=O groups by using Suitable agents (such as toluene sulfonyl hydrazide) and carry out reduction reaction；(g) for wherein R1And R2All represent H compound of formula I：Corresponding Formula X compound is reduced,
Figure A0081169600281
Wherein R3、R4、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above, in the presence of Suitable reducing agents (such as sodium borohydride, sodium cyanoborohydride) and suitable organic solvents (such as low-level chain triacontanol) or under the conditions of standard Wolff-Kischner well known by persons skilled in the art, with suitable reagent, such as methylsulfonyl hydrazine activates the end of the bridge C=O bases of Formula X compound；When activating C=O, the activation step can be in suitable organic solvents (such as low-level chain triacontanol, such as methanol, ethanol or IPA) in the presence of, carried out under room temperature to reflux temperature, reducing agent is added in reactant mixture afterwards, reduction reaction is under 60 DEG C to reflux temperature, it may be advantageous that carried out in the presence of suitable organic (such as acetic acid)；(h) for wherein R1And R2Expression-O (CH together2)2O- compound of formula I：Under suitable reaction condition, such as corresponding Formula X compound as defined above is set to be reacted with ethane -1,2- glycol by backflow in the presence of pTSA and suitable organic solvents (such as toluene)；(i) it is-(CH for wherein B2)nO- compound of formula I：Under such as Mitsunobu- classes reaction condition, such as under room temperature (such as 25 DEG C) to reflux temperature, in tertiary phosphine (such as tributylphosphine and triphenylphosphine), azoformic acid derivative (such as diethyl azodiformate or 1,1 '-(azo dicarbapentaborane) two piperidines) and suitable organic solvents (such as dichloromethane or toluene) in the presence of, by Formula X IWherein R1、R2、R3、R4、R5、R6、R41、R42、R43、R44、R45、R46, A and n be as defined above, with wherein R7The Formula X IA compounds reaction being as defined above,
            R7OH                      XIA；(j) for the compound of formula I for the N- oxide derivative forms for bridging bipiperidine-nitrogen：For example in the presence of 0 DEG C and suitable organic solvents (such as DCM), and in the presence of appropriate oxidizing agent (such as mCPBA), the corresponding bridge joint bipiperidine nitrogen-atoms of corresponding compound of formula I is aoxidized；(k) to then C1-4Compound of formula I (the wherein C of alkyl quaternary ammonium salts derivative form1-4Alkyl is connected with bridge joint bipiperidine nitrogen-atoms)：For example at room temperature, in the presence of suitable organic solvents (such as DMF), the bridge joint bipiperidine nitrogen-atoms and Formula X II compounds for making corresponding compound of formula I react,
            RbL3XII wherein RbRepresent C1-4Alkyl and L3It is leaving group, such as halogen, alkyl sulfonic acid ester group or aryl sulfonic acid ester group；Then agent (such as NH is provided in suitable counter ion4OAc purified in the presence of) (with such as HPLC)；(1) for wherein R5And R6Represent that H, A represent C1-6Alkylidene and B represents-N (R17)(CH2)n- compound of formula I：For example at 40 DEG C, in the presence of suitable organic solvents (such as acetonitrile), by Formula X III compounds,
Figure A0081169600301
Wherein AaRepresent C1-6Alkylidene and R1、R2、R3、R4、R41、R42、R43、R44、R45、R46And R47It is as defined above, is reacted with Formula X IV compounds,
           R7-(CH2)n-L2XIV wherein R7, n and L2It is as defined above；(m) for wherein R5Expression-NH2Compound of formula I：For example under unfavourable pressure, in the presence of appropriate catalysts (such as palladium/carbon) and suitable solvent (such as water-ethanol admixture), by the corresponding Formula X V compounds of hydro-reduction,Wherein R1、R2、R3、R4、R6、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above；(n) for wherein R5Expression-N (R13)C(O)NH(R15) compound of formula I：, will wherein R for example under room temperature (such as 25 DEG C) in the presence of suitable solvent (such as benzene)5Expression-N (R13) H corresponding compound of formula I and Formula X VI compounds react,
           R15N=C=O XVI wherein R15It is as defined above；(o) for wherein R5Expression-N (R13)C(O)R14Compound of formula I：, will wherein R in the presence of suitable solvent (such as dichloromethane or acetonitrile) and optionally in the presence of suitable alkali (such as triethylamine or potassium carbonate) for example under room temperature to reflux temperature5Expression-N (R13) H corresponding compound of formula I and Formula X VII compounds react,
           R14C(O)RxXVII wherein RxRepresent suitable leaving group, such as C1-4Alkoxy, halogen (such as Cl, Br) or p-nitrophenyl, and R14It is as defined above；(p) for wherein R5Expression-N (H) R12Compound of formula I (wherein R12As defined above, condition is that it does not indicate that H)：, will wherein R under the conditions of for example well known to those skilled in the art5Expression-NH2Corresponding compound of formula I and Formula X VIII compounds react,
           R12aL1XVIII wherein R12aRepresent R as defined above12, the difference is that it does not indicate that H and L1It is as defined above；(q) for wherein R5Expression-OR12Compound of formula I (wherein R12Represent C1-6Alkyl or optionally substituted aryl)：Under such as room temperature (such as 25 DEG C) to reflux temperature, under Mitsunobu class reaction conditions (i.e., in such as triphenylphosphine, azoformic acid derivative (such as 1,1 '-(azo dicarbapentaborane) two piperidines) and suitable organic solvents (such as dichloromethane) in the presence of), will wherein R5Expression-OH compound of formula I is reacted with XIX compounds；
           R12aOH XIX wherein R12aRepresent C1-6Alkyl or optionally substituted aryl；(r) for wherein R5Expression-OR12Compound of formula I (wherein R12Represent C1-6Alkyl or optionally substituted aryl)：Under such as room temperature (such as 25 DEG C) to reflux temperature, under Williamson class reaction conditions (i.e., in the presence of suitable alkali (such as KOH or NaH) and suitable organic solvents (such as dimethyl sulfoxide or DMF), by Formula X X compounds
Figure A0081169600321
Wherein L2、R1、R2、R3、R4、R6、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above, reacted with Formula X IX compounds as defined above；(s) for wherein R5Represent OR12And R12Represent C (O) R14Compound of formula I (wherein R14It is as defined above)：Under such as room temperature (such as 25 DEG C),, will wherein R as defined above in the presence of the organic solvent (such as THF) of suitable coupling reagent (such as 1- (3- dimethylamino-propyls) -3- ethyls be carbonized two imido), appropriate catalysts (such as DMAP) and reactionlessness5The corresponding compound of formula I and Formula X XI compounds for representing OH are reacted,
            R14CO2H XXI wherein R14It is as defined above；(t) for wherein R5Represent the compound of formula I of halogen：Replace wherein R with suitable halide reagent5Expression-OH corresponding compound of formula I with diethylaminosulfurtrifluoride reaction (for example, prepare wherein R5Represent the compound of fluorine)；(u) for wherein R3And/or R4Represent alkyl (if appropriate, such as C1-6Or C1-12Alkyl) compound of formula I：Under the conditions of well known to those skilled in the art, wherein R is alkylated3And/or R4Represent H (if appropriate) corresponding compound of formula I；(v) technology well known to those skilled in the art is used, by a R4Group is converted into another R4Group (such as general-(CH2)qC(O)OR8It is converted into-(CH2)qC(O)N(R9)R8, wherein R8、R9And q is as defined above)；Or (w) is for wherein R1And R2In one expression H, another expression-OH compound of formula I：In the presence of gentle reducing agent, such as sodium borohydride and suitable organic solvents (such as lower alcohol, such as methanol or ethanol), reduction corresponding Formula X compound as defined above；(x) for R2And R3In an expression-NH2, another represents H compound of formula I：In Suitable reducing agents (such as LiAlH4) in the presence of, such as under the conditions of well known to those skilled in the art, reduction-type XXIA compounds,
Figure A0081169600331
Wherein R3、R4、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above；(y) for wherein R1And R2In one or two all represent-N (R2c)R2dCompound of formula I (wherein R2cAnd R2dIn one or two all represent C1-6Alkyl)：Under the conditions of for example well known to those skilled in the art, with Formula X XIB compounds,
            R2eL1XXIB wherein R2eRepresent C1-6Alkyl and L1It is as defined above, is alkylated wherein R1And/or R2Expression-N (R2c)R2dCompound of formula I (if appropriate, wherein R2cAnd/or R2dRepresent H)；Or (z) uses technology well known to those skilled in the art, by R7On a substituent be converted into another substituent.
Formula II compound can be prepared as follows：For example, it is described according to the synthesis (method and step (e)) of compound of formula I above, by Formula X XII compounds,
Figure A0081169600341
Wherein R1、R2、R41、R42、R43、R44、R45And R46It is as defined above, with the Formula VIII compound reaction being as defined above；Or A represents CH wherein2And R5Represent OH or N (H) R12Formula II compound in the case of, for example, as described in the synthesis (method and step (d)) of compound of formula I above, Formula X XII compounds and the Formula VII compound being as defined above are reacted.
Wherein R1And R2All be H Formula II compound can, such as it is described according to the synthesis (method and step (g)) of compound of formula I above, prepared by reduction-type XXIII compounds,
Figure A0081169600342
Wherein R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B be as defined above, and wherein C=O groups can use Suitable agents, and such as toluene sulfonyl hydrazide is activated.
Formula IV compound can be prepared as follows：Under 0 DEG C to reflux temperature, in the presence of suitable alkali (such as triethylamine or potassium carbonate) and suitable organic solvents (such as toluene or dichloromethane), the Formula V A compounds being as defined above and Formula X XIV compounds are reacted,
           L1-C(O)-L1XXIV wherein L1It is as defined above, and two L therein1Group can be with identical or different.
Formula V compound can be prepared as follows：For example according to described in the synthetic method of formula IV compound above, the Formula II compound being as defined above and the Formula X XIV compounds being as defined above are reacted.
Formula IV compound can be prepared as follows：For example it is described according to the synthesis (method and step (a)) of compound of formula I above, the Formula X XII compounds being as defined above and the formula III compound being as defined above are reacted；Or it is described according to the synthesis (method and step (b)) of compound of formula I above, the Formula X XII compounds being as defined above and the formula IV compound being as defined above are reacted.
Or, Formula IV compound can be prepared as follows：For example according to described in the synthetic method of formula IV compound above, the Formula X XII compounds being as defined above and the Formula X XIV compounds being as defined above are reacted, then for example, it is described according to the synthesis (method and step (c)) of compound of formula I above, gained intermediate and Formula V A compounds are reacted.
Wherein R1And R2All be H Formula IV compound can, such as it is described according to the synthesis (method and step (g)) of compound of formula I above, prepared by reducing corresponding Formula X XV compounds,Wherein R3、R4、R41、R42、R43、R44、R45And R46It is as defined above, and wherein C=O groups can use Suitable agents, and such as toluene sulfonyl hydrazide is activated.
Wherein R41、R42、R45And/or R46One or more expression C1-3The Formula IV compound of alkyl can be prepared as follows：Can be for example in suitable highly basic (such as s-BuLi), N, N, N ', will wherein R in the presence of the solvent (such as THF) of N '-tetramethylethylened and reactionlessness41、R42、R45And/or R46The Formula IV compound and suitable alkylating reagent such as dimethyl suflfate for representing H (if appropriate) are reacted.
Formula VII compound can be prepared according to technology well known by persons skilled in the art.For example, Formula VII compound, wherein：(1) B represents-CH2O- and when X represents O, can be prepared as follows：For example at elevated temperature (such as 60 DEG C to reflux temperature), in suitable alkali (such as K2CO3Or NaOH) and suitable organic solvents (such as acetonitrile or toluene/water) in the presence of, the Formula X IA compounds being as defined above and Formula X XVI compounds are reacted,
Figure A0081169600361
Wherein R6And L2It is as defined above, or it is prepared by the other methods described according to this area；(2)R6When representing that H and X represent O, it can be prepared as follows：For example at -15 DEG C at room temperature, in Suitable reducing agents (such as NaBH4) and suitable organic solvents (such as THF) in the presence of, reduction-type XXVII compounds,Wherein R7It is as defined above with B, then for example at room temperature, in suitable alkali (such as K2CO3) and suitable organic solvents (such as acetonitrile) in the presence of, gained intermediate is carried out internal displacement reaction；(3) B represents C1-4Alkylidene ,-(CH2)nN(R17)-、-(CH2)nS(O)2- or-(CH2)n4) or-(CH (in rear three groups, n represents 1,2,3 or to O-2)mC(H)(OH)(CH2)n- and X when representing O, it can be prepared as follows：In the presence of appropriate oxidizing agent (such as mCPBA), such as by being flowed back in the presence of suitable organic solvents (such as DCM), oxidation-type XXVIII compounds,Wherein BaRepresent singly-bound, a C1-3Alkylidene ,-(CH2)n-1N(R17)-、-(CH2)n-1S(O)2- or-(CH2)n-14) or-(CH (in rear three groups, n represents 1,2,3 or to O-2)m-1C(H)(OH)(CH2)n- (in latter group, n is as defined above), and R in all cases17It is as defined above with m；Or (4) B represents-(CH2)nO- and X represents N (R12), and R12Expression-S (O)2-C1-4- alkyl or-C (O) OR14When, it can be prepared as follows：For example under 0 DEG C to reflux temperature, in the presence of suitable alkali (such as sodium hydroxide), suitable solvent (such as dichloromethane, water or its mixture), and if desired, in the presence of phase transfer catalyst (such as tetrabutylammonium disulfate), cyclization Formula X XVIIIA compounds
Figure A0081169600372
Wherein R12aExpression-S (O)2-C1-4- alkyl or-C (O) OR14And n, R6、R7、R14And L2It is as defined above.
Formula VIII compound can be prepared using standard technique.For example, Formula VIII compound, wherein：(1) B represents-(CH2)nDuring O-, it can be prepared as follows：Formula X IA compounds as defined above and Formula X XIX compounds are coupled,
      L4-(CH2)n-C(R5)(R6)-A-L2XXIX wherein L4The suitable leaving group (such as halogen) of expression and n, R5、R6, A and L2It is as defined above；Or (2) B represents-C (O) N (R17)-when, it can be prepared as follows：By Formula X XX compounds,
      R7N(H)R17XXX wherein R7And R17It is as defined above, is reacted with Formula X XXI compounds,
    L4-C(O)-C(R5)(R6)-A-L2XXXI wherein L4、R5、R6, A and L2It is as defined above；Reaction in above-mentioned two situations is carried out all under the conditions of well known to those skilled in the art.
Wherein A represents C2- alkylidene and R5Represent OR12, wherein R12Represent C1-6The Formula VIII compound of alkyl or optionally substituted aryl can be prepared as follows：For example under room temperature (such as 25 DEG C) to reflux temperature, in suitable alkali (such as K2CO3) and suitable organic solvents (such as acetonitrile) in the presence of, the Formula X IX compounds being as defined above and Formula X XXIA compounds are reacted,
Figure A0081169600381
Wherein RyRepresent C1-4(the two groups are optionally selected from C to alkyl or aryl by one or more1-4The substituent substitution of alkyl or halogen) and R6、R7It is as defined above with B, is L by ester functional group conversions then under the conditions of well known to those skilled in the art2Group (wherein L2It is as defined above).
Wherein B represents-(CH2)nS (O)-or-(CH2)nS(O)2- Formula VII and VIII compounds can be prepared as follows：In the presence of appropriate appropriate oxidizing agent (such as mCPBA) and suitable organic solvents, oxidation wherein B represents-(CH2)nS- (wherein n is as defined above) corresponding Formula VII and VIII compounds.
The mode that Formula IX and XI compounds can be similar to compound of formula I is prepared (see, e.g. method and step (a), (b), (c) or (d)).
Or, wherein A represents C2The Formula IX compound of alkylidene can be prepared as follows：For example at room temperature, in the presence of suitable organic solvents (such as ethanol), the Formula IV compound being as defined above and Formula X XXII compounds are reacted,
     R7- B-C (O)-CH=CH2XXXII wherein B and R7It is as defined above.
Formula X III compounds can be prepared as follows：Under the conditions of well known to those skilled in the art, R therefrom7Represent optionally substituted phenyl, R5And R6Both represent that H, B represent-N (R17)C(O)O(CH2)-, A represents AaAnd AaOptionally substituted benzyloxycarbonyl group unit (being deprotected) is removed in the corresponding compound of formula I being as defined above.
Formula X V compounds can be prepared as follows：, will wherein R in the presence of suitable solvent (such as dichloromethane) for example at -10-25 DEG C5Expression-OH corresponding compound of formula I is reacted with XXXIII compounds,
        RyS(O)2Cl XXXIII wherein Ry are as defined above, then under room temperature to reflux temperature, in suitable solvent (such as DMF) and suitable alkali (such as NaHCO3) in the presence of, reacted with suitable azide ion gun (such as sodium azide).
Or, Formula X V compounds can be prepared as follows：For example under conditions of similar to the preparation of above-mentioned compound of formula I (method and step (e)), the corresponding Formula IV compound that formula is as defined above is reacted with Formula X XXIIIA compounds,
        R7-B-C(R6)(N3)-A-L2XXXIIIA wherein L2、R6、R7, A and B be as defined above.
Compound XX can be prepared as follows：Under the conditions of well known to those skilled in the art, L is used2Group displacement wherein R5Represent the OH groups of OH compound of formula I.
Formula X XIA can be prepared as follows：For example at elevated temperature (as flowed back), in the presence of suitable organic solvents (such as methanol), by corresponding Formula X compound and azanol reaction.
