CN101541792A - Azaadamantane derivatives and methods of use - Google Patents
Azaadamantane derivatives and methods of use Download PDFInfo
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- CN101541792A CN101541792A CNA2007800418951A CN200780041895A CN101541792A CN 101541792 A CN101541792 A CN 101541792A CN A2007800418951 A CNA2007800418951 A CN A2007800418951A CN 200780041895 A CN200780041895 A CN 200780041895A CN 101541792 A CN101541792 A CN 101541792A
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Abstract
The invention relates to compounds that are azaadamantane derivatives, particularly ether- or amine-substituted azaadamantane derivatives and salts and prodrugs thereof, compositions comprising such compounds, methods of using such compounds and compositions, processes for preparing such compounds, and intermediates obtained during such processes.
Description
Background of invention
The cross reference of related application
The application requires the rights and interests of U.S. Provisional Patent Application series number of submitting on November 6th, 2,006 60/856,992 and the U.S. Provisional Patent Application series number of submitting on March 26th, 2,007 60/908,143, in this content of introducing these two applications in full as a reference.
Technical field
The present invention relates to azaadamantane (azaadamantane) derivative and more specifically be ether-or the azaadamantane derivatives of amine-replacements, comprise this type of compound compositions, use this compounds and composition prevention or treat the intermediates that obtain in disease and the method for illness, the process for preparing this compounds and these processes.
The explanation of correlation technique
NAChR (nAChR) is distributed widely in maincenter (CNS) and (PNS) neural system on every side.This receptoroid is in regulating the CNS function, particularly play a significant role by the release of regulating various neurotransmitters, and described neurotransmitter is including but not limited to vagusstoff, norepinephrine, Dopamine HCL, serotonin and GABA.Therefore, the physiological action that the nAChR mediation is very many, and directed being used for the treatment of property treatment and the relevant illnesss of the patient's condition such as cognitive function, learning and memory, neurodegeneration, pain, inflammation, psychosis, sensory gating, mood and emotion.
Many nAChR hypotypes are present in CNS and peripheral nervous system.Every kind of hypotype has different effects aspect the whole physiological function of adjusting.Usually, nAChR is the ionic channel that is made of the assembling of pentamer subunit protein.At least 12 kinds of subunit proteins-α 2-α 10 and β 2-β 4 in nervous tissue, have been identified.These subunits provide multiple homotype or special-shaped combination, and described combination is the reason of different receptor subtypes.For example, be responsible for having (α 4) with the high affine bonded advantage acceptor of cerebral tissue nicotine
2(β 2)
3The composition of (α 4 beta 2 subunit types), and another kind of main acceptor group comprises homotype (α 7)
5(α 7 hypotypes) acceptor.
Some compound as vegeto-alkali nicotine, interacts with all nAChR hypotypes, illustrates that this compounds has far-reaching physiological action.Have many useful characteristics though proved nicotine, the effect that is not all nicotine mediations is all expected.For example, the nicotine of therapeutic dose produces interferential gi tract and cardiovascular side effect, and its habituation and acute toxicity are well-known.Only provide potentiality that realize useful therapeutic action and the safety limit that improvement is arranged with the interactional part of some nAChR subtype-selective.
α 7 and α 4 β 2 nAChR have shown remarkable effect (Levin, E.D., J.Neurobiol.53:633-640,2002) on enhancing comprises cognitive function aspect study, memory and the attention.For example, α 7 nAChR have been associated with disease and illness, and described disease and illness relate to attention deficit disorder, attention deficit moves obstacle (ADHD), schizophrenia, alzheimer's disease (AD), mild cognitive impairment, senile dementia, Louis body dependency dementia, mongolism dependency dementia, AIDS dementia, Pick's disease and inflammation more.α 4 beta 2 receptor hypotypes relate to attention, cognition, epilepsy and pain control (Paterson and Norberg, Progress in Neurobiology 6175-111,2000) and smoking cessation or nicotine abstinence syndrome.
By giving the activity that subtype-selective nAChR part can change or regulate α 7 and α 4 β 2 nAChR.Described part can show the characteristic of antagonist, agonist or partial agonist.As the allosteric modulators compound also is known.
Though confirm that non-selective active compound is arranged known comprising among α 4 β 2 and the α 7 in a series of cholinocepter hypotypes, provide that to compare with other hypotype should be useful with comprising alpha 7-neuronal nAChR, α 4 β, 2 nAChR or α 7 and the interactional compound of α 4 β, 2 nAChR optionally.
The accompanying drawing summary
Fig. 1 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of anhydrous L-bitartrate of decane.
Fig. 2 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of L-hydrogen tartrate salt hydrate of decane.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 of Fig. 2 A for obtaining by thermogravimetry (TGA)
3,7] thermogram of L-hydrogen tartrate salt hydrate of decane.
Fig. 3 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of anhydrous phosphoric acid dihydric salt of decane.
Fig. 4 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of biphosphate salt hydrate of decane.
Fig. 4 A is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that obtains by thermogravimetry
3,7] thermogram of biphosphate salt hydrate of decane.
Fig. 5 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of anhydrous disuccinate of decane.
Fig. 6 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of disuccinate hydrate of decane.
Fig. 6 A is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that obtains by thermogravimetry
3,7] thermogram of disuccinate hydrate of decane.
Fig. 7 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of hydrochloride four/monohydrate of decane.
Fig. 8 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of hydrochloride sesquialter hydrate of decane.
Fig. 8 A is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that obtains by thermogravimetry
3,7] thermogram of hydrochloride sesquialter hydrate of decane.
Fig. 9 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of dihydrogen citrate salt of decane.
Figure 10 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of citric acid hydrogen salt of decane.
Figure 11 is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the powder x-ray diffraction figure of decane free alkali.
Fig. 5,7,9 and 11 according to they separately the single cell data of compound determine.
Summary of the invention
The present invention relates to azaadamantane derivatives, comprise this type of compound compositions, prepare the intermediates that obtain in the process of this compounds and these processes.More specifically, the present invention relates to ether-or the azaadamantane compound and relevant method and process thereof of amine-replacement.
One aspect of the invention relates to formula (I) compound
Or its pharmacy acceptable salt or prodrug, wherein
L
1For-O-or-NR
a-;
A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5
Ar
1Be aryl or heteroaryl;
Ar
2Be aryl or bicyclic heteroaryl;
Ar
3Be aryl or heteroaryl;
Ar
4Be bicyclic heteroaryl;
Ar
5Be aryl or heteroaryl;
L
2For key ,-O-,-NR
a-,-C (O) NR
a-or-CH
2-;
L
3For key ,-O-,-NR
a-or-CH
2-; With
R
aBe hydrogen or alkyl.
The present invention relates to the pharmaceutical composition that comprises The compounds of this invention on the other hand.This based composition can be according to the inventive method administration, a common part as treatment plan, be used for the treatment of or prevention and nAChR activity, and more especially α 7 nAChR activity, α 4 β, 2 nAChR activity or α 7nAChR activity and α 4 β, 2 nAChR two kinds of activity, diseases associated and illnesss.
Further aspect of the present invention relates to α 7 and the active method of α 4 β, 2 nAChR of regulating.This method is useful on treatment, prevention or not only treats but also prevent and α 7 and relevant especially mammiferous disease and the illness of two kinds of activity of α 4 β, 2 nAChR.
The further aspect of the present invention relates to selectivity and regulates for example active method of α 7 nAChR of AChR activity.This method is useful on treatment, prevention or not only treats but also prevent and relevant especially mammiferous disease and the illness of α 7 nAChR activity.Also be intended to relate to selectivity and regulate the active method of α 4 β, 2 nAChR.
These class methods are useful on disease and illness, described disease and illness relate to attention deficit disorder, attention deficit moves obstacle (ADHD) more, alzheimer's disease (AD), schizophrenia, mild cognitive impairment, age related memory defects (AAMI), senile dementia, the AIDS dementia, Pick's disease, Louis body dependency dementia, mongolism dependency dementia, schizophrenia, smoking cessation, nicotine abstinence syndrome, amyotrophic lateral sclerosis, Huntington Chorea, traumatic brain injury dependency CNS hypofunction, acute pain, post-operative pain, chronic pain, inflammatory pain, neuropathic pain, Infertility, circulation is not enough, wound healing dependency neovascularity growth (the more especially circulation around the vascular occlusion) lacks (need), the growth of skin graft vascularization dependency neovascularity lacks, ischemic, inflammation, serious poisonous disease, wound healing and other diabetes associated complication, and other general and refreshing footpath immunoregulatory activity.
The present invention also relates to the specific salts of some compound of the present invention and contain its composition and prepare the process of this compounds and salt thereof.
This paper has further described the intermediates that obtain in the process of composition, the method for using compound and preparation compound that compound comprises its salt, inclusion compound and this process.
Detailed Description Of The Invention
Term definition
When being common to this specification sheets and appended claims book, following term has following meanings:
Term " alkenyl " refers to contain 2-10 carbon and contains at least one by removing the straight or branched hydrocarbon of 2 formed carbon-to-carbon double bonds of hydrogen when being used for this paper.The representative example of alkenyl includes but not limited to vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl isophthalic acid-heptenyl and 3-decene base.
Term " alkenylene " refers to the straight or branched hydrocarbon deutero-divalent group by 2-10 the carbon atom that contains at least one two key.The representative example of alkenylene includes but not limited to-CH=CH-,-CH=CH
2CH
2-and-CH=C (CH
3) CH
2-.
Term " alkenyloxy " refers to append to by Sauerstoffatom the alkenyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkenyloxy includes but not limited to allyloxy, 2-butylene oxygen base and 3-butenyloxy.
Term " alkoxyl group " refers to append to by Sauerstoffatom the alkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, 2-propoxy-, butoxy, tert.-butoxy, pentyloxy and hexyloxy.
Term " alkoxyl group alkoxyl group " refers to append to by another alkoxyl group as defined herein the alkoxyl group as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxyl group alkoxyl group includes but not limited to tert.-butoxy methoxyl group, 2-ethoxy ethoxy, 2-methoxy ethoxy and methoxymethoxy.
Term " alkoxy alkoxy alkyl " refers to append to by alkyl as defined herein the alkoxyl group alkoxyl group as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxy alkoxy alkyl includes but not limited to tert.-butoxy methoxymethyl, oxyethyl group methoxy ylmethyl, (2-methoxy ethoxy) methyl and 2-(2-methoxy ethoxy) ethyl.
Term " alkoxyalkyl " refers to append to by alkyl as defined herein the alkoxyl group as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxyalkyl includes but not limited to tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxymethyl.
Term " alkoxy carbonyl " refers to append to by carbonyl as defined herein the alkoxyl group as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxy carbonyl includes but not limited to methoxycarbonyl, ethoxy carbonyl and tert-butoxycarbonyl.
Term " alkoxy carbonyl alkyl " refers to append to by alkyl as defined herein the alkoxy carbonyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxy carbonyl alkyl includes but not limited to 3-methoxycarbonyl propyl group, 4-ethoxy carbonyl butyl and 2-tert-butoxycarbonyl ethyl.
Term " alkoxyl group alkylsulfonyl " refers to append to by alkylsulfonyl as defined herein the alkoxyl group as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxyl group alkylsulfonyl includes but not limited to methoxyl group alkylsulfonyl, oxyethyl group alkylsulfonyl and propoxy-alkylsulfonyl.
Term " alkyl " refers to contain the straight or branched hydrocarbon of 1-10 carbon atom when being used for this paper.The representative example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 3-methyl hexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, n-heptyl, n-octyl, n-nonyl and positive decyl.
Term " alkyl-carbonyl " refers to append to by carbonyl as defined herein the alkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl-carbonyl includes but not limited to ethanoyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.
Term " alkyl-carbonyl alkyl " refers to append to by alkyl as defined herein the alkyl-carbonyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl-carbonyl alkyl includes but not limited to 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxo butyl and 3-oxo amyl group.
Term " alkyl-carbonyl oxygen base " refers to append to by Sauerstoffatom the alkyl-carbonyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl-carbonyl oxygen base includes but not limited to ethanoyl oxygen base, ethyl ketonic oxygen base and tertiary butyl ketonic oxygen base.
Term " alkylidene group " refers to the straight or branched hydrocarbon deutero-divalent group by 1-10 carbon atom.The representative example of alkylidene group includes but not limited to-CH
2-,-CH (CH
3)-,-C (CH
3)
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH
2CH
2-and-CH
2CH (CH
3) CH
2-.
Term " alkyl sulphinyl " refers to append to by sulfinyl as defined herein the alkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl sulphinyl includes but not limited to methylsulfinyl and ethyl sulfinyl.
Term " alkyl sulphinyl alkyl " refers to append to by alkyl as defined herein the alkyl sulphinyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl sulphinyl alkyl includes but not limited to methylsulfinyl methyl and ethyl sulfinyl methyl.
Term " alkyl sulphonyl " refers to append to by alkylsulfonyl as defined herein the alkyl as defined herein of parent molecular moiety when being used for this zhang.The representative example of alkyl sulphonyl includes but not limited to methyl sulphonyl and ethylsulfonyl.
Term " alkyl sulphonyl alkyl " refers to append to by alkyl as defined herein the alkyl sulphonyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl sulphonyl alkyl includes but not limited to sulfonyloxy methyl ylmethyl and ethylsulfonyl methyl.
Term " alkyl sulfenyl " refers to append to by sulphur atom the alkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl sulfenyl includes but not limited to methyl sulfenyl, ethyl sulfenyl, tertiary butyl sulfenyl and hexyl sulfenyl.
Term " alkyl sulfenyl alkyl " refers to append to by alkyl as defined herein the alkyl sulfenyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkyl sulfenyl alkyl includes but not limited to methyl sulfenyl methyl and 2-(ethyl sulfenyl) ethyl.
Term " alkynyl " is when being used for this paper, the straight or branched alkyl that refers to contain 2-10 carbon atom and contain at least one carbon-to-carbon triple bond.The representative example of alkynyl includes but not limited to ethynyl, 1-proyl, 2-propynyl, 3-butynyl, valerylene base and ethyl acetylene base.
Term " alkynylene " refers to by the straight or branched hydrocarbon deutero-divalent group that contains at least one triple-linked 2-10 carbon atom.The representative example of alkynylene includes but not limited to-C ≡ C-,-CH
2C ≡ C-,-CH (CH
3) CH
2C ≡ C-,-C ≡ CCH
2-and-C ≡ CCH (CH
3) CH
2-.
Term " alkynyloxy group " refers to append to by Sauerstoffatom the alkynyl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkynyloxy group includes but not limited to 2-third alkynyloxy group and 2-butyne oxygen base.
Term " aryl " refers to phenyl, bicyclic aryl or three cyclophane bases when being used for this paper.Bicyclic aryl be naphthyl, with Cycloalkylfused phenyl or with cycloalkenyl group condensed phenyl.The representative example of bicyclic aryl includes but not limited to dihydro indenyl, indenyl, naphthyl, dihydro naphthyl and tetralyl.Three cyclophane bases be anthracene or phenanthrene or with Cycloalkylfused bicyclic aryl or with cycloalkenyl group condensed bicyclic aryl or with phenyl condensed bicyclic aryl.The representative example of three cyclophane rings includes but not limited to camomile cyclic group, dihydro anthryl, fluorenyl and tetrahydrochysene phenanthryl.
Aryl of the present invention can be by 1; 2; 3; 4 or 5 independently are selected from following substituting group and replace: alkenyl; alkoxyl group; the alkoxyl group alkoxyl group; alkoxy alkoxy alkyl; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; the alkyl-carbonyl oxygen base; alkyl sulphinyl; the alkyl sulphinyl alkyl; alkyl sulphonyl; the alkyl sulphonyl alkyl; the alkyl sulfenyl; alkyl sulfenyl alkyl; alkynyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formyl radical; the formyl radical alkyl; halogen; haloalkyl; hydroxyl; hydroxyalkyl; sulfydryl; nitro;-NZ
1Z
2, and (NZ
3Z
4) carbonyl.
Term " alkoxy aryl " refers to append to by alkoxyl group as defined herein the aryl as defined herein of parent molecular moiety when being used for this paper.The representative example of alkoxy aryl includes but not limited to 2-phenyl ethoxy, 3-naphthalene-2-base propoxy-and 5-phenyl pentyloxy.
Term " aryl-alkoxy carbonyl " refers to append to by carbonyl as defined herein the alkoxy aryl as defined herein of parent molecular moiety when being used for this paper.The representative example of aryl-alkoxy carbonyl includes but not limited to benzyloxycarbonyl and naphthalene-2-ylmethoxy carbonyl.
Term " arylalkyl " refers to append to by alkyl as defined herein the aryl as defined herein of parent molecular moiety when being used for this paper.The representative example of arylalkyl includes but not limited to benzyl, 2-phenylethyl, 3-phenyl propyl and 2-naphthalene-2-base ethyl.
Term " arylalkyl sulfenyl " refers to append to by sulphur atom the arylalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of arylalkyl sulfenyl includes but not limited to 2-phenylethyl sulfenyl, 3-naphthalene-2-base rosickyite base and 5-phenyl penta sulfenyl.
Term " aryl carbonyl " refers to append to by carbonyl as defined herein the aryl as defined herein of parent molecular moiety when being used for this paper.The representative example of aryl carbonyl includes but not limited to benzoyl and naphthoyl.
Term " aryloxy " refers to append to by Sauerstoffatom the aryl as defined herein of parent molecular moiety when being used for this paper.The representative example of aryloxy includes but not limited to phenoxy group, naphthyloxy, 3-bromo phenoxy group, 4-chloro phenoxy group, 4-methylphenoxy and 3,5-dimethoxy phenoxy group.
Term " aromatic yloxy yl alkyl " refers to append to by alkyl as defined herein the aryloxy as defined herein of parent molecular moiety when being used for this paper.The representative example of aromatic yloxy yl alkyl includes but not limited to 2-phenoxy group ethyl, 3-naphthalene-2-base oxygen base propyl group and 3-bromo phenoxymethyl.
Term " artyl sulfo " refers to append to by sulphur atom the aryl as defined herein of parent molecular moiety when being used for this paper.The representative example of artyl sulfo includes but not limited to phenyl sulfenyl and 2-naphthyl sulfenyl.
Term " artyl sulfo alkyl " refers to append to by alkyl as defined herein the artyl sulfo as defined herein of parent molecular moiety when being used for this paper.The representative example of artyl sulfo alkyl includes but not limited to phenyl sulfenyl methyl, 2-naphthalene-2-base sulfenyl ethyl and 5-phenyl sulfenyl methyl.
Term " azido-" refers to-N when being used for this paper
3Group.
Term " carbonyl " refers to-C (O)-group when being used for this paper.
Term " carboxyl " refers to-CO when being used for this paper
2The H group.
Term " carboxyalkyl " refers to append to by alkyl as defined herein the carboxyl as defined herein of parent molecular moiety when being used for this paper.The representative example of carboxyalkyl includes but not limited to carboxymethyl, 2-carboxy ethyl and 3-carboxyl propyl group.
Term " cyano group " refers to-the CN group when being used for this paper.
Term " cyano group alkyl " refers to append to by alkyl as defined herein the cyano group as defined herein of parent molecular moiety when being used for this paper.The representative example of cyano group alkyl includes but not limited to cyano methyl, 2-cyano ethyl and 3-cyano group propyl group.
Term " cycloalkenyl group " is when being used for this paper, refer to contain 3-8 carbon and contain at least one by remove 2 formed carbon-to-carbon double bonds of hydrogen cyclic hydrocarbon.The representative example of cycloalkenyl group includes but not limited to 2-tetrahydrobenzene-1-base, 3-tetrahydrobenzene-1-base, 2,4-cyclohexadiene-1-base and 3-cyclopentenes-1-base.
Term " cycloalkyl " refers to monocycle, dicyclo or three-loop system when being used for this paper.Single-loop system is illustrated by the saturated cyclic alkyl that contains 3-8 carbon atom.The example of single-loop system comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Bicyclic system is illustrated by the single-loop system of bridge joint, and wherein monocyclic 2 adjacent or non-conterminous carbon atoms are by the alkylidene bridge connection of 1-3 other carbon atom.The representative example of bicyclic system includes but not limited to dicyclo [3.1.1] heptane, dicyclo [2.2.1] heptane, dicyclo [2.2.2] octane, dicyclo [3.2.2] nonane, dicyclo [3.3.1] nonane and dicyclo [4.2.1] nonane.Three-loop system is illustrated by bicyclic system, and wherein 2 of dicyclo non-conterminous carbon atoms are by the alkylidene bridge connection of key or 1-3 carbon atom.The representative example of three-loop system includes but not limited to three ring [3.3.10
3,7] nonane and three ring [3.3.1.1
3,7] decane (diamantane).
Cycloalkyl of the present invention is optional to be selected from following substituting group by 1,2,3,4 or 5 and to replace: alkenyl, alkoxyl group, alkoxyl group alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxyl group alkylsulfonyl, alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl sulphonyl, alkyl sulfenyl, alkyl sulfenyl alkyl, alkynyl, carboxyl, cyano group, formyl radical, halogenated alkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfydryl, oxo ,-NZ
1Z
2, and (NZ
3Z
4) carbonyl.
Term " cycloalkylalkyl " refers to append to by alkyl as defined herein the cycloalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of cycloalkylalkyl includes but not limited to cyclopropyl methyl, 2-cyclobutyl ethyl, cyclopentyl-methyl, cyclohexyl methyl and 4-suberyl butyl.
Term " naphthene base carbonyl " refers to append to by carbonyl as defined herein the cycloalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of naphthene base carbonyl includes but not limited to cyclopropyl carbonyl, 2-cyclobutyl carbonyl and cyclohexyl-carbonyl.
Term " cycloalkyl oxy " refers to append to by Sauerstoffatom as defined herein the cycloalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of cycloalkyl oxy includes but not limited to cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, suberyl oxygen base and ring octyl group oxygen base.
Term " cycloalkyl sulfenyl " refers to append to by sulphur atom as defined herein the cycloalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of cycloalkyl sulfenyl includes but not limited to cyclopropyl sulfenyl, cyclobutyl sulfenyl, cyclopentyl sulfenyl, cyclohexyl sulfenyl, cyclic group sulfenyl in heptan and ring octyl group sulfenyl.
Term " ethylenedioxy " refers to-O (CH when being used for this paper
2)
2The O-group, wherein the Sauerstoffatom of ethylenedioxy is connected to form 5 yuan of rings by 1 carbon atom and parent molecular moiety, and perhaps the Sauerstoffatom of ethylenedioxy is connected to form 6 yuan of rings by 2 adjacent carbonss and parent molecular moiety.
Term " formyl radical " refers to-C (O) H group when being used for this paper.
Term " formyl radical alkyl " refers to append to by alkyl as defined herein the formyl radical as defined herein of parent molecular moiety when being used for this paper.The representative example of formyl radical alkyl includes but not limited to formyl radical methyl and 2-formyl radical ethyl.
Term " halo " or " halogen " be when being used for this paper, refer to-Cl ,-Br ,-I or-F.
Term " halogenated alkoxy " refers to append to by alkoxyl group as defined herein at least 1 halogen as defined herein of parent molecular moiety when being used for this zhang.The representative example of halogenated alkoxy includes but not limited to chloro methoxyl group, 2-fluoro oxyethyl group, trifluoromethoxy and five fluorine oxyethyl groups.
Term " haloalkyl " refers to append to by alkyl as defined herein at least 1 halogen as defined herein of parent molecular moiety when being used for this paper.The representative example of haloalkyl includes but not limited to chloro methyl, 2-fluoro ethyl, trifluoromethyl, pentafluoroethyl group and 2-chloro-3-fluoro amyl group.
Term " heteroaryl " refers to bicyclic heteroaryl or bicyclic heteroaryl when being used for this paper.Bicyclic heteroaryl is to comprise heteroatomic 5 or 6 yuan of rings that at least one is selected from nitrogen, oxygen and sulphur.5 yuan of rings comprise 2 two keys and 6 yuan of rings comprise 3 two keys.5 or 6 yuan of heteroaryls are connected by any carbon atom or former the giving with parent molecular moiety of any commutable nitrogen that is included in the heteroaryl, and condition is to keep suitable valency.The representative example of bicyclic heteroaryl includes but not limited to furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazole Ji, oxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl and triazinyl.Bicyclic heteroaryl comprise with phenyl condensed bicyclic heteroaryl or with Cycloalkylfused bicyclic heteroaryl with cycloalkenyl group condensed bicyclic heteroaryl or with bicyclic heteroaryl condensed bicyclic heteroaryl.Bicyclic heteroaryl is connected with parent molecular moiety by any carbon atom or any commutable nitrogen-atoms that is included in the bicyclic heteroaryl, and condition is to keep suitable valency.The representative example of bicyclic heteroaryl includes but not limited to azaindole, benzimidazolyl-, benzofuryl Ben Bing oxadiazole base, benzoisoxazole, benzisothiazole benzoxazole, 1, the 3-benzothiazolyl, benzothienyl (benzothienyl) (or benzothienyl (benzothiophenyl)), the cinnolines base, the furo pyridine, indyl, indazolyl, dihydroindole ketone group (indolinonyl), isobenzofuran, pseudoindoyl, isoquinolyl, phthalazinyl (naphthyridinyl) oxadiazole base oxazole and pyridine (oxazolopyridine), quinolyl, quinoxalinyl, thiadiazolyl group, with the thienopyridine base.