Formula X XII compounds are known to document or are easy to be obtained with known technology.For example, wherein R1And R2Expression-O- (CH together2)2-O-、-(CH2)3-、-(CH2)4- or-(CH2)5-, and R41、R42、R43、R44、R45And R46All represent that H Formula X XII compounds can be prepared as follows：Under the conditions of well known to those skilled in the art, in Suitable reducing agents (such as LiAlH4) in the presence of, reduction-type XXXIV compounds,Wherein R1aAnd R2aExpression-O- (CH together2)2-O-、-(CH2)3-、-(CH2)4- or-(CH2)5-。
The mode that Formula X XXIIIA compounds can be similar to Formula X V compounds is prepared and (that is, prepared by corresponding alcohol).
It is valuably, Formula X, XXIII and XXV compounds (wherein in all cases, R45And R46Represent H), if appropriate, it can be prepared as follows：By (i) Formula X XXV compounds,
Figure A0081169600401
Wherein RzRepresent C1-10Alkyl or C1-3Alkaryl (such as alkyl phenyl, such as benzyl) and R41、R42、R43And R44It is as defined above, or (ii) 4- piperidones (or its protected derivative), if appropriate, and (1) Formula X XXVI compounds,
      R7-B-C(R5)(R6)-A-NH2XXXVI wherein R5、R6、R7, A and B be as defined above, or with (2) NH3(or it is by derivative of (such as benzyl) protection) reaction; it is above-mentioned it is each reaction in formaldehyde (i.e.; in the presence of suitable formaldehyde source; such as paraformaldehyde or formalin solution) in the presence of carry out; and in the case of Formula X and XXV reactions, using herein described in (such as method and step (c) above) method by C (O) OR of gained intermediatezGroup is converted into C (O) N (R3)(R4) group.
Form Formula X by this way, the reaction of XXIII and XXV compounds can be for example under room temperature to the reflux temperature concentration of reactant (depend on), in the presence of suitable solvent (such as ethanol or methanol), and preferably in organic acid (such as C1-6Carboxylic acid, especially acetic acid) in the presence of carry out.
Those skilled in the art are also clear that, wherein R1And R2All represent that H Formula X XII compounds also (that is, in the presence of formaldehyde, can pass through 4- piperidones (or its protected derivative) and NH by this method3(or its protected derivative) reacts) prepare, condition is then under suitable reaction condition, to reduce the intermediate being thusly-formed.
Those skilled in the art are also clear that this method can also be used for preparing wherein R41And R42It is H and R45And/or R46It is not H compound of formula I, such as by well known to those skilled in the art, including under the conditions of those described above, (i) will wherein R41And/or R42It is not that H Formula X XXV compounds and such as benzylamine or derivatives thereof react；(ii) removing-C (O) ORzUnit；(iii) react Formula VIII compound of the gained compound with being as defined above on its free bridge joint bipiperidine nitrogen-atoms；(iv) benzyl protecting group is sloughed；React gained compound formula III or IV compound on its free bridge joint bipiperidine nitrogen-atoms be as defined above (v).In some cases, end of the bridge carbonyl functional group is converted into required R along with the reaction1/R2Group.
Formula X XXIV compounds can be prepared according to technology well known to those skilled in the art.For example, wherein R1aAnd R2aExpression-(CH together2)3-、-(CH2)4- or-(CH2)5- Formula X XXIV compounds can be prepared as follows：For example at 120 DEG C, by Formula X XXVII compounds,
Figure A0081169600411
Wherein R1a’And R2a’Expression-(CH together2)3-、-(CH2)4- or-(CH2)5-, reacted with the mixture of phosphoric acid and sulfuric acid.
Formula X XXVI compounds are known to document or are easy to be obtained with known technology.Such as wherein R5Represent OH, R6Represent H and A represents CH2Formula X XXVI compounds can be by under the conditions of well known to those skilled in the art, will wherein R6Represent H and X represents that O Formula VII compound is reacted with ammonium hydroxide and prepared.
Known to formula III, VA, XIA, XII, XIV, XVI, XVII, XVIII, XIX, XXI, XXIB, XXIV, XXVI, XXVII, XXVIII, XXVIIIA, XXIX, XXX, XXXI, XXXIA, XXXII, XXXIII, XXXV and XXXVII and their derivative or commercially available or document, or can be by similar to method described herein, or pass through conventional synthesis process, according to standard technique, the raw material being easy to get by simplicity, is obtained using suitable reagent and reaction condition.
Technology well known to those skilled in the art can be used, the substituent on the aryl (such as phenyl) in compound defined herein, and on (if appropriate) heterocyclic radical is converted into the substituent of other requirements.For example, can be aminobenzene by nitrobenzene reduction, hydroxyl is converted into alkoxy, and alkoxy is hydrolyzed to hydroxyl etc..
The compound of the present invention can be separated using routine techniques from their reactant mixture.
It should be clear to those skilled in the art that in the above-mentioned methods, the functional group of midbody compound can be with, or need to be protected by protection group.
Functional group to be protected may be needed to include hydroxyl, amino and carboxylic acid.The Suitable protecting groups of hydroxyl include trialkylsilkl and diarylalkyl-silyl (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl and alkyl carbonyl epoxide (such as methyl-and ethylcarbonyl group epoxide).Suitable amino protecting group includes benzyl, t-butyloxycarbonyl, 9- fluorenylmethoxycarbonyl groups or benzyloxycarbonyl.Suitable carboxylic acid protecting group includes C1-6Alkyl or benzyl ester.
The protection and deprotection of functional group can be betided before or after any reactions steps as described herein.
Protection group can be removed according to technology known to professional and technical personnel in the field and as described below.
J W F McOmie are edited《Protection group in organic chemistry》(Protective Groupsin Organic Chemistry), Plenum Press (1973) and《Protection group in organic synthesis》(Protective Groups in Organic Synthesis), second edition, T W Greene＆ P G M Wutz, Wiley-Interscience (1991) describe the use of protection group comprehensively.
Professional and technical personnel in the field should understand, for by another, it is that more easily mode obtains the compounds of this invention in some cases, the various method steps being mentioned above can be carried out in a different order, and/or each reaction can entirely route different phase progress (i.e., pair intermediates different from those above concerning, can increase substituent with specific reaction and/or carry out chemical conversion).This particularly depends on some factors, such as the protection group strategy (if employed) of the property of other functional groups, the utilizability of key intermediate and use present in specific reactants.Obviously, the chemical process type being related to is by the type of the selection of reagent, the demand of protection group and the use that are used in the above-mentioned synthesis step of influence, and completes the order of synthesis.
Professional and technical personnel in the field are also clear that; although the protected derivative (they can be made before the final deprotection stage) of some compound of formula I may not have such pharmacological activity, they can form the compounds of this invention of pharmacological activity through parenteral or oral administration and after being metabolized in vivo.This analog derivative can be described as " prodrug ".And, it has been found that some compound of formula I can as other compound of formula I prodrug.
All prodrugs of compound of formula I are included within the scope of the present invention.
Some intermediates mentioned above are new.Therefore, on the other hand, the present invention is provided：(a) the Formula II compound being as defined above or its protected derivative, condition is R7Optionally substituted phenyl is not indicated that；(b) the Formula V compound being as defined above or its protected derivative, condition is R7Optionally substituted phenyl is not indicated that；(c) the Formula X compound being as defined above or its protected derivative；(d) the Formula X I being as defined above or its protected derivative；(e) the Formula X III compounds being as defined above or its protected derivative；(f) the Formula X V compounds being as defined above or its protected derivative；(g) the Formula X X compounds being as defined above or its protected derivative；(h) the Formula X XIII compounds being as defined above or its protected derivative, condition is R7Optionally substituted phenyl is not indicated that；(i) the Formula X XV compounds being as defined above or its protected derivative.Medical usage
The compounds of this invention has pharmacological activity because of it, thus is useful.Therefore, they can be denoted as medicine.
Therefore, another face, the present invention provides the compounds of this invention as medicine.
Particularly, the compounds of this invention shows cardiac electrophysiology activity, the activity for example proved in following experiments.
Therefore, it is contemplated that the compounds of this invention can be used for prevention and treatment arrhythmia cordis, especially atrial arrhythmia and ventricular arrhythmia.
Therefore, the compounds of this invention is signable for treatment or prevention heart disease or the disease relevant with heart disease, wherein arrhythmia cordis is considered as main, including ischemic heart disease, sudden heart disease, miocardial infarction, heart failure, openheart surgery and thrombotic disease.
In the treatment of arrhythmia cordis, it is found that the compounds of this invention optionally postpones the repolarization of heart, thus extend QT intervals, specifically it shows the activity of Group III medicine.Although it was found that the compounds of this invention shows Group III medicine activity, in the treatment of arrhythmia cordis, their active patterns may be not necessarily limited to such medicine.
On the other hand, the present invention provides a kind of method for treating arrhythmia cordis, and this method includes to patient or is susceptible to suffer from the compounds of this invention that the indication person applies therapeutically effective amount.Pharmaceutical preparation
The compounds of this invention typically can by oral administration, subcutaneous, intravenous, intra-arterial, it is transdermal, intranasal, suction or other parental be administered with pharmaceutical dosage forms, the pharmaceutical preparation is pharmaceutically acceptable formulation, and it includes the active component of free alkali, pharmaceutically acceptable ion-exchanger or nontoxic organic or inorganic acid addition salt form thereof.According to the disease for the treatment of and patient, and method of administration, composition can be applied with various dose.
The compounds of this invention can also be used to treat the medication combined of arrhythmia cordis and/or other angiocardiopathies with any other.
Therefore, on the other hand, the present invention, which is provided, includes the compounds of this invention and pharmaceutically acceptable assistant agent, the pharmaceutical preparation of diluent or carrier.
When being treated with parenteral introduction to people, the suitable daily dosage of the compounds of this invention is about 0.05-5.0mg/kg body weight.
The present invention has the advantages that to effectively antagonize arrhythmia cordis.
Compared with the known compound of this area, the compounds of this invention also has the following advantages that：More effectively, more hypotoxicity, broader field of activity (including show I classes, II classes, Group III and/or IV class medicines joint activity (especially except Group III medicine activity in addition to, also show the activity of I classes, II classes and/or IV class medicines)), more effective, longer action time, less side effect (including relatively low cause arrhythmia cordis effect, the incidence of such as Torsade de points), be more easy to absorb or also there are other more useful pharmacological propertieses.Biological test tests main electro physiology effects of the A in anaesthetized guinea pig
Use weight 660-1100g cavy.Before experiment, by animal cage at least one week, allow animal ad lib and drinking public water supply in this period.
By intraperitoneal injection amobarbital (40-50mg/kg) induced anesthesia, and insert the catheter into arteria carotis (being used for recording blood pressure and collection blood sample) and jugular vein (for being transfused medicine).Needle electrode is placed on four limbs to record ECG (II leads).Thermistor is put into the rectum and animal is placed on heating cushion, rectal temperature regulation is arrived 37.5-38.5 DEG C.
Implement tracheotomy and artificial ventilation is carried out to animal with room air with meiofauna ventilator, so that vim and vigour are maintained at its normal range (NR).To reduce independence influence, the vagus nerve of both sides is cut off in neck, 15 minutes intravenous administration 0.5mg/kg Propranolols before experiment starts.
The external membrane of heart for making left ventricle by the thoracotomy in left side exposes, and places the attraction electrode of customization to record monophasic action potential (MAP) on left ventricular free wall.It is maintained at electrode to be able to record that on the position of acceptable signal enough for a long time, otherwise moves on to the electrode on new position.Bipolar electrode for pace-making is clamped into atrium sinistrum.Paced with the constant current stimulator of customization (duration is 2ms, twice of diastole threshold value).In whole research process, there is the time of 1 minute in every 5 minutes to pace heart just above the frequency of normal sinus heart rate.
With Mingograph ink mist recordings instrument (Siemens-Elema, Sweden) recording blood pressure, MAP signal and lead II ECG.All signals are collected during last 10 seconds and last 10 seconds of ensuing sinus rhythm paced every time with PC (sample frequency is 1000Hz).These signals are handled with the custom program developed to gather and analyzing the physiological signal determined in experimental animal (referring to Axenborg and Hirsch, Comput.Methods Programs Biomed.41,55 (1993)).
Process of the test is included during pace-making and sinus rhythm, is spaced the two groups of Basal control records of collection in 5 minutes.After second of control record of collection, jugular vein conduit is injected with the substances of 30 seconds the first dosage by 0.2mL volumes.After three minutes, start to pace and carry out new record.5 minutes after previous administration, the substances of subsequent dose are given.During each experiment, successive administration 6-10 times.Data analysis
In the numerous variable elements determined from the analysis, 3 most important parameters of selection are used to compare and select reactive compound.75% MAP perdurabgilities when polarizing again during selected 3 variable elements are pace-makings, Atrial-ventricular (AV) conduction time during pace-making (be defined as atrial pacing pulses and ventricle MAP start between interval) and heart rate (being defined as the RR intervals during sinus rhythm).To evaluate the hemodynamic conditions of anesthetized animal, systolic pressure and diastolic pressure are determined.In addition, measuring ECG to evaluate arrhythmia cordis and/or morphological change.
The average value for compareing record twice is set as zero, represents continuously to give the influence recorded after substances to deviate the percent change of the value.The intergal dose imposed before record every time is mapped by drawing these percentages, dose-response curve can be built.In this way, experiment can produce three dose-response curves every time, and one is MAP perdurabgility curves, and one is AV conduction time curves, and one is sinus rhythm (RR intervals) curve.A kind of averaged curve of all experiments carried out with Test Materials is calculated, and valence value is drawn by averaged curve.Data point as obtained by linear correlation, builds all dose-response curves in these experiments.There is the index (D of Group III electro physiology efficiency with the intergal dose of extension 10%MAP perdurabgilities (away from baseline) as studied material10).Test the metabolic stability of B test compounds
In-vitro screening is carried out to determine the metabolic stability of the compounds of this invention.
Use the liver S-9 compositions of the dog with NADPH confactors, people, rabbit and rat.Condition determination is as follows：S-9 (3mg/mL), NADPH (0.83mM), Tris-HCl buffer solutions (50mM) (pH7.4) and 10 μM of substances.
Start reaction by adding substances, 0, after 1,5,15 and 30 minutes by making the pH of sample rise to 10 (NaOH；1mM) terminating reaction.After solvent extraction, determined by LC (fluorescence/UV is detected) relative to interior target test compound concentration.
The percentage of the test compound remained after calculating 30 minutes simultaneously calculates (t with this1/2) and measuring as metabolic stability.
The present invention is illustrated by the following examples.
Embodiment General Experimental Procedures
Mass spectrum is recorded with following devices：The ternary QMSs of Finnigan MAT TSQ700 (FAB-MS) for being provided with electronic spraying interface and the VGPlatform II mass spectrographs (LC-MS) for being provided with electronic spraying interface, the type gas chromatographs of Hewlett Packard 6890 being connected by Hewlett Packard HP-5-MS GC posts with Hewlett-Packard 5973A type mass spectrographs, or Shimadzu QP-5000 GC/ mass spectrographs (CI, methane).1H NMR and13C NMR measure adds 400 and 500 spectrometers with BRUKER ACP 300 and Varian UNITY, respectively in 300,400 and 500MHz H1Under frequency and 75.5,100.6 and 125.7MHz's13Operated under C frequencies.Or carried out with the spectrometers of BRUKER ACE 200 with 50.3MHz frequency13C NMR are determined.
According to the easy degree of spectrum resolution, spectrum can indicate or not indicate rotational isomer.Unless otherwise indicated, chemical displacement value relative to the ppm as interior target solvent to provide.The synthesis of intermediate
Embodiment A4- (2- Oxiranylmethoxies) benzonitrile
By epoxychloropropane (800mL) and K2CO3(414g) is added in solution of the 4-hydroxybenzonitrile of stirring (238g) in 2.0L MeCN, and the reactant mixture flows back 2 hours under an inert atmosphere.The hot solution is filtered, filtrate is concentrated, the oil clarified makes it be crystallized in Di Iso Propyl Ether, the product that yield is 75% is obtained.13C NMR(CDCl3)：δ 44.4,49.7,69.0,104.5,115.3,118.9,134.0,161.6
Embodiment B2 (S)-oxiranylmethyl radical 3- nitrobenzene-sulfonic acid esters
By m-nitrobenzene sulfonyl chloride (12.6g；57mmol) it is added to (- 20 DEG C) (R)-(+)-glycidol (5.5g of cooling；74mmol) with TEA (10.3mL；In solution 74mmol).The reactant mixture is stirred 96 hours at -20 DEG C.Filter the solution, filtrate is with tartaric acid (10%w/w), salt solution and H2O is washed and concentrated, and obtains the title compound of yield 97%.1H NMR(CDCl3)：δ 2.62 (dd, 1H), 2.84 (dd, 1H), 3.22 (m, 1H), 4.07 (dd, 1H), 4.49 (dd, 1H), 7.80 (t, 1H), 8.25 (m, 1H), 8.52 (m, 1H), 8.78 (m, 1H)
Embodiment C4- [(2S)-Oxiranylmethoxy] benzonitrile
According to the method described in above example A, the title compound is prepared by (R)-(-)-epoxychloropropane, yield is 90%.
Embodiment D4- [(2R)-Oxiranylmethoxy] benzonitrile
According to the method described in above example A, the title compound is prepared by (S)-(-)-epoxychloropropane.[α]D 20=-14.1 ° of (c=1.0；Acetone)1H NMR(CDCl3)：δ 2.79 (1H, m)；2.98 (1H, m)；3.39 (1H, m)；3.98 (1H, m)；4.37 (1H, m)；6.99 (2H, d)；7.60 (2H, d).