Heteroaryl of the present invention is optional by 1; 2; 3 or 4 independently are selected from following substituting group and replace: alkenyl; alkoxyl group; the alkoxyl group alkoxyl group; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; the alkoxyl group alkylsulfonyl; alkyl; alkyl-carbonyl; a heatable brick bed base carbonylic alkyl; the alkyl-carbonyl oxygen base; the alkyl sulfenyl; alkyl sulfenyl alkyl; alkynyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formyl radical; halogenated alkoxy; haloalkyl; halogen; hydroxyl; hydroxyalkyl; sulfydryl; nitro;-NZ
1Z
2(NZ
3Z
4) carbonyl.The heteroaryl that the present invention is replaced by hydroxyl can be used as tautomer and occurs.Heteroaryl of the present invention is contained all tautomers that comprise non-aromatics tautomer.In addition, nitrogen heteroatom can be chosen wantonly by quaternary ammoniated or be oxidized to the N-oxide compound.
Term " heteroaryl alkoxyl group " refers to append to by alkoxyl group as defined herein the heteroaryl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroaryl alkoxyl group includes but not limited to furans-3-ylmethoxy, 1H-imidazoles-2-ylmethoxy, 1H-imidazol-4 yl methyl, 1-(pyridin-4-yl) oxyethyl group, the pyridin-3-yl methoxyl group, 6-chloro-pyridine-3 ylmethoxy, the pyridin-4-yl methoxyl group, (6-(trifluoromethyl) pyridin-3-yl) methoxyl group, (6-(cyano group) pyridin-3-yl) methoxyl group, (2-(cyano group) pyridin-4-yl) methoxyl group, (5-(cyano group) pyridine-2-yl) methoxyl group, (2-(chloro-) pyridin-4-yl) methoxyl group, pyrimidine-5-ylmethoxy, 2-(pyrimidine-2-base) propoxy-, thiophene-2-ylmethoxy, with the thiene-3-yl-methoxyl group.
Term " heteroarylalkyl " refers to append to by alkyl as defined herein the heteroaryl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroarylalkyl includes but not limited to furans-3-ylmethyl, 1H-imidazoles-2-ylmethyl, 1H-imidazol-4 yl methyl, 1-(pyridine-4 base) ethyl, the pyridin-3-yl methyl, 6-chloro-pyridin-3-yl methyl, the pyridin-4-yl methyl, (6-(trifluoromethyl) pyridin-3-yl) methyl, (6-(cyano group) pyridin-3-yl) methyl, (2-(cyano group) pyridin-4-yl) methyl, (5-(cyano group) pyridine-2-yl) methyl, (2-(chloro-) pyridin-4-yl) methyl, pyrimidine-5-ylmethyl, 2-(pyrimidine-2-base) propyl group, thiophene-2-ylmethyl, with the thiene-3-yl-methyl.
Term " heteroarylalkyl carbonyl " refers to append to by carbonyl as defined herein the heteroarylalkyl as defined herein of parent molecular moiety when being used for this paper.
Term " heteroarylalkyl sulfenyl " refers to append to by sulphur atom the heteroarylalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroarylalkyl sulfenyl includes but not limited to furans-3-ylmethyl sulfenyl, 1H-imidazoles-2-ylmethyl sulfenyl, 1H-imidazol-4 yl methyl sulfenyl, pyridin-3-yl methyl sulfenyl, 6-chloro-pyridin-3-yl methyl sulfenyl, pyridin-4-yl methyl sulfenyl, (6-(trifluoromethyl) pyridin-3-yl) methyl sulfenyl, (6-(cyano group) pyridin-3-yl) methyl sulfenyl, (2-(cyano group) pyridin-4-yl) methyl sulfenyl, (5-(cyano group) pyridine-2-yl) methyl sulfenyl, (2-(chloro-) pyridin-4-yl) methyl sulfenyl, pyrimidine-5-ylmethyl sulfenyl, 2-(pyrimidine-2-base) propyl group sulfenyl, thiophene-2-ylmethyl sulfenyl, with thiene-3-yl-methyl sulfenyl.
Term " heteroaryl carbonyl " refers to append to by carbonyl as defined herein the heteroaryl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroaryl carbonyl includes but not limited to furans-3-base carbonyl, 1H-imidazoles-2-base carbonyl, 1H-imidazol-4 yl carbonyl, the pyridin-3-yl carbonyl, 6-chloro-pyridin-3-yl carbonyl, the pyridin-4-yl carbonyl, (6-(trifluoromethyl) pyridin-3-yl) carbonyl, (6-(cyano group) pyridin-3-yl) carbonyl, (2-(cyano group) pyridin-4-yl) carbonyl, (5-(cyano group-pyridine-2-yl) carbonyl, (2-(chloro) pyridin-4-yl) carbonyl, pyrimidine-5-base carbonyl, the pyrimidine-2-base carbonyl, thiophene-2-base carbonyl, with the thiene-3-yl-carbonyl.
Term " heteroaryl oxygen base " refers to append to by Sauerstoffatom the heteroaryl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroaryl oxygen base includes but not limited to furans-3-base oxygen base, 1H-imidazoles-2-base oxygen base, 1H-imidazol-4 yl oxygen base, pyridin-3-yl oxygen base, 6-chloro-pyridin-3-yl oxygen base, pyridin-4-yl oxygen base, (6-(trifluoromethyl) pyridin-3-yl) oxygen base, (6-(cyano group) pyridin-3-yl) oxygen base, (2-(cyano group) pyridin-4-yl) oxygen base, (5-(cyano group) pyridine-2-yl) oxygen base, (2-(chloro) pyridin-4-yl) oxygen base, pyrimidine-5-base oxygen base, pyrimidine-2-yloxy, thiophene-2-base oxygen base and thiene-3-yl-oxygen base.
Term " heteroaryl oxygen base alkyl " refers to append to by alkyl as defined herein the heteroaryl oxygen base as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroaryl oxygen base alkyl includes but not limited to pyridin-3-yl oxygen ylmethyl and 2-quinoline-3-base oxygen base ethyl.
Term " heteroaryl sulfenyl " refers to append to by sulphur atom the heteroaryl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroaryl sulfenyl includes but not limited to pyridin-3-yl sulfenyl and quinoline-3-base sulfenyl.
Term " heteroaryl sulfenyl alkyl " refers to append to by alkyl as defined herein the heteroaryl sulfenyl as defined herein of parent molecular moiety when being used for this paper.The representative example of heteroaryl sulfenyl alkyl includes but not limited to pyridin-3-yl sulfenyl methyl and 2-quinoline-3-base sulfenyl ethyl.
Term " heterocycle " or " heterocyclic " refer to monocyclic heterocycles, bicyclic heterocycle or tricyclic heterocyclic when being used for this paper.Monocyclic heterocycles be comprise that at least one independently is selected from 0, heteroatomic 3,4,5,6 or 7 yuan of rings of N and S.3 or 4 yuan of rings comprise 1 heteroatoms that is selected from O, N and S.5 yuan of rings comprise 0 or 1 two key and 1,2 or 3 heteroatoms that is selected from O, N and S.6 or 7 yuan of rings comprise 0,1 or 2 two key and 1,2 or 3 heteroatoms that is selected from O, N and S.Monocyclic heterocycles is connected with parent molecular moiety by any carbon atom or any nitrogen-atoms that is included in the monocyclic heterocycles.The representative example of monocyclic heterocycles includes but not limited to azetidinyl, azepan base (azepanyl), the ethylenimine base, Diazesuberane base (diazepanyl), 1, the 3-alkyl dioxin, 1, the 3-dioxolanyl, 1,3-dithiolane base, 1,3-dithiane base, imidazolinyl, imidazolidyl, the isothiazoline base, isothiazole alkyl; isoxazoline-3-yl; isoxazole alkyl, morpholinyl oxadiazole quinoline base oxadiazole alkyl oxazolinyl oxazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolinyl, pyrazolidyl, pyrrolinyl, pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, the Thiadiazoline base, the thiadiazoles alkyl, thiazolinyl, thiazolidyl, thio-morpholinyl, 1,1-titanium dioxide thio-morpholinyl (1,1-dioxidothiomorpholinyl) (thiomorpholine sulfone), thiapyran base and trithian base.Bicyclic heterocycle be with phenyl condensed 5 or 6 yuan of monocyclic heterocycles or with Cycloalkylfused 5 or 6 yuan of monocyclic heterocycles with cycloalkenyl group condensed 5 or 6 yuan of monocyclic heterocycles or with monocyclic heterocycles condensed 5 or 6 yuan of monocyclic heterocycles.Bicyclic heterocycle is connected with parent molecular moiety by any carbon atom or any nitrogen-atoms that is included in the bicyclic heterocycle.The representative example of bicyclic heterocycle includes but not limited to 1,3-benzo dioxolyl (1,3-benzodioxolyl), 1,3-benzo dithiole base (1,3-benzodithiolyl), 2,3-dihydro-1,4-benzo dioxine base (benzodioxinyl), benzo dioxolyl, 2,3-dihydro-1-benzofuryl, 2,3-dihydro-1-benzothienyl, chromenyl and 1,2,3, the 4-tetrahydric quinoline group.Tricyclic heterocyclic be with phenyl condensed bicyclic heterocycle or with Cycloalkylfused bicyclic heterocycle with cycloalkenyl group condensed bicyclic heterocycle or with monocyclic heterocycles condensed bicyclic heterocycle.Tricyclic heterocyclic is connected with parent molecular moiety by any carbon atom or any nitrogen-atoms that is included in the tricyclic heterocyclic.The representative example of tricyclic heterocyclic includes but not limited to 2,3,4,4a, and 9,9a-six hydrogen-1H-carbazyl, 5a, 6,7,8,9,9a-six diphenyl hydrogens are [b, d] furyl and 5a also, and 6,7,8,9,9a-six diphenyl hydrogens are [b, d] thienyl also.
Heterocycle of the present invention is optional by 1; 2; 3 or 4 independently are selected from following substituting group and replace: alkenyl; alkoxyl group; the alkoxyl group alkoxyl group; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; the alkoxyl group alkylsulfonyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; the alkyl-carbonyl oxygen base; the alkyl sulfenyl; alkyl sulfenyl alkyl; alkynyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formyl radical; halogenated alkoxy; haloalkyl; halogen; hydroxyl; hydroxyalkyl; sulfydryl; oxo;-NZ
1Z
2(NZ
3Z
4) carbonyl.
Term " heterocycle alkoxyl group " refers to append to by alkoxyl group as defined herein the heterocyclic group as defined herein of parent molecular moiety when being used for this paper.The representative example of heterocycle alkoxyl group includes but not limited to 2-pyridin-3-yl oxyethyl group, 3-quinoline-3-base propoxy-and 5-pyridin-4-yl pentyloxy.
Term " Heterocyclylalkyl " refers to append to by alkyl as defined herein the heterocycle as defined herein of parent molecular moiety when being used for this paper.The representative example of Heterocyclylalkyl includes but not limited to piperidin-4-yl methyl, piperazine-1-ylmethyl, 3-methyl isophthalic acid-tetramethyleneimine-1-base butyl, (1R)-3-methyl isophthalic acid-tetramethyleneimine-1-base butyl, (1S)-3-methyl isophthalic acid-tetramethyleneimine-1-base butyl.
Term " Heterocyclylalkyl carbonyl " refers to append to by carbonyl as defined herein the Heterocyclylalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of Heterocyclylalkyl carbonyl includes but not limited to piperidin-4-yl methyl carbonyl, piperazine-1-ylmethyl carbonyl, 3-methyl isophthalic acid-tetramethyleneimine-1-base butyl carbonyl, (1R)-3-methyl isophthalic acid-tetramethyleneimine-1-base butyl carbonyl, (1S)-3-methyl isophthalic acid-tetramethyleneimine-1-base butyl carbonyl.
Term " Heterocyclylalkyl sulfenyl " refers to append to by sulphur atom the Heterocyclylalkyl as defined herein of parent molecular moiety when being used for this paper.The representative example of Heterocyclylalkyl sulfenyl includes but not limited to 2-pyridin-3-yl ethyl sulfenyl, 3-quinoline-3-base propyl group sulfenyl and 5-pyridin-4-yl amyl group sulfenyl.
Term " heterocycle carbonyl " refers to append to by carbonyl as defined herein the heterocycle as defined herein of parent molecular moiety when being used for this paper.
Term " heterocycle carbonylic alkyl " refers to append to by alkyl as defined herein the heterocycle carbonyl as defined herein of parent molecular moiety when being used for this paper.
Term " heterocyclic oxy group " refers to append to by Sauerstoffatom the heterocyclic radical as defined herein of parent molecular moiety when being used for this paper.The representative example of heterocyclic oxy group includes but not limited to pyridin-3-yl oxygen base and quinoline-3-base oxygen base.
Term " heterocyclic oxy group alkyl " refers to append to by alkyl as defined herein the heterocyclic oxy group as defined herein of parent molecular moiety when being used for this paper.The representative example of heterocyclic oxy group alkyl includes but not limited to pyridin-3-yl oxygen ylmethyl and 2-quinoline-3-base oxygen base ethyl.
Term " heterocycle sulfenyl " refers to append to by sulphur atom the heterocyclic radical as defined herein of parent molecular moiety when being used for this paper.The representative example of heterocycle sulfenyl includes but not limited to pyridin-3-yl sulfenyl and quinoline-3-base sulfenyl.
Term " heterocycle sulfenyl alkyl " refers to append to by alkyl as defined herein the heterocycle sulfenyl as defined herein of parent molecular moiety when being used for this paper.The representative example of heterocycle sulfenyl alkyl includes but not limited to pyridin-3-yl sulfenyl methyl and 2-quinoline-3-base sulfenyl ethyl.
Term " hydroxyl " refers to-the OH group when being used for this paper.
Term " hydroxyalkyl " refers to append to by alkyl as defined herein at least one hydroxyl as defined herein of parent molecular moiety when being used for this paper.The representative example of hydroxyalkyl includes but not limited to methylol, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyl amyl group and 2-ethyl-4-hydroxyl heptyl.
Term " hydroxy-protective group " or " O-blocking group " refer to protect hydroxyl to avoid the substituting group of untoward reaction influence in building-up process.The example of hydroxy-protective group includes but not limited to the methyl ether that replaces, for example methoxymethyl, benzyloxymethyl, 2-methoxy ethoxy methyl, 2-(trimethyl silyl)-ethoxyl methyl, benzyl and trityl group; THP trtrahydropyranyl ether; The ethyl ether that replaces, for example 2,2, the 2-three chloro ethyl and the tertiary butyls; Silyl ether, for example trimethyl silyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; Cyclic acetal and ketal, for example methylene radical acetal, acetonide and benzylidene acetal; Cyclic ortho ester, for example methoxyl group methylene radical; Cyclic carbonate; With the ring-type boric acid ester.Hydroxy-protective group commonly used is disclosed in T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis (blocking group of organic synthesis), the 3rd edition, John Wiley﹠amp; Sons is among the New York (1999).
Term " low-grade alkenyl " is when being used for this paper, is the subclass of the alkenyl that defines of this paper, and refers to contain the alkenyl of 2-4 carbon atom.The example of low-grade alkenyl is vinyl, propenyl and butenyl.
Term " lower alkoxy " is when being used for this paper, is the subclass of the alkoxyl group that defines of this paper, and refers to append to by Sauerstoffatom as defined herein the low alkyl group as defined herein of parent molecular moiety.The representative example of lower alkoxy includes but not limited to methoxyl group, oxyethyl group, propoxy-, 2-propoxy-, butoxy and tert.-butoxy.
Term " low alkyl group " is when being used for this paper, is the subclass of the alkyl that defines of this paper, and refers to contain the straight or branched alkyl of 1-4 carbon atom.The example of low alkyl group is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.
Term " low alkyl group sulfenyl " is an alkyl sulfenyl subclass when being used for this paper, and refers to append to by sulphur atom the low alkyl group as defined herein of parent molecular moiety.The representative example of low alkyl group sulfenyl includes but not limited to methyl sulfenyl, ethyl sulfenyl and tertiary butyl sulfenyl.
Term " low-grade alkynyl " is when being used for this paper, is the subclass of the alkynyl that defines of this paper, and refers to contain the alkynyl of 2-4 carbon atom.The example of low-grade alkynyl is ethynyl, proyl and butynyl.
Term " elementary halogenated alkoxy " is when being used for this paper, is the subclass of the halogenated alkoxy that defines of this paper, and refers to contain the straight or branched halogenated alkoxy of 1-4 carbon atom.The representative example of elementary halogenated alkoxy includes but not limited to trifluoromethoxy, trichlorine methoxyl group, dichloro methoxyl group, fluorine methoxyl group and five fluorine oxyethyl groups.
Term " low-grade halogenated alkyl " is when being used for this paper, is the subclass of the haloalkyl that defines of this paper, and refers to contain the straight or branched haloalkyl of 1-4 carbon atom.The representative example of low-grade halogenated alkyl includes but not limited to trifluoromethyl, trichloromethyl, dichloromethyl, methyl fluoride and pentafluoroethyl group.
Term " sulfydryl " refers to-the SH group when being used for this paper.
Term " mercaptoalkyl " refers to append to by alkyl as defined herein the sulfydryl as defined herein of parent molecular moiety when being used for this paper.The representative example of mercaptoalkyl includes but not limited to 2-mercaptoethyl and 3-sulfydryl propyl group.
Term " methylene-dioxy " refers to-OCH when being used for this paper
2The O-group, wherein the Sauerstoffatom of methylene-dioxy is connected with parent molecular moiety by two adjacent carbon atoms.
Term " nitrogen-protecting group group " refers to be intended to protect amino those groups of avoiding the untoward reaction influence in building-up process when being used for this paper.Preferred nitrogen-protecting group group is ethanoyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl radical, benzenesulfonyl, tert-butoxycarbonyl (Boc), tertiary butyl ethanoyl, trifluoroacetyl group and trityl group (trityl).
Term " nitro " refers to-NO when being used for this paper
2Group.
Term " NZ
1Z
2" when being used for this paper, refer to append to two group Z of parent molecular moiety by nitrogen-atoms
1And Z
2Z
1And Z
2Independently be selected from hydrogen, alkyl, alkyl-carbonyl, alkoxy carbonyl, aryl, arylalkyl, formyl radical and (NZ separately
5Z
6) carbonyl.In some example of the present invention, Z
1And Z
2The nitrogen-atoms that connects with them forms heterocycle.NZ
1Z
2Representative example include but not limited to amino, methylamino, acetylamino, ethanoyl methylamino, phenyl amino, benzylamino, azetidinyl, pyrrolidyl and piperidyl.
Term " NZ
3Z
4" when being used for this paper, refer to append to two group Z of parent molecular moiety by nitrogen-atoms
3And Z
4Z
3And Z
4Independently be selected from hydrogen, alkyl, aryl and arylalkyl separately.NZ
3Z
4Representative example include but not limited to amino, methylamino, phenyl amino and benzylamino.
Term " NZ
5Z
6" when being used for this paper, refer to append to two group Z of parent molecular moiety by nitrogen-atoms
5And Z
6Z
5And Z
6Independently be selected from hydrogen, alkyl, aryl and arylalkyl separately.NZ
5Z
6Representative example include but not limited to amino, methylamino, phenyl amino and benzylamino.
Term " (NZ
3Z
4) carbonyl " when being used for this paper, refer to append to the NZ as defined herein of parent molecular moiety by carbonyl as defined herein
3Z
4Group.(NZ
3Z
4) representative example of carbonyl includes but not limited to aminocarboxyl, (methylamino) carbonyl, (dimethylamino) carbonyl and (ethyl-methyl hydrogen base) carbonyl.
Term " oxo " refers to=the O part when being used for this paper.
Term " sulfinyl " refers to-S (O)-group when being used for this paper.
Term " alkylsulfonyl " refers to-SO when being used for this paper
2-group.
Term " tautomer " is when being used for this paper, refers to that proton moves to another atom of same compound from an atom of compound, wherein the compound that two or more structures are different balance each other.
Though can think that usually asterisk is used to represent that it is indefinite that the accurate subunit of acceptor is formed, for example α 3 β 4
*Expression comprises and the α 3 of other subunit combinations and the acceptor of β april protein, forms clear and definite and indefinite acceptor but term α 7 used herein is intended to comprise wherein accurate subunit.For example, term α 7 used herein comprises with (α 7) 5 acceptors and the α 7 of imitating
*Acceptor, its expression contain the nAChR of at least one α 7 subunit.
Compound of the present invention
Compound of the present invention can have the formula described in the summary of the invention (I) structure.
Within the scope of the invention, compound of the present invention has following formula
L wherein
1, Ar
1, Ar
2, L
2, L
3, Ar
3, Ar
4And Ar
5As definition in the cotype (I).
In one embodiment, compound of the present invention can have formula (II) structure, wherein L
1And Ar
1As definition in the previous formula (I).In the compound of formula (II), Ar
1Can more particularly be selected from the group of following structure:
D wherein
1, E
1, F
1, J
1, K
1, and X
8-X
11Independently be-CR separately
1Or N; X
12-X
15, M
1And M
2Independent separately is CR
1, N or C; G
1For-O-, NR
1a, or-S-; Y
1For-CR
1Or N; Y
2For-CR
1Or N; Y
3For NH ,-O-or-S-; R
1For hydrogen, alkyl, alkoxyl group, alkoxy carbonyl, cyano group, halogen, nitro ,-NR
bR
c, haloalkyl or-C (O) NR
bR
cR
1aBe hydrogen or alkyl; R
bAnd R
cIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl.At Ar
1In the group of expression, preferred D
1, E
1, F
1, J
1, and K
1In at the most two be N.At Ar
1In the group of expression, preferred group X
12-X
15Or X
8-X
11In at the most two be N.At Ar
1In the group of expression, X
12-X
15One of be C.At Ar
1In the group of expression, M
1Or M
2Be C.Preferably, Ar
1Be imidazolyl, isoxazolyl, furyl, oxazolyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, 1,3-thiazoles base, 1,3,4-thiadiazolyl group, 1,3,4-oxadiazole base, benzoxazolyl, 1,3-benzothiazolyl.Preferred Ar
1Group is pyridazinyl, pyridyl, 1,3-thiazoles base, 1,3,4-thiadiazolyl group, 1,3,4-oxadiazole base, benzoxazole-2-base or 1,3-benzothiazolyl.In special embodiment, L
1For-O-and Ar
1As described in this paper formula (I) or any special or embodiment preferred.In another special embodiment, L
1For-NR
a-and Ar
1As described in this paper formula (I) or any special or embodiment preferred.
In another embodiment, compound of the present invention can have formula (III) structure, wherein L
1, Ar
2, L
2, and Ar
3Described in previous formula (I) compound.In the compound of formula (III), Ar
2Can more particularly be selected from the group of following structure:
D wherein
2, E
2, F
2, J
2, and K
2Independently be-CT separately
2Or N; G
2For-O-,-NR
2a, or-S-; At above (i), (ii) and in each group (iii), one by T
2Or R
2a(R wherein
2aBe T
2) expression substituting group be-L
2-Ar
3And other is by T
2The substituting group of expression be hydrogen, alkyl, alkoxyl group, alkoxy carbonyl, cyano group, halogen, nitro or-NR
bR
cR
2aBe hydrogen, alkyl or T
2And R
bAnd R
cIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl.Ar
3Can more particularly be selected from the group of following structure:
D wherein
3, E
3, F
3, J
3, K
3, and X
8, X
9, X
10, and X
11Independently be-CR separately
3Or N; X
16, X
17, X
18, X
19, M
1, and M
2Independently be-CR separately
3, N or C; G
3For-O-,-NR
3a, or-S-; Y
1And Y
2For-CR
3Or N; Y
3For NH ,-O-or-S-; R
3Be hydrogen, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl, cyano group, halogen, halogenated alkoxy, haloalkyl, hydroxyl, nitro, R
eR
fN-or aryl; R
3aBe hydrogen, alkyl, alkyl-carbonyl, trityl or aryl, wherein aryl is preferably phenyl; R
eAnd R
fIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl, or R
eAnd R
fThe nitrogen-atoms that connects with them forms heterocycle separately.R
3Preferred aryl groups is the optional phenyl that is replaced by halogen, alkyl or cyano group.R wherein
eAnd R
fAdopt heterocycle to be preferably pyrrolidyl, piperidyl or piperazinyl separately together to form ring.At Ar
3In the group of expression, preferred D
3, E
3, F
3, J
3, and K
3In at the most two be N.At Ar
3In the group of expression, preferred group X
16-X
19Or X
8-X
11In at the most two be N.At Ar
3In the group of expression, X
16, X
17, X
18, or X
19One of be C.At Ar
3In the group of expression, M
1Or M
2Be C.A special embodiment relates to wherein L
1For-O-or-NR
1aAnd L
2Formula (III) compound for-O-.Also consider to relate to wherein L
1For-O-or-NR
1aAnd L
2Formula (III) compound for key.Preferably, L
1For-O-and L
2Be Ar in formula (III) compound of key
2And Ar
3As described in previous formula (I) compound or as described in the previous special or embodiment preferred.In a special embodiment, the present invention relates to formula (III) compound, wherein L
1For-O-or-NR
aAr
2Be phenyl or heteroaryl ring; L
2For key ,-O-,-NR
a-,-CH
2-or-C (O) NR
3-; And Ar
3Be aryl or heteroaryl ring, preferred phenyl, pyrazinyl or pyridyl.