Embodiment E3- benzyls -3,7- diazabicyclo [3.3.1] nonane (a) 3,7- dibenzyl -3,7- diazabicyclo [3.3.1] nonane
According to J.Org.Chem.41,1593, (1976) method described in, the difference is that using 3,7- dibenzyl -3,7- diazabicyclos [3.3.1] nonane -9- ketone (also according to J.Org.Chem.41, prepared by the method described in 1593 (1976)) replaces N- Benzyl-N-methyl bispidone, prepares the subhead compound.(b) 3- benzyls -3,7- diazabicyclo [3.3.1] nonane
By 3,7- dibenzyl -3,7- diazabicyclo [3.3.1] nonane (1.97g；6.4mmol；Obtained by previous step (a)) EtOH (95%) and at one atm is dissolved in, with 5% Pd/C hydrogenations until TLC shows that reaction is complete.By celite pad Filtration of catalyst, be concentrated under reduced pressure residue, obtains the title compound of quantitative yield.13C NMR(CDCl3)：δ 30.1,33.4,36.0,52.5,59.6,64.3,126.9,128.3,128.7,138.8
Embodiment F3,7- diazabicyclo [3.3.1] nonane -3- carboxylates (a) 7- benzyls -9- epoxides -3,7- diazabicyclo [3.3.1] nonane -3- carboxylates
By paraformaldehyde (4.00g；127mmol) it is added to benzylamine (13.7g；In ethanol (190mL) solution 126mmol).The solution is heated to 60 DEG C, acetic acid (15.2g was added with 2 hours；In ethanol (160mL) solution 252mmol).It is stirred for after 1 hour, the solution is cooled to room temperature.The solution is added to the 1- tertbutyloxycarbonyl -4- piperidones (25.5g that (with 2 hours) has been heated to 60 DEG C；127mmol) with paraformaldehyde (4.80g；In ethanol (270mL) solution 152mmol).After backflow overnight, the solution is cooled to room temperature.Evaporating ethanol.In toluene: extraction post processing is carried out in water, makes the material in toluene: filters silica gel in ethyl acetate system.Eluant, eluent is evaporated, the area % (HPLC) of purity 90 is obtained, yield is 60% solid matter (37.4g).By being crystallized in isopropanol, purity is obtained for 98 area % (HPLC), and yield is 70% compound.MS(EI；70eV)：M/z 91 (100%), m/z 57 (42%), m/z 273 (32%), m/z 330 (5%)13C NMR(CDCl3)：δ 28.72,47.71,49.91,50.60,58.83,59.16,61.96,80.18,127.37,128.45,128.89.137.57,154.89,213.66 (being used as reference with TMS) (b) 7- benzyl -9- epoxides -3,7- diazabicyclo [3.3.1] nonane -3- carboxylates (another preparation method)
By benzylamine (6.51g；60.2mmol), acetic acid (72.3g, 1200mmol), paraformaldehyde (3.71g；120mmol) with 1- tertbutyloxycarbonyl -4- piperidones (12.0g；60.2mmol) it is added in ethanol (300mL).The solution is heated to 65 DEG C and stirred 2 hours at such a temperature.As above step (a) is described is post-processed, and obtains 15.78g purity for 92 area % (HPLC), and yield is 70% material.Recrystallized in isopropanol, obtain purity for 94 area % (HPLC), yield is 54% compound.(c) 7- benzyls -3,7- diazabicyclo [3.3.1] nonane -3- carboxylates
By 4- toluene sulfonyl hydrazides (12.4mmol；2.30g) with 7- benzyls -9- epoxides -3,7- diazabicyclo [3.3.1] nonane -3- carboxylates (10.1mmol；4.00g；Obtained by previous step (a)) it is dissolved in isopropanol (30mL) and is heated to reflux 2 hours.Add acetic acid (2.5mmol；Sodium cyanoborohydride (12.1mmol, 0.76g) and the mixture is heated to reflux 0.15g) and again 2 hours.The slurry is cooled to room temperature, filtering.Concentrate filtrate and in toluene：Extraction post processing is carried out in water.Toluene solution is concentrated, 0.95g purity is obtained for 90 area % (GC), yield is 60% subhead compound.MS(EI；70eV)：M/z 259 (100%), m/z 91 (95%), m/z 169 (45%), m/z57 (35%), m/z 316 (25%)13C NMR(CDCl3)：δ 28.67,28.95,31.11,47.55,48.38,58.70,58.96,63.46,78.71,126.57,128.00,128.53,138.94,155.20 (being used as reference with TMS) (d) 3,7- diazabicyclos [3.3.1] nonane -3- carboxylates
The method described according to above example E (b), slough 7- benzyls -3, the benzyl of 7- diazabicyclos [3.3.1] nonane -3- carboxylates (being obtained by previous step (c)), obtains the title compound of quantitative yield.13C NMR(CDCl3)：δ 28.05,28.29,31.33,48.35,49.11,51.53,79.34,155.16
Embodiment G4- [3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile
The EtOAc (600mL) of HCl saturations is added to 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- carboxylates (62g；Referring to International Patent Application PCT/SE98/02276) embodiment 2) ethyl acetate (600mL) solution in and by the mixture stir 4 hours.Removal of solvent under reduced pressure, residue is dissolved in MeCN (1.3L), adds K2CO3(100g).The suspension is stirred 12 hours and filtered.Filtrate is concentrated, the title compound that yield is 90% is obtained.13C NMR(CDCl3)：The preparation of δ 28.9,29.2,32.3,50.9,57.7,60.8,62.1,66.0,71.2,104.0,115.3,119.1,133.9,162.1 (title compound easily can be converted into hydrochloride using standard technique) compound of formula I
Embodiment 17- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo-[3.3.1] nonane -3- formamides
By ethyl isocyanate (1.42g, 16.6mmol) it is added to 4- { [(2S) -3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxypropyls] epoxide } benzonitrile) (5.0g, 20mmol, referring to above example G) in solution in 30mL dichloromethane.The mixture was stirred at room temperature after 4 hours and is concentrated in vacuo, through silica gel column chromatography with dichloromethane: methanol (95: 5) is purified by flash, and obtains the title compound of 3.2g (51%).13C NMR(CDCl3)：δ 15.52,29.19,29.50,31.89,35.77,48.00,49.17,57.21,60.49,61.83,65.41,70.71,103.88,115.34,119.15,133.78,133.84,158.87,162.19
Embodiment 27- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (Cvclopropvlmethvl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) isocyanic acid cyclopropylmethyl ester
Cyclopropyl-methylamine (1.4g, 19.7mmol) is added in 1, THF (10mL) solution of 1 '-carbonyl dimidazoles (3.2g, 19.7mmol).After resulting solution is stirred at room temperature overnight, distilled, obtain 0.4g (21%) subhead compound.(b) 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (Cvclopropvlmethvl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By isocyanic acid cyclopropylmethyl ester (0.4g, 4mmol, obtained by above step (a)) it is added to 4- [3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (1.2g, 4mmol, referring to above example G) DCM solution in.The solution is stirred overnight, is then concentrated in vacuo.Gained residue is through silica gel column chromatography with dichloromethane: methanol (93: 7) is purified by flash, and obtains 0.85g (50%) title compound.13C NMR(CDCl3)：δ 3.29,11.21,29.31,29.61,32.10,46.11,48.14,49.39,57.24,60.58,62.04,65.46,70.76,104.03,115.37,119.18,133.88,158.97,162.22 embodiment 34- ({ (2S) -2- hydroxyls -3- [7- (4- morpholinyl carbonyls) -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] propyl group } epoxide) benzonitrile
4- { [(2S) -3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxypropyls] epoxide } benzonitrile) (2.0g, 6.6mmol, it is prepared by the method similar to above example G) DCM (10mL) solution with the NaOH aqueous solution (0.8mL 10M solution), then handled with 4- morpholines formyl chloride (1.2g, 8mmol).Gained mixture was stirred at room temperature after 30 minutes, water is added.Organic layer is separated, is washed with 2M NaOH, then is separated with after salt water washing, (MgSO is dried4) and be concentrated in vacuo.By residue recrystallization twice, for the first time in isopropanol, then recrystallize in ethanol, obtain 0.73g (26.5%) title compound.13C NMR(CDCl3)：δ 23.36,29.59,30.05,32.34,47.45,49.51,52.18,56.86,60.78,62.82,65.35,66.66,70.82,104.03,115.33,119.17,133.88,162.23,164.99
Embodiment 47- { 3- (4- cyano-benzene oxygens) -2- [(mesyl) amino]-propyl group }-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides (a) 4- (3- amino -2- hydroxy propyloxy groups) benzonitrile
4- (2- Oxiranylmethoxies) benzonitrile (100g, 0.57mol, referring to above example A) is added in the mixture of dense ammonium hydroxide aqueous solution (500mL) and isopropanol (300mL).Gained slurry is stirred at room temperature 3 days.Filter the reactant mixture and remove insoluble accessory substance, filter vacuum is concentrated to give crude product, it is crystallized in acetonitrile, obtain 50g (46%) subhead compound.(b) 2- (4- cyano-benzene oxygens) -1- { [(mesyl) amino] methyl } ethyl methane sulfonate ester
By mesyl chloride (17.5g, 153mmol) it is slowly added to (- 10 DEG C) 4- (3- amino -2- hydroxy propyloxy groups) benzonitrile (13.3g of cooling, 69mmol, obtained by above step a) and solution of 4- (dimethylamino) pyridine (0.2g, 1.64mmol) in pyridine (100mL) in.The yellow solution is stirred at room temperature 1.5 hours, and DCM is re-dissolved in after vacuum concentration.The solution is washed twice with 2MHCl and uses NaHCO3After solution washed once, organic phase is separated, (MgSO is dried4) and be concentrated in vacuo, obtain 23.5g (100%) subhead compound.(c) 4- { [1- (mesyl) aziridine -2- bases] methoxyl group } benzonitrile
2- (4- cyano-benzene oxygens) -1- { [(mesyl) amino] methyl } ethyl methane sulfonate ester (23.5g of stirring; 67mmol; by above step (b) obtain) acetonitrile (200mL) solution potassium carbonate (30g; 210mmol) handle, form thicker precipitation.After 1 hour, another part potassium carbonate (30g, 210mmol) is added.After room temperature continues to stir 2 hours, reactant mixture, filter vacuum concentration are filtered.The grease (13g) of gained is crystallized in toluene, obtain 8g (47%) subhead compound.Mp 79-81 DEG C (d) N- { 2- (7- benzyls -3,7- diazabicyclo [3.3.1] nonyl- 3- yls) -1- [(4- cyano-benzene oxygens)-methyl] ethyl } Methanesulfomide
By 3- benzyls -3; 7- diazabicyclos [3.3.1] nonane (2g; 10mmol; referring to above example E) and 4- { [1- (mesyl) aziridine -2- bases] methoxyl group } benzonitrile (2.5g; 10mmol, is obtained by above-mentioned steps (c)) backflow of mixture in isopropanol stays overnight.Then the mixture is concentrated in vacuo, obtains residue, be dissolved in water (pH3) and extracted with ether.Water layer is alkalized with 2M NaOH and extracted with DCM.Dichloromethane layer is separated, dries and is concentrated in vacuo, obtain residue, through column chromatography DCM: methanol: methanol solution gradient elution (98: 2: 0~97: 0: 3) purifying of ammonia, obtain 2.5g (53%) subhead compound.(e) N- [2- (4- cyano-benzene oxygens) -1- (3,7- diazabicyclos [3.3.1] nonyl- 3- ylmethyls) ethyl] Methanesulfomide
By N- { 2- (7- benzyls -3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -1- [(4- cyano-benzene oxygens) methyl] ethyl Methanesulfomide (2.3g 4.9mmol, obtained by previous step (d)) aqueous methanol solution (95%；55mL) hydrogenated at room temperature with 5%Pd/C.By the way that through celite pad Filtration of catalyst, residue filtrate is concentrated in vacuo, 1.6g crude products are obtained.Recrystallize in methyl alcohol, obtain 0.3g (16%) subhead compound.(f) 7- { 3- (4- cyano-benzene oxygens) -2- [(mesyl) amino] propyl group }-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By N- [2- (4- cyano-benzene oxygens) -1- (3,7- diazabicyclos [3.3.1] nonyl- 3-1- ylmethyls) ethyl] Methanesulfomide (0.29g, 0.77mmol, obtained by previous step (e)) suspension ethyl isocyanate (66 μ L in DCM (10mL)
R2And R3Independently represent H, C1-4Alkyl (optionally replaced and/or terminated by one or more nitros or cyano group), OR7、N(R7a)R7b、OC(O)R8Or formation-O- (CH together2)2-O-、-(CH2)3-、-(CH2)4- or-(CH2)5-；R7And R8Independently represent H, C1-6Alkyl or-(CH2)b(latter two group is optionally replaced and/or terminated selected from following substituent by one or more-aryl：- OH, halogen, cyano group, nitro, C1-4Alkyl and/or C1-4Alkoxy)；R7aAnd R7bIndependently represent H or C1-6Alkyl；B represents 0,1,2,3 or 4；R4Represent H or C1-6Alkyl；D represents H, C1-4Alkyl ,-OR9Or-(CH2)cN(R10)(R11)；R9Represent H, C1-6Alkyl ,-C (O) R12、-(CH2)d- aryl or-(CH2)d-Het2(rear three groups are optionally replaced by one or more selected from following substituent：- OH, halogen, cyano group, nitro, C1-4Alkyl, C1-4Alkoxy, C (O) R13、C(O)OR14And/or-N (H) S (O)eR15)；R10Represent H, C1-6Alkyl ,-(CH2)f- aryl ,-C (NH) NH2、-S(O)2R15a、-[C(O)]gN(R16)(R17)、-C(O)R18Or-C (O) OR19；E represents 0,1 or 2；G represents 1 or 2；R11Represent H, C1-6Alkyl ,-C (O) R20Or-(CH2)h(latter group is optionally replaced and/or terminated (if appropriate) selected from following substituent by one or more-aryl：- OH, cyano group, halogen, amino, nitro, C1-6Alkyl and/or C1-6Alkoxy)；R12、R13、R14、R16、R17、R18、R19And R20Independently represent H, C1-6Alkyl, Het3Or-(CH2)j(rear three groups are optional for-aryl
0.84mmol) handle, obtain a settled solution.The mixture was stirred at room temperature after 1 hour, is concentrated in vacuo, then through column chromatography, is purified by flash with 5%MeOH DCM solution, title compound is obtained with 73% yield.13C NMR(CDCl3)：δ 15.41,28.88,29.18,30.77,35.87,41.78,47.93,48.65,49.98,58.24,58.51,60.15,68.82,104.51,115.28,118.95,134.05,158.58,161.55
Embodiment 57- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- isopropyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 7- benzyls-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
Isopropyl isocyanate (1.7g, 20mmol) is slowly added in DCM (10mL) solution of 3- benzyls -3,7- diazabicyclo [3.3.1] nonane (3.1g, 14.3mmol, referring to above example E).After the mixture is stirred at room temperature overnight, vacuum concentration obtains 4.2g (97%) subhead product.(b) N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 7- benzyl-N- isopropyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (4.2g, 14mmol, is obtained by previous step (a)) solution in methanol/water (mixtures of 17ml 15: 2) hydrogenates at ambient pressure with 5%Pd/C.By celite pad Filtration of catalyst, filter vacuum is concentrated, 2.6g (87%) subhead compound is obtained.(c) 7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 4- [(2S)-Oxiranylmethoxy] benzonitrile (0.55g, 3.14mmol, referring to above example C) and N- isopropyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (0.85g, 4mmol, is obtained by previous step (b)) mixture in isopropanol/water (6.5mL 12: 1 mixture) is stirred overnight at 60 DEG C.Then the mixture is concentrated in vacuo, residue is re-dissolved in DCM.Organic solution first uses water, and salt water washing is then used again, dries (MgSO4) and be concentrated in vacuo, obtain the title compound of 91% yield.13C NMR(CDCl3)：δ 23.49,29.29,31.78,42.26,47.71,49.09,56.92,60.27,61.65,65.19,70.61,103.54,115.21,119.09,133.65,158.11,162.08
Embodiment 67- [(2R) -3- (4- cyano group -2- { [(2- cyano ethyls) amino] carbonyl } phenoxy group) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 7- Benzyl-N-ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By (0 DEG C) 3- benzyls -3 of cooling, 7- diazabicyclos [3.3.1] nonane (32.45g, 0.15mol, referring to above example E) DCM (300mL) solution handled by the way that ethyl isocyanate (11.4g, 0.16mol) is added dropwise.The solution was stirred at room temperature after 2 hours, was concentrated in vacuo.Gained residue is purified through silica gel chromatograph DCM: MeOH (100: 0~90: 10) gradient elution, obtains 36.4g (84%) subhead compound.(b) N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 7- Benzyl-N-ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (4.4g, 15.3mmol, is obtained by previous step (a)) solution in hydrous ethanol solution (25mL, 95%) hydrogenates with 5%Pd/C at ambient pressure.Through celite pad Filtration of catalyst, residue vacuum concentration obtains 2.88g (95%) subhead compound.(c) the bromo- 2 hydroxybenzoic acid methyl esters of 5-
By Br2(52g) is slowly added to the gaultherolin (50g under stirring；330mmol) in the solution in 300mL acetic acid.The mixture was stirred at room temperature after 10 hours, was poured into frozen water, and precipitation is recrystallized in methyl alcohol, obtained the subhead compound that yield is 83%.(d) 5- cyano-2-hydroxys methyl benzoate
By the bromo- 2 hydroxybenzoic acid methyl esters (190.8g of 5-；Obtained by previous step (c)) and CuCN (73.9g) backflow 7 hours in DMF (500mL).Temperature is dropped to after 80 DEG C, add HCl (500mL) and FeCl3(165.0g).The reactant mixture is stirred after 30 minutes, concentrates and is assigned to H2In O and DCM.Organic layer is dried, concentrates and is recrystallized in methyl ethyl ketone, the subhead compound that yield is 61% is obtained.(e) 5- cyano group-N- (2- cyano ethyls) -2-Hydroxylbenzamide
By 5- cyano-2-hydroxy methyl benzoates (20g, 0.113mol, obtained by previous step (d)), 3- aminopropionitriles (15.4g, 0.22mol) and Cymag (1g, 20mmol) flow back in methanol (200mL) and stay overnight.TLC display reactions are incomplete, then add DMSO (50mL), and continue to flow back again 5 hours.The solution is concentrated in vacuo, adds after water, adds concentrated hydrochloric acid, until precipitation is formed.Product is filtered out, is washed with water and dries, obtain 19.4g (80%) subhead compound.(f) 5- cyano group-N- (2- cyano ethyls) -2- [(2R)-Oxiranylmethoxy] benzamide
By 5- cyano group-N- (2- cyano ethyls) -2-Hydroxylbenzamide (2.1g, 9.8mmol, obtained by previous step (e)) and 10 equivalents (S)-epoxychloropropane in isopropanol: (55mL, 10: mixture in 1) flow back and stayed overnight water.After the mixture is concentrated in vacuo, residue is purified by flash through column chromatography with ethyl acetate, obtains 0.63g (24%) subhead compound.(g) 7- [(2R) -3- (4- cyano group -2- { [(2- cyano ethyls) amino] carbonyl } phenoxy group) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 5- cyano group-N- (2- cyano ethyls) -2- [(2R)-Oxiranylmethoxy] benzamide (0.63g, 2.3mmol, obtained by previous step (f)) and N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (0.59g, 3mmol, obtained by previous step (b)) in isopropanol: water (33mL, 10: the mixture in 1) is stirred at reflux overnight.After the reactant mixture is concentrated in vacuo, residue is purified by flash through column chromatography with DCM: MeOH (9: 1), obtains 0.78g (73%) title compound.13C NMR(CDCl3)：δ 15.40,15.55,17.94,28.04,29.21,29.55,31.31,32.03,35.69,35.89,36.21,47.93,48.65,49.36,57.00,60.47,61.05,65.32,72.21,105.39,114.37,118.22,118.45,123.28,136.36,136.45,158.53,159.20,160.08,163.75ES-MS (M+1)+ 469.0(m/z)
Embodiment 77- ((2S) -3- { 4- cyano group -2- [(cyclopropylamino) carbonyl]-phenoxy group } -2- hydroxypropyls)-N- ethyls -3,7- diazabicyclo [3.3.1] formamide of nonane -3 (a) N '-cyclopropyl -5- cyano-2-hydroxy benzamides
Cyclopropylamine (14.3g) and Na (100mg) are added to 5- cyano-2-hydroxy methyl benzoates (10.0g；By previous step (d) obtain) DMSO (40mL) solution in.The reactant mixture is heated to 80 DEG C in sealing steel vessel and keeps staying overnight, is diluted with water, is acidified and is extracted with ethyl acetate, subhead compound (11.0g) is obtained after organic layer concentration.(b) 5- cyano group-N- cyclopropyl -2- [(2S)-Oxiranylmethoxy] benzamide
By N '-cyclopropyl -5- cyano-2-hydroxy benzamides (1.56g, 7.7mmol, obtained by previous step (a)), (2S)-oxiranylmethyl radical 3- nitrobenzene-sulfonic acids ester (2g, 7.7mmol, referring to above example B) and K2CO3The mixture of (1.16g, 8.4mmol) in 2- butanone (15mL) is stirred 18 hours at 60 DEG C.After the mixture is concentrated in vacuo, residue is in Di Iso Propyl Ether: is crystallized in MeCN (9: 1), obtains 0.97g (97%) subhead compound.(c) 7- ((2S) -3- { 4- cyano group -2- [(cyclopropylamino) carbonyl] phenoxy group } -2- hydroxypropyls)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 5- cyano group-N- cyclopropyl -2- [(2S)-Oxiranylmethoxy] benzamide (0.97g, 3.8mmol, obtained by previous step (b)) and N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (0.89g, 4.5mmol, referring to example 6 above (b)) in isopropyl：Water (22mL, 10: the mixture backflow in 1) is stayed overnight.Solvent is removed in vacuum, gained residue is purified by flash through silica gel column chromatography with DCM: MeOH (9: 1), obtains 1.37g (79%) title compound.13C NMR(CDCl3)：δ 6.62,6.78,15.81,23.55,29.61,29.90,32.48,36.20,48.32,49.84,53.68,57.48,60.92,62.06,65.61,71.72,105.42,113.69,118.64,123.78,136.26,136.77,159.70,159.97,164.75 embodiment 8N- ethyls -7- (4- nitrophenethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 1- (2- bromoethyls) -4- nitrobenzene (1.6g, 7.0mmol), N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides (1.0g, 5.1mmol, referring to example 6 above (b)) and K2CO3The mixture of (1.38g, 10mmol) is stirred at room temperature overnight.Then filter the mixture and be concentrated in vacuo, gained residue is purified through column chromatography with DCM: MeOH (100: 0~90: 10) gradient elution, obtains 1.5g (85%) title compound.13C NMR(CDCl3)：δ 15.71,28.83,30.11,33.03,35.67,47.97,59.22,59.49,123.34,129.65,146.26,149.15,157.95
Embodiment 9N- (cyano methyl) -7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) isocyanic acid cyano methyl ester
The method described according to example 2 above (a), substitutes cyclopropyl-methylamine with 2- aminoacetonitriles and prepares the title compound.(b) N- (cyano methyl) -7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described using example 2 above (b), Cvclopropvlmethvl isocyanates is substituted with isocyanic acid cyano methyl ester (being obtained by previous step (a)), title compound is obtained with the yield of 26% (step (a) and (b) are calculated together).13C NMR(CDCl3)：δ 28.99,29.27,29.47,31.77,48.32,49.33,56.88,60.33,61.61,65.32,70.63 103.96,115.31,117.63,119.21,133.93,157.74,162.08
Embodiment 10N- ethyls -7- { 4- [(mesyl) amino] phenethyl } -3,7- diazabicyclos-[3.3.1] nonane -3- formamides (a) 4- [(mesyl) amino] phenethyl methanesulfonates
30 minutes are used, mesyl chloride (45g, 0.39mol) is added drop-wise in pyridine (200mL) solution of (- 5 DEG C) the 4- Aminophenethyl alcohols (25.2g, 0.18mol) of cooling.The mixture is stirred at room temperature overnight after 0 DEG C is stirred 1 hour.In the mixture that gained red suspension is poured into ice (300mL) and concentrated hydrochloric acid (60mL).The pink precipitate to be formed is filtered out, is re-dissolved in DCM, dries and is handled with activated carbon.Resulting solution is concentrated in vacuo, residue is obtained, through re-crystallizing in ethyl acetate, 34.5g (64%) subhead compound is obtained.Mp 133-134 DEG C (b) N- ethyls -7- { 4- [(mesyl) amino] phenethyl } -3,7- diazabicyclos-[3.3.1] nonane -3- formamides
By N- ethyls -3; 7- diazabicyclos [3.3.1] nonane -3- formamides (1g; 5mmol; referring to example 6 above (b)), 4- [(mesyl) amino] phenethyl methanesulfonates (1.5g; 5mmol, is obtained by previous step (a)) and NaHCO3The mixture of (3g, 35.7mmol) in MeCN (50mL) flows back 3 hours under nitrogen atmosphere.Reactant mixture is filtered and is concentrated in vacuo and obtains 2.2g crude products, short column of silica gel is filtered, is eluted with MeOH/2N HCl.The pH of cut is risen to 6 and is extracted with DCM, obtain 0.2g title compounds.13C NMR(CDCl3)：δ 15.75,28.87,30.23,32.58,35.64,35.76,39.14,48.18,59.17,60.26,121.41,129.85,134.72
Embodiment 117- [3- (4- cyano-benzene oxygens) -2- fluoropropyls]-N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
The method described according to example 1 above, with 4- [3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (referring to above example G) substitute 4- { [(2S) -3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxypropyls] epoxide } benzonitrile the title compound is made.(b) 7- [3- (4- cyano-benzene oxygens) -2- fluoropropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (1.0g, 2.7mmol, by previous step (a) obtain) DCM (2.5mL) solution be cooled to -78 DEG C.DCM (2.5mL) solution of (diethylamino) sulfur trifluoride is slowly added under agitation.Continue to stir 35 minutes, during which reactant is warming to room temperature.Add dichloromethane, reactant mixture NaHCO3Wash and be concentrated in vacuo.Gained residue is purified by flash through column chromatography with DCM: MeOH (98: 2), obtains 0.68g (67%) title compound.13C NMR(CDCl3)：δ 15.63,29.00,30.33,35.70,47.78,47.93,58.36,58.67,59.82,60.39,68.60,68.89,89.56,91.86,104.15,115.56,119.25,133.97,157.61,161.92
Embodiment 127- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [2- oxos -2- (propylcarbamic)-ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 2- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] ethyl acetate
By (0 DEG C) 4- [3- (3 of cooling, 7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (23.1g, 77mmol, referring to above example G) DCM (700mL) solution 2- ethyl isocyanatoacetates (9.92g, 77mmol) handle, be then stirred at room temperature 7 hours.The reactant mixture is concentrated in vacuo, 33.6g (100%) subhead compound is obtained.(b) 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [2- oxos -2- (propylcarbamic)-ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By 2- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] ethyl acetate (0.76g 1.8mmol, by previous step (a) obtain), propylamine (5mL, 3.6g, 69.1mmol) 75 DEG C are warming in seal pipe and keeps staying overnight with mixtures of the NaCN (0.01g, 0.2mmol) in methanol (10mL).It is concentrated in vacuo and removes solvent, residue is diluted with sodium carbonate liquor.The aqueous mixture is extracted with DCM, separating obtained organic layer, is dried and is concentrated in vacuo.Gained residue is through column chromatography, with dichloromethane: methanol (100: 0~90: 10) gradient elution is purified, and obtains the title compound that yield is 70%.13C NMR(CDCl3)：δ 11.36,22.65,29.12,29.42,31.78,41.15,44.75,48.15,49.10,56.99,60.40,61.35,65.33,70.74,103.99,115.27,119.12,133.91,158.71,162.10,170.62
Embodiment 137- { 3- (4- cyano-benzene oxygens) -2- [(4- morpholinyl carbonyls) amino] propyl group }-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides (a) 3- (4- cyano-benzene oxygens) -2- hydroxypropylamino carboxylates
(0 DEG C) 4- (3- amino -2- hydroxy propyloxy groups) benzonitrile (44.6g, 0.23mol, referring to example 4 above (a)) of cooling is THF: H2O (1.5L, 1: the solution in 1) is handled with two dimethyl dicarbonate butyl esters (53g, 0.24mol).The mixture is stirred at room temperature overnight, and sodium chloride, and separating obtained organic layer are added afterwards.Water layer is extracted with ether, and the organic layer of merging is dried and is concentrated in vacuo.Gained grease (70g) filters short column of silica gel, then in ether: is recrystallized in Di Iso Propyl Ether, obtains 50g subhead compounds.(b) 2- [(tert-butoxycarbonyl) amino] -1- [(4- cyano-benzene oxygens) methyl] ethyl methane sulfonate ester
With 1.5 hours, mesyl chloride (22.3g 0.195mol) is added to (0 DEG C) 3- (4- the cyano-benzene oxygens) -2- hydroxypropylamino carboxylates (51.2g for keeping cooling in an inert atmosphere, 0.177mol, obtained by previous step (a)) and solution of 4- (dimethylamino) pyridine (1.3g, 10.6mmol) in pyridine (250mL) in.The reactant mixture was stirred at room temperature after 2 hours, added water and DCM.Organic layer is separated, is washed with water, (MgSO is dried4) and vacuum concentration obtains 68.1g (100%) subhead compound.(c) 2- [(4- cyano-benzene oxygens) methyl] -1- aziridine carboxylates
Under an inert atmosphere, by (0 DEG C) 2- [(tert-butoxycarbonyl) amino] -1- [(4- Cyano-phenoxies) methyl] ethyl methane sulfonate ester (30.6g of cooling, 82.6mmol, obtained by previous step (b)) and the 50wt.%NaOH aqueous solution (60mL) processing of solution of the tetrabutylammonium disulfate (3g, 8.8mmol) in DCM (100mL).Stirring gained mixture, made temperature slowly be warmed to room temperature, is then extracted with ether by 4 hours.Organic layer is washed with water and is concentrated in vacuo, and obtains residue and is purified through column chromatography (dichloromethane eluant).In ether: crystallized in Di Iso Propyl Ether, obtain the subhead compound of quantitative yield.(d) 2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate
By N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (2.88g, 14.6mmol, referring to example 6 above (b)) and 2- [(4- cyano-benzene oxygens) methyl] -1- aziridine carboxylates (4.0g, 14.6mmol, is obtained by previous step (c)) backflow of mixture in isopropanol (20mL) stays overnight.The reactant mixture is concentrated in vacuo, 7.4g yellow oils are obtained, by it through column chromatography, is purified with DCM: MeOH (100: 0~90: 10) gradient elution, obtains 3.33g subhead compounds.(e) 7- [2- amino -3- (4- cyano-benzene oxygens) propyl group]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate (2.4g, 5.1mmol, is obtained by previous step (d)) solution in the ethyl acetate with hydrochloric acid saturation is stirred at room temperature 1 hour.It is concentrated in vacuo after the reactant mixture, gained residue is re-dissolved in water.Aqueous solution NaHCO3The aqueous solution is handled and extracted with DCM, is concentrated in vacuo after organic layer is dried, is obtained 2g subhead compounds.(f) 7- { 3- (4- cyano-benzene oxygens) -2- [(4- morpholinyl carbonyls) amino] propyl group }-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By (5 DEG C) 7- [2- amino -3- (4- cyano-benzene oxygens) propyl group]-N- ethyls -3 of cooling, 7- diazabicyclos [3.3.1] nonane -3- formamides (0.33g, 0.7mmol, obtained by previous step (e)) and triethylamine (0.4mL, 3.0mmol) the 4- morpholine formyl chlorides (0.11g of the solution in DCM (5mL), 0.7mmol) handle, then stirred 3 hours at 5 DEG C.Continue after being stirred at room temperature overnight, the reaction of TLC analysis shows is not complete, then adds other 4- morpholines formyl chloride (40mg, 0.27mmol).Continue after being stirred at room temperature overnight, add sodium bicarbonate solution.Organic layer is separated, dries and is concentrated in vacuo, 400mg crude products are obtained, through silica gel column chromatography, with dichloromethane: the methanol solution (95: 5) of ammonia is purified by flash, and obtains 250mg title compounds.13C NMR(CDCl3)：δ 161.94,158.26,157.81,133.94,119.15,115.37,103.90,67.26,66.66,60.66,60.51,57.99,48.93,48.37,47.39,44.06,35.93,30.71,29.34,29.02,15.51
Embodiment 14N- (4- cyano group phenethyl) -7- (4- oxos heptyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 3- benzyls -7- [3- (2- propyl group -1,3- dioxolanes -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane
By 3- benzyls -3,7- diazabicyclos [3.3.1] nonane (10.5g, 48.5mmol, referring to above example E), 2- (3- bromopropyls) -2- propyl group -1,3- dioxolanes (11.5g, 48.5mmol, Bajrowicsz etc., Tetrahedron, 41 (1985) 1833) and K2CO3The mixture backflow of (13.8g, 0.1mol) in MeCN (50mL) is stayed overnight.The reactant mixture is filtered and is concentrated in vacuo, 18.8g (100%) subhead compound is obtained.(b) 3- [3- (2- propyl group-DOX -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane
By 3- benzyls -7- [3- (2- propyl group -1,3- dioxolanes -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane (18.8g, 4.85mmol, by previous step (a) obtain) ethanol (100mL) solution hydrogenated at ambient pressure with 5%Pd/C.Through celite pad Filtration of catalyst, filtrate is concentrated in vacuo, 13.7g (100%) subhead compound is obtained.(c) N- (4- cyano group phenethyl) -7- (4- oxos heptyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By 4- (2- amino-ethyls) benzonitrile (1.0g, 6.9mmol, Wiley etc., Bioorg.Med.Chem.Lett., 6 (1996) 2387) anhydrous THF (10mL) solution use 1,1 '-carbonyl dimidazoles (1.17g, 7.2mmol) processing, and the mixture is stirred 30 minutes.By 3- [3- (2- propyl group -1,3- dioxolanes -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane (1.3g, 4.6mmol, obtained by previous step (b)) THF (5mL) solution be added in the reactant mixture, and continue to be stirred at room temperature overnight.Then the solution is concentrated in vacuo, gained residue is diluted with MeOH and 2M HCl, the solution is stirred at room temperature 2 hours.Make the mixture in alkalescence and extracted with DCM.Organic layer is separated, dries and is concentrated in vacuo, obtain residue, the residue is purified by flash through flash chromatography with DCM: MeOH (92: 8), obtain 0.57g (30%) title compound.13C NMR(CDCl3)：δ 13.73,17.21,20.85,28.79,30.38,36.91,39.84,41.83,44.73,47.94,57.65,59.05,110.06,118.93,129.67,132.20,145.52,157.47,211.67
Embodiment 15N '-(4- cyanobenzoyls) -7- (4- oxos heptyl) -3,7- diazabicyclos [3.3.1] nonane -3- carbonohydrazides
By 4- Cyanophenacyl hydrazines (0.82g, 5.0mmol) with 1,1 '-carbonyl dimidazoles (0.82g, 5mmol) mixture in THF (15mL) is stirred at room temperature 10 minutes, then 3- [3- (2- propyl group-DOX -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane (1.44g is added, 5.0mmol, referring to example 14 above (b)).After the reactant mixture is stirred at room temperature overnight, it is concentrated in vacuo.Gained residue is dissolved in DCM, is washed with water.Separation organic layer is simultaneously concentrated in vacuo, and is obtained residue, is dissolved in methanol/2M HCl.It is evaporated in vacuo methanol and extracts the remaining aqueous solution with DCM, obtains 0.5g (25%) title compound through Flash silica gel (dichloromethane: the methanol solution of ammonia is eluant, eluent) after purification.13C NMR(CDCl3)：δ 213.21,164.24,157.01,136.31,132.19,128.24,118.11,115.11,58.65,57.89,48.38,44.31,40.55,31.52,29.12,21.60,17.08,13.69