In another embodiment, compound of the present invention can have formula (IV) structure, wherein L
1, Ar
4, L
3, and Ar
5Definition is as cotype (I) compound.Preferably, in formula (IV) compound, Ar
4-L
3-Ar
5Group is to be selected from following group:
Y wherein
4For-NR
4a-,-O-or-S-; Y
5And Y
6For-N-,-CR
4-or C, condition is Y
5Or Y
6One of be C; R
4Be hydrogen, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl, cyano group, halogen, halogenated alkoxy, haloalkyl, hydroxyl, nitro, oxo or R
eR
FN-; R
4aBe hydrogen or alkyl; R
eAnd R
fIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl, or R
eAnd R
fThe nitrogen-atoms that connects with them forms heterocycle separately, and wherein heterocycle is preferably pyrrolidyl, piperidyl or piperazinyl; X
4For-N-,-CR
X4-or C, X
5For-N-,-CR
X5-or C, X
6For-N-,-CR
X6-or C, and X
7For-N-,-CR
X7-or C, condition is X
4, X
5, X
6Or X
7Have only one to can be-N-, have only one for C, and remaining must be different from-N-, and R
X4, R
X5, R
X6And R
X7Independent separately is hydrogen or alkyl.Preferred Ar4 is 1,3-benzothiazole-2-base.
Ar in formula (IV) compound
5Suitable and preferred group is the Ar suc as formula the definition of (II) compound
1Or suc as formula the Ar of (III) compound definition
3
In addition, the present invention also is intended to formula (IV) compound or formula (VII) compound
Or its pharmacy acceptable salt or prodrug, wherein L
1For-O-or-NR
a-; A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5Ar
1Be aryl or heteroaryl; Ar
2Be aryl or heteroaryl; Ar
3Be aryl or heteroaryl; Ar
4Be bicyclic heteroaryl; Ar
5Be aryl or heteroaryl; L
2For key ,-O-,-NR
a-,-CH
2-or-C (O) NR
a-; L
3For key ,-O-,-NR
a-or-CH
2-; And R
1Be hydrogen or alkyl.
Further, the compound of formula (IV) or formula (VII) is as the prodrug of formula (I) compound.
Specific embodiment is considered as a part of the present invention, includes but not limited to formula (I) compound or its salt or prodrug, for example:
(4s)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-phenyl pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-phenyl pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[6-(1H-indoles-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[6-(1H-indoles-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[6-(1-thionaphthene-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[6-(1-thionaphthene-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(1H-indoles-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(thionaphthene-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl thiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(3-chloro-phenyl-)-thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(3-chloro-4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(4-fluorophenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(3, the 5-difluorophenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound; 5-[2-(1-aza-tricycle [3.3.1.1
3,7] decane-(4s)-and Ji oxygen base) thiazole-5-yl]-Indolin-2-one;
5-[2-(1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound-(4s)-and Ji oxygen base) thiazole-5-yl]-Indolin-2-one (indolin-2-one);
(4s)-4-[5-(2-Trifluoromethyl-1 H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-6-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indol-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(pyridin-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(furans-2-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(furans-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(thiene-3-yl-)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(pyrazoles-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-bromo-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound;
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(1H-indoles-6-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(1H-indoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(thionaphthene-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(pyrazoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenoxy group-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4r)-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-(6-phenylpyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[6-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-(5-pyridine bromide-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(indoles-6-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(indoles-4-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(3-aminomethyl phenyl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(3-chloro-phenyl-)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-4N-[5-(3-chloro-phenyl-benzene-3-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(1-pyridine oxide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(2-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(2-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-picoline-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[4-(trifluoromethyl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-fluorinated pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-iodo pyridin-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] niacinamide;
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1H-pyrazol-1-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(4-chloro-phenyl-) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(3,4 '-dipyridyl-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(6-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-formonitrile HCN;
(4s)-and 4-[(5-thiophene-2-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1H-indoles-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-{[6-(1H-indoles-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1H-indoles-6-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-{[6-(1H-indoles-6-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
5-{5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-yl }-1,3-dihydro-2H-indol-2-one;
(4r)-and 4-{[6-(1-cumarone-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5,6-two bromo pyridin-3-yls) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-fluorinated pyridine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(3,3 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridine-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
6-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl pyridine-2-carboxamide;
(4s)-and 4-[(2-chloro-pyridine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-methyl pyridazine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrimidine-2-yloxy)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-brominated pyrimidine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrimidine-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrimidine-4-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-Chloropyrimide-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1-trityl-1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-pyridin-4-yl pyrimidine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrazine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
4-[(6-methylpyrazine-2-yl) oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(6-phenyl pyrazines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(1,3-thiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(5-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-[4-(trifluoromethoxy) phenyl]-1,3-thiazoles-2-yl } the oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(4-chloro-phenyl-)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
4-{2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-1,3-thiazoles-5-yl } aniline;
(4s)-and 4-[(5-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(5-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyrimidine-5-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(2-methoxy pyrimidine-5-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(2-tetramethyleneimine-1-yl pyrimidines-5-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(6-piperazine-1-yl pyridines-3-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1H-pyrazol-1-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-propyl group-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-isobutyl--1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-ethanoyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-isoxazole-4-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-chloro-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.11
3,7] decane;
(4s)-and 4-{[4-(1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-phenyl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-pyridin-4-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl-1,3-thiazoles-4-methane amide;
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-(4-chloro-phenyl-)-1,3-oxazole-4-methane amide;
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-phenyl-1,3-oxazole-4-methane amide;
(4s)-and 4-{[5-(3-bromo phenyl)-1,3,4-thiadiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-{5-[1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-1,3,4-thiadiazoles-2-yl } phenol;
(4s)-N-pyridin-3-yl-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-(5-bromo-6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[6-(1H-indoles-6-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[6-(1H-indol-3-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-4-[5-(1H-indoles-5-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-6-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(1H-indoles-5-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(1H-indoles-6-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane; Aza-tricycle [3.3.1.1
3,7] decane; With
(4r)-4-[5-(1-cumarone-5-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane.
The compounds of this invention can be used as the steric isomer that wherein has asymmetric or chiral centre and exists.According to substituent configuration around the chiral element, these steric isomers be " R " or " S ' type.Term " R " and " S " configuration of being used for this paper are defined in IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl.Chem., 1976,45:13-30.The present invention has considered various steric isomers and composition thereof, and it is all particularly including within the scope of the present invention.Steric isomer comprises enantiomorph, diastereomer and enantiomorph or non-enantiomer mixture.The various single stereoisomers of The compounds of this invention can be asymmetric with containing of commercially available acquisition or synthetic the making of raw material of chiral centre, perhaps by the preparation racemic mixture, makes by the well-known Split Method of those skilled in the art then.These method for splitting examples have: (1) is connected mixture of enantiomers on the chiral adjuvant, by recrystallization or the separating obtained non-enantiomer mixture of chromatography, choose wantonly and discharge the optically-active pure products from auxiliary, as be same as Fumiss, Hannaford, Smith, and Tatchell, " Vogel ' s Textbook of Practical OrganicChemistry ", the 5th edition (1989), Longman Scientific﹠amp; Technical, Essex CM202JE, described in the England, perhaps (2) directly separate the optically active enantiomorph mixture on chiral chromatographic column, perhaps (3) substep recrystallization method.
More specifically, The compounds of this invention can be with formula (Ia) and (Ib) the form existence of representative.
The azaadamantane of isomer (Ia) and isomer (Ib) partly is an achirality, yet connects L
1C-4 carbon be considered to pseudoasymmetric.Formula (Ia) and the compound of (Ib) representing are diastereomers.According to Synthesis, 1992,1080, Becker, D.P.; Flynn is described in the D.L. and according to Stereochemistry of Organic Compounds, E.L.Eliel, S .H Wilen; John Wiley and Sons stipulate among the Inc.1994, and 4r is appointed as in the assignment of configuration of formula (Ia) structure.And use identical method 4s is appointed as in the assignment of configuration of formula (Ib) structure.
Isomer (Ia) and (Ib) can according to scheme described herein or the experiment synthesize with various single stereoisomers separately.Alternative ground, when using stereoisomer mixture in synthetic, isomer (Ia) and (Ib) can synthesize is together isolated individual isomer by chromatography then from two kinds of mixture of isomers.By being included in amine salt in formula (I) compound with enantiomer-pure carboxylic acid Steppecd crystallization, mixture that also can the separating isomerism body.
Can consider two kinds of mixture of isomers are used to regulate the effect of nAChR.And, can consider formula (Ia) and individual isomer (Ib) are used to separately regulate the effect of nAChR.Therefore, consider formula (Ia) and (Ib) compound mixture or by formula (Ia) or (Ib) the independent individual isomer of representative of compound, all can effectively regulate the more especially effect of α 7 nAChR, α 4 β, 2 nAChR or α 7nAChR and α 4 β 2 nAChR associating of nAChR, thereby it is comprised within the scope of the invention.
More specifically, preferred compound is considered as a part of the present invention, comprises
L wherein
1, L
2, L
3, Ar
1, Ar
2, Ar
3, Ar
4, and Ar
5As defined herein.
Moreover consideration will can be used for the formula V compound of production (I) compound and use
Comprise within the scope of the invention.
And, within the scope of the invention, comprise the compound of formula (VI) and the compound of formula (VII)
Or its pharmacy acceptable salt or prodrug, wherein L
1For-O-or-NR
a-; A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5Ar
1Be aryl or heteroaryl; Ar
2Be aryl or bicyclic heteroaryl; Ar
3Be aryl or heteroaryl; Ar
4Be bicyclic heteroaryl; Ar
5Be aryl or heteroaryl; L
2For key ,-O-,-NR
8-,-CH
2-or-C (O) NR
a-; L
3For key ,-O-,-NR
a-or-CH
2-; And R
aBe hydrogen or alkyl.
In addition, the compound of formula (IV) is as the prodrug of formula (I) compound.Further, the compound of formula (VII) is as the prodrug of formula (I) compound.
Specific embodiment is considered as a part of the present invention, includes but not limited to the compound of formula (VI), for example:
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex (N-borane complex);
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(1-pyridine oxide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(2-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(2-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(4-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(4-picoline-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-{[4-(trifluoromethyl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(5-fluorinated pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(5-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(5-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(5-iodo pyridin-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] niacinamide N-borane complex;
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-{[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-{[5-(4-chloro-phenyl-) pyridine-3-yI] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(3,4 '-dipyridyl-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(6-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-and 4-[(6-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(5-fluoro-pyridine-2-base oxygen base)-1-azepine-three ring [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(5-fluoro-pyridine-2-base oxygen base)-1-azepine-three ring [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(6-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-formonitrile HCN N-borane complex N-borane complex;
(4s)-and 4-[(5,6-two bromo pyridin-3-yls) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-4-(pyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-and 4-[(5-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-and 4-[(4-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-4-(3,3 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4r)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-and 4-[(2-chloro-pyridine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-and 4-[(6-methyl pyridazine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-4-(pyrimidine-2-yloxy)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-and 4-[(5-brominated pyrimidine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-4-(pyrimidine-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4s)-4-(pyrazine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
4-[(6-methylpyrazine-2-yl) oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4r)-and 4-[(6-phenyl pyrazines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex N-borane complex;
(4r)-4-(1,3-thiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(5-[4-(trifluoromethoxy) phenyl]-1,3-thiazoles-2-yl } the oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(5-pyrimidine-5-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex; With
(4s)-and 4-[(4-chloro-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex.
Specific embodiment is considered as a part of the present invention, includes but not limited to the compound of formula (VII), for example:
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound;
(4s)-5-4-[2-(1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound-Ji oxygen base) thiazole-5-yl]-Indolin-2-one; Or
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound.
Salt character
The specific salts of The compounds of this invention also obtains identifying and describing in this article.More specifically, such salt is (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] anhydrous L-bitartrate, L-hydrogen tartrate salt hydrate, anhydrous phosphoric acid dihydric salt, biphosphate salt hydrate, anhydrous disuccinate, disuccinate hydrate, hydrochloride four/monohydrate, hydrochloride sesquialter hydrate, dihydrogen citrate salt and the citric acid hydrogen salt (monohydrogen citrate) of decane.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of anhydrous L-bitartrate of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 1).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the anhydrous L-bitartrate solid of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of anhydrous L-bitartrate of decane is 4.96 ± 0.20,9.99 ± 0.20,11.77 ± 0.20,14.62 ± 0.20,14.99 ± 0.20,18.14 ± 0.20,18.44 ± 0.20,19.48 ± 0.20,20.05 ± 0.20,21.02 ± 0.20,21.38 ± 0.20,22.76 ± 0.20,24.74 ± 0.20,26.65 ± 0.20 and 32.19 ± 0.20.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of L-hydrogen tartrate salt hydrate of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 2).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the L-bitartrate hydrate solids of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of L-hydrogen tartrate salt hydrate of decane is 4.63 ± 0.20,9.26 ± 0.20,13.43 ± 0.20,13.91 ± 0.20,15.98 ± 0.20,17.86 ± 0.20,21.36 ± 0.20 and 22.33 ± 0.20.TGA (Fig. 2 A) shows (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] dehydration of L-hydrogen tartrate salt hydrate of decane.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of anhydrous phosphoric acid dihydric salt of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 3).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the anhydrous phosphoric acid dihydric salt solid of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of anhydrous phosphoric acid dihydric salt of decane is 5.14 ± 0.20,10.31 ± 0.20,11.20 ± 0.20,13.17 ± 0.20,13.47 ± 0.20,15.61 ± 0.20,16.69 ± 0.20,17.27 ± 0.20,17.50 ± 0.20,18.56 ± 0.20,18.90 ± 0.20,19.41 ± 0.20,20.93 ± 0.20,21.80 ± 0.20,22.53 ± 0.20,23.96 ± 0.20,26.01 ± 0.20 and 26.44 ± 0.20.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of biphosphate salt hydrate of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 4).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the dihydrogen phosphate hydrate solids of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of biphosphate salt hydrate of decane is 5.28 ± 0.20,9.82 ± 0.20,10.61 ± 0.20,13.79 ± 0.20,14.24 ± 0.20,15.13 ± 0.20,16.65 ± 0.20,16.95 ± 0.20,18.35 ± 0.20,19.52 ± 0.20,19.84 ± 0.20,21.55 ± 0.20,23.85 ± 0.20,24.26 ± 0.20 and 25.80 ± 0.20.TGA (Fig. 4 A) shows (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] dehydration of biphosphate salt hydrate of decane.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of anhydrous disuccinate of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 5).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the anhydrous disuccinate solid of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of anhydrous disuccinate of decane is 12.53 ± 0.20,13.50 ± 0.20,14.76 ± 0.20,16.98 ± 0.20,18.07 ± 0.20,18.34 ± 0.20,18.35 ± 0.20,18.88 ± 0.20,19.62 ± 0.20,19.67 ± 0.20,20.00 ± 0.20,20.71 ± 0.20,23.64 ± 0.20,23.96 ± 0.20,25.61 ± 0.20 and 36.29 ± 0.20.Also obtained (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the crystal unit cell parameters of anhydrous disuccinate of decane, and record: a is 12.958 (17)
B is 7.561 (10)
C is 39.66 (5)
With β be 94.54 (2) °, be 3873.51 thereby obtain unit-cell volume
Wherein a, b and c represent that separately lattice length and β are the structure cell angle.The crystallization in monocline P21/c spacer of this salt.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of disuccinate hydrate of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 6).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the disuccinate hydrate solids of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of disuccinate hydrate of decane is 8.92 ± 0.20,10.94 ± 0.20,11.71 ± 0.20,13.41 ± 0.20,14.90 ± 0.20,17.61 ± 0.20,17.92 ± 0.20,18.19 ± 0.20,19.60 ± 0.20,22.58 ± 0.20,26.19 ± 0.20 and 27.07 ± 0.20.TGA (Fig. 6 A) shows (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] dehydration of disuccinate hydrate of decane.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (1 salt: crystalline solid 0.25 water) can be identified by the characteristic peak by its powder x-ray diffraction figure (Fig. 7) for the hydrochloride four/monohydrate of decane.The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] hydrochloride four/monohydrate solid of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of hydrochloride four/monohydrate of decane is 5.19 ± 0.20,12.96 ± 0.20,13.00 ± 0.20,14.88 ± 0.20,14.98 ± 0.20,15.61 ± 0.20,17.79 ± 0.20,18.26 ± 0.20,18.93 ± 0.20,20.02 ± 0.20,20.67 ± 0.20,20.86 ± 0.20,21.72 ± 0.20,22.38 ± 0.20,22.55 ± 0.20,24.09 ± 0.20 and 26.10 ± 0.20.Also obtained (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the crystal unit cell parameters of hydrochloride four/monohydrate of decane, and record: a is 19.440 (7)
B is 9.969 (4)
C is 35.322 (13)
With β be 105.325 (17) °, be 6601.91 thereby obtain unit-cell volume
Wherein a, b and c represent that separately lattice length and β are the structure cell angle.The crystallization in monocline P21/c spacer of this salt.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (1 salt: crystalline solid 1.5 water) can be identified by the characteristic peak by its powder x-ray diffraction figure (Fig. 8) for the hydrochloride sesquialter hydrate of decane.The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the hydrochloride sesquialter hydrate solids of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of hydrochloride sesquialter hydrate of decane is 4.94 ± 0.20,9.93 ± 0.20,14.09 ± 0.20,14.90 ± 0.20,17.85 ± 0.20,19.92 ± 0.20,21.72 ± 0.20,22.43 ± 0.20,22.63 ± 0.20 and 23.95 ± 0.20.TGA (Fig. 8 A) shows (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] dehydration of hydrochloride sesquialter hydrate of decane.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of dihydrogen citrate salt of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Fig. 9).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the dihydrogen citrate salt solid of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of dihydrogen citrate salt of decane is 7.98 ± 0.20,11.98 ± 0.20,12.45 ± 0.20,15.76 ± 0.20,16.00 ± 0.20,17.75 ± 0.20,18.79 ± 0.20,18.82 ± 0.20,20.59 ± 0.20,22.25 ± 0.20,22.61 ± 0.20,24.16 ± 0.20,24.79 ± 0.20,25.06 ± 0.20,26.21 ± 0.20 and 29.43 ± 0.20.Also obtained (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the crystal unit cell parameters of dihydrogen citrate salt of decane, and record: a is 22.651 (8)
B is 9.992 (3)
C is 10.338 (4)
With β be 101.961 (5) °, be 2288.99 thereby obtain unit-cell volume
Wherein a, b and c represent that separately lattice length and β are the structure cell angle.The crystallization in monocline P21/c spacer of this salt.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline solid of citric acid hydrogen salt of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Figure 10).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the citric acid hydrogen salt solid of decane.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of citric acid hydrogen salt of decane is 9.37 ± 0.20,9.62 ± 0.20,10.30 ± 0.20,11.24 ± 0.20,12.18 ± 0.20,13.73 ± 0.20,15.55 ± 0.20,16.17 ± 0.20,16.37 ± 0.20,16.76 ± 0.20,18.35 ± 0.20,18.67 ± 0.20,18.89 ± 0.20,19.98 ± 0.20,20.48 ± 0.20,20.94 ± 0.20,21.54 ± 0.20 and 22.02 ± 0.20.
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] free alkali of decane can identify by the characteristic peak by its powder x-ray diffraction figure (Figure 11).The technician in analytical chemistry field should be able to easily identify (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 by the few as characteristic peak among its powder x-ray diffraction figure
3,7] the decane free alkali.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the position, 2 θ angle of characteristic peak among the powder x-ray diffraction figure of decane free alkali is 7.18 ± 0.20,10.19 ± 0.20,13.90 ± 0.20,14.37 ± 0.20,14.40 ± 0.20,14.66 ± 0.20,15.09 ± 0.20,15.21 ± 0.20,18.13 ± 0.20,18.43 ± 0.20,19.41 ± 0.20,19.88 ± 0.20 (two peaks), 20.09 ± 0.20,20.46 ± 0.20,21.66 ± 0.20,23.08 ± 0.20,26.84 ± 0.20,28.71 ± 0.20 and 30.90 ± 0.20.Also obtain (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the crystal unit cell parameters of decane free alkali, and record: a is 6.4427 (17)
B is 9.895 (3)
C is 13.102 (4)
And α is 70.145 (4) °, and β is that 81.691 (4) ° and γ are 73.391 (4) °, is 751.787 thereby obtain unit-cell volume
Wherein a, b and c represent that separately lattice length and α, β and γ are the structure cell angle.The crystallization in three oblique P-1 spacers of this salt.
Term used herein " pure basically " is when being used for describing (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.11
3,7] during the salt of decane, the purity that is meant salt is greater than about 90%.(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline form of decane do not contain any other compound of having an appointment more than 10%, and particularly do not contain (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 that has an appointment more than 10%
3,7] any other form of decane, for example amorphous, solvent version, non-solvent form, desolvation form and enantiomorph.
More preferably, the purity that the salt of " pure basically " is meant salt is greater than about 95%, wherein (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline form of decane do not contain any other compound of having an appointment more than 5%, and particularly do not contain (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 that has an appointment more than 5%
3,7] any other form of decane, for example amorphous, solvent version, non-solvent form, desolvation form and enantiomorph.
More preferably, the purity that the salt of " pure basically " is meant salt is greater than about 97%, wherein (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] crystalline form of decane do not contain any other compound of having an appointment more than 3%, and particularly do not contain (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 that has an appointment more than 3%
3,7] any other form of decane, for example amorphous, solvent version, non-solvent form, desolvation form and enantiomorph.
Also be intended to relate to and comprise (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] composition of decane salt.The pharmaceutical composition that is suitable for comprises pure basically (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 for preparing with one or more pharmaceutically acceptable carriers of non-toxicity described in previous composition
3,7] decane salt.Comprise (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] this based composition of decane salt is by administration and can be used in the method for the present invention described in previous The compounds of this invention, except replacing the compound with the salt that needs, this should be to understand easily to those skilled in the art.
The powder x-ray diffraction of sample (PXRD) analysis is carried out in such a way.By being layered on the specimen holder and with microslide, the skim sample flattens sample gently, the sample that the preparation powder x-ray diffraction is analyzed.For example, sample can grind to form fine powder or the sample of limiting the quantity of is broken into pieces with glass microscope slide with mortar and pestle.Sample is moved in one of following three kinds of configurations: ring-type in bulk (circular bulk holder), quartzy zero background board, hot microscope carrier fixer (similarly fixing) with zero background board.
Application is equipped with incident beam germanium monochromator so that Cu-K to be provided
α 1The Inel G3000 diffractometer (difrractometer) of light beam is collected diffractogram.X-ray generator is operated under 40kV voltage and 30mA electric current.Inel G3000 has position sensitive detector, monitors all diffraction datas simultaneously.Detector is calibrated by cross the straight bundle of 90 degree, 2 θ angles collection decay in seven seconds at interval with 1 degree.(NIST 640c) examines calibration with reference standard silicon line position.Sample is placed on the aluminium specimen holder, and make slide glass maintenance level.
Rigaku Miniflex diffractometer (30kV and 15mA can be used in alternative ground; X-ray source: Cu; Scope: 2.00-40.00 ° of 2 θ; Sweep velocity: 1-5 °/minute) or Scintag X1 or X2 diffractometer (the 2kW standard focuses on the X-x ray tube, carries liquid nitrogen or Peltier cooling germanium solid state detector; 45kV and 40mA; X-ray source: Cu; Range:2.00-40.00 ° of 2 θ; Sweep velocity: 1-5 °/minute), carry out the X-ray powder diffraction.
Report in the mode that contains the position, angle (2 θ) that allows ± 0.20 ° of variation the peak position of characteristic powder X-ray diffraction figure.± 0.10 ° variation is intended to be used for two kinds of powder x-ray diffraction figure of comparison.In fact, if from the scope of the position, designated angle, diffractogram peak (2 θ) among the figure (its for measure peak position ± 0.20 °), with from the scope of the position, designated angle, diffractogram peak (2 θ) among another figure (its for measure peak position ± 0.20 °), if and those scopes of peak position have overlappingly, these two peaks are considered to have identical position, angle (2 θ) so.For example, be changed to 5.20 °, be the scope of the admissible variation permission of comparison purpose peak specified location at 5.00 °-5.40 ° if measure peak position from the diffractogram peak among the figure.Be changed to 5.35 ° if measure peak position from contrast peak in another diffractogram, admissible variation allows the peak specified location 5.15 °-5.55 ° scope, the peak of these two comparisons is considered to have identical position, angle (2 θ) so, because have overlapping between these two scopes of peak position.
The monocrystalline X-ray diffraction analysis of sample is carried out in such a way.By selected monocrystalline being sticked on the glass needle (pins) sample that the preparation X-ray diffraction is analyzed with epoxy adhesive.Application has Broker SMART System (50kv and the 40mA of APEX area detector; X-ray source: Mo), collect the X-ray diffraction data.Collect data at-100 ℃.
The thermogravimetric analysis of sample is carried out in such a way.Use Mettler Toledo ModelTGA/SDTA 851e thermogravimetric analysis instrument, working sample weight is to the variation of sample temperature.Experimentize and analyze with Mettler STARe software.Experiment parameter is: example weight 2-20mg places open aluminium dish; 10 ℃ of rate of heating per minutes, N
2Purifying flow velocity is per minute 50mL.Sample is heated to 200 ℃ with 10 ℃ of speed of per minute from 25 ℃.
Inventive method
Compound of the present invention and composition are useful on nAChR, the more especially effect of α 7 nAChR regulated.Especially, compound of the present invention and the composition illness that can be used for treating or prevent to regulate by α 7nAChR.Usually, this type of illness can be regulated mammiferous α 7nAChR by selectivity and be improved, preferably by for example giving compound of the present invention or composition as the part of treatment plan separately or with another kind of promoting agent combination.