Embodiment 164- { 2- amino -3- [7- (1- piperidino carbonyls) -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] propoxyl group } benzonitrile (a) 7- benzyls -3,7- diazabicyclo [3.3.1] nonyl- 3- bases (1- piperidyls) ketone
The subhead compound passes through 3- benzyls -3,7- diazabicyclos [3.3.1] nonane (referring to above example E) and 1- piperidine formyl chlorine (Boon, J.Chem.Soc., (1947) 307,313) it is prepared by the method for reaction.(b) 3,7- diazabicyclos [3.3.1] nonyl- 3- bases (1- piperidyls) ketone
The method described according to example 14 above (b), with 7- benzyls -3,7- diazabicyclos [3.3.1] nonyl- 3- bases (1- piperidyls) ketone (being obtained by previous step (a)) substitutes 3- benzyls -7- [3- (2- propyl group -1,3- dioxolanes -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane, the subhead compound is obtained with quantitative yield.(c) 2- (4- cyano-benzene oxygens) -1- { [7- (1- piperidino carbonyls) -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] methyl } ethylcarbamate
By 2- [(4- cyano-benzene oxygens) methyl] -1- aziridine carboxylates (1.92g, 7mmol, referring to example 13 above (c)) and 3,7- diazabicyclos [3.3.1] nonyl- 3- bases (1- piperidyls) ketone (1.85g, 7mmol, is obtained by previous step (a)) mixture in isopropanol (15mL) flows back 30 hours.It is concentrated in vacuo after the solution, obtains 3.7g crude products, through chromatogram, be purified by flash with 2.5%MeOH DCM solution, obtains 2.0g (56%) subhead compound.(d) 4- { 2- amino -3- [7- (1- piperidino carbonyls) -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] propoxyl group } benzonitrile
By (0 DEG C) 2- (4- cyano-benzene oxygens) -1- { [7- (1- piperidino carbonyls) -3 of cooling, 7- diazabicyclos [3.3.1] nonyl- 3- yls] methyl } ethylcarbamate (1.9g, 3.7mmol, is obtained by previous step (c)) ethyl acetate solution handled with the ethyl acetate of HCl saturations.After the mixture is stirred 4 hours, it is concentrated in vacuo.Gained residue is dissolved in water, NaHCO is used3Make it in alkalescence and extracted with DCM.Organic layer is separated, dries and is concentrated in vacuo, obtain 1.5g (100%) title compound.13C NMR(CDCl3)：δ 24.73,25.72,29.62,29.95,32.11,47.44,48.14,49.53,50.98,57.87,60.57,62.59,72.03,103.90,115.30,119.22,133.91,162.23,164.35
Embodiment 17N- ethyls -7- { 2- hydroxyls -3- [4- (1H- imidazoles -1- bases) phenoxy group] propyl group } -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 1- [4- (2- Oxiranylmethoxies) phenyl] -1H- imidazoles
By 4- (1H- imidazoles -1- bases) phenol (10g, 60mmol), K2CO3The mixture of (8.63g, 60mmol) and 2- oxiranylmethyl radical 3- nitrobenzene-sulfonic acids esters (15.5g, 60mmol, referring to above example B) in DMF (140mL) is stirred overnight in 40 DEG C.Then the mixture is concentrated in vacuo, gained residue is diluted with DCM, is washed with water, is concentrated in vacuo after drying.Then the crude product is through flash chromatography, with dichloromethane: methanol (100: 0~70: 30) gradient elution is purified, and obtains 3.4g, (72.6%) title compound.(b) N- ethyls -7- { 2- hydroxyls -3- [4- (1H- imidazoles -1- bases) phenoxy group] propyl group } -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By 1- [4- (2- Oxiranylmethoxies) phenyl] -1H- imidazoles (3.16g, 14.6mmol, obtained by previous step (a)) and N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (2.88g 14.6mmol, referring to example 6 above (b)) are in isopropanol: H2O (18mL, 9: the mixture in 1) flows back 3 hours, is concentrated in vacuo and through acid/base abstraction purification, obtains 4.4g (72.6%) title compound.13C NMR(CDCl3)：δ 15.52,29.13,29.44,31.84,35.70,47.92,49.07,57.21,60.44,61.94,65.45,70.76,115.49,118.58,122.90,129.86,130.56,135.66,158.16,158.78
Embodiment 18N- [3- (4- cyano-benzene oxygens) propyl group] -7- (2- hydroxyethyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 4- (3- bromines propoxyl group) benzonitrile
By 1,3- dibromopropanes (1.02L；10mol) it is added to the 4-hydroxybenzonitrile (238g under stirring；2mol)、K2CO3(276.4g；2mol) in the suspension in MeCN (2.7L).The reactant mixture is flowed back 4 hours, filters and concentrates.Residue is recrystallized in isopropyl ether, obtains the subhead compound that yield is 69%.(b) 4- [3- (1,3- dioxo -1,3- dihydro -2H- iso-indoles -2- bases) propoxyl group] benzonitrile
By 4- (3- bromines propoxyl group) benzonitrile (20g, 84mmol, referring to upper step (a)) and mixture of the potassium phthalimide (15.5g, 84mmol) in DMF (120mL) stirred 4 hours in 95 DEG C.Then the solution is concentrated in vacuo, gained residue is dissolved in DCM and is washed with water.Organic layer is separated, (Na is dried2SO4) and be concentrated in vacuo, obtain 25.5g (99%) subhead compound.(c) 4- (3- amino propoxyl group) benzonitrile
By 4- [3- (1,3- dioxos -1,3- dihydro -2H- iso-indoles -2- bases) propoxyl group] benzonitrile (25.5g, 83mmol, obtained by previous step (b)) and hydrazine hydrate (4.15g, after 83mmol) mixture in methanol (100mL) flows back 1 hour, water (120mL) is added.It is evaporated under reduced pressure after methanol, adds concentrated hydrochloric acid (120mL).After gained mixture is heated 1.5 hours with steam bath, the cool overnight in refrigerator.Filter out gained to precipitate, filter vacuum is concentrated.Add water in gained residue and make the solution alkaline.The aqueous solution is extracted with DCM, then separates organic layer, is dried and is concentrated in vacuo, obtains 6g (41%) subhead compound.(d) 7- benzyls -3,7- diazabicyclo [3.3.1] nonane -3- ethanol
By the way that prepared by 3- benzyls -3,7- diazabicyclo [3.3.1] nonane (referring to above example E) and ethylene bromohyrin reaction into the compound, yield is 72%.(e) 3,7- diazabicyclos [3.3.1] nonane -3- ethanol
According to the method described in example 14 above (b), with 7- benzyls -3,7- diazabicyclos [3.3.1] nonane -3- ethanol (being obtained by previous step (d)) substitutes 3- benzyls -7- [3- (2- propyl group -1,3- dioxolanes -2- bases) propyl group] the obtained subhead compound of -3,7- diazabicyclos [3.3.1] nonane.(f) N- [3- (4- cyano-benzene oxygens) propyl group] -7- (2- hydroxyethyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides
According to the method described in example 14 above (c), 3 are used respectively, 7- diazabicyclos [3.3.1] nonane -3- ethanol (being obtained by previous step (e)) and 4- (3- amino propoxyl group) benzonitrile (being obtained by above-mentioned steps (c)) substitute 3- [3- (2- propyl group -1,3- dioxolanes -2- bases) propyl group] -3,7- diazabicyclos [3.3.1] nonane and 4- (2- amino-ethyls) benzonitrile, the title compound is prepared, yield is 11%.13C NMR(CDCl3)：δ 162.04,158.99,133.66,118.99,115.03,103.35,66.55,60.24,57.87,57.18,50.02,48.63,37.93,31.81,29.26,28.96 embodiment 19N- { [7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] carbonyl } -4- methyl benzenesulfonamides
To 4- [3- (3; 7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (200mg; 0.66mmol; referring to above example G) chloroform (20mL) solution in tolysulfonyl based isocyanate (110 μ L are added dropwise; 96% purity; 0.136g, 0.69mmol chloroformic solution (4mL), are handled.White precipitate is formed immediately, is then concentrated in vacuo the mixture.By the crude product so obtained followed by silica gel chromatography, with hexane: ethyl acetate: methanol solution (75: 75: the 50) elution of ammonia, obtain the title compound of 53% yield.13C NMR(CDCl3)：δ 15.77,29.18,32.37,36.13,48.72,52.27,56.32,109.83,113.13,118.27,118.93,120.10,127.80,131.39,132.46,132.73,134.62,138.75,159.14,167.09
Embodiment 20N- pi-allyls -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By allylamine (125 μ L, 1.66mmol) and 1, mixture of the 1 '-carbonyl-diimidazole (269mg, 1.66mmol) in THF (10mL) is stirred at room temperature 40 minutes.Then the mixture is handled with THF (5mL) solution of 4- [3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (referring to above example G), and continues to be stirred overnight.The mixture is concentrated in vacuo, gained residue is through silica gel chromatography, with hexane: the methanol solution (1: 1) of ammonia is eluted, and obtains the title compound that yield is 57%.13C NMR(MeOD)：δ 29.37,30.79,41.95,42.91,58.91,59.55,61.12,66.52,70.75,103.31,113.81,115.39,118.72,133.73,135.57,136.06,158.93,162.67
Embodiment 217- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [2- (2- thienyls) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 19 above, substitutes tolysulfonyl based isocyanate with 2- (2- isocyanatoethyls) thiophene, prepares title compound, yield is 83%.13C NMR(CDCl3)：δ 29.19,29.50,30.59,32.11,42.26,47.94,49.37,56.23,60.47,61.95,65.32,70.74,103.88,115.36,119.52,123.69,125.25,127.04,133.90,142.19,158.74,162.22
Embodiment 227- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [3- (ethylamino) -3- oxopropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 3- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] ethyl propionate
The method described according to example 12 above (a), substitutes 2- ethyl isocyanatoacetates with 3- isocyanate groups ethyl propionate and prepares the subhead compound.Yield is 90%.(b) 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [3- (ethylamino) -3- oxopropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 12 above (b), 3- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3 are used respectively, 7- diazabicyclos [3.3.1] nonyl- 3- yls }-carbonyl) amino] ethyl propionate (being obtained by previous step (a)) and ethamine replacement 2- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] ethyl acetate and propylamine, the title compound is prepared, yield is 22%.13C NMR(CDCl3)：δ 172.46,162.17,158.89,133.96,119.14,115.37,104.16,65.27,61.73,60.58,56.97,49.23,47.89,37.51,36.60,34.26,32.00,29.54,29.16,14.87
Embodiment 23N- (1- cyano ethyls) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 2- aminopropionitriles
At -78 DEG C, lactonitrile (28g, 375mmol) is added in the liquefied ammonia in reaction tube.The test tube is sealed and is stirred at room temperature overnight.Evaporation removes deammoniation, and gained crude product can be used to the next step without purifying.(b) N- (1- cyano ethyls) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By 1 hour, by 2- aminopropionitriles (250mg, 3.58mmol, obtained by previous step (a)) and N- ethyl diisopropyl amines (0.67mL, 0.50g, 3.84mmol) mixture in DCM (9mL) is added to and (uses syringe pump) in triphosgene (352mg, 1.19mmol) DCM (7mL) solution.Gained mixture was stirred at room temperature after 1 hour, add 4- [3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (1.08g, 3.58mmol, referring to above example G) and N- ethyl diisopropyl amines (0.67mL, 0.50g, 3.84mmol) mixture in DCM (14mL).Stirring 20 minutes is further continued for, the solution is then concentrated in vacuo and by gained residue through flash chromatography, with dichloromethane: methanol (95: 5) is purified by flash, and obtains the title compound of yield 65%.13C NMR(CDCl3)：δ 20.02,20.16,29.11,29.32,29.46,31.91,37.83,37.89,48.23,48.47,49.36,49.61,56.95,60.26,60.51,61.58,62.077,65.43,70.69,104.06,115.40,119.27,120.77,133.96,157.08,162.21
Embodiment 247- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2,2,2- trifluoroethyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 2 above 3 (b), substitutes 2- aminopropionitriles with 2,2,2- trifluoroethylamines, prepares the title compound, yield is 46%.13C NMR(CDCl3)：δ 29.11,29.42,31.79,42.17,42.51,48.36,49.58,57.09,60.45,61.77,65.39,70.76,104.08,115.39,119.23,123.28,126.05,133.93,157.76,162.21
Embodiment 257- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [2- oxos -2- (1- piperidyls)-ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 12 above (b), substitutes propylamine with piperidines and prepares the title compound, yield is 49%.13C NMR(CDCl3)：δ 24.33,25.41,26.06,28.74,29.29,29.44,32.13,42.67,43.10,45.30,47.99,48.09,49.14,49.28,57.18,60.42,61.90,65.55,70.77,94.22,103.89,115.24,115.43,119.24,133.74,134.02,158.49,162.20,167.42
Embodiment 26N- (1,3- benzodioxole -5- bases) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 2 above 3 (b), substitutes 2- aminopropionitriles with 1,3- benzodioxole -5- ammonia and prepares the title compound, yield is 33%.13C NMR(CDCl3)：δ 162.22,156.51,147.47,143.20,133.98,133.83,119.41,115.40,113.68,107.68,103.83,103.59,100.96,70.70,65.98,61.34,60.34,57.87,49.17,48.13,31.52,29.41,29.11
Embodiment 277- [3- (4- cyanophenylaminos) propyl group]-N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 4- [(3- hydroxypropyls) amino] benzonitrile
After the mixture of 4- fluorobenzonitriles (12.0g, 99.1mmol) and 3- amino -1- propyl alcohol (59.6g, 793mmol) is stirred 3 hours under 80 DEG C and inert atmosphere, water (150mL) is added.The mixture is cooled to room temperature, then extracted with ether.Organic layer is separated, (Na is dried2SO4), filter and be concentrated in vacuo, obtain 17g (97%) title compound as oil of placed crystallization.(b) 3- (4- cyanophenylaminos) propyl group 4- toluene sulfonic acide esters
By (0 DEG C) 4- [(3- hydroxypropyls) amino] benzonitrile (17g of cooling, 96.5mmol, by previous step (a) obtain) anhydrous MeCN (195mL) solution triethylamine (9.8g, 96.5mmol) processing, then handled with Butyltriphenylphosphonium chloride (20.2g, 106mmol).After the mixture is stirred 90 minutes at 0 DEG C, it is concentrated in vacuo.Water (200mL) is added into residue, the aqueous solution is extracted with DCM.Organic phase is through drying (Na2SO4), filter and be concentrated in vacuo.Gained residue crystallization purifying in isopropanol, obtains 24.6g (77%) subhead compound.(c) 2- { [(7- benzyls -3,7- diazabicyclo [3.3.1] nonyl- 3- yls) carbonyl] amino } ethyl acetate
The method described according to example 5 above (a), with 4- [3- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -2- hydroxy propyloxy groups] benzonitrile (referring to above example G) and 2- ethyl isocyanatoacetates substitute 3- benzyls -3 respectively, 7- diazabicyclos [3.3.1] nonane and isopropyl isocyanate, the subhead compound is prepared, yield is 99%.(d) 7- benzyls-N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 12 above (b), with 2- { [(7- benzyls -3,7- diazabicyclos [3.3.1] nonyl- 3- yls) carbonyl] amino } ethyl acetate (by previous step (c) acquisition) replacement 2- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] ethyl acetate prepares the subhead compound, and yield is 88%.(e) N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
The method described according to example 5 above (b), with 7- benzyls-N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (being obtained by previous step (d)) substitute 7- benzyls-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides and prepare the title compound.(f) 7- [3- (4- cyanophenylaminos) propyl group]-N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
By N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (3.35g, 12.5mmol are obtained by previous step (e)), K2CO3(6.9g, 50mmol) with sodium iodide (0.19g, 1.25mmol) 3- (4- cyanophenylaminos) the propyl group 4- toluene sulfonic acide esters (4.2g of the mixture in acetonitrile (600mL), 12.7mmol, obtained by previous step (b)) handle and stir 5 hours under reflux, then it is stirred at room temperature again 21 hours.The mixture is filtered, is concentrated in vacuo, so obtained residue diluted with water.The aqueous solution is extracted with DCM, separates organic layer, is dried and is concentrated in vacuo.The crude on silica gel chromatogram purification so obtained, is eluted with DCM: MeOH (95: 5), obtains 3.08g (58%) title compound.13C NMR(CDCl3)：δ 11.49,22.85,25.11,29.09,31.03,40.78,41.40,44.80,48.41,56.22,59.32,97.43,111.99,120.97,133.74,151.98,157.92,170.37 dichloromethane: methanol (9: 1) is purified by flash, obtain 0.8g (30%) title compound.13C NMR(CDCl3)：δ 162.18,133.92,119.24,115.34,103.92,69.07,67.86,59.52,58.42,48.18,35.68,30.25,28.81,15.69
Embodiment 297- [4- (4- cyano-phenyls) -4- (3,4- dimethoxys phenoxy group) butyl]-N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 4- [1- (3,4- dimethoxy phenoxy group) -3- cyclobutenyls] benzonitrile
By (0 DEG C) 4- (1- hydroxyl -3- cyclobutenyls) benzonitrile (14.6g of cooling, 84.3mmol) with 3,4- syringol (19.5g, 125.4mmol) tributylphosphine (32.14mL, 97% purity, 25.6g of the mixture in toluene (500mL), 126.4mmol), then handled with 1,1 '-(azo dicarbapentaborane) two piperidines (31.8g, 126.4mmol).After addition is finished, the reactant mixture retrogradation simultaneously makes temperature rise to 15 DEG C.Other toluene (500mL) is added, and the mixture is stirred at room temperature overnight.Tributylphosphine oxide precipitation is filtered to remove, filtrate is concentrated in vacuo, obtains 65.8g crude products.Through silica gel chromatography, with toluene: methanol (98: 2) is eluted, and obtains 17.9g subhead compounds.(b) 4- [1- (3,4- dimethoxy phenoxy group) -4- hydroxybutyls] benzonitrile