In addition, the method of disease, illness or the defective that the present invention relates to treat or prevent to regulate by alpha 7 nicotinic acetylcholine receptor, α 4 β, 2 nAChRs or α 7 and 2 two kinds of nAChRs of α 4 β, wherein disease, illness or damagedly be selected from dysmnesia, cognitive disorder, neurodegeneration or neurodevelopment obstacle or its combination, this method comprises formula (I) compound or its pharmacy acceptable salt or the prodrug of administering therapeutic appropriate amount
L wherein
1For-O-or-NR
a-; A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5Ar
1Be aryl or heteroaryl; Ar
2Be aryl or bicyclic heteroaryl; Ar
3Be aryl or heteroaryl; Ar
4Be bicyclic heteroaryl; Ar
5Be aryl or heteroaryl; L
2For key ,-O-,-NR
3-,-CH
2-,-C (O) NR
a-; L
3For key ,-O-,-NR
a-or-CH
2-; And R
aBe hydrogen or alkyl.
The invention still further relates to treatment or prevention by the disease of alpha 7 nicotinic acetylcholine receptor adjusting or the method for illness, comprise the step of the formula of using (I) compound, wherein disease or illness are selected from dysmnesia, cognitive disorder, neurodegeneration and neurodevelopment obstacle.
The invention still further relates to treatment or prevention by the disease of alpha 7 nicotinic acetylcholine receptor adjusting or the method for illness, comprise the step of the formula of using (I) compound, wherein disease or illness are selected from attention deficit disorder, attention deficit moves obstacle (ADHD) more, alzheimer's disease (AD), mild cognitive impairment, schizophrenia, senile dementia, the AIDS dementia, Pick's disease, Louis body dependency dementia, mongolism dependency dementia, amyotrophic lateral sclerosis, Huntington Chorea, traumatic brain injury dependency CNS hypofunction, acute pain, post-operative pain, chronic pain and inflammatory pain.
The invention still further relates to treatment or prevention by the disease of alpha 7 nicotinic acetylcholine receptor adjusting or the method for illness, comprise the step of the formula of using (I) compound, wherein disease or illness are schizophrenia.
The invention still further relates to the disease that treatment or prevention regulated by the alpha 7 nicotinic acetylcholine receptor or the method for illness, comprise step with combined administration formula (I) compound of atypical antipsychotic agents.
The invention still further relates to treatment or prevention by the disease of alpha 7 nicotinic acetylcholine receptor adjusting or the method for illness, the step that comprises the formula of using (I) compound, wherein disease or illness are Infertility, circulation deficiency, wound healing dependency neovascularity growth (the more especially circulation around the vascular occlusion) shortage, skin graft vascularization dependency neovascularity growth shortage, ischemic, inflammation (those particularly relevant with rheumatoid arthritis inflammation), wound healing and other diabetes associated complication.
The invention still further relates to the disease that treatment or prevention regulated by 2 two kinds of nAChRs of α 7 and α 4 β or the method for illness, comprise the step of the formula of using (I) compound, wherein disease or illness are selected from the illness that α 7 and 2 two kinds of nAChRs of α 4 β involve.They comprise attention deficit disorder, attention deficit moves obstacle (ADHD) more, alzheimer's disease (AD), mild cognitive impairment, schizophrenia, senile dementia, the AIDS dementia, Pick's disease, Louis body dependency dementia, mongolism dependency dementia, amyotrophic lateral sclerosis, Huntington Chorea, inflammation, all kinds sacroiliitis, smoking cessation, nicotine abstinence syndrome, traumatic brain injury, acute pain, post-operative pain, osteoarthritis pain, nervosa and inflammatory chronic pain state.
The compound of the inventive method includes but not limited to the specified or compound specifically mentioned in addition among the embodiment, all can regulate and usually to nAChR, more especially α 7 nAChR have avidity.As α 7 nAChR parts, The compounds of this invention can be used for treating or preventing the disease or the illness of multiple α 7 nAChR-mediation.Some compound of the present invention comprises that except that α 7 nAChR are had the avidity α 4 β 2 nAChR are also had avidity.
For example, α 7 nAChR have shown remarkable effect (Levin, E.D., J.Neurobiol.53:633-640,2002) on enhancing comprises cognitive function aspect study, memory and the attention.Like this, α 7 parts are applicable to treatment and memory and/or cognitive diseases associated and illness, and described disease comprises with illness for example attention deficit disorder, attention deficit move obstacle (ADHD), alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, Pick's disease, Louis body dependency dementia and mongolism dependency dementia and the cognitive defect relevant with schizophrenia more.
In addition, the nAChR that comprises α 7 has been presented at and has related to nicotine external (Jonnala, R.B. and Buccafusco; J.J., J.Neurosci.Res.66:565-572,2001) and the interior (Shimohama of body; S. etc., Brain Res.779:359-363,1998) cytoprotection.More specifically, neurodegeneration is the basis of several carrying out property CNS illnesss (including but not limited to the CNS hypofunction that alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington Chorea, Louis body dependency dementia and traumatic brain injury cause).For example, the amyloid-beta peptide relevant with alzheimer's disease causes that the functional defect of α 7 nAChR has been regarded as key factor (Liu, the Q.-S. of the cognitive defect morbidity relevant with disease, Kawai, H., Berg, D.K., PNAS 98:4734-4739,2001).The α 7 selective ligands protection approach that can affect the nerves; cause the tau protein phosphorylated to reduce; this hyperphosphorylation is to form the necessary (Bitner etc. of neurofibrillary tangles in the relevant pathology of multiple τ such as alzheimer's disease and multiple other dementia; Soc.Neuroscience, 2006 abst 325.6).The activation that has shown α 7 nAChR can be blocked this neurotoxicity (Kihara, T. etc., J.Biol.Chem.276:13541-13546,2001).Like this, improve the defective that α 7 active selective ligands can be resisted alzheimer's disease and other neurodegenerative disease.
α 7 nAChR also relate to the neurodevelopment aspect, as the nerve generation of brain.(Falk, L. etc., Developmental Brain Research 142:151-160,2003; Tsuneki, H., etc., J.Physiol. (London) 547:169-179,2003; Adams, GE., etc., Developmental BrainResearch 139:175-187,2002).Like this, α 7 nAChR can be used for impaired diseases associated of prevention or treatment and neurodevelopment or illness, as schizophrenia.(Sawa?A.，Mol.Med.9：3-9，2003)。
Several compounds that α 4 β, 2 neuronal nicotinic receptors (NNR) had a high-affinity with preclinical models that attention deficit/how moving obstacle (ADHD) is relevant in shown and can improve attention and cognitive behavior that described ADHD disease was characterised in that was moving, be not absorbed in and the core symptom of impulsion.For example full agonist ABT-418 cognitive model before various clinical of α 4 β 2 NNR is effective.Transdermal administration ABT-418 demonstrates in 32 adults' controlled clinical trial and is effective in general treatment ADHD and is effective in treatment attention/cognitive defect (Wilens, T.E especially; Biederman, J.; Spencer, T.J.; Bostic, J.; Prince, J.; Monuteaux, M.C.; Soriano, J.; Fince, C.; Abrams, A.; Rater, M.; Polisner, D.The American Journal of Psychiatry (1999) 156 (12), 1931-1937).Equally, ABT-418 demonstrates the useful signal effect in the tentative test of alzheimer's disease.α 4 β 2 selectivity partial agonist ABT-089 have demonstrated at rodent and primate model and have improved attention, learning and memory defective.ABT-089 and another α 4 β2Ji Dongji ispronicline have demonstrated effectively in tentative clinical trial.Except cognition, with the α interactional compound of 4 β, 2 nAChR such as ABT-594 and other compound before pain clinical and demonstrated effective in the clinical model.Therefore, regulate α 7 and 2 two kinds of active parts of α 4 β and can in morbid state (as relating to cognitive and attention deficit, pain, nerve degenerative diseases etc.), have the more result of treatment of wide spectrum.
Schizophrenia is a kind of disease of complexity, it is characterized in that perception, cognition and emotion are unusual.There are important evidence prompting α 7 nAChR to relate to this disease, are included in the shortage (Sawa A., Mol.Med 9:3-9,2003 that measure these acceptors among the necrotomy patient; Leonard, S.Eur.J.Pharmacol.393:237-242,2000).The shortage of sensation course (gate) is one of schizoid sign.These shortages can be by the stdn of nicotine part (Adler L.E. etc., Schizophrenia Bull.24:189-202,1998 that act on α 7 nAChR; Stevens, K.E. etc., Psychopharmacology 136:320-327,1998).More studies show that recently stimulates α 4 β 2 nAChRs also to help effect (Radek etc., Psychopharmacology (Berl) .2006187:47-55 of nicotine in sensory gating BA/2 mouse model.Therefore, α 7 and α 7/ α 4 β 2 parts confirm potential in treatment schizophrenia.
The blood vessel generation, a kind of process that relates to the neovascularity growth is important to useful system function, the circulation around described system function such as wound healing, skin graft vascularization and promotion circulation as the increase vascular occlusion.Non-selective nicotine sample nAChR agonist shown can stimulate blood vessel take place (Heeschen, C. etc., Nature Medicine 7:833-839,2001).Shown that the blood vessel of improvement relates to the activation of α 7 nAChR (Heeschen, C. etc., J.Clin.Invest.110:527-536,2002).For example, the disease that relates to inflammation, ischemic, myocardial ischemia and wound healing as the improvement in the diabetics and α 7 nAChR active relevant (Jacobi, J., etc., Am.J.Pathol.161:97-104,2002).Therefore, α 7 subtype-selective nAChR parts provide stimulates the improvement potential that blood vessel takes place and side effect improves.
A group α 7 in the spinal cord or α 4 β 2 nAChR regulate the neurotransmission (Cordero-Erausquin, M. and Changeux, J.-P.PNAS98:2803-2807,2001) relevant with the effect of nicotine compound alleviating pain.α 7 nAChR or and α 7/ α 4 β 2 parts confirm to have the treatment pain status to comprise acute pain, post-operative pain and the chronic pain state treatment potential of (comprising inflammatory pain and neuropathic pain).And α 7 nAChR are expressed in the surface that relates to the main scavenger cell of inflammatory reaction, and activation α 7 is known from experience the release (Wang, H. etc., Nature 421:384-388,2003) of the cytokine that suppresses TNF and other triggering inflammatory reaction.Therefore, selectivity α 7 parts confirm to have the potential of the disease (comprising the disease relevant with the sacroiliitis of various ways) that the treatment inflammation involves.
The mammalian sperm acrosomal reaction is important exocytosis in the fertilization process of sperm to ovum.The activation that has shown α 7 nAChR on the spermoblast be acrosomal reaction the basis (Son, J.H. and Meizel, S.Biol.Reproduct.68:1348-13532003).Therefore, 7 doses of confirmations of selectivity α have the effect of treatment Infertility.
The compounds of this invention is particularly useful in treatment and prevention influence memory, cognition, neurodegeneration, neurodevelopment and schizoid disease or illness.
Schizophrenia dependency cognitive impairment limits the ability of patient's normal function usually, and conventional available treatment (as using atypical antipsychotic agents) can not fully be treated symptom.(Rowley, M. etc., J.Med.Chem.44:477-501,2001).This type of cognitive defect and nicotine cholinergic system dysfunction, particularly α 7 receptor actives declines relevant (Friedman, J.I. etc., Biol Psychiatry, 51:349-357,2002).Therefore, α 7 receptor activators can provide effective treatment, are used to improve the cognitive function with the schizophreniac of atypical antipsychotic agents treatment.Therefore, the combination of α 7nAChR part and atypical antipsychotic agents can provide the therapeutic efficiency of improvement.The specific examples of suitable atypical antipsychotic agents includes but not limited to leoponex, risperidone, olanzapine, Quetiapine (quietapine), Ziprasidone, zotepine and Zomaril etc.
The actual dose level of activeconstituents in pharmaceutical composition of the present invention is transformable, so that obtain the amount of active compound for the effective realization expection of concrete patient, composition and administering mode therapeutic response.The dosage level of selecting will depend on particular compound activity, route of administration, to treat the severity of disease and will treat disease of patient and medical history previously.Yet, in the art technology scope, begin to be lower than the compound dosage of realizing expection therapeutic action desired level, increase dosage then gradually, until the effect that realizes expection.
When being used for above or other when treatment, a kind of The compounds of this invention of treatment significant quantity can be used with the form (when this type of form exists) of pure form or pharmacy acceptable salt, ester, acid amides or prodrug.Alternative ground can be with compound with the pharmaceutical composition administration, and described pharmaceutical composition comprises the compound of interest with one or more pharmaceutically acceptable carrier combinations.The The compounds of this invention of phrase " treatment significant quantity " refers to the compound of sanatory q.s, is applicable to therapeutic treatment with rational benefit/risk-benefit risks.Yet the total usage that should understand The compounds of this invention and composition every day will be determined in the scope that rational medicine is judged by the doctor in charge.For any concrete patient, concrete treatment effective dose level will depend on multiple factor, comprise the illness that will treat and the severity of illness; The activity of used particular compound; Used concrete composition; Patient's age, body weight, general situation, sex and diet; The administration time of used particular compound, route of administration and excretion rate; The course of treatment; With combination of used particular compound or the medicine that uses simultaneously; And the well-known similar factor of medical field.For example, in the scope that art technology is known, begin, increase dosage then gradually, until the effect that realizes expection to be lower than the compound dosage of realizing expection therapeutic action desired level.
Total dose every day of administration of human or zootic The compounds of this invention is that about 0.10 μ g/kg body weight is to about 10mg/kg body weight.More preferred dose can be about 0.10 μ g/kg body weight to about 1mg/kg body weight.If desired, effective per daily dose can be divided into multidose and be used for administration.Therefore, unit-dose composition can comprise such amount or its approximate number to form per daily dose.
Prepare method of the present invention
When being used for description scheme and embodiment, some abbreviation is intended to have following meanings: Bu represents butyl; DMAP represents 4-dimethylaminopyridine; DMF represents dimethyl formamide; DME represents 1, the 2-glycol dimethyl ether; EDAC represents N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride; Et represents ethyl; EtOAc represents ethyl acetate; Eq. represent equivalent; HOBt representation hydroxy benzotriazole; HPLC represents high pressure liquid chromatography; MCPBA represents metachloroperbenzoic acid; The Me represent methylidene; MeOH represents methyl alcohol; OAc represents acetoxyl group; OTf represents fluoroform sulphonate; Pd/C represents palladium/carbon; Ph represents phenyl; THF represents tetrahydrofuran (THF); Represent thin-layer chromatography with TLC.
The reaction of example is to carry out in being fit to agents useful for same and raw material and the suitable just solvent that generation transforms in the scheme.According to the functionality that exists on the molecule, described conversion may need to change the order of synthesis step or select a kind of particular procedure scheme and do not select another kind, to obtain required compound of the present invention.
Nitrogen-protecting group group can be used for protecting the amido that exists in the described compound.These class methods and some suitable nitrogen-protecting group groups are described among Greene and the Wuts (Protective Groups In OrganicSynthesis, Wiley and Sons, 1999).For example, suitable nitrogen-protecting group group includes but not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), ethanoyl and trifluoroacetyl group.More specifically, can be by removing the Boc blocking group as trifluoroacetic acid or salt acid treatment with acid.Can remove Cbz and Bn blocking group by catalytic hydrogenation.The available hydrogen oxonium ion removes ethanoyl and trifluoroacetyl group blocking group.
Scheme 1
As shown in scheme 1, formula
1Compound (is purchased the Co. from Aldrich Chemical, [4746-97-8]) in the presence of alkali such as potassium tert.-butoxide in solvent such as ethylene glycol dimethyl ether, when (TOSMIC is purchased the Co. from Aldrich Chemical with tolysulfonyl methyl isocyanide, [36635-61-7]) when handling, obtain formula
2Compound.Formula
2Compound when handling in THF with lithium aluminum hydride, obtains formula
3Compound.Formula
3Compound when handling in company with sulfuric acid with Paraformaldehyde 96, obtains formula in ethanol
4Compound (1-azaadamantane-4-ketone).At Synthesis, 1992,1080, Becker, D.P; Flynn can find this synthetic to further describe among the D.L..
As shown in scheme 2, formula
4Compound (1-azaadamantane-4-ketone) when with borine-when the THF complex compound is handled, obtain the amine of borine complexing in THF, when it is further handled in methyl alcohol with reductive agent such as sodium borohydride, obtains by (r) and (s) formula formed of isomer mixture
5Compound.Formula
5Thereby compound can further be handled (rs) mixture of acquisition formula (I) compound according to the method shown in the scheme 3-11, maybe can be single (r) or (s) isomer with mixture separation, thereby handle production (I) compound simple (r) or (s) isomer according to the method shown in the scheme 3-11 then.For realize separating (r) isomer and (s) isomer, in the presence of 4-dimethylaminopyridine, in solvent such as methylene dichloride, with formula
5Compound is handled as the phenylformic acid (for example Chlorodracylic acid) and N-(3-the dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (EDAC) that replace with reagent, obtains formula
6With
7Compound.Formula
6With
7The mixture of compound can obtain separating by using chromatographic run well known by persons skilled in the art.The individual isomer formula
6Compound or formula
7Compound when further using sodium-hydroxide treatment in the mixture of THF and water, obtains formula respectively
8Compound or
9Compound.
Scheme 3
As shown in scheme 3, formula
10Compound can be a formula
8With
9The mixture of compound or formula
8Compound or
9Compounds represented individual isomer or lack the corresponding unhindered amina of borine group, when it is used for sodium hydride, potassium tert.-butoxide or two (trimethyl silyl) potassium amide (potassium bis (trimethylsilylamide)) of DMF, in THF or DMSO, handle, use formula subsequently
11Compound (wherein X is that chlorine, bromine, fluorine or iodine and A are defined as formula (I) compound, is more particularly the Ar of formula (II) compound
1Or the Ar of formula (III) compound similarly
2) handle, obtain formula
12Compound.Formula
12Compound when handling with palladium/carbon with aqueous hydrochloric acid or in methyl alcohol, obtains representing the formula of The compounds of this invention in acetone
13Compound.
Scheme 4
As shown in scheme 4, formula
15With
16Compound represent the compound of formula A-X separately, wherein A is Ar
1And be defined in the formula (I) and X is a chlorine or bromine.Formula
15And formula
16Compound can by shown in formula H
2N-Ar
1Compound obtains.Formula H
2N-Ar
1(formula
14) compound, wherein D
1, E
1, F
1, J
1, and K
1Independently be-CR separately
1aOr N, G is-O-,-NR
1a, or-S-, R
1For hydrogen, alkyl, alkoxyl group, alkoxy carbonyl, cyano group, halogen, nitro or-NR
bR
c, R
1aBe hydrogen or alkyl, R
bAnd R
cThe n that independently is group shown in hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl and the scheme 4 separately is 0,1,2 or 3, when it uses cuprous bromide and nitrite tert-butyl to handle in acetonitrile, obtains formula
15Compound.Alternative ground, formula
14Compound, wherein Ar
1As definition in the above scheme 4, when in acetic acid aqueous solution, using copper powder, aqueous hydrochloric acid, when Sodium Nitrite is handled, obtaining formula
16Compound.In addition, work as formula
15Compound or formula
16When compound is subjected to reaction conditions shown in the scheme 3, obtain representing the formula of The compounds of this invention
17Compound, the A group that wherein comprises is defined as the Ar in the formula (I)
1Or Ar
2
As shown in scheme 5, formula
18Compound, wherein G is-O-, NR
1a, or-S-, and R
1aBe hydrogen or alkyl, when in the presence of the cesium carbonate solvent such as but not limited to THF in Ar wherein
3Definition is as the formula of cotype (I) compound
19During compound treatment, obtain formula
20Compound, A-X compound (formula described in its representative scheme 3
11Compound), wherein A defines-Ar as cotype (I)
2-L
2-Ar
3Work as formula
20Compound and formula
10When compound is handled according to condition shown in the scheme 3, the acquisition formula
21Compound.Work as formula
21The usefulness palladium/when carbon was handled, the formula of The compounds of this invention was represented in acquisition to compound with aqueous hydrochloric acid or in methyl alcohol in acetone
22Compound, the A group that wherein comprises are defined as in the formula (I)-Ar
2-L
2-Ar
3
Scheme 6
As shown in scheme 6, formula
23Compound, wherein D, E, J, K and M independently are-CR separately
2a-,-CX
2-or-N-, X
2Be halogen, haloalkyl, cyano group or nitro, when with nitrite tert-butyl and Tetrafluoroboric acid or Sodium Nitrite and Tetrafluoroboric acid processing, obtain formula
24Compound.Formula
24Compound is used formula at alkali in the presence of such as but not limited to two (hexamethyl dimethyl silanyl) potassium amides (potassium bis (hexamethyldi-silylamine)) among the sodium hydride among the DMF, potassium tert.-butoxide among the THF or the THF
10During compound treatment, obtain formula
25Compound.Formula
25Compound is handled with palladium/carbon with aqueous hydrochloric acid or in methyl alcohol in acetone, obtains representing the formula of The compounds of this invention
26Compound.
Scheme 7
As shown in scheme 7, formula
27Compound, wherein Ar
2Be defined in formula (I) compound and X
3For halogen or-the O-trifluoromethyl sulfonyl, can obtain according to the method shown in scheme 3,4 or 6, when its at Ar
3-B (OH)
2, palladium catalyst well known by persons skilled in the art and salt of wormwood exists down, in the mixture or alcoholic solvent such as ethanol of solvent such as but not limited to diox and water, when heating, obtains representing the formula of The compounds of this invention under heating condition
28Compound, wherein A is-Ar
2-L
2-Ar
3, and L
2Be key.Alternative ground comprises the formula of boric acid or boric acid ester
30Compound, wherein R
xBe hydrogen or alkyl, can obtain according to method as herein described, when its in the presence of palladium catalyst well known by persons skilled in the art and salt of wormwood, mixed solvent such as but not limited to diox and alcoholic solvent such as ethanol in, under heating condition, use Ar
3-X (Ar wherein
3Be defined in formula (I) compound and X be chlorine, bromine or-the O-trifluoromethyl sulfonyl) when handling, also obtain formula
28Compound.
As shown in scheme 8, formula
10Compound is used formula in DMF in the presence of sodium hydride
32Compound (wherein X is chlorine, bromine or iodine, J is-O-or-S-, and X
16-X
19, L
3, and Ar
5Definition is as being same as formula (IV) compound) when handling, obtain formula
33Compound.Formula
33When compound is handled with palladium/carbon with aqueous hydrochloric acid or in methyl alcohol, obtain representing the formula of The compounds of this invention in acetone
34Compound, wherein A is-Ar
4-L
3-Ar
5
Scheme 9
As shown in scheme 9, formula
4The compound formula
35When compound and reductive agent are handled such as but not limited to sodium triacetoxy borohydride, obtain formula
36Compound.The general condition of this conversion comprises formula
4Compound and formula
35Compound stirs in the presence of Glacial acetic acid and/or sal epsom in solvent such as THF, adds reductive agent subsequently.Alternative ground, formula
37Compound can pass through formula
4Compound formula R
a-NH
2The amine reductive amination obtain, it is further used formula A-X such as but not limited to tetrakis triphenylphosphine palladium and alkali in the presence of such as but not limited to yellow soda ash at palladium catalyst
z(compound
11a) (wherein A is defined in the formula (I) and X
2For halogen or-OTf) handle, also obtain representing the formula of The compounds of this invention
36Compound, wherein L
1For in formula (I) compound-NR
a-.
As shown in scheme 10, formula
38Compound (Ar wherein
2, E
2, and D
2Definition is as being same as formula (III) compound), when using formula
39Compound, cupric oxide (II) and alkali such as cesium carbonate during heat treated, obtain formula in solvent such as DMF
40Compound.With formula
41Compound is handled with alkali such as potassium tert.-butoxide in solvent dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF), then with formula
40Compound one reacts, and then handles with aqueous hydrochloric acid in acetone, obtains formula
42Compound.Alternative ground, formula
42Compound can be by using formula in the presence of ferric acetyl acetonade, cupric oxide (II) and alkali such as cesium carbonate
39Compound treatment also heats by formula in solvent such as DMF
43Compound obtains.
Scheme 11
As shown in scheme 11, formula
44Ester (Ar wherein
2Being defined in formula (III) compound and X is halogen), when 25～40 ℃ of temperature, in solvent such as water and alcoholic acid mixture, use alkali such as sodium hydroxide, potassium hydroxide or potassium hydroxide treatment in the time of 30 minutes to 2 hours, obtain formula
45Compound.Formula
45Compound can be under amido linkage formation condition well known to those skilled in the art and formula
46The compound coupling obtains formula
47Compound.For example, in solvent such as pyridine with formula
45Compound and formula
46Compound, hydroxybenzotriazole, Dimethylamino pyridine and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride chemical combination obtains formula
47Compound.Alternative ground, formula
45Compound can be converted into corresponding chloride of acid by reaction in pure thionyl chloride.Chloride of acid then or nearly room temperature, in the presence of alkali such as triethylamine in methylene dichloride, can with formula
46The compound reaction obtains formula
47Compound.Condition described in the application scheme 3, formula
47Compound can be converted into formula
48Compound.
In addition, by using oxidizer treatment, formula (I) compound can be converted into formula (VII) compound that azaadamantane wherein exists with the N-oxide compound.The example of oxygenant includes but not limited to aqueous hydrogen peroxide and metachloroperbenzoic acid.This reaction in the mixture of solvent such as but not limited to acetonitrile, water, methylene dichloride, acetone or preferred acetonitrile of its mixture and water, was reacted about 1 hour to about 4 days for about 0 ℃ to about 80 ℃ in temperature usually.
Compound of the present invention can separate and purifying with the well-known method of organic synthesis those skilled in the art with intermediates.Separate and the example of purifying compounds ordinary method can include but not limited at solid carrier such as silica gel, aluminum oxide or with the chromatography on the alkyl silyl deutero-silicon-dioxide, optional with after the Activated Carbon Pretreatment at the recrystallization method of high or low temperature, tlc, under different pressures, distill, vacuum-sublimation, and grinding, as be described in " Vogel ' s Textbook ofPractical Organic Chemistry ", the 5th edition (1989), Fumiss, Hannaford, Smith, and Tatchell, pub.Longman Scientific﹠amp; Technical, Essex CM20 2JE, England.
The compounds of this invention has at least one basic nitrogen, so usable acid is handled compound to form required salt.For example, can be with compound and acid-respons to obtain required salt.Salt can be collected by any suitable manner.The example that is fit to the acid of this reaction includes but not limited to tartrate, lactic acid, Succinic Acid and amygdalic acid, atrolactinic acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, naphthene sulfonic acid, carbonic acid, fumaric acid, gluconic acid, acetate, propionic acid, Whitfield's ointment, hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, citric acid or hydroxybutyric acid, camphorsulfonic acid, oxysuccinic acid, toluylic acid, aspartic acid, L-glutamic acid etc.Preferred salt includes but not limited to tosilate, L-bitartrate, dihydrogen phosphate, disuccinate, hydrochloride, dihydrogen citrate salt and citric acid hydrogen salt (monohydrogencitrate).More preferably Citrate trianion.
To understand The compounds of this invention better and prepare the process of compound with the inventive method by reference the following example, described embodiment is intended to illustrate as an example, does not limit the scope of the invention.
Embodiment
Method A: etherificate
1-azaadamantane-4-alcohol N-borane complex (1 equivalent) and the solution (0.5-1M) of heteroaryl halogenide (1.1 equivalent) in dry DMF are cooled to-20～0 ℃, with sodium hydride (1.5 equivalents; 95%, Aldrich) handle.After 15 minutes, remove cooling bath, allow mixture be warming up to room temperature.When determining that according to the TLC analysis the pure N-borane complex of 1-azaadamantane-4-exhausts (1-2 hour usually),, and stirred 1 hour the mixture dilute with water.Collect the solid product that generates by filtering, wash with water, drying under reduced pressure obtains required product.
Method B: etherificate
With 1-azaadamantane-4-alcohol (or with 1-azaadamantane-4-alcohol N-borane complex, 1 equivalent) and the solution of heteroaryl halogenide (1.1 equivalent) in anhydrous tetrahydro furan (～0.5M) under nitrogen atmosphere, be cooled to 0 ℃, be used for the potassium tert.-butoxide (1.0M of THF; 1 equivalent; Aldrich) drip processing.Remove ice bath, allow mixture be warming up to ambient temperature overnight.Behind the dilute with water, with mixture with chloroform (3x) extraction, with the extract after merging by purified by flash chromatography (with containing 1%NH
4The 5-10%MeOH-CHCl of OH
3Gradient elution silica gel), obtain required product.
Method C: boronation (Deboronation) is taken off in acid
With the suspension of 1-azaadamantane N-borane complex (1 equivalent) in acetone (～0.5M) be cooled to 0 ℃, handle with 3N HCl (4 equivalent).After 15 minutes, remove ice bath, the mixture stirring is exhausted until TLC monitoring borane complex (use alkaline KMnO
4Dyestuff can be looked at borane complex straight).Then pH value of solution is adjusted to～pH 10 with 5N NaOH,,, filters, under reduced pressure concentrate through anhydrous magnesium sulfate drying with chloroform (3x) extraction.With the material that generates HPLC[through flash chromatography [Analogix prepackage silica gel cylinder, the 5-50% gradient of ammonium hydroxide-methyl alcohol-chloroform (2: 20: 78) in chloroform] or preparation
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes] purifying, obtaining required product is its free alkali.(Stotter，P.L.；Friedman，M.D.；Dorsey，G.O.；Shiely，R.W.；Williams，R.F.；Minter，D.E.，Heterocycles?1987，25，251)。
Boronation is taken off in method D:Pd/C-catalysis
With the methanol solution of 1-azaadamantane N-borane complex with 10% palladium/carbon (～10%, by weight; Aldrich) handle, exhaust (spending the night usually) up to TLC or HPLC indication starting material.In some cases, of short duration heated solution to 50 is ℃ with accelerated reaction.By removing by filter catalyzer, product is through the HPLC[of flash chromatography [Analogix prepackage silica gel cylinder, the 5-50% gradient of ammonium hydroxide-methyl alcohol-chloroform (2: 20: 78) in chloroform] or preparation
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes] purifying, obtain required product.
Method E. Suzuki coupling (Suzuki Coupling)
Heteroaryl halogenide (1 equivalent), heteroaryl-boric acid or heteroaryl-boric acid ester (2 equivalent), salt of wormwood (4 equivalent) and tetrakis triphenylphosphine palladium (0) (0.04 equivalent that will contain azaadamantane; Strem) pack into the flask of band dottle pin lid (septum cap).With the flask capping plug, find time, clean the solvent mixture 1 of packing into, 4-diox-water (3: 1 with nitrogen;～0.1M halogenide), add by dottle pin.With mixture heating up to 90 ℃ maintenance 3-8 hour.After reaction is finished, mixture is diluted with EtOAc, wash with water, extract filters through dried over mgso.The HPLC[of material through preparation will be generated
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10), UV detects at 254nm] purifying.To contain the part set of required product, concentrate under the vacuum,, filter, obtain required product with methyl alcohol or ethyl acetate dilution.
The anhydrous Suzuki coupling of method F.
Pack in the flask with band dottle pin lid aryl halide (1 equivalent), heteroaryl-boric acid or heteroaryl-boric acid ester (2 equivalent), salt of wormwood (3 equivalent) and [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II) methylene dichloride mixture (0.2 equivalent; Aldrich) and anhydrous 1,4-diox-ethanol (1: 1;～0.1M halogenide).Mixture is cleaned with nitrogen, be heated to 90 ℃ and kept 2 hours.After the cooling, mixture is concentrated, through the HPLC[of preparation
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10), UV detects at 254nm] purifying.To contain the part set of required product, concentrate under the vacuum,, filter, obtain required product free alkali with methyl alcohol or ethyl acetate dilution.
The coupling of method G. microwave Suzuki
In the microwave reaction pipe, mix heteroaryl halogenide (～0.1mmol), heteroaryl-boric acid or heteroaryl-boric acid ester (3 equivalent), two (triphenylphosphine) palladium chloride (II) (0.1 equivalent; Aldrich) and biphenyl-2-base dicyclohexylphosphontetrafluoroborate (0.03 equivalent; Strem), add solvent 1 subsequently, 4-diox (1.0mL), ethanol (1.0mL) and aqueous sodium carbonate (1.0M; 1.0mL).With the seal of tube, will be reflected in the microwave reactor 300W and be heated to 150 ℃ and kept 10 minutes.After being cooled to room temperature, with mixture 5%Na
2CO
3CHCl is used in dilution
3(3x) extraction.Organic extraction salt water washing through merging, dry (Na
2SO
4), filter, under reduced pressure concentrate, with the HPLC[of material that generates through preparing
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10)] purifying, obtain the product free alkali.Alternative ground, product through the HPLC of preparation acidic conditions [
XTerra RP18 post, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-50% gradient of acetonitrile in the 0.1%TFA aqueous solution] following purifying, obtain trifluoroacetate.
The formation of method H. salt
To stir rapidly in the free base solution in ethyl acetate-ethanol, ethanol, the Huo diox in room temperature, and with tosic acid monohydrate (1 equivalent; Aldrich; Add with the solution in the ethyl acetate) or fumaric acid (1 equivalent, Aldrich; Add with the solution in the methyl alcohol) or HCl-diox (1-2 equivalent; 4M; Aldrich) handle.Stir after 2-16 hour, by filtering collecting precipitation, clean with ethyl acetate, drying obtains title compound.
Method I: etherificate
With 1-azaadamantane-4-alcohol (or with 1-azaadamantane-4-alcohol N-borane complex, 1 equivalent) and potassium tert.-butoxide (1.1 equivalent) in the solution of anhydrous dimethyl sulphoxide (～0.5M) stirring at room 1 hour.Add heteroaryl halogenide (2.2 equivalent), with reaction mixture in stirred overnight at room temperature.At Waters Nova-
HR Cl8 6 μ m
Prep-
On the cylinder (40x100mm), used 10%～100% gradient of acetonitrile in the 10mM ammonium acetate solution through 12 minutes, flow velocity 70mL/ minute,, obtain required compound the HPLC purifying of reaction mixture through preparation.
Method J: acid is taken off boronation and is separated with hydrochloride
With the suspension of 1-azaadamantane N-borane complex (1 equivalent) in acetone (～0.5M) be cooled to 0 ℃, handle with 3N HCl (5-10 equivalent).After 15 minutes, remove ice bath, the mixture stirring is exhausted until TLC monitoring borane complex (use alkaline KMnO
4Dyestuff can be looked at borane complex straight).Reaction mixture under reduced pressure concentrates.With the material that generates be dissolved in MeOH (～0.1M), and stirring at room 30 minutes.The reconcentration reaction mixture.Residuum is dissolved in the MeOH of minimum, slowly added diethyl ether/MeOH 9: 1 then, grind, obtain required product powder.Product by filtering separation, is washed dried overnight in the vacuum drying oven with other diethyl ether.
The coupling of method K. Suzuki
Pack into the flask of band dottle pin lid of heteroaryl halogenide (1 equivalent), heteroaryl-boric acid or heteroaryl-boric acid ester (1.2-2.0 equivalent), salt of wormwood (2.5 equivalent) and (triphenylphosphine) palladium chloride (II) (0.05 equivalent) that will contain azaadamantane.With the flask capping plug, find time, clean with nitrogen, the DMF that packs into (～0.1M halogenide) adds by dottle pin.With mixture heating up to 65 ℃ maintenance 18 hours.After reaction is finished, mixture is diluted with ethyl acetate, wash with water, extract filters through dried over mgso.At Waters Nova-
HR Cl8 6 μ m
Prep-
On the cylinder (40x100mm), used 10%～100% gradient of acetonitrile in the 10mM ammonium acetate solution in 12 minutes, flow velocity 70mL/ minute, the HPLC purifying of material through preparing with generating obtained required compound.
Method L: remove acid-sensitive sense blocking group
The mixed solution of the compound (1 equivalent) that will contain acid-sensitive sense blocking group (for example trityl) in acetone (～0.5M) be cooled to 0 ℃, handle with 3N HCl (4 equivalent).After 15 minutes, remove ice bath, mixture is stirred split until TLC monitoring and protecting group.With 5N NaOH with the pH regulator of solution to～pH 10, with chloroform (3x) extraction,, filter through anhydrous magnesium sulfate drying, under reduced pressure concentrate.With the material that generates HPLC through flash chromatography [Analogix prepackage silica gel cylinder, the 5-50% gradient of ammonium hydroxide-methyl alcohol-chloroform (2: 20: 78) in chloroform] or preparation
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes] purifying, obtaining required product is its free alkali.
Embodiment 1
(4s)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 1A
4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method B by 1-azaadamantane-4-alcohol (3: 2 non-enantiomer mixtures; 150mg, 0.979mmol; Referring to WO 9215579) and 3,6-dichloro-pyridazine (182mg, 1.22mmol; Aldrich) prepare, obtain the stereoisomer mixture of title compound: MS (DCI/NH
3) m/z=266 (M+H)
+
Embodiment 1B
(4s)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
(100mg is 0.38mmol) further through flash chromatography (25g silica gel, the NH of 2-12% gradient with the mixture of a part of embodiment 1A
4OH-MeOH (1: 10)/CHCl
3) purifying, obtain the single stereoisomers of title compound: TLC R
f=0.33[silica gel, NH
4OH-MeOH-CHCl
3(1: 12: 87)].
Embodiment 1C
(4r)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
(100mg is 0.38mmol) further through flash chromatography (25g silica gel, the NH of 2-12% gradient with the mixture of a part of embodiment 1A
4OH-MeOH (1: 10)/CHCl
3) purifying, obtain the single stereoisomers of title compound: TLC R
f=0.28[silica gel, NH
4OH-MeOH-CHCl
3(1: 12: 87)].
Embodiment 1D
(4s)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 1B (28mg, 0.075mmol) and tosic acid monohydrate (0.016g, 0.083mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.65 of methyl alcohol-D4) (s, 1H), 1.82 (d, J=12.5Hz, 2H), 2.17 (s, 2H), 2.26 (d, J=12.5Hz, 2H), 3.17 (d, J=12.5Hz, 4H), 3.31 (d, J=13.9Hz, 2H), 5.55 (t, J=3.2Hz, 1H), 6.98 (d, J=9.2Hz, 1H), 7.37 (d, J=9.2Hz, 1H).MS (DCI/NH
3) m/z=226 (M+H)
+C
13H
16ClN
3OC
7H
8O
3S0.3H
2The analytical calculation value of O: C, 54.18; H, 5.59; N, 9.84; Measured value: C, 54.16; H, 5.55; N, 9.22.
(4r)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 1C (12mg, 0.045mmol) and tosic acid monohydrate (9.5mg, 0.049mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.74 of methyl alcohol-D4) (s, 1H), 2.00-2.23 (m, 6H), 3.02 (d, J=11.9Hz, 2H), 3.18 (s, 2H), 3.51 (d, J=13.2Hz, 2H), 5.57 (s, 1H), 7.00 (d, J=9.2Hz, 1H), 7.38 (d, J=9.2Hz, 1H).MS (DCI/NH
3) m/z=226 (M+H)
+C
13H
16ClN
3OC
7H
8O
3The analytical calculation value of S: C, 54.85; H, 5.52; N, 9.59; Measured value: C, 54.46; H, 5.42; N, 9.37.
Embodiment 3
(4s)-4-(6-phenyl pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] trifluoroacetate of decane
According to method G by the product of embodiment 1B (31mg, 0.11mmol) and phenyl-boron dihydroxide (41mg, 0.34mmol; Aldrich) preparation is through the HPLC[of preparation
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the acetonitrile of 5-50% gradient in the 0.1%TFA aqueous solution] purifying, obtain title compound:
1H NMR (300MHz, and the δ ppm 1.97 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.22 (s, 1H), 2.41 (d, J=13.2Hz, 2H), 2.68 (s, 2H), 3.60 (s, 2H), 3.72 (s, 3H), 5.68 (s, 1H), 7.37 (d, J=9,2Hz, 1H), and 7.47-7.59 (m, 3H), 7.94-8.01 (m, 2H), 8.12 (d, J=9.2Hz, 1H).MS (DCI/NH
3) m/z=308 (M+H)
+C
19H
21N
3OC
2HF
3O
20.5H
2The analytical calculation value of O: C, 58.60; H, 5.39; N, 9.76; Measured value: C, 58.32; H, 4.98; N, 9.62.
Embodiment 4
(4r)-4-(6-phenyl pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method G, by product (50mg, 0.19mmol) phenyl-boron dihydroxide (46mg, the 0.37mmol of embodiment 1C; Aldrich) free alkali of preparation title compound is converted into its HCl salt according to method H subsequently:
1H NMR (300MHz, and the δ ppm 2.10-2.22 of methyl alcohol-D4) (m, 2H), 2.22-2.33 (m, 3H), 2.66 (s, 2H), 3.51 (d, J=12.5Hz, 2H), 3.59 (s, 2H), 3.87 (d, J=12.5Hz, 2H), 5.60 (t, J=3.4Hz, 1H), 7.39 (d, J=9.5Hz, 1H), and 7.47-7.60 (m, 3H), 7.92-8.03 (m, 2H), 8.13 (d, J=9.5Hz, 1H).MS (DCI/NH
3) m/z=308 (M+H)
+C
19H
21N
3OHCl0.3H
2The analytical calculation value of O: C, 65.34; H, 6.52; N, 12.03; Measured value: C, 65.33; H, 6.47; N, 12.01.
(4s)-and 4-[6-1H-indoles-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane disalt
Hydrochlorate
According to method G, by the product of embodiment 1B (46mg, 0.17mmol) and 5-indyl boric acid (84mg, 0.52mmol; Maybridge) free alkali of preparation title compound is converted into dihydrochloride according to method H subsequently:
1H NMR (300MHz, the δ ppm 2.01 of methyl alcohol-D4) (d, J=13.4Hz, 2H), 2.25 (s, 1H), 2.41 (d, J=13.4Hz, 2H), 2.71 (s, 2H), 3.62 (s, 2H), 3.75 (s, 4H), 5.63 (s, 1H), 6.68 (d, J=3.1Hz, 1H), 7.44 (d, J=3.1Hz, 1H), 7.62-7.69 (m, 1H), and 7.71-7.80 (m, 1H), 7.90 (d, J=9,5Hz, 1H), 8.27 (s, 1H), 8.62 (d, J=9.5Hz, 1H).MS (DCI/NH
3) m/z=374 (M+H)
+C
21H
22N
4O2HCl1.4H
2The analytical calculation value of O: C, 56.74; H, 6.08; N, 12.60; Measured value: C, 56.74; H, 6.05; N, 12.44.
Embodiment 6
(4r)-4-[6-(1H-indoles-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane disalt
Hydrochlorate
According to method G, (31mg is 0.11mmol) with 5-indyl boric acid (55mg, 0.34mmol by the product of embodiment 1C; Maybridge) coupling prepares the free alkali of title compound, and this material is converted into dihydrochloride according to method H:
1H NMR (300MHz, and the δ ppm 2.15 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.25-2.39 (m, 3H), 2.69 (s, 2H), 3.55 (d, J=11.9Hz, 2H), 3.61 (s, 2H), 3.89 (d, J=12.9Hz, 2H), 5.52 (t, J=3.2Hz, 1H), 6.70 (d, J=3.1Hz, 1H), 7.46 (d, J=3.1Hz, 1H), 7.65-7.78 (m, 2H), 7.99 (d, J=9.5Hz, 1H), 8.30 (d, J=2.0Hz, 1H), 8.72 (d, J=9.5Hz, 1H).MS (DCI/NH
3) m/z=347 (M+H)
+C
21H
22N
4O2HClH
2The analytical calculation value of O: C, 57.67; H, 5.99; N, 12.81; Measured value: C, 57.49; H, 5.94; N, 12.56.
Embodiment 7
(4s)-4-[6-(1-thionaphthene-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Two (trifluoroacetates)
According to method G by the mix product of embodiment 1A (125mg, 0.470mmol) and 2-benzo [b] thiophene-5-base-4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane (171mg, 0.658mmol; Maybridge) preparation.HPLC[through preparation
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the acetonitrile of 5-50% gradient in the 0.1%TFA aqueous solution] separate the steric isomer that needs, obtain title compound:
1H NMR (300MHz, the δ ppm1.98 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.23 (s, 1H), 2.42 (d, J=13.6Hz, 2H), 2.69 (s, 2H), 3.60 (s, 2H), 3.73 (s, 4H), 5.70 (s, 1H), 7.39 (d, J=9.5Hz, 1H), 7.50 (d, J=5.Hz, 1H), 7.68 (d, J=5.4Hz, 1H), 7.95-8.02 (m, 1H), 8.03-8.11 (m, 1H), 8.21 (d, J=9.5Hz, 1H), 8.45 (s, 1H).MS (DCI/NH
3) m/z=364 (M+H)
+C
21H
21N
3OS1.4C
2HF
3O
2The analytical calculation value: C, 54.65; H, 4.32; N, 8.03.Measured value: C, 54.61; H, 4.09; N, 8.04.
(4r)-4-[6-(1-thionaphthene-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Two (trifluoroacetates)
Separate the steric isomer of embodiment 7 by the HPLC of preparation, obtain title compound:
1HNMR (300MHz, the δ ppm 2.12-2.34 of methyl alcohol-D4) (m, 5H), 2.67 (s, 2H), 3.51 (d, J=12.2Hz, 2H), 3.59 (s, 2H), 3.88 (d, J=12.5Hz, 2H), 5.61 (t, J=3.4Hz, 1H), 7.38 (d, J=9.2Hz, 1H), 7.50 (d, J=5.1Hz, 1H), 7.67 (d, J=5.4Hz, 1H), and 7.96-8.01 (m, 1H), 8.04-8.09 (m, 1H), 8.21 (d, J=9.5Hz, 1H), 8.44 (d, J=1.4Hz, 1H), MS (DCI/NH
3) m/z=364 (M+H)
+C
21H
21N
3OS1.1C
2HF
3O
20.25H
2The analytical calculation value of O: C, 56.47; H, 4.62; N, 8.52; Measured value: C, 56.56; H, 4.33; N, 8.54.
Embodiment 9
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 9A
1-azaadamantane-4-alcohol N-borane complex.
With 1-azaadamantane-4-ketone (29g, 190mmol; Referring to Becker, D.P.; Flynn, D.L.Synthesis 1992,1080) solution in anhydrous tetrahydro furan (200mL) cools off in ice-water bath, and (1.0M is in THF with borine-THF complex compound; 200mL, 200mmol; Aldrich) drip processing.After stirring 30 minutes, mixture with methyl alcohol (1000mL) dilution, is used sodium borohydride (8.8g, 230mmol; Aldrich) handled keeps about 5-7 ℃ of internal temperature.Mixture was stirred 2 hours, remove ice bath then, continue to stir 4 hours.On rotatory evaporator, remove volatile constituent, with residuum be dissolved in chloroform (～500mL), with the washing of saturated aqueous sodium carbonate.Water layer chloroform extraction, organic phase filter through dried over mgso.Generate material through flash chromatography (Analogix 400g 65x220mm silicagel column, ethyl acetate in hexane through 50 minutes 5-95% gradient) purifying, obtain inseparable 3.7: 1.0 isomer mixtures [according at δ 3.96 (t, main) and δ 3.82 (t, accessory)
1H NMR signal (integration of chloroform-D)] (33g, 200mmol; 100% productive rate).Use KmnO
4Dyeing can be looked at the product spot on the TLC plate (silica gel) straight.
Embodiment 9B
(4s)-4-(4-chlorinated benzene methanoyl)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
Embodiment 9C
(4r)-4-(4-chlorinated benzene methanoyl)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
With embodiment 9A product (28g, 170mmol; 3.2: 1.0 non-enantiomer mixtures), 4-chloro-benzoic acid (28.0g, 179mmol; Aldrich) and 4-Dimethylamino pyridine (4.2g, 34mmol; Aldrich) methylene dichloride (700mL) solution is cooled to 0 ℃, with N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (EDAC; 42.0g, 219mmol; Aldrich) handle.After 1 hour, mixture is warming up to room temperature, and stirs and spend the night.Solution is washed with saturated sodium bicarbonate subsequently fast with 1M HCl (200mL),, filter through dried over mgso.It is a collection of through flash chromatography (Analogix 400g 65x220mm silicagel column, ethyl acetate in hexane through 45 minutes 5-55% gradient) purifying with～5g to generate material.
Embodiment 9B(4s) steric isomer: TLC R
f=0.49 (silica gel, 3: 1 hexanes-EtOAc).
1HNMR (300MHz, the δ ppm 1.76 of chloroform-D) (d, J=12.5Hz, 2H), 2.06 (s, 1H), 2.16-2.33 (m, 4H), 3.12-3.32 (m, 6H), 5.26 (t, J=3.2Hz, 1H), 7.45 (dt, J=8.7,2.4,2.1Hz, 2H), 8.00 (dt, J=8.7,2.4,2.1Hz, 2H).MS(DCI/NH
3)m/z＝321/323(M+H)
+。C
16H
21BClNO
2The analytical calculation value: C, 62.88; H, 6.93; N, 4.58.Measured value: C, 63.00; H, 6.80; N, 4.50.
Embodiment 9C(4r) steric isomer: TLC R
f=0.34 (silica gel, 3: 1 hexanes-EtOAc).
1HNMR (300MHz, the δ ppm 1.84-2.11 of chloroform-D) (m, 5H), 2.24 (s, 2H), 3.03 (d, J=12.5Hz, 2H), 3.14 (s, 2H), 3.46 (d, J=13.2Hz, 2H), 5.16 (t, J=3.2Hz, 1H), 7.39-7.51 (m, 2H), 7.89-8.05 (m, 2H).MS(DCI/NH
3)m/z＝321/323(M+H)
+。C
16H
21BClNO
2The analytical calculation value: C, 62.88; H, 6.93; N, 4.58; Measured value: C, 62.83; H, 6.95; N, 4.53.