By 15 minutes, by borane-dimethyl sulfide (methyl sulfide), (2M is in ether for compound, 11mL, 22mmol) it is added drop-wise to (- 5 DEG C) 4- [1- (3 of cooling, 4- dimethoxys phenoxy group) -3- cyclobutenyls] benzonitrile (17.6g, 56.8mmol, by previous step (a) obtain) anhydrous THF (15mL) solution in (period makes reaction temperature rise to 0C).Gained mixture stirs dichloromethane: methanol (9: 1) is purified by flash, and obtains 0.8g (30%) title compound.13C NMR(CDCl3)：δ 162.18,133.92,119.24,115.34,103.92,69.07,67.86,59.52,58.42,48.18,35.68,30.25,28.81,15.69
Embodiment 297- [4- (4- cyano-phenyls) -4- (3,4- dimethoxys phenoxy group) butyl]-N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 4- [1- (3,4- dimethoxy phenoxy group) -3- cyclobutenyls] benzonitrile
By (0 DEG C) 4- (1- hydroxyl -3- cyclobutenyls) benzonitrile (14.6g of cooling, 84.3mmol) with 3,4- syringol (19.5g, 125.4mmol) tributylphosphine (32.14mL, 97% purity, 25.6g of the mixture in toluene (500mL), 126.4mmol), then handled with 1,1 '-(azo dicarbapentaborane) two piperidines (31.8g, 126.4mmol).After addition is finished, the reactant mixture retrogradation simultaneously makes temperature rise to 15 DEG C.Other toluene (500mL) is added, and the mixture is stirred at room temperature overnight.Tributylphosphine oxide precipitation is filtered to remove, filtrate is concentrated in vacuo, obtains 65.8g crude products.Through silica gel chromatograph, with toluene: methanol (98: 2) is purified by flash, 17.9g subhead compounds are obtained.(b) 4- [1- (3,4- dimethoxy phenoxy group) -4- hydroxybutyls] benzonitrile
By 15 minutes, by borane-dimethyl sulfide compound, (2M is in ether, 11mL, 22mmol) it is added drop-wise to (- 5 DEG C) 4- [1- (3 of cooling, 4- dimethoxys phenoxy group) -3- cyclobutenyls] benzonitrile (17.6g, 56.8mmol, by previous step (a) obtain) anhydrous THF (15mL) solution in (period makes reaction temperature rise to 0 DEG C).After gained mixture is stirred 1.5 hours at 0-10 DEG C, it is set to be warming to room temperature.Continue at such a temperature after stirring 3.5 hours, add water (22mL) and four hydrated sodium perborates (11g, 66mmol).The two-phase mixture was stirred at room temperature after 2 hours, and separate aqueous layer is simultaneously extracted with ether.The organic layer of merging salt water washing, dries and is concentrated in vacuo.Gained residue is through silica gel chromatograph, with isopropanol: ethyl acetate: heptane (5: 25: 70) is purified by flash, and obtains 14.5g (77%) subhead compound.(c) 4- (4- cyano-phenyls) -4- (3,4- dimethoxy phenoxy group) butyl methanesulfonate
By mesyl chloride (3.4mL, 5.0g, DCM (15mL) solution 44mmol) is slowly added to (- 5 DEG C) 4- [1- (3 of cooling, 4- dimethoxys phenoxy group) -4- hydroxybutyls] benzonitrile (11g, 34mmol, by previous step (b) obtain) and triethylamine (7mL, 5.2g, 50.6mmol) in the mixture in DCM (50mL), during addition, temperature is no more than 2 DEG C.Continue at 0-5 DEG C after stirring 2 hours, add water.Separating obtained organic layer, is washed with water, after separating again, dries, obtains the subhead compound of 100% yield.(d) 7- [4- (4- cyano-phenyls) -4- (3,4- dimethoxy phenoxy group) butyl] -3,7- diazabicyclos [3.3.1] nonane -3- carboxylates
By 4- (4- cyano-phenyls) -4- (3,4- dimethoxys phenoxy group) butyl methanesulfonate (522mg, 1.29mmol, by previous step (c) obtain), 3,7- diazabicyclos [3.3.1] nonane -3- carboxylates (307mg, 1.356mmol, referring to above example F) and K2CO3(216mg, 1.56mmol) is in chloroform: acetonitrile (10mL, 1: the mixture in 1) is stirred 23 hours at 70 DEG C.The reactant mixture is filtered, filtrate is concentrated in vacuo, obtains 708mg crude products.The crude product, with toluene: methanol (97: 3~10: 1) gradient elution is purified, obtains 607mg (88%) subhead compound through flash chromatography.(e) 4- [4- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -1- (3,4- dimethoxy phenoxy group)-butyl] benzonitrile
(0 DEG C) 7- [4- (4- cyano-phenyls) -4- (3 of cooling, 4- dimethoxys phenoxy group) butyl] -3,7- diazabicyclos [3.3.1] nonane -3- carboxylates (1.92g, 3.6mmol, is obtained by previous step (d)) ethyl acetate (20mL) solution handled with the ethyl acetate (30mL) of hydrochloric acid saturation.By gained mixture after 0-5 DEG C is stirred 2 hours, it is concentrated in vacuo.Gained residue is dissolved in acetonitrile (50mL) and uses K2CO3The processing of (3.5g, 25.2mmol) and water (2.25mL).The mixture was stirred at room temperature after 3 hours, was filtered to remove solid, and solvent (adding toluene azeotropic to remove water) is then removed in vacuum, 1.5g subhead compounds are obtained.(f) 7- [4- (4- cyano-phenyls) -4- (3,4- dimethoxy phenoxy group) butyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
4- [4- (3,7- diazabicyclos [3.3.1] nonyl- 3- yls) -1- (3,4- dimethoxys phenoxy group) butyl] benzonitrile (109mg, 0.25mmol, by previous step (e) obtain) chloroform (1.43mL) solution ethyl isocyanate (18.6 μ L, 16.8mg, 0.237mmol) MeCN (0.5mL) solution processing.Gained mixture is stirred at room temperature 30 hours.Then the solution is added to Ion Exchange Solid Phase extraction short column (SiO2, 0.5g, purchased from ISOLUTE) on.The short column is washed with chloroform (2.5mL), and (3 × 2.5mL) is then eluted with MeCN.Thus purity is obtained (to determine by HPLC higher than 90%：UV 254nm and ELS detect) title compound (93mg, 73%).MS (ES) m/z=507 (M+1)+, 505 (M-1)-
Embodiment 307- (3- { 4- cyano group -2- [(cyclopropylamino) carbonyl] phenoxy group } -2- hydroxyl-propyls)-N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides (a) 5- cyano group-N- cyclopropyl -2- [2- Oxiranylmethoxies] benzamide
The method described according to example 7 above (b), the subhead compound is prepared with 2- oxiranylmethyl radical 3- nitrobenzene-sulfonic acids ester (prepared by the method for being similar to above example B).(b) 7- benzyls-N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides
DCM (100mL) solution of (0 DEG C) 3- benzyls -3,7- diazabicyclo [3.3.1] nonane (10g, 46mmol, referring to above example E) of cooling is handled with phenyl isocyanate (4.9mL, 45mmol).The mixture is stirred at room temperature 30 minutes.The product of white crystals is formed, 10g (66%) subhead compound is filtrated to get.(c) N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By ethanol (100mL) solution of 7- benzyl-N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides (10g, 29.8mmol, by previous step (b) obtain) 10%Pd/C hydrogenated over night at ambient pressure.Through celite pad Filtration of catalyst, residue is concentrated in vacuo, the subhead compound of quantitative yield is obtained.(d) 7- (3- { 4- cyano group -2- [(cyclopropylamino) carbonyl] phenoxy group } -2- hydroxyl-propyls)-N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 5- cyano group-N- cyclopropyl -2- [2- Oxiranylmethoxies] benzamide (0.8g, 3.1mmol, obtained by previous step (a)) and N- phenyl -3,7- diazabicyclos [3.3.1] nonane -3- formamides (0.9g, 3.6mmol, is obtained by previous step (c)) in isopropanol: H2O (10mL, 9: the mixture in 1) flows back 180 minutes, then adds dichloromethane, and solvent is removed in vacuum.Gained residue is purified by flash through flash chromatography with DCM: MeOH (9: 1), obtains 1g (64%) title compound.13C NMR(CDCl3)：δ 6.33,6.56,23.23,29.18,29.51,31.66,48.27,49.60,53.44,57.94,60.51,65.74,71.28,104.93,113.46,118.45,119.54,119.65,122.88,123.27,128.84,136.07,156.44,159.69,164.53
Embodiment 31N- (4- cyano-phenyls) -7- [3- (ethylsulfonyl) propyl group] -3,7- diazabicyclos [3.3.1] nonane -3- formamides (a) 3- (ethylsulfonyl) propyl group 4- methyl benzoic acid esters
By triethylamine (13.36g; 132mmol) it is added drop-wise to 3- (ethylsulfonyl) -1- propyl alcohol (13.4g; 88mmol; Martin-Smith etc.; J.Pharm.Pharmacol., 19, (1967) 649) and paratoluensulfonyl chloride (16.78g; 88mmol) in the mixture in DCM (150mL), slight exothermic reaction is produced.After addition is finished, the reactant mixture is washed twice with aqueous ammonium chloride solution, then separates organic layer, is dried and is concentrated in vacuo.Gained residue is recrystallized in ether/DCM, obtains 17.9g (65%) subhead compound.(b) 7- [(4- cyanophenylaminos) carbonyl] -3,7- diazabicyclos [3.3.1] nonane -3- carboxylates
Suspension of 3,7- diazabicyclos [3.3.1] nonane -3- carboxylates (2.0g, 8.8mmol, referring to above example F) in chloroform (15mL) is handled with 4- isocyanate groups benzonitrile (1.53g, 10.6mmol).The mixture is stirred at room temperature 1.5 hours, and some solid particles are during which observed in the mixture.For dissolved particles, 10mL chloroforms are added.The mass spectral analysis of the mixture shows that raw material has been depleted, and solvent is then removed in vacuum.Gained residue is purified through flash chromatography with DCM: MeCN (5: 1~2: 1) gradient elution, obtains 2.31g (71%) subhead compound.(c) N- (4- cyano-phenyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides
(0 DEG C) 7- [(4- cyanophenylaminos) carbonyl] -3 of cooling, ethyl acetate (40mL) solution of 7- diazabicyclos [3.3.1] nonane -3- carboxylates (2.2g 5.94mmol are obtained by previous step (b)) is handled 30 minutes with the ethyl acetate (65mL) of hydrochloric acid saturation.By gained mixture after room temperature is stirred for 4 hours, it is concentrated in vacuo, obtains the hydrochloride of 1.8g (99%) subhead compound.(d) N- (4- cyano-phenyls) -7- [3- (ethylsulfonyl) propyl group] -3,7- diazabicyclos [3.3.1] nonane -3- formamides
N- (4- cyano-phenyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides (67.6mg, 0.25mmol are obtained by previous step (c)) and K2CO3(80mg; 0.57mmol) 3- (ethylsulfonyl) propyl group 4- toluene sulfonic acide esters (153mg of the mixture in DMF (0.5mL); 0.50mmol, by previous step (a) obtain) MeCN (1.0mL) solution handle.Gained suspension is cooled down and filtered after 50 DEG C are stirred 5 days.Then filtrate is added to Ion Exchange Solid Phase extraction short column (CBA, 2g, purchased from ISOLUTE).After 1 hour, short column uses CHCl with chloroform (3 × 2.5mL)3∶MeOH∶Et3N (8: 1: 1) eluted product, obtains purity and (is determined higher than 90% by HPLC：UV 254nm and ELS detect) title compound (63.6mg, 63%).MS(ES)：M/z=405 (M+1)+, m/z=403 (M-1)-
Embodiment 327- { 3- [(2- cyano-1 H-indol -4- bases) epoxide] -2- hydroxypropyls }-N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 4- (2- Oxiranylmethoxies) -1H- indoles -2- nitriles (1.0g, 4.7mmol, Pitha etc., J.Med.Chem., 30 (1987) 612) and N- phenyl -3,7 diazabicyclos [3.3.1] nonane -3- formamides (1.4g, 5.5mmol, referring to example 3 above 0 (d)) are in isopropanol：H2(10mL, 9: the mixture in 1) was stirred after 3 hours under reflux are concentrated in vacuo O.Gained residue is purified through silica gel column chromatography with DCM: MeOH (99: 1~97: 3) gradient elution, obtains 0.8g (37%) title compound.13C NMR(CDCl3)：δ 29.03,29.39,31.27,48.37,49.31,57.89,60.42,61.41,66.07,70.04,100.72,104.39,105.13,111.31,114.95,117.66,120.18,120.30,123.00,126.54,128.84,138.39,139.16,152.55,156.29 embodiment 337- [(7- cyano group -2,3- dihydros-Isosorbide-5-Nitrae-Ben Bing bioxin -2- bases) methyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides (a) 5- bromo- 2- (3- chlorine-2-hydroxyls propoxyl group) benzaldehyde
The mixture of the bromo- Benzaldehyde,2-hydroxies of 5- (20.1g, 0.1mol), epoxychloropropane (25mL, 0.32mol) and 6 drop piperidines was stirred after 6 hours under reflux, is concentrated in vacuo.Gained residue is dissolved in dichloromethane (25mL) and handled with concentrated hydrochloric acid HCl (10mL).The gained mixture was stirred at room temperature after 3 hours, and organic layer is washed with water, separation, is dried and is concentrated in vacuo, obtains 28.2g (96%) the subhead compounds.The compound can be directly used for the next step without any purifying.(b) the bromo- 2- of 5- (3- chlorine-2-hydroxyls propoxyl group) phenyl formic acid esters
The bromo- 2- of 5- (3- chlorine-2-hydroxyls propoxyl group) benzaldehyde (28.2g, 96mmol, by previous step (a) obtain) DCM (200mol) solution with 3- chlorine benzylhydroperoxide (25g, 70-75% purity, about 100mmol) handle.Resulting exothermic reaction makes the mixture flow back 20 minutes.Continue after stirring 3 days, filter the mixture (to remove the 3- chlorobenzoic acids of precipitation).Filtrate solution of potassium carbonate and water washing, dry and are concentrated in vacuo, obtain 26.1g subhead compounds.The compound can be used to the next step without any purifying.(c) (bromo- 2, the 3- dihydros of 7--Isosorbide-5-Nitrae-Ben Bing bioxin -2- bases) methanol
The bromo- 2- of 5- (3- chlorine-2-hydroxyls propoxyl group) phenyl formic acid esters (26.1g, 84mmol, by previous step (b) obtain) ethanol (100mL) solution potassium hydroxide (6.1g, 85% purity, about 92mmol) water (10mL) solution processing.After gained mixture flows back 1.5 hours, filter and be concentrated in vacuo.Gained residue is dissolved in ethyl acetate and salt water washing is used.Organic layer is separated, dries and is concentrated in vacuo, obtain 28.8g crude products.The crude on silica gel column chromatography, with ether: hexane (70: 30) is purified by flash, obtains 10.0g (49.1%) subhead compound.(d) 3- (hydroxymethyl) -2,3- dihydros-Isosorbide-5-Nitrae-Ben Bing bioxin -6- nitriles
By (7- bromo- 2,3- dihydros -1,4- Ben Bing bioxin (dioxin) -2- bases) methanol (10.0g, 41.2mmol, obtained by previous step (c)) and CuCN (4.0g, 45.3mmol) mixture in DMF (10mL, through molecular sieve drying) is stirred 4.5 hours at 170 DEG C.The reactant mixture falls in the sodium cyanide solution of warm to (8.10g, 165mmol NaCN are dissolved in 25mL H2O in).Gained mixture toluene and DCM extractions.The organic layer of merging is washed with water, and then uses salt water washing, dries and is concentrated in vacuo.Gained residue is crystallized in toluene and DCM, obtain 2.8g (35%) subhead compound.(e) (7- cyano group -2,3- dihydro-Isosorbide-5-Nitrae-Ben Bing bioxin -2- bases) methylmethanesulfonate ester
By mesyl chloride (1.81g, dichloromethane (5mL) solution 15.8mmol) is added drop-wise to (0 DEG C) 3- (hydroxymethyl) -2 of cooling, 3- dihydros -1,4- Ben Bing bioxin -6- nitriles (2.75g, 14.4mmol, obtained by previous step (d)) and mixture of the pyridine (1.26g, 16mmol) in DCM (25mL) in.After addition is finished, the mixture is stirred 1 hour at 0 DEG C, is then stirred at room temperature overnight.TLC analysis shows are now reacted not completely, then add other mesyl chloride (0.4g, 3.5mmol) and pyridine (0.5mL, 0.49g, 6.2mmol).After the mixture is flowed back 3.5 hours, washed twice with saturated sodium bicarbonate solution, dry and be concentrated in vacuo.The crude product (4.5g) so obtained is purified by flash through flash chromatography with DCM, and 3.5g subhead compounds are obtained after placed crystallization.(f) 7- [(7- cyano group -2,3- dihydro-Isosorbide-5-Nitrae-benzodioxan -2- bases) methyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By (7- cyano group -2,3- dihydros -1,4- Ben Bing bioxin -2- bases) methylmethanesulfonate ester (150mg, 0.9mmol, by previous step (e) obtain), N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (186mg, 0.94mmol, referring to example 6 above (b)), K2CO3(265mg, 2.0mmol) and NaI (14mg, 0.09mmol) are in CH3Mixture in CN flows back 20 hours.Solvent, gained residue DCM and water process is removed in vacuum.Organic layer is separated, (Na is dried2SO4) and be concentrated in vacuo.Gained residue is purified by flash through flash chromatography with DCM: MeOH (95: 5), obtains 113.2mg (34%) title compound.13C NMR(CDCl3)：δ 15.61,29.19,30.72,35.72,47.78,58.34,59.02,60.64,67.01,71.38,71.49,71.60,104.10,120.76,120.89,125.39,125.79,143.50,147.80,157.46
Embodiment 347- { [(2S) -6- cyano group -4- (mesyl) -3; 4- dihydros -2H-1; 4- benzoxazine -2- bases] methyl]-N- ethyls -3; 7- diazabicyclos [3.3.1] nonane -3- formamides (a) (2R) -2- (hydroxymethyl) -3; 4- dihydros -2H-1,4- benzoxazine -6- nitriles