Embodiment 9D
(4r)-4-(1-aza-tricycle [3.3.1.1
3,7
] decane-4-alcohol) the N-borane complex
With embodiment 9C product (10.0g, 32, tetrahydrofuran (THF) 7mmol) (20mL) suspension is handled with 5M sodium hydroxide (20mL), and mixture heating up to 50 ℃ was kept 4 hours.Mixture is diluted with chloroform, wash with water, water extracts with other chloroform again.Product obtains product through flash chromatography (Analogix 80g 40x170mm silicagel column, the 10-95% gradient of ethyl acetate in hexane) purifying:
1H NMR (300MHz, the δ ppm 0.82-2.02 of methyl alcohol-D4) (br m, 3H), 1.76 (d, J=11.9Hz, 2H), 1.83-1.99 (m, 6H), 2.81 (d, J=12.2Hz, 2H), 3.00 (s, 2H), 3.37 (d, J=12.9Hz, 2H), 3.82 (s, 1H).MS(DCI/NH
3)m/z＝183(M+H)
+。
Embodiment 9E
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method B by the product of embodiment 9D (500mg, 2.99mmol) and 2-chloro-5-pyridine bromide (1.15g, 5.99mmol; Aldrich) prepare, do not carried out the material of other purifying: MS (DCI/NH
3) m/z=309/311 (M-BH
3+ H)
+
Embodiment 9F
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 9E (732mg, 2.11mmol) preparation obtains title compound:
1H NMR (300MHz, and the δ ppm 1.73 of methyl alcohol-D4) (s, 1H), 1.95-2.07 (m, 4H), 2.11-2.22 (m, 2H), 2.96 (d, J=12.9Hz, 2H), 3.13 (s, 2H), 3.45 (d, J=12.9Hz, 2H), 5.28 (t, J=3.2Hz, 1H), 6.80 (d, J=8.8Hz, 1H), 7.78 (dd, J=8.8,2.7Hz, 1H), 8.17 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝309/311(M+H)
+。
Embodiment 9G
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosic acid of decane
Salt
According to method H by the product of embodiment 9F (70mg 0.23mmol) makes:
1H NMR (300MHz, the δ ppm 2.02-2.14 of methyl alcohol-D4) (m, 2H), 2.16-2.26 (m, 3H), 2.36 (s, 3H), 2.49 (s, 2H), 3.44 (d, J=11.9Hz, 2H), 3.55 (s, 2H), 3.79 (d, J=12.2Hz, 2H), 5.31 (t, J=3.6Hz, 1H), 6.85 (dd, J=8.8,0.7Hz, 1H), 7.19-7.26 (m, 2H), 7.70 (ddd, J=8.3,1.9,1.7Hz, 2H), 7.84 (dd, J=8.6,2.5Hz, 1H), 8.21 (dd, J=2.7,0.7Hz, 1H).MS(DCI/NH
3)m/z＝309/311(M+H)
+。C
14H
17BrN
2OC
7H
8O
3The analytical calculation value of S: C 52.39, and H 5.23, and N 5.82; Measured value: C52.29, H 5.17, and N 5.73.
(4s)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 10A
(4s)-4-(1-aza-tricycle [3.3.1.1
3,7
] decane-4-alcohol) the N-borane complex
(25.0g, tetrahydrofuran (THF) 81.8mmol) (50mL) suspension is handled with 5M sodium hydroxide (50mL) with embodiment 9B product.After 1 hour, with mixture heating up to 50 ℃ maintenance 3 hours.On rotary evaporator, remove most of solvents, residuum through flash chromatography (Analogix 220g 65x120mm silicagel column, the 5-95% gradient of ethyl acetate in hexane) purifying, obtained product:
1H NMR (300MHz, δ ppm 0.87-2.09 (br m, the 3H of methyl alcohol-D4); BH
3), 1.59 (d, J=12.5Hz, 2H), 1.78-1.98 (m, 2H), 2.22 (d, J=12.5Hz, 2H), 2.97-3.18 (m, 6H), 3.96 (t, J=3.4Hz, 1H).MS(DCI/NH
3)m/z＝183(M+H)
+。
Embodiment 10B
(4s)-4-(1-aza-tricycle [3.3.1.1
3,7
] decane-4-alcohol
(1.00g, acetone 6.00mmol) (30mL) solution is cooled to 0 ℃, handles with 3N HCl (10mL) with embodiment 10A product.After 10 minutes, remove ice bath, mixture was stirred 4 hours.On rotary evaporator, solution concentration is extremely done, with methanol azeotropic (3x).The white solid that generates is suspended in EtOAc (25mL), is cooled to 0 ℃, anhydrous ammonia is fed in the mixture bubbled about 1 minute.Behind the restir 15 minutes, mixture is filtered, cleans, concentrate and obtain product with EtOAc:
1H NMR (300MHz, the δ ppm 1.51-1.84 of chloroform-D) (m, 5H), 2.26 (d, J=11.9Hz, 2H), 2.36 (s, 1H), 2.99 (d, J=12.9Hz, 2H), 3.09 (s, 2H), 3.25 (d, J=13.6Hz, 2H), 4.00 (s, 1H).MS(ESI)m/z＝154(M+H)
+。
Embodiment 10C
(4s)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method B, by the hydrochloride of embodiment 10 product B (220mg, 1.16mmol) and 2,5-two bromo pyridine (550mg, 2.30mmol; Aldrich) at THF (2.4mL, 2.4mmol; 1.0M; Aldrich) using excessive potassium tert.-butoxide in makes: MS (DCI/NH
3) m/z=309/311 (M+H)
+
Embodiment 10D
(4s)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method F, by the product of embodiment 10C (45mg, 0.14mmol) and phenyl-boron dihydroxide (operation of application method H is translated into tosilate for 25mg, the 0.20mmol) title compound of preparation free alkali:
1H NMR (300MHz, and the δ ppm 1.94 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.20 (s, 1H), 2.36 (s, 5H), 2.41 (s, 1H), 2.57 (s, 2H), 3.58 (s, 2H), 3.70 (s, 4H), 5.47 (t, J=3.4Hz, 1H), 7.09 (d, J=8.5Hz, 1H), 7.22 (d, J=7.8Hz, 2H), 7.30-7.41 (m, 1H), 7.42-7.51 (m, 2H), 7.56-7.63 (m, 2H), 7.67-7,75 (m, 2H), 8.07 (dd, J=8.6,2.5Hz, 1H), 8.40 (d, J=2.4Hz, 1H).MS (DCI/NH
3) m/z=307 (M+H)
+C
20H
22N
2O1.3C
7H
8O
3S0.5H
2The analytical calculation value of O: C, 64.81; H, 6.24; N, 5.19 measured values: C, 64.77; H, 6.30; N, 5.15.
Embodiment 11
(4r)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 11A
(4r)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E by the product of embodiment 9F (496mg, 1.60mmol) and phenyl-boron dihydroxide (480mg, 3.1mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.75 of methyl alcohol-D4) (s, 1H), 2.00-2.25 (m, 6H), 2.98 (d, J=12.9Hz, 2H), 3.15 (s, 2H), 3.51 (d, J=12.9Hz, 2H), 5.33 (s, 1H), 6.90-6.96 (m, 1H), 7.30-7.38 (m, 1H), 7.40-7.48 (m, 2H), and 7.54-7.61 (m, 2H), 7.94 (dd, J=8.6,2.5Hz, 1H), 8.35 (d, J=2.4Hz, 1H).MS(ESI)m/z＝307(M+H)
+。
Embodiment 11B
(4r)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 11A (277mg 0.904mmol) makes:
1H NMR (300MHz, and the δ ppm 2.07-2.19 of methyl alcohol-D4) (m, 2H), 2.20-2.31 (m, 3H), 2.36 (s, 5H), 2.56 (s, 2H), 3.49 (d, J=12.5Hz, 2H), 3.57 (s, 2H), 3.85 (d, J=12.2Hz, 2H), 5.38 (t, J=3.4Hz, 1H), 7.16 (d, J=8.5Hz, 1H), 7.23 (d, J=8.1Hz, 3H), and 7.34-7.42 (m, 1H), 7.43-7.52 (m, 2H), and 7.58-7.64 (m, 2H), 7.66-7.74 (m, 3H), 8.14 (dd, J=8.8,2.7Hz, 1H), 8.45 (d, J=2.4Hz, 1H) .MS (DCI/NH
3) m/z=307 (M+H)
+C
20H
22N
2OC
7H
8O
3The analytical calculation value of S: C, 67.76; H, 6.32; N, 5.85; Measured value: C, 67.70; H, 6.39; N, 5.74.
Embodiment 12
(4s)-4-[5-(1H-indoles-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method G by the product of embodiment 10C (45mg, 0.14mmol) and 5-indyl boric acid (33mg, 0.204mmol; Maybridge) make: MS (DCI/NH
3) m/z=346 (M+H)
+
Embodiment 13
(4r)-4-[5-(1H-indoles-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E by the product of embodiment 9F (45mg, 0.14mmol) and 5-indyl boric acid (33mg, 0.204mmol; Maybridge) make:
1H NMR (300MHz, CHCl
3) δ ppm 1.76-1.86 (m, 2H), 2.26 (s, 2H), 2.39 (d, J=11.5Hz, 2H), and 3.26-3.44 (m, 5H), 5.37 (t, J=3.2Hz, 1H), 6.61 (t, J=2.5Hz, 1H), 6.85 (d, J=8.5Hz, 1H), 7.25-7.30 (m, 1H), 7.31-7.41 (m, 1H), 7.48 (d, J=8.5Hz, 1H), 7.77 (s, 1H), 7.86 (dd, J=8.5,2.7Hz, 1H).MS (DCI/NH
3) m/z=346 (M+H)
+C
22H
22N
3O1.6H
2The analytical calculation value of O: C, 70.79; H, 6.80; N, 11.26; Measured value: C, 70.78; H, 6.44; N, 10.91.
Embodiment 14
(4r)-4-[5-(thionaphthene-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 14A
(4r)-4-[5-(thionaphthene-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E, by the product of embodiment 9F (45mg, 0.14mmol) and 2-benzo [b] thiophene-5-base-4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane (53mg, 0.204mmol; Maybridge) make: MS (DCI/NH
3) m/z=363 (M+H)
+
Embodiment 14B
(4r)-4-[5-(thionaphthene-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method H by the product of embodiment 14A (50mg 0.14mmol) makes:
1H NMR (300MHz, and the δ ppm 1.94 of methyl alcohol-D4) (d, J=12.9Hz, 2H), 2.20 (s, 1H), 2.34-2.46 (m, 5H), 2.58 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 5.48 (t, J=3.1Hz, 1H), 7.00 (dd, J=8.5,0.7Hz, 1H), 7.22 (d, J=8.1Hz, 2H), 7.44 (dd, J=5.6,0.8Hz, 1H), 7.57 (dd, J=8.5,1.4Hz, 1H), 7.62 (d, J=5.4Hz, 1H), 7.70 (d, J=8.1Hz, 2H), 7.98 (d, J=8.5Hz, 1H), 8.03-8.10 (m, 2H), 8.44 (dd, J=2.5,0.8Hz, 1H).MS (DCI/NH
3)m/z＝363(M+H)
+。C
22H
22N
2OSC
7H
8O
3The analytical calculation value of S: C, 65.14; H, 5.66; N, 5.24; Measured value: C, 64.78; H, 5.26; N, 5.18.
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 15A
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
With the product of embodiment 10A (1.00g, 5.99mmol), 2-chloro-5-iodo pyridine (1.44g, 6.01mmol; Aldrich), cuprous iodide (I) (110mg, 0.60mmol; Aldrich), phenanthrolene (220mg, 1.2mmol; Aldrich), cesium carbonate (3.9g, 12mmol; Aldrich) mixture in toluene (6mL) is heated to 110 ℃ under powerful the stirring and kept 3 days.Black mixture is cooled to room temperature,, passes through diatomite filtration with the methylene dichloride dilution.Crude material through flash chromatography (Analogix 34g silicagel column, the ethyl acetate 5-60% gradient in hexane) purifying, is obtained title compound:
1H NMR (300MHz, the δ ppm 1.65-1.75 of methyl alcohol-D4) (m, 2H), 1.96 (s, 1H), 2.16-2.27 (m, 4H), 3.14 (s, 2H), 3.16-3.27 (m, 4H), 4.76 (t, J=3.1Hz, 1H), 7.36 (dd, J=8.8,0.7Hz, 1H), 7.52 (dd, J=8.8,3.1Hz, 1H), 8.12 (dd, J=3.1,0.7Hz, 1H).MS(DCI/NH
3)m/z＝279/281(M+H)
+。
Embodiment 15B
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 15A (210mg 0.60mmol) makes:
1H NMR (300MHz, and the δ ppm 1.67 of methyl alcohol-D4) (s, 1H), 1.83 (d, J=12.9Hz, 2H), 2.04 (s, 2H), 2.31 (d, J=12.2Hz, 2H), and 3.08-3.18 (m, 4H), 3.22-3.27 (m, 2H), 4.75 (t, J=3.2Hz, 1H), 7.35 (dd, J=8.8,0.7Hz, 1H), 7.50 (dd, J=8.8,3.1Hz, 1H), 8.10 (d, J=3.1Hz, 1H).MS(DCI/NH
3)m/z＝265/267(M+H)
+。
Embodiment 15C
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 15B (40mg 0.15mmol) makes:
1H NMR (300MHz, the δ ppm 1.90 of methyl alcohol-D4) (d .J=13.2Hz, 2H), 2.18 (s, 1H), 2.30-2.41 (m, 5H), 2.46 (s, 2H), 3.56 (s, 2H), 3.57-3.74 (m, 4H), 4.88 (t, J=3.4Hz, 1H), 7.20-7.25 (m, 2H), 7.39 (d, J=8.8Hz, 1H), 7.55 (dd, J=8.8,3.1Hz, 1H), 7.70 (dt, J=8.1,1.9Hz, 2H), 8.17 (dd, J=3.1,0.7Hz, 1H).MS(DCI/NH
3)m/z＝265/267(M+H)
+。C
14H
17ClN
2OC
7H
8O
3S0.05H
2The analytical calculation value of O: C, 57.61; H, 5.78; N, 6.40; Measured value: C, 57.23; H, 5.71; N, 6.34.
Embodiment 16
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 16A
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 10A (419g, 2.51mmol) and 5-fluoro-2-nitropyridine (420mg, 2.9mmol; Referring to Application No. 20040209886) make:
1HNMR (300MHz, the δ ppm 1.68-1.78 of chloroform-D) (m, 2H), 2.07 (s, 1H), 2.20-2.35 (m, 4H), 3.19-3.34 (m, 6H), 4.74 (t, J=3.4Hz, 1H), 7.42 (dd, J=9.0,2.9Hz, 1H), 8.26-8.31 (m, 2H).MS(DCI/NH
3)m/z＝290(M+H)
+。
Embodiment 16B
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to product (599mg, 207mmol) preparation of method C by embodiment 16A.Product precipitates from reaction mixture separates out, so by filtering its collection, drying obtains title compound:
1H NMR (300MHz, and the δ ppm 1.95 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.21 (s, 1H), 2.38 (d, J=13.6Hz, 2H), 2.53 (s, 2H), 3.59 (s, 2H), and 3.61-3.79 (m, 4H), 5.11 (t, J=3.4Hz, 1H), 7.80 (dd, J=9.2,2.7Hz, 1H), and 8.31-8.38 (m, 2H).MS(+ESI)m/z＝276(M+H)
+。
Embodiment 17
(4s)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane dihydrochloride
Embodiment 17A
(4s)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
Under nitrogen atmosphere (60psi (sterling/square inch)), with the product of embodiment 16B (380mg, 1.2mmol) solution in THF-MeOH (10mL, 1: 1) is with blue Buddhist nun (Raney) nickel (401mg, 6.83mmol) handle, with mixture heating up to 50 ℃ maintenance 1 hour.After removing by filter catalyzer, product is through the HPLC[of preparation
XTerra RPl8 post, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10), UV detects at 254nm] purifying.To contain the part set of required compound, concentrate under the vacuum,, filter, obtain title compound with the methyl alcohol dilution:
1H NMR (300MHz, the δ ppm 1.66 of methyl alcohol-D4) (s, 1H), 1.80 (d, J=12.5Hz, 2H), 1.99 (s, 2H), 2.28-2.39 (m, 2H), 3.01-3.12 (m, 4H), 3.24 (ddd, J=14.1,2.4,2.2Hz, 2H), 4.45 (t, J=3.2Hz, 1H), 6.57 (dd, J=9.2,0.7Hz, 1H), 7.27 (dd, J=9.0,2.9Hz, 1H), 7.67 (dd, J=3.1,0.7Hz, 1H).MS(+ESI)m/z＝246(M+H)
+。
Embodiment 17B
(4s)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane dihydrochloride
According to method H by the product of embodiment 17A (81mg, 0.33mmol) and HCl-diox (160 μ l, 0.66mmol; Aldrich 4.0M) makes:
1H NMR (300MHz, and the δ ppm 1.92 of methyl alcohol-D4) (d, J=12.2Hz, 2H), 2.19 (s, 1H), 2.34 (d, J=13.2Hz, 2H), 2.46 (s, 2H), 3.56 (s, 2H), 3.58-3.74 (m, 4H), 4.77 (t, J=3.2Hz, 1H), 7.04 (dd, J=9.5,0.7Hz, 1H), 7.73 (dd, J=3.1,0.7Hz, 1H), 7.89 (dd, J=9.5,2.7Hz, 1H).MS(+ESI)m/z＝246(M+H)
+。C
14H
19N
3O2HCl0.5H
2The analytical calculation value of O: C, 51.38; H, 6.78; N, 12.84; Measured value: C, 51.06; H, 6.47; N, 12.68.
Embodiment 18
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 18A
((4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to product (500g, 2.99mmol) 5-fluoro-2-nitropyridine (500mg, the 3.5mmol of method A by embodiment 9D; Referring to Application No. 20040209886) make:
1H NMR (300MHz, and the δ ppm 1.84-1.95 of chloroform-D) (m, 2H), 2.01-2.13 (m, 3H), 2.30 (s, 2H), 3.00 (d, J=12.5Hz, 2H), 3.15 (s, 2H), 3.48 (d, J=13.6Hz, 2H), 4.60 (t, J=3.2Hz, 1H), 7.43 (dd, J=8.8,3.1Hz, 1H), and 8.24-8.30 (m, 2H).MS(DCI/NH
3)m/z＝290(M+H)
+。
Embodiment 18B
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 18A (599mg 2.07mmol) makes:
1H NMR (300MHz, methyl alcohol-D4): δ ppm 1.76 (s, 1H), 2.00-2.13 (m, 4H), and 2.16-2.28 (m, 2H), 2.99 (d, J=12.9Hz, 2H), 3.15 (s, 2H), 3.48 (d, J=12.9Hz, 2H), 4.96 (t, J=3.2Hz, 1H), 7.70 (dd, J=9.0,2.9Hz, 1H), and 8.25-8.36 (m, 2H).MS(+ESI)m/z＝276(M+H)
+
Embodiment 18C
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 18B (25mg, 0.091mmol) and tosic acid monohydrate (17mg, 0.091mmol; Aldiich) make:
1H NMR (300MHz, the δ ppm 2.07-2.30 of methyl alcohol-D4) (m, 5H), 2.36 (s, 3H), 2.51 (s, 2H), 3.47 (d, J=11.9Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=12.5Hz, 2H), 5.01 (t, J=3.4Hz, 1H), 7.23 (d, J=8.1Hz, 2H), 7.70 (d, J=8.1Hz, 2H), 7.79 (dd, J=9.0,2.9Hz, 1H), 8.31-8.37 (m, 2H).MS (+ESI) m/z=276 (M+H)
+.C
14H
17N
3O
3C
7H
8O
3S0.9H
2The analytical calculation value of O: C, 54.39; H, 5.83; N, 9.06; Measured value: C, 54.32; H, 5.87; N, 8.97.
Embodiment 19
(4r)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane dihydrochloride
Embodiment 19A
(4r)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
Under nitrogen atmosphere (60psi), (322mg, 1.17mmol) (400mg 6.82mmol) handles the solution in THF-MeOH (10mL, 1: 1), and mixture heating up to 50 ℃ was kept 1 hour with Raney Ni with the product of embodiment 18B.After removing by filter catalyzer, product is through the HPLC[of preparation
XTerra RPl8 post, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10), UV detects at 254nm] purifying.To contain the part set of required compound, concentrate under the vacuum,, filter, obtain title compound with the methyl alcohol dilution:
1H NMR (300MHz, and the δ ppm 1.71 of methyl alcohol-D4) (s, 1H), 1.89-2.01 (m, 4H), 2.10-2.20 (m, 2H), 2.93 (dd, J=12.5,1.0Hz, 2H), 3.11 (s, 2H), 3.49 (d, J=12.9Hz, 2H), 4.45 (t, J=3.4Hz, 1H), 6.57 (dd, J=8.8,0.7Hz, 1H), 7.26 (dd, J=9.0,2.9Hz, 1H), 7.65 (dd, J=3.1,0.7Hz, 1H).MS(+ESI)m/z＝246(M+H)
+。
Embodiment 19B
(4r)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane dihydrochloride
According to method H by the product of embodiment 19A (50mg, 0.20mmol) and HCl-diox (100 μ L, 0.41mmol; Aldrich 4.0M) makes:
1H NMR (300MHz, and the δ ppm 2.00-2.12 of methyl alcohol-D4) (m, 2H), 2.16-2.29 (m, 3H), 2.46 (s, 2H), 3.45 (d, J=12.2Hz, 2H), 3.55 (s, 2H), 3.81 (d, J=12.2Hz, 2H), 4.64 (t, J=3.4Hz, 1H), 7.03 (dd, J=9.5,0.7Hz, 1H), 7.72 (d, J=2.7Hz, 1H), 7.89 (dd, J=9.7,2.9Hz, 1H).MS(+ESI)m/z＝246(M+H)
+。C
14H
19N
3O2HCl1.1H
2The analytical calculation value of O: C, 49.74; H, 6.92; N, 12.43; Measured value: C, 49.57; H, 6.75; N, 12.37.
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 20A
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 10A (1.67g, 10.0mmol) and 2,5-two bromo thiazole (2.90g, 11.9mmol; Aldrich) make:
1H NMR (300MHz, the δ ppm1.69 of chloroform-D) (d, J=12.2Hz, 2H), 2.01 (s, 1H), 2.19 (d, J=12.9Hz, 2H), 2.39 (s, 2H), 3.13-3.25 (m, 6H), 5.19 (t, J=3.4Hz, 1H), 7.03 (s, 1H).MS(DCI/NH
3)m/z＝329/331(M+H)
+。
Embodiment 20B
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 20A (3.1g 94mmol) makes:
1H NMR (300MHz, the δ ppm 1.68 of methyl alcohol-D4) (s, 1H), 1.87 (d, J=11.5Hz, 2H), 2.10-2.31 (m, 4H), 3.04-3.17 (m, 6H), 5.22 (t, J=3.4Hz, 1H), 7.11 (s, 1H).
Embodiment 20C
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 20B (80mg 0.25mmol) makes:
1H NMR (300MHz, and the δ ppm 1.94 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.18 (s, 2H), 2.28 (d, J=13.2Hz, 2H), 2.37 (s, 3H), 2.61 (s, 2H), 3.56 (s, 2H), 3.57-3.74 (m, 4H), 5.37 (t, J=3.2Hz, 1H), 7.15 (s, 1H), 7.23 (d, J=8.1Hz, 2H), 7.70 (d, J=8.1Hz, 2H).C
12H
15BrN
2OSC
7H
8O
3S0.5H
2The analytical calculation value of O: C, 45.97; H, 4.87; N, 5.64; Measured value: C, 45.64; H, 4.63; N, 5.57.
Embodiment 21
(4s)-4-(thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 21A
(4s)-4-(thiazol-2-yl oxygen base) 11-aza-tricycle [3.3.1.1
3,7
] decane
Under hydrogen balloon, (93mg uses 10%Pd/C (10mg under the powerful stirring of ethanol 0.30mmol) (3mL) solution with embodiment 20B product; Aldrich) handled 7 hours.Mixture is removed by filter catalyzer, use washed with methanol.Compound is through the HPLC[of preparation
XTerra RPl8 5 μ posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required compound, concentrate under the vacuum, obtain title compound:
1H NMR (300MHz, the δ ppm 1.68 of methyl alcohol-D4) (s, 1H), 1.87 (d, J=11.9Hz, 2H), 2.18 (s, 2H), 2.27 (d, J=12.9Hz, 2H), 3.04-3.17 (m, 6H), 5.16 (t, J=3.4Hz, 1H), 6.88 (d, J=3.7Hz, 1H), 7.12 (d, J=3.7Hz, 1H).MS(DCI/NH
3)m/z＝237(M+H)
+。
Embodiment 21B
(4s)-4-(thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 21A (30mg 0.13mmol) makes:
1H NMR (300MHz, the δ ppm 1.94 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.18 (s, 1H), 2.31 (d, J=13.6Hz, 2H), 2.37 (s, 3H), 2.61 (s, 2H), 3.56 (s, 2H), 3.58-3.74 (m, 4H), 5.33 (t, J=3.4Hz, 1H), 6.94 (d, J=3.7Hz, 2H), 7.15 (d, J=4.1Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.71 (d, J=8.5Hz, 2H).MS (DCI/NH
3) m/z=237 (M+H)
+C
12H
16N
2OSC
7H
8O
3The analytical calculation value of S: C, 55.86; H, 5.92; N, 6.86; Measured value: C, 55.48; H, 5.95; N, 6.84.
Embodiment 22
(4s)-4-(5-phenyl thiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 22A
(4s)-4-(5-phenyl thiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E by the product of embodiment 20B (100mg, 0.317mmol) and phenyl-boron dihydroxide (80mg, 0.66mmol; Aldrich) make:
1H NMR (300MHz, the δ ppm 1.70 of methyl alcohol-D4) (s, 1H), 1.89 (d, J=11.9Hz, 2H), 2.18-2.35 (m, 4H), 3.09-3.19 (m, 4H), 5.22 (t, J=3.4Hz, 1H), 7.25-7.32 (m, 1H), 7.34-7.42 (m, 3H), 7.47-7.53 (m, 2H).MS(DCI/NH
3)m/z＝313(M+H)
+。
Embodiment 22B
(4s)-4-(5-phenyl thiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 22A (85mg 0.27mmol) makes:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.20 (s, 1H), 2.28-2.39 (m, 5H), 2.66 (s, 2H), 3.58 (s, 2H), 3.60-3.76 (m, 4H), 5.38 (t, J=3.2Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.27-7.34 (m, 1H), 7.35-7.42 (m, 2H), 7.44 (s, 1H), 7.48-7.54 (m, 2H).MS(DCI/NH
3)m/z＝313(M+H)
+。C
18H
20N
2OSC
7H
8O
3The analytical calculation value of S: C, 61.96; H, 5.82; N, 5.78; Measured value: C, 61.71; H, 5.74; N, 5.71.
Embodiment 23
(4s)-4-[5-(4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 23A
(4s)-4-[5-(4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E by the product of embodiment 20B (100mg, 0.317mmol) and 4-anisole ylboronic acid (100mg, 0.66mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.69 of methyl alcohol-D4) (s, 1H), 1.89 (d, J=11.9Hz, 2H), 2.21 (s, 2H), 2.29 (d, J=12.9Hz, 2H), and 3.08-3.17 (m, 4H), 3.26-3.29 (m, 2H), 3.81 (s, 3H), 5.18 (t, J=3.4Hz, 1H), 6.91-6.97 (m, 2H), 7.26 (s, 1H), 7.42 (ddd, J=9.3,2.7,2.5Hz, 2H).MS(DCI/NH
3)m/z＝343(M+H)
+。
Embodiment 23B
(4s)-4-[5-(4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method H by the product of embodiment 23A (87mg 0.25mmol) makes:
1H NMR (300MHz, the δ ppm 1.95 of methyl alcohol-D4) (d, J=12.9Hz, 2H), 2.19 (s, 1H), 2.32 (d, J=13.6Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.57 (s, 2H), 3.59-3.76 (m, 4H), 3.81 (s, 3H), 5.34 (t, J=3.4Hz, 1H), 6.90-6.99 (m, 2H), 7.23 (d, J=8.5Hz, 2H), 7.29 (s, 1H), 7.39-7.47 (m, 2H), 7.71 (d, J=8.1Hz, 2H).MS(ESI)m/z＝343(M+H)
+。C
19H
22N
2O
2SC
7H
8O
3The analytical calculation value of S: C, 60.68; H, 5.88; N, 5.44; Measured value: C, 60.57; H, 5.87; N, 5.37.
Embodiment 24
(4s)-4-[5-(3-chloro-phenyl-)-thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to toluene
Sulfonate
Embodiment 24A
(4s)-4-[5-(3-chloro-phenyl-)-thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E by the product of embodiment 20B (100mg, 0.317mmol) and 3-chlorophenylboronic acid (100mg, 0.66mmol; Aldrich) make:
1H NMR (300MHz, the δ ppm 1.69 of methyl alcohol-D4) (s, 1H), 1.89 (d, J=12.5Hz, 2H), 2.18-2.35 (m, 4H), 3.08-3.18 (m, 4H), 3.26-3.29 (m, 2H), 5.24 (t, J=3.2Hz, 1H), 7.29 (dt, J=8.1,1.6Hz, 1H), 7.36 (t, J=7.8Hz, 1H), 7.43 (ddd, J=7.6,1.5,1.4Hz, 1H), 7.48 (s, 1H), 7.54 (t, J=1.7Hz, 1H).MS(ESI)m/z＝347/349(M+H)
+。
Embodiment 24B
(4s)-4-[5-(3-chloro-phenyl-)-thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to toluene
Sulfonate
According to method H by the product of embodiment 24A (96mg 0.28mmol) makes:
1H NMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.20 (s, 1H), 2.27-2.39 (m, 5H), 2.66 (s, 2H), 3.58 (s, 2H), 3.61-3.76 (m, 4H), 5.40 (t, J=3.2Hz, 1H), 7.23 (d, J=8.5Hz, 2H), 7.31 (dt, J=7.8,1.7Hz, 1H), 7.37 (t, J=7.5Hz, 1H), 7.44 (dt, J=7.5,1.7Hz, 1H), 7.51 (s, 1H), 7.55 (t, J=1.9Hz, 1H), 7.67-7.75 (m, 2H).MS(ESI)m/z＝347/349(M+H)
+。C
18H
19ClN
2OSC
7H
8O
3S0.2H
2The analytical calculation value of O: C, 57.45; H, 5.28; N, 5.36; Measured value: C, 57.13; H, 5.31; N, 5.10.
(4s)-4-[5-(3-chloro-4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
Embodiment 25A
(4s)-4-[5-(3-chloro-4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
Alkane
According to method E by the product of embodiment 20B (100mg, 0.317mmol) and 3-chloro-4-p-methoxy-phenyl-boric acid (120mg, 0.63mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.70 of methyl alcohol-D4) (s, 1H), 1.89 (d, J=11.9Hz, 2H), and 2.17-2.35 (m, 4H), 3.09-3.18 (m, 4H), 3.26-3.30 (m, 2H), 3.90 (s, 3H), 5.21 (t, J=3.4Hz, 1H), 7.09 (d, J=8.8Hz, 1H), 7.32 (s, 1H), 7.40 (dd, J=8.5,2.4Hz, 1H), 7.53 (d, J=2.4Hz, 1H).MS(ESI)m/z＝377/379(M+H)
+。
Embodiment 25B
(4s)-4-[5-(3-chloro-4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
According to method H by the product of embodiment 25A (105mg 0.278mmol) makes:
1H NMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=12.9Hz, 2H), 2.36 (s, 3H), 2.65 (s, 2H), 3.58 (s, 2H), 3.60-3.76 (m, 4H), 3.91 (s, 3H), 5.37 (t, J=3.2Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 7.23 (d, J=8.1Hz, 2H), 7.35 (s, 1H), 7.41 (dd, J=8.5,2.4Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.71 (d, J=8.1Hz, 2H).MS(ESI)m/z＝377/379(M+H)
+。C
19H
21ClN
2O
2SC
7H
8O
3S0.2H
2The analytical calculation value of O: C, 56.50; H, 5.36; N, 5.07; Measured value: C, 56.15; H, 5.40; N, 5.02.
Embodiment 26
(4s)-4-[5-(4-fluorophenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane to toluene
Sulfonate
According to method E by the product of embodiment 20B (75mg, 0.24mmol) and 4-fluorophenyl-boric acid (73mg, 0.46mmol; Aldrich) preparation free alkali, the operation by method H converts its salt to then:
1H NMR (300MHz, the δ ppm 1.91-2.01 of methyl alcohol-D4) (m, 2H), 2.19 (s, 1H), 2.32 (d, J=13.5Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.52-3.77 (m, 6H) 5.38 (s, 1H), 7.14 (d, J=24.1Hz, 2H), and 7.37-7.40 (m, 1H), 7.48-7.58 (m, 2H), 7.70 (d, J=8.1Hz, 2H).MS (DCI/NH
3)m/z＝331。C
18H
19FN
2OSC
7H
8O
3The analytical calculation value of S: C, 59.74; H, 5.41; N, 5.57; Measured value: C, 53.36; H, 5.13; N, 5.50.
Embodiment 27
(4s)-4-[5-(3, the 5-difluorophenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method E by the product of embodiment 20B (75mg, 0.24mmol) and 3,5-difluorophenyl-boric acid (75mg, 0.46mmol; Aldrich) preparation free alkali, the operation by method H converts its salt to then:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=15.2Hz, 2H), 2.18 (s, 1H), 2.32 (d, J=14.9Hz, 2H), 2.36 (s, 3H), 2.63 (s, 2H), 3.49-3.76 (m, 6H), 5.41 (s, 1H), 6.79-6.97 (m, 1H), 7.15-7.19 (m, 2H), 7.21-7.24 (m, 2H), 7.58 (s, 1H), 7.71 (m, 2H).MS(DCI/NH
3)m/z＝349。C
18H
18F
2N
2OSC
7H
8SO
3The analytical calculation value: C, 57.68; H, 5.03; N, 5.38; Measured value: C, 55.49; H, 5.17; N, 5.14.
Embodiment 28
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 28A
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
(110mg is 0349mmol) with 5-indyl boric acid (140mg, 0.72mmol by embodiment 20B product according to method E; Frontier) make: MS (DCI/NH
3) m/z=352.
Embodiment 28B
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method H by the product of embodiment 28A (72mg 0.20mmol) makes:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=13.6Hz, 2H), 2.20 (s, 1H), and 2.29-2.38 (m, 5H), 2.65 (s, 2H), and 3.59-3.75 (m, 6H), 5.34 (t, J=3.2Hz, 1H), 6.46 (d, J=3.4Hz, 1H), and 7.19-7.32 (m, 5H), 7.40 (d, J=8.5Hz, 1H), 7.65-7.74 (m, 3H).MS (DCI/NH
3) m/z=352 (M+H)
+C
20H
21N
3OSC
7H
8O
3S0.25H
2The analytical calculation value of O: C, 61.40; H, 5.63; N, 7.96.Measured value: C, 61.36; H, 5.64; N, 7.86.
Embodiment 29
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane-1-oxygen
Change thing
With embodiment 28A product (105mg, methyl alcohol 0.30mmol) (4mL) solution 3-chloroperoxybenzoic acid (mCPBA; 70-75%; 71.0mg, 0.30mmol; Aldrich) handle, and stirred 4 hours in envrionment temperature.The HPLC[of material through preparation will be generated
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10)] purifying, obtain title compound:
1H NMR (300MHz, and the δ ppm 1.70-2.02 of methyl alcohol-D4) (m, 2H), 2.10-2.29 (m, 1H), 2.29-2.47 (m, 1H), 2.58-2.78 (m, 2H), 3.57-3.67 (m, 5H), 5.32 (t, J=3.3Hz, 1H), 6.46 (d, J=3.0Hz, 1H), 7.26 (d, J=3.3Hz, 1H), and 7.27-7.31 (m, 2H), 7.36-7.42 (m, 1H), 7.66 (d, J=1.3Hz, 1H).MS(DCI/NH
3)m/z＝368(M+H)
+。
(4s)-5-4-[2-(1-aza-tricycle [3.3.1.1
3,7
] decane-4-base oxygen base) thiazole-5-yl]-Indolin-2-one
According to method E, by the product of embodiment 20B (200mg, 063mmol) and 5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-Indolin-2-one (260mg, 1.0mmol; Referring to Application No. 20050245531) make:
1H NMR (300MHz, and the δ ppm 1.52-1.79 of methyl alcohol-D4) (m, 1H), 1.80-2.00 (m, 2H), 2.07-2.43 (m, 4H), 3.00-3.20 (m, 5H), 3.35 (s, 2H), 5.20 (t, J=3.2Hz, 1H), 6.90 (d, J=8.1Hz, 1H), 7.30 (s, 1H), 7.35 (dd, J=8.1,2.0Hz, 1H), 7.43 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝368(M+H)
+。
Embodiment 31
(4s)-5-4-[2-(1-aza-tricycle [3.3.1.1
3,7
] decane-1-oxide compound-4-base oxygen base) thiazole-5-yl]-Yin
Diindyl is expired-2-ketone
With embodiment 30 products (100mg, methyl alcohol 0.27mmol) (4mL) solution 3-chloroperoxybenzoic acid (mCPBA; 70-75%; 71.0mg, 0.30mmol; Aldrich) handle, and stirred 4 hours in envrionment temperature.The HPLC[of material through preparation will be generated
XTerra RP 18 posts, 5 μ, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10)] purifying, obtain title compound:
1H NMR (300MHz, and the δ ppm 1.71-1.94 of methyl alcohol-D4) (m, 2H), 2.07-2.26 (m, 2H), 2.29-2.45 (m, 1H), 2.58-2.80 (m, 2H), 3.44-3.75 (m, 8H), 5.34 (t, J=3.2Hz, 1H), 6.90 (d, J=8.1Hz, 1H), 7.32 (s, 1H), 7.35 (dd, J=8.1,1.7Hz, 1H), 7.43 (d, J=1.3Hz, 1H).MS(DCI/NH
3)m/z＝384(M+H)
+。
Embodiment 32
(4s)-4-[5-(2-Trifluoromethyl-1 H-indoles-5-yl)-thiazol-2-yl oxygen base]-the 1-aza-tricycle
[3.3.1.1
3,7
] tosilate of decane
According to method E, by the product of embodiment 20B (100mg, 0.30mmol) and 5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-2-(trifluoromethyl)-1H-indoles (197mg, 0.64mmol; Application No. 2005043347) title compound of preparation free alkali, the operation according to method H is translated into salt then:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.2Hz, 2H), 2.13 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.60 (s, 2H), 3.48-3.71 (m, 6H), 5.35 (s, 1H), 6.91 (s, 1H), 7.22 (d, J=7.8Hz, 2H), 7.34-7.39 (m, 1H), 7.48 (s, 2H), 7.71 (d, J=8.1Hz, 2H), 7.78 (s, 1H).MS(DCI/NH
3)m/z＝420(M+H)
+。C
21H
20F
3N
3OSC
7H
8O
3The analytical calculation value of S: C, 56.84; H, 4.77; N, 7.10; Measured value: C, 55.39; H, 4.57; N, 7.02
Embodiment 33
(4s)-4-[5-(1H-indoles-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method E, by the product of embodiment 20B (110mg, 0.349mmol) and indoles-4-boric acid (120mg, 0.72mmol; Frontier) title compound of preparation free alkali, the operation according to method H is translated into salt then:
1H NMR (300MHz, the δ ppm 1.97 of methyl alcohol-D4) (d, J=12.2Hz, 2H), 2.21 (s, 1H), 2.28-2.44 (m, 5H), 2.68 (s, 2H), 3.58 (s, 2H), 3.62-3.77 (m, 4H), 5.39 (s, 1H), 6.71 (dd, J=3.4,1.0Hz, 1H), and 7.09-7.19 (m, 2H), 7.23 (d, J=7.8Hz, 2H), 7.34 (d, J=3.1Hz, 1H), 7.37-7.43 (m, 1H), 7.47 (s, 1H), 7.71 (d, J=8.1Hz, 2H).MS (DCI/NH
3) m/z=352 (M+H)
+C
20H
21N
3OSC
7H
8O
3S0.2H
2The analytical calculation value of O: C, 61.50; H, 5.62; N, 7.97.Measured value: C, 61.48; H, 5.59; N, 7.91.
Embodiment 34
(4s)-4-[5-(1H-indoles-6-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method E, by the product of embodiment 20B (110mg, 0.349mmol) and indoles-6-boric acid (120mg, 0.72mmol; Frontier) title compound of preparation free alkali, the operation according to method H is translated into salt then:
1H NMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (d, J=14.2Hz, 2H), 2.21 (s, 1H), 2.28-2.46 (m, 5H), 2.66 (s, 2H), 3.58 (s, 2H), 3.61-3.77 (m, 4H), 5.35 (t, J=3.2Hz, 1H), 6.45 (dd, J=3.1,1.0Hz, 1H), 7.12-7.25 (m, 3H), 7.27 (d, J=3.1Hz, 1H), 7.35 (s, 1H), 7.45-7.51 (m, 1H), 7.55 (d, J=8.1Hz, 1H), 7.71 (d, J=8.1Hz, 2H).MS (DCI/NH
3) m/z=352 (M+H)
+, C
20H
21N
3OSC
7H
8O
3S0.2H
2The analytical calculation value of O: C, 61.50; H, 5.62; N, 7.97; Measured value: C, 61.48; H, 5.59; N, 7.91.
(4s)-4-[5-(1H-indol-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 35A
(4s)-4-[5-(1-benzenesulfonyl-1H-indol-3-yl)-thiazol-2-yl oxygen base]-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
According to method E by the product of embodiment 20B (110mg, 0.349mmol) and 1-benzenesulfonyl-1H-indol-3-yl boric acid (220mg, 0.72mmol; Aldrich) make: MS (DCI/NH
3) m/z=492 (M+H)
+
Embodiment 36B
(4s)-4-[5-(1H-indol-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
With the product of embodiment 35A (150mg, 0.31mmol) and salt of wormwood (100mg, 0.76mmol) the solution reflux in methyl alcohol (3mL) is 90 minutes.After the cooling, remove and desolvate, residuum is water-soluble, and mixture extracts with ethyl acetate (3x).With the extract salt water washing that merges, dry (Na
2SO
4), filter, concentrate the title compound that obtains free alkali.According to method H this material is converted into salt:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.9Hz, 2H), 2.21 (s, 1H), 2.30-2.40 (m, 5H), 2.66 (s, 2H), 3.58 (s, 2H), 3.62-3.79 (m, 4H), 5.35 (t, J=3.6Hz, 1H), 7.08-7.25 (m, 4H), 7.29 (s, 1H), 7.39-7.44 (m, 1H), 7.45 (s, 1H), 7.67-7.77 (m, 3H).MS (DCI/NH3) m/z=352 (M+H)
+C
20H
21N
3OSC
7H
8O
3The analytical calculation value of S: C, 61.93; H, 5.58; N, 8.02; Measured value: C, 61.56; H, 5.20; N, 7.77.
Embodiment 36
(4s)-4-[5-(pyridin-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane two (right
Tosylate)
Embodiment 36A
(4s)-4-[5-(pyridin-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method E by the product of embodiment 20B (100mg, 0.317mmol) and 4-pyridyl boric acid (100mg, 0.814mmol; Aldrich) make:
1H NMR (300MHz, the δ ppm 1.70 of methyl alcohol-D4) (s, 1H), 1.90 (d, J=11.9Hz, 2H), 2.19-2.34 (m, 4H), 3.09-3.19 (m, 4H), 5.31 (t, J=3.2Hz, 1H), 7.53-7.58 (m, 2H), 7.78 (s, 1H), 8.46-8.52 (m, 2H).MS(DCI/NH
3)m/z＝314(M+H)
+。
Embodiment 36B
(4s)-4-[5-(pyridin-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane two (right
Tosylate)
According to method H by the product of embodiment 36A (77mg, 0.24mmol) and tosic acid monohydrate (93mg, 0.49mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.98 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.22 (s, 1H), 2.26-2.39 (m, 8H), 2.69 (s, 2H), 3.59 (s, 2H), 3.63-3.78 (m, 4H), 5.57 (t, J=3.2Hz, 1H), 7.22 (d, J=8.5Hz, 4H), 7.67-7.74 (m, 4H), 8.12-8.17 (m, 2H), 8.25 (s, 1H), 8.67-8.73 (m, 2H).MS(ESI)m/z＝314(M+H)
+。C
17H
19N
3OS2C
7H
8O
3S0.2H
2The analytical calculation value of O: C, 56.29; H, 5.39; N, 6.35; Measured value: C, 56.03; H, 5.29; N, 6.12.
Embodiment 37
(4s)-4-[5-(furans-2-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane two (right
Tosylate)
According to method E, by the product of embodiment 20B (101mg, 0.32mmol) and 2-furyl boric acid (53mg, 0.48mmol; Aldrich) title compound of preparation free alkali, the operation according to method H is translated into salt then:
1H NMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.19 (s, 1H), 2.33 (d, J=13.6Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.52-3.77 (m, 6H), 5.36 (s, 1H), 6.52 (d, J=21.0Hz, 2H), 7.22 (d, J=8.1Hz, 2H), 7.33 (s, 1H), 7.51 (d, J=1.4Hz, 1H), 7.70 (d, J=8.1Hz, 2H).MS(DCI/NH
3)m/z＝304(M+H)
+。C
16H
17N
2O
2SC
7H
8O
3The analytical calculation value of S: C, 58.21; H, 5.52; N, 5.90; Measured value: C, 55.59; H, 5.18; N, 5.55.
Embodiment 38
(4s)-4-[5-(furans-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane two (right
Tosylate)
According to method E, by the product of embodiment 20B (101mg, 0.32mmol) and 3-furyl boric acid (53mg, 0.48mmol; Aldrich) title compound of preparation free alkali, the operation according to method H is translated into salt then:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.19 (s, 1H), 2.33 (d, J=13.6Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), and 3.52-3.77 (m, 6H), 5.36 (s, 1H), 7.16 (s, 1H), 7.23 (d, J=8.1Hz, 3H), 7.67-7.74 (m, 4H).MS(DCI/NH
3)m/z＝304(M+H)
+。C
16H
17N
2O
2SC
7H
8O
3The analytical calculation value of S: C, 58.21; H, 5.52; N, 5.90; Measured value: C, 55.77; H, 4.99; N, 5.57.
Embodiment 39
(4s)-4-[5-(thiene-3-yl-)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane two is (to first
Benzene sulfonate)
According to method E, by the product of embodiment 20B (110mg, 0.35mmol) and 3 thienylboronic acid (77mg, 0.60mmol; Aldrich) title compound of preparation free alkali, the operation according to method H is translated into salt then:
1H NMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.19 (s, 1H), 2.32 (d, J=13.9Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.51-3.78 (m, 6H), 5.36 (s, 1H), 7.22 (d, J=8.4Hz, 2H), 7.30 (dd, J=5.1,1.4Hz, 1H), 7.34 (s, 1H), 7.42-7.52 (m, 2H), 7.70 (d, J=8.1Hz, 2H).MS(DCI/NH
3)m/z＝320(M+H)
+。C
16H
17N
2OS
2C
7H
8SO
3The analytical calculation value: C, 53.74; H, 5.13; N, 8.55; Measured value: C, 53.51; H, 5.37; N, 10.89.
(4s)-4-[5-(pyrazoles-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane two (right
Tosylate)
According to method E, by the product of embodiment 20B (111mg, 0.315mmol) and 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (272mg, 0.624mmol; JP 2005232071) preparation, application operating or method L deprotection subsequently, and form salt according to method H:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.19 (s, 1H), 2.32 (d, J=13.9Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), and 3.51-3.78 (m, 6H), 5.36 (s, 1H), and 7.13-7.31 (m, 3H), 7.71 (d, J=8.4Hz, 2H), 7.80 (s, 2H).MS(DCI/NH
3)m/z＝304(M+H)
+。
Embodiment 41
(4s)-4-(5-bromo-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to first
Benzene sulfonate
Embodiment 41A
(4s)-4-(5-bromo-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
According to method A, by the product of embodiment 10A (1.3g, 8.0mmol) and 2,5-two bromos-1,3,4-thiadiazoles (2.1g, 8.8mmol; Preparation is described in Yasuda, T.; Imase, T.; Sasaki, S.; Yamamoto, T.Macromolecules 2005,38, and 1500) make:
1H NMR (300MHz, the δ ppm 1.72 of chloroform-D) (d, J=11.9Hz, 2H), 2.03 (s, 1H), 2.17 (d, J=12.9Hz, 2H), 2.48 (s, 2H), 3.15-3.26 (m, 6H), 5.34 (t, J=3.6Hz, 1H).
Embodiment 41B
(4s)-4-(5-bromo-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 41A (1.35g 4.09mmol) makes:
1HNMR (300MHz, the δ ppm 1.68 of methyl alcohol-D4) (s, 1H), 1.84-1.95 (m, 2H), 2.24 (s, 4H), 3.07-3.17 (m, 4H), 3.25-3.29 (m, 2H), 5.34 (t, J=3.1Hz, 1H).MS(ESI)m/z＝316/318(M+H)
+。
Embodiment 41C
(4s)-4-(5-bromo-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to first
Benzene sulfonate
According to method H by the product of embodiment 41B (80mg 0.25mmol) makes:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=14.2Hz, 2H), 2.19 (s, 1H), 2.30 (d, J=13.9Hz, 2H), 2.36 (s, 3H), 2.68 (s, 2H), 3.57 (s, 2H), 3.59-3.76 (m, 4H), 5.47 (t, J=3.4Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.66-7.74 (m, 2H).MS(ESI)m/z＝316/318(M+H)
+。C
11H
14BrN
3OSC
7H
8O
3The analytical calculation value of S: C, 44.26; H, 4.54; N, 8.60; Measured value: C, 44.35; H, 4.58; N, 8.61.
Embodiment 42
(4s)-4-(1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosic acid of decane
Salt
Embodiment 42A
(4s)-4-(1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
Under hydrogen balloon, (100mg uses 10%Pd/C (10mg under the powerful stirring of ethanol 0.32mmol) (3mL) solution with embodiment 41B product; Aldrich) handled 3 days.Because reaction is not finished, and removes by filter catalyzer, uses washed with methanol, make the fresh Pd/C reaction conditions of its experience again.After 6 hours, filtering mixt, compound is through the HPLC[of preparation
XTerra RPl8 5 μ posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required compound, concentrate under the vacuum, obtain title compound:
1H NMR (300MHz, the δ ppm 1.69 of methyl alcohol-D4) (s, 1H), 1.90 (d, J=13.6Hz, 2H), 2.20-2.33 (m, 4H), 3.07-3.20 (m, 4H), 5.30 (t, J=2.9Hz, 1H), 8.88 (s, 1H).MS(DCI/NH
3)m/z＝238(M+H)
+。
Embodiment 42B
(4s)-4-(1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosic acid of decane
Salt
According to method H by the product of embodiment 42A (38mg, 0.16mmol) preparation:
1H NMR (300MHz, and the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.20 (s, 1H), 2.31 (d, J=13.2Hz, 2H), 2.37 (s, 3H), 2.70 (s, 2H), 3.58 (s, 2H), 3.61-3.77 (m, 4H), 5.46 (t, J=3.2Hz, 1H), 7.23 (d, J=8.5Hz, 2H), 7.71 (d, J=8.1Hz, 2H), 8.94 (s, 1H).MS(DCI/NH
3)m/z＝238(M+H)
+。C
11H
15N
3OSC
7H
8O
3S0.3H
2The analytical calculation value of O: C, 52.10; H, 5.73; N, 10.13; Measured value: C, 51.94; H, 5.69; N, 9.76.