The mixture of 3- amino-4-hydroxies benzonitrile (25g, 0.186mol) and S- epoxychloropropane (10.7g, 0.22mol) in ethanol water (500mL, 99%) is stirred 24 hours in 60 DEG C.After the mixture is concentrated in vacuo, ethanol (500mL) is added, K is then added2CO3(27g, 0.195mol).After gained mixture flows back 1 hour, filtering.After filter vacuum is concentrated, the grease of 61g black is obtained.The grease is diluted with water (500mL), is then extracted twice with DCM and ethyl acetate.The organic extract liquid of merging obtains the subhead compound of 20g (57%) yellow crystal through drying and being concentrated in vacuo.(b) (2R) -6- cyano group -4- (mesyl) -3,4- dihydros -2H-1,4- benzoxazine -2- bases] methylmethanesulfonate ester
By mesyl chloride (45g, 0.395mol) it is added drop-wise to (0 DEG C) (the 2R) -2- (hydroxymethyl) -3 of cooling, 4- dihydros -2H-1,4- benzoxazine -6- nitriles (30g, 0.158mol, obtained by previous step (a)) and the mixture of pyridine (200mL, excess) in.After the mixture is stirred at room temperature overnight, it is concentrated in vacuo.Gained residue water process, and it is separated by filtration crystallized product.The crystallized product is recrystallized in acetonitrile, obtain 29g pure substances.Its mother liquor is concentrated in vacuo, residue is obtained, it is crystallized in chloroform, another batch of (7.5g) product is obtained.The total recovery of the subhead compound is 36.5g (67%).(c) 7- { [(2S) -6- cyano group -4- (mesyl) -3,4- dihydros -2H-1,4- benzoxazine -2- bases] methyl }-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
(2R) -6- cyano group -4- (mesyl) -3; 4- dihydros -2H-1; 4- benzoxazine -2- bases] methylmethanesulfonate ester (1g; 2.89mmol; by previous step (b) obtain) MeCN (5mL) solution triethylamine (8mL; 5.8g; 57.4mmol) processing; then N- ethyls -3 are used; 7- diazabicyclos [3.3.1] nonane -3- formamides (0.85g; 4.33mmol, referring to example 6 above (b)) processing.Gained mixture is stirred at room temperature overnight after 70 DEG C are stirred 5 hours.After the mixture is concentrated in vacuo, acid/base abstraction purification is used, then through flash chromatography, is purified by flash with DCM: MeOH, 100mg (14%) title compound is obtained.13C NMR(CDCl3)：δ 15.63,28.87,29.09,30.48,35.73,39.50,45.96,47.65,48.11,59.03,59.19,60.59,73.40,104.15,118.72,119.90,124.92,126.51,128.92,150.04,157.74
Embodiment 357- [2- ({ 2- [4; 5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls] acetyl group } amino) ethyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides (a) 4- [(E) -1- (4- cyanobenzoyls) -2- (dimethylamino) vinyl] benzonitrile
Under an inert atmosphere; by N; dinethylformamide dimethyl acetal (135.2g; 0.29mol) it is added drop-wise to (60 DEG C) 4- [2- (4- cyano-phenyls) acetyl group] benzonitrile (60.2g of heating; 0.24mol, Ashley etc., J.Chem.Soc. (1942) 103; 110) in 1,2- dimethoxyethane solutions.Then filter gained mixture and be concentrated in vacuo, obtain residue, it is crystallized in MeOH.Obtain 27.9g (38%) subhead compound.(b) 2- [4.5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls] ethyl acetate
4- [(E) -1- (4- cyanobenzoyls) -2- (dimethylamino) vinyl] benzonitrile (6.2g; 20mmol by previous step (a) obtain) ethanol water (100mL; 99%) with 2- diazanyl ethyl acetate hydrochlorides (3.5g, 22.6mmol) processing.After the mixture is stirred at room temperature overnight, it is concentrated in vacuo.After gained residue diluted with water, the aqueous mixture is extracted with DCM.Then organic layer is separated, dries and is concentrated in vacuo, obtain residue, it is recrystallized in ether, obtain 1.7g (23.5%) subhead compound.(c) 2- [4,5- bis- (4- cyano-phenyls) -1- pyrazol-1-yls]-N- (2- hydroxyethyls)-acetamide
By 2- [4,5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls] ethyl acetate (3.9g, 10.9mmol, by previous step (b) obtain), 2- amino -1- ethanol (1.3g, 2l.8mmol) mixture (0.8g, 76mmol) with triethylamine is stirred overnight at 100 DEG C.Water and DCM are added, the product of crystallization is separated by filtration, obtains 3.53g subhead compounds.(d) 2- [4,5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls]-N- (2- bromoethyls)-acetamide
By 2- [4,5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls]-N- (2- hydroxyethyls) acetamide (0.7g, 1.88mmol, by previous step (c) obtain), N- bromine succinimides (0.75g, 5.64mmol) stirred under reflux 3 hours with mixture of the triphenylphosphine (2.22g, 8.4mmol) in DCM (100mL).Make after reactant mixture cooling, be washed with water.Organic layer is separated, dries and is concentrated in vacuo, obtain residue, by it by flash chromatography, with ether: methanol (95: 5) is purified by flash, obtain the subhead compound that 0.7g is mixed with triphenylphosphine oxide.The product can be directly used for the next step without purifying.(e) 7- [2- ({ 2- [4,5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls] acetyl group } amino) ethyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides
By 2- [4,5- bis- (4- cyano-phenyls) -1H- pyrazol-1-yls]-N- (2- bromoethyls) acetamide (0.7g, 1.6mmol, by previous step (d) obtain), N- ethyls -3,7- diazabicyclos [3.3.1] nonane -3- formamides (0.32g, 1.6mmol, referring to example 6 above (b)) and K2CO3The mixture of (0.55g, 4mmol) in acetonitrile (15mL) is stirred overnight under reflux.Extracted with ether and water, isolated organic layer is dried and is concentrated in vacuo.Gained residue is purified by flash with ether: MeOH (95: 5) through silica gel chromatograph, obtains 0.27g title compounds.13C NMR(CDCl3)：δ 15.77,29.18,32.37,36.13,48.72,52.27,56.32,109.83,113.13,118.27,118.93,120.10,127.80,131.39,132.46,132.73,134.62,138.75,159.14,167.09
Embodiment 36
Using similar to methods described herein, being also prepared for following compounds (all these compounds are all the title compounds of embodiment 36)：7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- propyl group -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [2- (4- cyano-benzene oxygens) ethyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- tetrahydrochysenes -2H- pyrans -2- bases -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- (4- cyano group phenethyl)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N, N- dimethyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate；7- (3- (4- cyano-benzene oxygens) -2- { [(ethylamino) carbonyl] amino } propyl group)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- (3- (4- cyano-benzene oxygens) -2- { [(ethylamino) carbonyl] amino } propyl group)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- (3- (4- cyano-benzene oxygens) -2- { [(dimethylamino) carbonyl] amino } propyl group)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylidene dicarbamate；7- [2- (acetyl-amino) -3- (4- cyano-benzene oxygens) propyl group]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [3- (2,4- dicyanobenzenes epoxide) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；(1S) -2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate；7- [(2S) -2- [(amino carbonyl) amino] -3- (4- cyano-benzene oxygens) propyl group]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；(1R) -2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate；N- acetyl group -7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- acetyl group -7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- methyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- methyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano group -2- { [(2- cyano ethyls) amino] carbonyl } phenoxy group) -2- hydroxypropyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；(1R) -2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylidene dicarbamate；7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- propyl group -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- propyl group -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- ((2S) -3- 4- cyano group -2- [(methylamino) carbonyl] phenoxy group] and -2- hydroxypropyls)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- propionos -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- propionos -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [2- (4- cyano-phenyls) -2- hydroxyethyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2-propynyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- (4- cyano group phenethyl)-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；N- ethyls -7- [(2S) -2- hydroxyls -3- (4-nitrophenoxy) propyl group] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；(1S) -2- (4- cyano-benzene oxygens) -1- ({ 7- [(ethylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylidene dicarbamate；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (Cvclopropvlmethvl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (4- nitrobenzophenones) -7- (4- oxos heptyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2-propynyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- (3- { 4- cyano group -2- [(cyclopropylamino) carbonyl] phenoxy group } -2- hydroxypropyls)-N- propionos -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- phenyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [(2R) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (Cvclopropvlmethvl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；(1R) -2- (4- cyano-benzene oxygens) -1- ({ 7- [(propanoylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate；7- (3- { 4- cyano group -2- [(isopropylamino) carbonyl] phenoxy group } -2- hydroxypropyls)-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；2- (4- cyano-benzene oxygens) -1- ({ 7- [(propanoylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate；2- (4- cyano-benzene oxygens) -1- ({ 7- [(isopropylamino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethyl (methyl) carbamate；7- [3- (4- cyano-benzene oxygens) -2- (methylamino) propyl group]-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- { 3- (4- cyano-benzene oxygens) -2- [methyl (methyl sulphonyl) amino] propyl group }-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；N- (tert-butyl group) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [2- amino -3- (4- cyano-benzene oxygens) propyl group] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；2- [7- (amino carbonyl) -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] -1- [(4- cyano-benzene oxygens) methyl] ethylcarbamate；2- (4- cyano-benzene oxygens) -1- ({ 7- [(tetrahydrochysene -2H- pyrans -2- bases amino) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } methyl) ethylcarbamate；N- (4- cyano-phenyls) -7- (4- oxos heptyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2,2- Dimethylpropanoyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (tert-butoxy) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；2- [7- (amino carbonyl) -3,7- diazabicyclos [3.3.1] nonyl- 3- yls] -1- [(4- cyano group -2- methylphenoxies) methyl] ethyl tert-butyl carbamate；7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- isopropyls-N- methyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；N- (4- cyano group phenethyl) -7- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；N- (tert-butoxy) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- methyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；N- (4- cyano group phenethyl) -7- (3,4- Dimethoxyphenethyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- cyclopropyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [2- amino -3- (4- cyano-benzene oxygens) propyl group]-N- (tert-butyl group) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- [3- (4- cyano-benzene oxygens) propyl group] -7- [5- (ethylamino) -5- oxopentyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3,5- dimethyl -4- isoxazolyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyanophenylaminos) propyl group]-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [4- (4- cyano-phenyls) -4- hydroxybutyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；{ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonylamino Ethyl formate；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2,6- Dimethoxyphenyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (4- cyano-phenyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- benzyls -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- hexyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；3- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] ethyl propionate；N- (4- butoxy phenyls) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3- cyano-phenyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3,4- Dimethoxyphenyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；2- [({ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonyl) amino] butyl acetate；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (4- methoxyphenyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3,4- Dimethoxyphenethyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3,4- dimethoxy-benzyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3,4,5- trimethoxyphenyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (3,4- dihydros -2H-1,5- benzos dioxepine (benzodioxepin) -7- bases) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2,6- 3,5-dimethylphenyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；{ 7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } carbonylamino isopropyl formate；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- (2- fluoro ethyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- { 2- [(Cvclopropvlmethvl) amino] -2- oxoethyls } -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (tert-butyl group) -7- { 2- hydroxyls -3- [(2- methyl isophthalic acids-oxo -1,2- dihydro -4- isoquinolyls) epoxide] propyl group } -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (1- cyano group -1- Methylethyls) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [2- amino -3- (4- cyano-benzene oxygens) propyl group]-N- (1,3- benzodioxole -5- ylmethyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- isopropyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；4- (3- { 7- [(2,6- dimethyl -4- morpholinyls) carbonyl] -3,7- diazabicyclos [3.3.1] nonyl- 3- yls } -2- hydroxy propyloxy groups) benzonitrile；N- [cyano group (4- fluorophenyls) methyl] -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (cyano methyl) -7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- methyl -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [4- (4- cyano-benzene oxygens) -2- hydroxybutyls]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [4- (4- cyano-phenyls) butyl]-N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [4- (4- cyano-phenyls) butyl]-N- propyl group -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [2- amino -4- (4- cyano-benzene oxygens) butyl]-N- propyl group -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [4- (4- cyano-phenyls) butyl]-N- ethyls -3,7- diazabicyclo [3.3.1] nonane -3- formamides；7- [3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [2- (2- methoxy ethoxies) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (4- cyano-phenyls) -7- (3,3- dimethyl -2- oxos butyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (4- cyano-phenyls) -7- (3,4- Dimethoxyphenethyl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (4- cyano-phenyls) -7- (Cvclopropvlmethvl) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (4- cyano-phenyls) -7- [2- (2- methoxy ethoxies) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；N- (4- cyano-phenyls) -7- [2- (2,3- dihydros-Isosorbide-5-Nitrae-Ben Bing bioxin -6- bases) -2- oxoethyls] -3,7- diazabicyclos [3.3.1] nonane -3- formamides；7- [3- (4- acetyl group -1- piperazinyls) propyl group]-N- (4- cyano-phenyls) -3,7- diazabicyclos [3.3.1] nonane -3- formamides；With 7- [(2S) -3- (4- cyano-benzene oxygens) -2- hydroxypropyls]-N- [2- oxos -2- (propylcarbamic) ethyl] -3,7- diazabicyclos [3.3.1] nonane -3- formamides.
Embodiment 37 tests the title compound of above-described embodiment in experiment A, measures their D10Value is more than 6.0.Abbreviation AcOH=acetic acid ADDP=1, atm.=atmospheric pressure CBz=benzyloxycarbonyl CDI=carbonyl dimidazoles Bu=butyl DCM=dichloromethane DMF=dimethylformamide DMSO=dimethyl sulfoxide Et=ethyl EtOAc=ethyl acetate EtOH=ethanol ESI=electronic sprayings interface h=hours IPA=isopropanol i-PrOH=isopropanol LC=liquid chromatogram HPLC=high performance liquid chromatography mCPBA=metachloroperbenzoic acid Me=methyl MeCN=acetonitrile MeOH=methanol min.=minutes Ms=methanesulfonates (salt) MS=mass spectrum NADPH=nicotinamide-adenine dinucleotide phosphates of mesyl=mesyls of eq.=equivalents FAB=fast atom bombardments aqueous 1 '-(azo dicarbapentaborane) two piperidines aq.=, the TEA=triethylamine THF=tetrahydrofuran tlc=thin-layer chromatography TMS=tetramethylsilane prefixes n- of reduction form NMR=nuclear magnetic resonance OSu=O- succinyl groups Pd/C=palladiums/carbon pTSA=p-methyl benzenesulfonic acid rt.=room temperature satd.=saturations, s-, i-, iso-, t- and tert- have usual implication：Just, it is different, secondary and tertiary.

Claims (37)

1. compound of formula I or its pharmaceutical usable derivatives,
Figure A0081169600021
Wherein R1And R2Independently represent H, C1-4Alkyl, OR2bOr N (R2c)R2d, or formation-O- (CH together2)2-O-、-(CH2)3-、-(CH2)4- or-(CH2)5-；R2b、R2cAnd R2dIndependently represent H or C1-6Alkyl；R3Represent H, C1-6Alkyl or and R4C is represented together3-6(alkylidene is optionally interrupted and/or optionally by one or more C alkylidene by O atom1-3Alkyl replaces)；R4Represent H, C1-12Alkyl, C1-6(latter two group is optionally replaced and/or terminated selected from following substituent by one or more alkoxy：- OH, halogen, cyano group, nitro, C1-4Alkyl and/or C1-4Alkoxy) ,-(CH2)q- aryl ,-(CH2)q- oxygen aryl ,-(CH2)q-Het1(rear three groups are optionally (in-(CH2)q- part and/or aryl/Het1Part) replaced by one or more selected from following substituent：- OH, halogen, cyano group, nitro ,-C (O) R10、-C(O)OR11、-N(H)S(O)2R11a、C1-6Alkyl and/or C1-6Alkoxy) ,-(CH2)qN(H)C(O)R8、-(CH2)qS(O)2R8、-(CH2)qC(O)R8、(CH2)qC(O)OR8、-(CH2)qC(O)N(R9)R8, or and R3C is represented together3-6(alkylidene is optionally interrupted and/or by one or more C alkylidene by O atom1-3Alkyl replaces)；Q represents 0,1,2,3,4,5 or 6；R8Represent H, C1-6(latter group is optionally replaced and/or terminated selected from following substituent by one or more for alkyl, aryl：- OH, halogen, cyano group, nitro ,-C (O) R10、-C(O)OR11、-N(H)S(O)2R11a、C1-6Alkyl and/or C1-6Alkoxy), or and R9C is represented together3-7Alkylidene；R9Represent H, C1-4Alkyl or and R8C is represented together3-7Alkylidene；Het1Represent to contain one or more 5-12 circle heterocycles selected from oxygen, nitrogen and/or sulphur, the heterocycle also optionally includes one or more=O substituents；R41、R42、R43、R44、R45Or R46Independently represent H or C1-3Alkyl；R5Represent H, halogen, C1-3Alkyl ,-OR12、-N(R13)R12, or and R6Expression=O together；R6Represent H, C1-4Alkyl or and R5Expression=O together；R12Represent H, C1-6Alkyl ,-S (O)2-C1-4- alkyl ,-C (O) R14、-C(O)OR14、-C(O)N(R15)R15aOr (latter group is optionally replaced and/or terminated selected from following substituent by one or more aryl：- OH, halogen, cyano group, nitro ,-C (O) R10、-C(O)OR11、-N(H)S(O)2R11a、C1-6Alkyl and/or C1-6Alkoxy)；R13Represent H or C1-4Alkyl；R14Represent H or C1-6Alkyl；R15And R15aIndependently represent H or C1-4Alkyl, or C is represented together3-6Alkylidene, the alkylidene is optionally interrupted by O atom；A represents singly-bound, a C1-6Alkylidene ,-N (R16)(CH2)r- or-O (CH2)r- (in latter two group ,-(CH2)r- base is connected with bridging the nitrogen-atoms of bipiperidine)；B represents singly-bound, a C1-4Alkylidene ,-(CH2)nN(R17)-、-(CH2)nS(O)p-、-(CH2)nO- (in rear three groups ,-(CH2)n- base is with carrying R5And R6Carbon atom be connected) ,-C (O) N (R17In)-(latter group ,-C (O)-base is with carrying R5And R6Carbon atom be connected) ,-N (R17)C(O)O(CH2)n-、-N(R17)(CH2)n- (in latter two group, N (R17) base with R5And R6Carbon atom be connected) or-(CH2)mC(H)(OH)(CH2)n- (in latter group ,-(CH2)m- base is with carrying R5And R6Carbon atom be connected)；M represents 1,2 or 3；N and r independently represent 0,1,2,3 or 4；P represents 0,1 or 2；R16And R17Independently represent H or C1-4Alkyl；R7Represent C1-6Alkyl, aryl or Het2, all these groups optionally replace and/or are terminated (if appropriate) selected from following substituent by one or more：- OH, cyano group, halogen, amino, nitro, Het3、-C(O)R10、-C(O)OR11、C1-6Alkyl, C1-6Alkoxy ,-N (H) S (O)2R18、-S(O)2R19、-OS(O)2R20、-N(H)C(O)N(H)R21、-C(O)N(H)R22And/or aryl (latter group is optionally replaced by one or more cyano group)；Het2And Het3Independently represent to contain one or more heteroatomic 5-12 circle heterocycles selected from oxygen, nitrogen and/or sulphur, and they optionally include one or more=O substituents；R18、R19And R20Independently represent C1-6Alkyl；R21And R22Independently represent independently to represent H or C1-6Alkyl (is optionally terminated) by cyano group；And in all cases, R10And R11Independently represent H or C1-6Alkyl.In all cases, R11aRepresent C1-6Alkyl；Condition is：(a) when A and B are singly-bound and R7When being optionally substituted aryl, R5And R6Not all it is H；(b) when A represents a singly-bound, R5And R6Expression=O not together；Work as R (c)5Expression-OR12Or-N (R13)R12When, then：(i) A does not indicate that-N (R16)(CH2)r- or-O (CH2)r-；And/or (ii) represents-(CH as B2)nN(R17)-、-(CH2)nS(O)p- or-(CH2)nDuring O-, n not tables
Show 0.
2. the compound of claim 1, wherein R1Represent H.
3. the compound of claim 1 or 2, wherein R2Represent H.
4. the compound of any one of preceding claims, wherein R3Represent H, C1-2Alkyl；Or and R4C is represented together4-5Alkylidene, the alkylidene is optionally interrupted and/or is optionally replaced by one or more methyl by O atom.
5. the compound of claim 4, wherein R3Represent H.
6. the compound of any one of preceding claims, wherein R4Represent H；Straight or branched and/or saturated or unsaturated and/or ring-type, acyclic and/or part cyclic/acyclic C1-8Alkyl (alkyl is optionally replaced and/or by O atom interval by one or more cyano group or halogen group)；C1-6Alkoxy；-(CH2)qS(O)2R8、-(CH2)qC(O)OR8、-(CH2)qN(H)C(O)R8、-(CH2)qC(O)R8(in rear four groups, q represents 0,1 or 2 and R8Represent straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-4Alkyl, or (phenyl is optionally by one or more cyano group and/or C for phenyl1-3Alkyl replaces))；-(CH2)qC(O)N(R9)R5(in latter group, q represents 0,1 or 2 and R8And R9Independently represent H, straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-4Alkyl, or C is represented together4-6Alkylidene)；-(CH2)q- phenyl ,-(CH2)q- phenyl or-(CH2)q-Het1(in rear three groups, q represents 0,1,2 or 3 ,-(CH2)q- part is optionally replaced by cyano group, and phenyl or Het1Part is optionally replaced by one or more selected from following substituent：Cyano group, nitro, the C of straight or branched1-4The C of alkyl, straight or branched1-4Alkoxy and N (H) S (O)2R11a)；Or and R3C is represented together4-5Alkylidene, the group replaces optionally by O atom interval and/or optionally by one or more methyl.
7. the compound of any one of preceding claims, wherein R5Represent H；Fluorine；OR12(wherein R12Represent H, phenyl (optionally by one or more methoxy substitutions) or C (O) N (H) R15a(wherein R15aRepresent the C of straight or branched1-4Alkyl))；-N(R13)(R12) (wherein R12Represent H, C1-2Alkyl ,-S (O)2-C1-2Alkyl ,-C (O) R14(wherein R14Represent C1-2Alkyl) ,-C (OOR14(wherein R14Represent the C of straight or branched1-5Alkyl) or-C (O) N (R15)(R15a) (wherein R15And R15aIndependently represent the C of H or straight or branched1-3Alkyl represents C together4-5Alkylidene, the alkylidene is optionally by O atom interval) and R13Represent H or C1-2Alkyl)；Or and R6Together, expression=O.
8. the compound of claim 7, wherein R5Represent H, OH or-N (H) C (O) N (R15)(R15a)。
9. the compound of any one of preceding claims, wherein R6Represent H or C1-2Alkyl or and R5Expression=O together.
10. the compound of claim 9, wherein R6Represent H.
11. the compound of any one of preceding claims, wherein A represent a singly-bound, the C of straight or branched1-4Alkylidene (group is also optionally by O intervals) ,-N (H) (CH2)r- or-O (CH2)r- (in latter two group, r is 1 or 2).
12. the compound of claim 11, wherein A represent-CH2- or-(CH2)2-。
13. the compound of any one of preceding claims, wherein B represent singly-bound, a C1-4Alkylidene ,-(CH2)nO-、-(CH2)nS(O)2-、-(CH2)nN (H)-or-N (H) (CH2)n- (in the case of latter four kinds, n is 0,1,2 or 3).
14. the compound of claim 13, wherein B represent singly-bound ,-a CH2N (H)-or-CH2O-。
15. the compound of any one of preceding claims, wherein R7Represent straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-6Alkyl (is optionally replaced and/or terminated by OH)；Het2(optionally replaced by one or more selected from following substituent：Cyano group, C1-3Alkyl, phenyl (latter group is optionally replaced by one or more cyano group) ,=O, C (O) R10(wherein R10It is the C of straight or branched1-3Alkyl) or S (O)2R19(wherein R19It is C1-2Alkyl))；Or phenyl (is optionally replaced by one or more selected from following substituent：Cyano group, nitro, the C of straight or branched1-3The C of alkyl, straight or branched1-3Alkoxy, fluorine, chlorine, C (O) N (H) R22(wherein R22Represent straight or branched and/or acyclic, ring-type and/or part cyclic/acyclic C1-4Alkyl, the alkyl is optionally terminated by cyano group), N (H) S (O)2R18(wherein R18Represent C1-2Alkyl) or Het3)。
16. the compound of claim 15, wherein R7Represent phenyl (by cyano group (preferably relative to 4 of B) and one or more optional C (O) N (H) R22Substituent replaces).
17. the compound of any one of preceding claims, wherein R41、R42、R43、R44、R45And R46All represent H.
18. a kind of pharmaceutical preparation, including such as the compound and pharmaceutically acceptable assistant agent, diluent or carrier of any one of claim 1-17 definition.
19. a kind of pharmaceutical preparation for being used to preventing or treating arrhythmia cordis, the compound defined containing such as any one of 1-17.
20. as the medicine compound that such as any one of claim 1-17 is defined.
21. for prevent or treat arrhythmia cordis as any one of claim 1-17 define compound.
22. preparing the purposes in being used to prevent or treat the medicine of arrhythmia cordis as the compound as any one of claim 1-17 is defined of active component.
23. the purposes of claim 22, arrhythmia cordis therein is room or ventricular arrhythmia.
24. a kind of prevention or the method for treating arrhythmia cordis, this method are included to the individual administration therapeutically effective amount for suffering from or being susceptible to suffer from such a disease disease such as the compound of any one of claim 1-17 definition.
25. a kind of prepare such as the method for compound of formula I defined in claim 1, including：(a) for wherein R3It is H compound of formula I：By Formula II compound,
Figure A0081169600061
Wherein R1、R2、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1, reacted with formula III compound,
         R4- N=C=O III wherein R4As defined in claim 1；(b) carbonic acid derivative of Formula II compound as defined above and formula IV is reacted,
        (R3)(R4)NC(O)-L1IV wherein L1Represent leaving group and R3And R4As defined in claim 1；(c) by Formula V compound,Wherein L1As defined above and R1、R2、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1, reacted with Formula V A compounds,
        (R3)(R4) NH VA wherein R3And R4As defined in claim 1；(d) CH is represented for wherein A2And R5Expression-OH or-N (H) R12Compound of formula I：By Formula IV compound,Wherein R1、R2、R3、R4、R41、R42、R43、R44、R45And R46As defined in claim 1, reacted with Formula VII compound,
Figure A0081169600082
Wherein X represents O or N (R12) and R6、R7、R12With B as defined in claim 1；(e) Formula IV compound as defined above and Formula VIII compound are reacted,Wherein L2Represent leaving group and R5、R6、R7, A and B as defined in claim 1；(f) for wherein R5Represent H or OH and R6Represent H compound of formula I：Reduction-type IX compounds,
Figure A0081169600091
Wherein R1、R2、R3、R4、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1；(g) for wherein R1And R2In one expression H or OH, another represent H compound of formula I：Corresponding Formula X compound is reduced,
Figure A0081169600092
Wherein R3、R4、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1；(h) for wherein R1And R2Expression-O (CH together2)2O- compound of formula I：Corresponding Formula X compound it will be reacted as defined above with ethane -1,2- glycol；(i) it is-(CH for wherein B2)nO- compound of formula I：By Formula X I,
Figure A0081169600101
Wherein R1、R2、R3、R4、R5、R6、R41、R42、R43、R44、R45、R46, A and n as defined in claim 1, with wherein R7Formula X IA compounds are reacted as defined in claim 1,
              R7OH                 XIA；(j) for the compound of formula I for the N- oxide forms for bridging bipiperidine-nitrogen：Aoxidize the corresponding bridge joint bipiperidine nitrogen-atoms of corresponding compound of formula I；(k) to then C1-4The compound of formula I of alkyl quaternary ammonium salts derivative form (wherein the alkyl is connected with bridge joint bipiperidine nitrogen-atoms)：Make corresponding compound of formula I, bridge and reacted in bipiperidine nitrogen original with Formula X II compounds at it,
              RbL3XII wherein RbRepresent C1-4Alkyl and L3It is leaving group；(l) for wherein R5And R6Represent that H, A represent C1-6Alkylidene and B represents N (R17)(CH2)n- compound of formula I：By Formula X III compounds,Wherein AaRepresent C1-6Alkylidene and R1、R2、R3、R4、R41、R42、R43、R44、R45、R46And R47As defined in claim 1, reacted with Formula X IV compounds,
            R7-(CH2)n-L2XIV wherein L2It is as defined above and R7With n as defined in claim 1；(m) for wherein R5Expression-NH2Compound of formula I：Corresponding Formula X V compounds are reduced,
Figure A0081169600112
Wherein R1、R2、R3、R4、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1；(n) for wherein R5Expression-N (R13)C(O)NH(R15) compound of formula I：By wherein R5Expression-N (R13) H corresponding compound of formula I and Formula X VI compounds react,
             R15N=C=O XVI wherein R15As defined in claim 1；(o) for wherein R5Expression-N (R13)C(O)R14Compound of formula I：By wherein R5Expression-N (R13) H corresponding compound of formula I and Formula X VII compounds react,
             R14C(O)RxXVII wherein RxRepresent suitable leaving group, and R14As defined in claim 1；(p) for wherein R5Expression-N (H) R12Compound of formula I (wherein R12As defined in claim 1, condition is that it does not indicate that H)：By wherein R5Expression-NH2Corresponding compound of formula I and Formula X VIII compounds react,
             R12aL1XVIII wherein R12aRepresent R as defined in claim 112, condition is that it does not indicate that H and L1It is as defined above；(q) for wherein R5Expression-OR12Compound of formula I (wherein R12Represent C1-6Alkyl or optionally substituted aryl)：By wherein R5Expression-OH compound of formula I is reacted with XIX compounds；
             R12aOH XIX wherein R12aRepresent C1-6Alkyl or optionally substituted aryl；(r) for wherein R5Expression-OR12Compound of formula I (wherein R12Represent C1-6Alkyl or optionally substituted aryl)：By Formula X X compounds,Wherein L2As defined above and R1、R2、R3、R4、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1, reacted with Formula X IX compounds as defined above；(s) for wherein R5Represent OR12And R12Represent CO (R14) compound of formula I：By wherein R5The corresponding compound of formula I and Formula X XI compounds for representing OH are reacted,
             R14CO2H XXI wherein R14As defined in claim 1；(t) for wherein R5Represent the compound of formula I of halogen：Replace wherein R with suitable halide reagent5Expression-OH corresponding compound of formula I；(u) for wherein R3And/or R4Represent the compound of formula I of alkyl (if appropriate)：It is alkylated wherein R3And/or R4Represent H (if appropriate) corresponding compound of formula I；(v) by a R4Group is converted into another R4Group；(w) for wherein R2And R3In an expression-NH2, another represents H compound of formula I：Reduction-type XXIA compounds,
Figure A0081169600131
Wherein R3、R4、R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1；(x) for wherein R1And R2In one or two all represent-N (R2c)R2dCompound of formula I (wherein R2cAnd R2dIn one or two all represent C1-6Alkyl)：With Formula X XIB compounds,
             R2eL1XXIB wherein R2eRepresent C1-6Alkyl and L1As defined in claim 1, it is alkylated wherein R1And/or R2Expression-N (R2c)R2dCompound of formula I (if appropriate), wherein R2cAnd/or R2dRepresent H (if appropriate)；(y) by R7On a substituent be converted into another substituent；Or (z) sloughs the protection group of the protected derivative such as compound of formula I defined in claim 1.
26. the Formula II compound defined such as claim 25 or its protected derivative, condition is R7Optionally substituted phenyl is not indicated that.
27. the Formula V compound defined such as claim 25 or its protected derivative, condition is R7Optionally substituted phenyl is not indicated that.
28. the Formula X compound defined such as claim 25 or its protected derivative.
29. the Formula X I defined such as claim 25 or its protected derivative.
30. the Formula X III compounds defined such as claim 25 or its protected derivative.
31. the Formula X V compounds defined such as claim 25 or its protected derivative.
32. the Formula X X compounds defined such as claim 25 or its protected derivative.
33. Formula X XIII compounds or its protected derivative,
Figure A0081169600141
Wherein R5、R6、R7、R41、R42、R43、R44、R45、R46, A and B as defined in claim 1.
34. Formula X XV compounds or its protected derivative,
Figure A0081169600151
Wherein R3、R4、R41、R42、R43、R44、R45And R46As defined in claim 1.
35. a kind of formula X, Formula X XIII or Formula X XV compounds (wherein in all cases, R45And R46Represent H) method, including one of following reactions steps (if appropriate)：By (i) Formula X XXV compounds,Wherein RzRepresent C1-10Alkyl or C1-3Alkaryl and R41、R42、R43And R44As 1 define, or (ii) 4- piperidones (or its protected derivative), with (if appropriate)：(1) Formula X XXVI compounds,
      R7-B-C(R5)(R6)-A-NH2XXXVI wherein R5、R6、R7, A and B as defined in claim 1, or (2) NH3(or its protected derivative) is reacted, and above-mentioned each reaction is carried out in the presence of formaldehyde, and in the case of Formula X and Formula X XV compounds, then by C (O) OR of gained intermediatezGroup is converted into C (O) N (R3)(R4) group.
36. the method for claim 35, wherein the reaction is carried out in the presence of organic acid.
37. the method for claim 36, wherein the organic acid is acetic acid.
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