Embodiment 43
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 43A
1-azaadamantane-4-alcohol N-borane complex.
With 1-azaadamantane-4-ketone (29g, 190mmol; Referring to Becker, D.P.; Flynn, D.L.Synthesis 1992,1080) solution in anhydrous tetrahydro furan (200mL) cools off in ice-water bath, and (1.0M is in THF with borine-THF complex compound; 200mL, 200mmol; Aldrich) drip processing.After stirring 30 minutes, reaction mixture with methyl alcohol (1000mL) dilution, is used sodium borohydride (8.8g, 230mmol; Aldrich) handled keeps about 5-7 ℃ of internal temperature.Mixture was stirred 2 hours, remove ice bath then, continue to stir 4 hours.On rotatory evaporator, remove volatile constituent, with residuum be dissolved in chloroform (～500mL), with the washing of saturated aqueous sodium carbonate.Water layer chloroform extraction, organic phase filter through dried over mgso.Generate material through flash chromatography (Analogix 400g 65x220mm silicagel column, ethyl acetate in hexane through 50 minutes 5-95% gradient) purifying, obtain inseparable 3.7: 1.0 isomer mixtures [according at δ 3.96 (t, main) and δ 3.82 (t, accessory)
1H NMR signal (CDCl
3) integration].Use KmnO
4Dyeing can be looked at the product spot on the TLC plate (silica gel) straight.
Embodiment 43B
4-chloro-benzoic acid (4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base ester N-borane complex
With
Embodiment 43C
4-chloro-benzoic acid (4r)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base ester N-borane complex
With 1-azaadamantane-4-alcohol N-borane complex (28g, 170mmol; 3.2: 1.0 non-enantiomer mixtures), 4-chloro-benzoic acid (28.0g, 179mmol; Aldrich) and 4-Dimethylamino pyridine (4.2g, 34mmol; Aldrich) methylene dichloride (700mL) solution is cooled to 0 ℃, with N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (42.0g, 219mmol; Aldrich) handle.After 1 hour, reaction mixture is warming up to room temperature, and stirs and spend the night.Solution is washed with saturated sodium bicarbonate subsequently fast with 1MHCl (200mL), through dried over mgso.It is a collection of through flash chromatography (Analogix 400g 65x220mm silicagel column, ethyl acetate in hexane through 45 minutes 5-55% gradient) purifying with～5g to generate material.
Embodiment 43B: main (4s) isomer: TLC R
f=0.49 (silica gel, 3: 1 hexane-EtO Ac).
1H?NMR(300MHz，CDCl
3)δppm?1.76(d，J＝12.5Hz，2H)，2.06(s，1H)，2.16-2.33(m，4H)，3.12-3.32(m，6H)，5.26(t，J＝3.2Hz，1H)，7.45(dt，J＝8.7，2.4，2.1Hz，2H)，8.00(dt，J＝8.7，2.4，2.1Hz，2H)。MS(DCI/NH
3)m/e?321/323(M+H)
+。C
16H
21BClNO
2The analytical calculation value: C 62.88, and H 6.93, N4.58; Measured value C 63.00, H 6.80, and N 4.50.
Embodiment 43C: accessory (4r) isomer .TLC R
f=0.34 (silica gel, 3: 1 hexanes-EtOAc).
1HNMR(300MHz，CDCl
3)δppm?1.84-2.11(m，5H)，2.24(s，2H)，3.03(d，J＝12.5Hz，2H)，3.14(s，2H)，3.46(d，J＝13.2Hz，2H)，5.16(t，J＝3.2Hz，1H)，7.39-7.51(m，2H)，7.89-8.05(m，2H)。MS(DCI/NH
3)m/e?321/323(M+H)
+。C
16H
21BClNO
2The analytical calculation value: C 62.88, and H 6.93, and N 4.58; Measured value C62.83, H 6.95, and N 4,53.
Embodiment 43D
(4s)-4-(1-aza-tricycle [3.3.1.1
3,7
] decane-4-alcohol) the N-borane complex
With 4-chloro-benzoic acid (4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base ester N-borane complex (handle with 5M sodium hydroxide (50mL) for embodiment 43B, 25.0g by tetrahydrofuran (THF) 81.8mmol) (50mL) suspension.After 1 hour, with mixture heating up to 50 ℃ maintenance 3 hours.Remove most of solvents at rotary evaporator, residuum obtains the title product through flash chromatography (Analogix 220g 65x120mm silicagel column, the 5-95% gradient of ethyl acetate in hexane) purifying:
1H NMR (300MHz, δ ppm 0.87-2.09 (br m, the 3H of methyl alcohol-d4); BH
3), 1.59 (d, J=12.5Hz, 2H), 1.78-1.98 (m, 2H), 2.22 (d, J=12.5Hz, 2H), 2.97-3.18 (m, 6H), 3.96 (t, J=3.4Hz, 1H).MS(DCI/NH
3)m/e?183(M+H)
+。
Embodiment 43E
2-chloro-5-phenyl-[1,3,4] thiadiazoles
With 2-amino-5-phenyl-[1,3,4] thiadiazoles (6.45g, the 36.4mmol that stirs; Aldrich) and copper (230mg, 3.6mmol; Aldrich) in hydrochloric acid (36mL, 12M) and the suspension of Glacial acetic acid (180mL) be cooled to 0 ℃, with Sodium Nitrite (2.64g, 38.2mmol; Aldrich) water (12mL) solution dripped through 40 minutes and handles., after 4 hours mixture is poured in the frozen water in stirring at room.The aqueous solution is with chloroform (3x) extraction, and the extract after merging is continuous with 5% sodium bicarbonate and salt water washing, through dried over sodium sulfate.Coarse products is filtered with chloroform by short silica gel plug, obtains the title product:
1H NMR (300MHz, CDCl
3) δ ppm 7.46-7.55 (m, 3H), 7.85-7.93 (m, 2H).MS(DCI/NH
3)m/e?197/199(M+H)
+。
Embodiment 43F
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
With (4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-alcohol N-borane complex (embodiment 43D, 2.31g is 13.8mmol) with 2-chloro-5-phenyl-[1,3,4] thiadiazoles (embodiment 43E, 2.78g, 14.1mmol) solution in dry DMF (20mL) is cooled to 0 ℃, and with sodium hydride (500mg, 20.8mmol; Aldrich, 95%) handle.Observe strong foaming, solution becomes orange.After 15 minutes, remove cooling bath, will react and stir 4 hours.The reaction mixture dilute with water, and stir and spend the night.Collect the precipitation that generates by filtering, wash with water, dry under the vacuum, obtain the title product:
1H NMR (300MHz, CDCl
3) δ ppm 1.73 (d, J=12.5Hz, 2H), 2.04 (s, 1H), 2.22 (d, J=13.2Hz, 2H), 2.54 (s, 2H), 3.17-3.28 (m, 6H), 5.38 (t, J=3.6Hz, 1H), 7.42-7.51 (m, 3H), 7.77-7.87 (m, 2H).MS(+ESI)m/e328(M+H)
+。
Embodiment 43G
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
(A-913958.0)
With (4s)-4-(5-phenyl-[1,3,4] thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (1.77mmol) suspension in acetone (18mL) is cooled to 0 ℃ to decane N-borane complex for embodiment 43F, 580mg, handles with 3N HCl (6mL).Suspension is slowly clarified, and begins to form precipitation then.After 20 minutes, remove ice bath, mixture was stirred 2 hours.Then solution is alkalized to pH 10 with 5N NaOH, with chloroform (3x) extraction, through anhydrous magnesium sulfate drying.With the material that generates through flash chromatography [Analogix 34g 25mm silicagel column, the 5-50% gradient of ammonium hydroxide-methyl alcohol-chloroform (2: 20: 78) in chloroform] purifying.By HPLC[Waters XTerra RP 18, the 5 μ posts of preparation, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] be further purified.To contain part (only peak center) set of required product, and concentrate and obtain the title product:
1H NMR (300MHz, the δ ppm 1.71 of methyl alcohol-d4) (s, 1H), 1.92 (d, J=12.5Hz, 2H), 2.29 (s, 4H), and 3.10-3.21 (m, 4H), 3.30-3.38 (m, 2H), 5.35 (t, J=3.1Hz, 1H), 7.46-7.54 (m, 3H), 7.80-7.89 (m, 2H).MS(+ES1)m/e?314(M+H)
+。C
17H
19NO
3The analytical calculation value of S: C 65.15, and H 6.11, and N 13.41; Measured value C64.94, H 6.10, and N 13.41.
Embodiment 44
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane-1-oxidation
Thing
(50mg, methanol solution 0.16mmol) are cooled to 0 ℃, with 3-chloroperoxybenzoic acid (70-75% with embodiment 43B product; 39mg, 0.16mmol; Aldrich) handle.After 30 minutes, remove ice bath, continue to stir and spend the night.Enriched mixture through flash chromatography (Analogix 15g silicagel column, the 5-50% gradient of ammonium hydroxide-methyl alcohol-chloroform (2: 20: 78) in chloroform) purifying, obtains title compound with residuum:
1H NMR (300MHz, and the δ ppm 1.85 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.20 (d, J=12.9Hz, 2H), 2.37 (s, 1H), 2.77 (s, 2H), 3.50-3.59 (m, 4H), and 3.63-3.72 (m, 2H), 5.49 (t, J=3.6Hz, 1H), 7.48-7.55 (m, 3H), and 7.82-7.88 (m, 2H).MS(+ESI)m/z＝330(M+H)
+。
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane fumaric acid
Salt
Embodiment 45A
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
According to method A by the product of embodiment 9D (500mg, 2.99mmol) and 2-chloro-5-phenyl-1,3,4-thiadiazoles (600mg, 3.05mmol; WO 2003094831) make:
1H NMR (300MHz, the δ ppm 1.87-2.08 of chloroform-D) (m, 5H), 2.51 (s, 2H), 3.00 (dd, J=13.4,1.2Hz, 2H), 3.14 (s, 2H), 3.46 (d, J=13.6Hz, 2H), 5.31 (t, J=3.4Hz, 1H), 7.43-7.49 (m, 3H), 7.80-7.85 (m, 2H).MS(+ESI)m/z＝328(M+H)
+。
Embodiment 45B
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 45A (960mg 2.90mmol) makes:
1H NMR (300MHz, and the δ ppm 1.76 of methyl alcohol-D4) (s, 1H), 2.06 (d, J=11.9Hz, 2H), 2.17-2.29 (m, 4H), 3.04 (d, J=12.9Hz, 2H), 3.16 (s, 2H), 3.45 (d, J=13.6Hz, 2H), 5.37 (s, 1H), 7.47-7.53 (m, 3H), and 7.81-7.88 (m, 2H).MS(DClTNH
3)m/z＝314(M+H)
+。
Embodiment 45C
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane fumaric acid
Salt
According to method H by the product of embodiment 45B (860mg, 2.74mmol) and fumaric acid (318mg, 2.74mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 2.06-2.32 of methyl alcohol-D4) (m, 5H), 2.70 (s, 2H), 3.49 (d, J=12.5Hz, 2H), 3.56 (s, 2H), 3.80 (d, J=12.2Hz, 2H), 5.42 (t, J=3.4Hz, 1H), 6.69 (s, 2H), 7.49-7.55 (m, 3H), and 7.82-7.88 (m, 2H).MS(+ESI)m/z＝314(M+H)
+。C
17H
19NO
3SC
4H
4O
4The analytical calculation value: C, 58.73; H, 5.40; N, 9.78; Measured value: C, 58.79; H, 5.52; N, 9.70.
Embodiment 46
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
Embodiment 46A
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
The N-borane complex
According to method A by embodiment 10A product (254mg, 1.5mmol) and 2-bromo-5-(4-fluorophenyl)-1,3,4-thiadiazoles (402mg, 1.5mmol; WO 2003044020) make:
1H NMR (300MHz, the δ ppm 1.26 of chloroform-D) (s, 1H), 1.74 (d, J=12.2Hz, 2H), 2.05 (s, 1H), 2.22 (d, J=13.2Hz, 1H), 2.54 (s, 2H), 3.17-3.33 (m, 6H), and 5.33-5.47 (m, 1H), 7.08-7.24 (m, 2H), 7.76-7.96 (m, 2H).MS(DCI/NH
3)m/z＝346(M+H)
+。
Embodiment 46B
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
According to method C with the product of embodiment 46A (operation by method H is translated into tosilate then for 204mg, 0.59mmol) deprotection:
1H NMR (300MHz, and the δ ppm 1.99 of methyl alcohol-D4) (d, J=13.6Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.19-7.32 (m, 4H), 7.71 (d, J=8.1Hz, 2H), and 7.85-7.95 (m, 2H).MS(DCI/NH
3)m/z＝332(M+H)
+。C
17H
18FN
3OSC
7H
8O
3The analytical calculation value of S: C, 57.24; H, 5.20; N, 8.34; Measured value: C, 56.08; H, 5.16; N, 8.31.
Embodiment 47
(4r)-4-[5-(4-fluorophenyl 1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
Embodiment 47A
(4r)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
The N-borane complex
According to method A by the product of embodiment 9D (203mg, 1.22mmol) and 2-bromo-5-(4-fluorophenyl)-1,3,4-thiadiazoles (316mg, 1.22mmol; Referring to WO 2003044020) make:
1HNMR (300MHz, and the δ ppm 1.70 of chloroform-D) (s, 1H), 1.96-2.08 (m, 2H), 2.12-2.23 (m, 4H), 3.01 (d, J=12.9Hz, 2H), 3.16 (s, 2H), 3.49 (d, J=13.2Hz, 2H), 5.46 (s, 1H), 7.08-7.19 (m, 2H), 7.75-7.87 (m, 2H).MS(DCI/NH3)m/z＝346(M+H)
+。
Embodiment 47B
(4r)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
According to method C with the product of embodiment 47A (operation by method H is translated into tosilate then for 204mg, 0.59mmol) deprotection:
1H NMR (300MHz, and the δ ppm 2.05-2.32 of methyl alcohol-D4) (m, 5H), 2.36 (s, 3H), 2.71 (s, 2H), 3.42-3.63 (m, 4H), 3.81 (d, J=12.5Hz, 2H), 5.41 (s, 1H), 7.18-7.32 (m, 4H), 7.70 (d, J=8.1Hz, 2H), 7.90 (dd, J=8.9,5.2Hz, 2H).MS(DCI/NH
3)m/z＝332(M+H)
+。C
17H
18FN
3OSC
7H
8O
3The analytical calculation value of S: C, 57.21; H, 5.20; N, 8.34; Measured value: C, 55.19; H, 5.40; N, 8.02.
Embodiment 48
(4s)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
Embodiment 48A
2-bromo-5-(3-fluorophenyl)-1,3, the 4-thiadiazoles
Cupric bromide (II) (1.37g, 0.615mmol with the brute force stirring; Acros) and amyl nitrite (1.20g, 10.2mmol) suspension in acetonitrile (20mL) is with 5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base amine (1.00g, 0.512mmol; Aldrich) portioning adds processing.The mixture stirring is spent the night, quench, with ether (2x) extraction with saturated ammonium chloride.With the organic phase drying (MgSO that merges
4), filter, concentrate, residuum obtains title compound through flash chromatography (Analogix 12g silicagel column, the ethyl acetate 5-85% gradient in hexane) purifying:
1H NMR (300MHz, the δ ppm 7.29-7.38 of methyl alcohol-D4) (m, 1H), 7.57 (td, J=8.1,5.8Hz, 1H), 7.71-7.79 (m, 2H).MS(+ESI)m/z＝259/261(M+H)
+。
Embodiment 48B
(4s)-4-[5-(3-fluorophenyl 1,, 3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
The N-borane complex
According to method A by the product of embodiment 10A (257mg, 1.5mmol) and the product of embodiment 48A (398mg 1.5mmol) makes:
1H NMR (300MHz, and the δ ppm 1.26 of chloroform-D) (s, 1H), 1.74 (d, J=12.2Hz, 2H), 2.05 (s, 1H), 2.22 (d, J=13.2Hz, 1H), 2.54 (s, 2H), and 3.17-3.33 (m, 6H), 5.33-5.47 (m, 1H), and 7.10-7.25 (m, 1H), 7.37-7.53 (m, 1H), and 7.54-7.70 (m, 2H).MS(DCI/NH
3)m/z＝346(M+H)
+。
Embodiment 48C
(4s)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
According to method C with the product of embodiment 48B (operation by method H is translated into tosilate then for 245mg, 0.71mmol) deprotection:
1H NMR (300MHz, and the δ ppm 1.99 of methyl alcohol-D4) (d, J=13.6Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=8.5Hz, 2H), 7.25-7.32 (m, 1H), 7.49-7.58 (m, 1H), 7.62-7.73 (m, 4H).MS(DCI/NH
3)m/z＝332(M+H)
+。C
17H
18FN
3OSC
7H
8O
3The analytical calculation value of S: C, 57.24; H, 5.20; N, 8.34; Measured value: C, 56.97; H, 4.90; N, 8.22.
Embodiment 49
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
Embodiment 49A
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
The N-borane complex
According to method A by the product of embodiment 9D (203mg, 1.38mmol) and the product of embodiment 48A (398mg 1.5mmol) makes:
1H NMR (300MHz, and the δ ppm 1.70 of chloroform-D) (s, 1H), 1.96-2.08 (m, 2H), 2.12-2.23 (m, 4H), 3.01 (d, J=12.9Hz, 2H), 3.16 (s, 2H), 3.49 (d, J=13.2Hz, 2H), 5.46 (s, 1H), 7.08-7.19 (m, 2H), 7.75-7.87 (m, 2H).MS(DCI/NH
3)m/z＝346(M+H)
+。
Embodiment 49B
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Tosilate
According to method C with the product of embodiment 49A (operation by method H is translated into tosilate then for 245mg, 0.71mmol) deprotection:
1H NMR (300MHz, methyl alcohol-D
4) δ ppm 2.05-2.32 (m, 5H), 2.36 (s, 3H), 2.71 (s, 2H), 3.42-3.63 (m, 4H), 3.81 (d, J=12.5Hz, 2H), 5.41 (s, 1H), 7.18-7.32 (m, 4H), 7.70 (d, J=8.1Hz, 2H), 7.90 (dd, J=8.9,5.3Hz, 2H).MS(DCI/NH
3)m/z＝332(M-HH)
+。C
17H
18FN
3OSC
7H
8O
3The analytical calculation value of S: C, 57.21; H, 5.20; N, 8.34; Measured value: C, 55.19; H, 5.40; N, 8.02.
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
Embodiment 50A
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
Alkane N-borane complex
According to method B by the product of embodiment 10A (131mg, 0.785mmol) and 2-bromo-5-(1H-indoles-5-yl)-1,3,4-thiadiazoles (200mg, 0.714mmol; Referring to WO2003044020) preparation, through flash chromatography (Analogix 80g 40x120mm silicagel column, the 5-85% gradient of ethyl acetate in hexane) purifying, obtain title compound:
1H NMR (300MHz, the δ ppm 1.73 of chloroform-D) (d, J=12.5Hz, 2H), 2.05 (s, 1H), 2.24 (d, J=12.9Hz, 2H), 2.55 (s, 2H), 3.18-3.27 (m, 6H), 5.36 (t, J=3.6Hz, 1H), 6.64 (ddd, J=3.4,2.0,1.0Hz, 1H), 7.29 (dd, J=3.2,2.5Hz, 1H), 7.46 (ddd, J=8.6,0.8,0.7Hz, 1H), 7.75 (dd, J=8.5,1.7Hz, 1H), 8.04-8.07 (m, 1H), 8.35 (s, 1H).MS(+ESI)m/z＝353(M+H)
+。
Embodiment 50B
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
According to method D by the product of embodiment 50A (operation of application method H is translated into tosilate then for 140mg, the 0.38mmol) title compound of preparation free alkali:
1H NMR (300MHz, and the δ ppm 1.99 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.22 (s, 1H), 2.29-2.40 (m, 5H), 2.73 (s, 2H), 3.59 (s, 2H), 3.63-3.79 (m, 4H), 5.47 (t, J=3.2Hz, 1H), 6.56 (dd, J=3.2,0.8Hz, 1H), and 7.19-7.27 (m, 2H), 7.34 (d, J=3.4Hz, 1H), 7.49 (ddd, J=8.6,0.8,0.7Hz, 1H), 7.63 (dd, J=8.5,1.7Hz, 1H), 7.71 (ddd, J=8.3,2.0,1.9Hz, 2H), 8.04 (dd, J=1.7,0.7Hz, 1H).MS(+ESI)m/z＝353(M+H)
+。C
19H
20N
4OSC
7H
8O
3S0.2H
2The analytical calculation value of O: C, 59.12; H, 5.42; N, 10.61; Measured value: C, 58.77; H, 5.11; N, 10.35.
Embodiment 51
(4s)-and 4-[5-(1H-indoles-6-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
Embodiment 51A
(4s)-and 4-[5-(1H-indoles-6-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
Alkane
According to method F by the product of embodiment 41B (100mg, 0.316mmol) and indoles-6-boric acid (102mg, 0.632mmol; Frontier) make:
1H NMR (300MHz, and the δ ppm 1.71 of methyl alcohol-D4) (s, 1H), 1.92 (d, J=12.2Hz, 2H), and 2.26-2.37 (m, 5H), 3.12-3.22 (m, 5H), 5.33 (t, J=3.1Hz, 1H), 6.52 (d, J=3.1Hz, 1H), 7.39 (d, J=3.1Hz, 1H), 7.47 (dd, J=8.3,1.5Hz, 1H), 7.64 (d, J=8.1Hz, 1H), 7.87-7.92 (m, 1H).MS(+ESI)m/z＝353(M+H)
+。
Embodiment 51B
(4s)-and 4-[5-(1H-indoles-6-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
According to method H by the product of embodiment 51A (18mg 0.052mmol) makes:
1H NMR (300MHz, and the δ ppm 1.99 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.22 (s, 1H), and 2.30-2.41 (m, 5H), 2.73 (s, 2H), 3.59 (s, 2H), 3.64-3.78 (m, 4H), 5.49 (t, J=3.4Hz, 1H), 6.53 (dd, J=3.2,0.8Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.40 (d, J=3.1Hz, 1H), 7.48 (dd, J=8.1,1.7Hz, 1H), 7.65 (d, J=8.5Hz, 1H), 7.71 (ddd, J=8.3,2.0,1.9Hz, 2H), and 7.89-7.92 (m, 1H).MS(+ESI)m/z＝353(M+H)
+。C
19H
20N
4OSC
7H
8O
3S1.5H
2The analytical calculation value of O: C, 56.61; H, 5.66; N, 10.16; Measured value: C, 56.65; H, 5.49; N, 9.89.
Embodiment 52
(4s)-and 4-[5-(1H-indoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
The tosilate of alkane
According to method F by the product of embodiment 41B (190mg, 0.60mmol) and indoles-4-boric acid (192mg, 1.19mmol; Frontier) title compound of preparation free alkali, the operation of application method H is translated into tosilate then:
1H NMR (300MHz, the δ ppm1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.19 (s, 1H), 2.33 (d, J=13.5Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.52-3.77 (m, 6H), 5.36 (s, 1H), 7.04 (d, J=3.0Hz, 1H), 7.17-7.27 (m, 3H), 7.43 (d, J=3.4Hz, 1H), 7.49 (d, J=6.7Hz, 1H), 7.58 (d, J=8.1Hz, 1H), 7.70 (d, J=8.1Hz, 2H).MS(DCI/NH
3)m/z＝354(M+H)
+。C
19H
20N
4OS.C
7H
8O
3The analytical calculation value of S: C, 59.92; H, 5.38; N, 10.68; Measured value: C, 56.90; H, 5.11; N, 10.13.
Embodiment 53
(4s)-and 4-[5-(thionaphthene-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
]
The tosilate of decane
According to method F, by the product of embodiment 41B (193mg, 0.60mmol) and 2-(benzo [b] thiophene-5-yl)-4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane (317mg, 0.74mmol; Maybridge) title compound of preparation free alkali, the operation of application method H is translated into tosilate then:
1H NMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.19 (s, 1H), 2.33 (d, J=13.6Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.52-3.77 (m, 6H), 5.36 (s, 1H), 7.22 (d, J=8.8Hz, 2H), 7.49 (d, J=5.4Hz, 1H), 7.67-7.75 (m, 3H), 7.85 (dd, J=8.4,1.7Hz, 1H), 8.05 (d, J=8.8Hz, 1H), 8.32 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝370(M+H)
+。C
19H
19N
3OS
2C
7H
8O
3The analytical calculation value of S: C, 57.65; H, 5.02; N, 7.76; Measured value: C, 56.45; H, 4.59; N, 7,45.
Embodiment 54
(4s)-and 4-[5-(pyrazoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Two (tosilate)
Embodiment 54A
(4s)-and 4-[5-(1-trityl-1H-pyrazoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
According to method F by the product of embodiment 41B (120mg, 0.38mmol) and 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (335mg, 0.77mmol; JP 2005232071) make:
1H NMR (300MHz, and the δ ppm 1.70 of chloroform-D) (s, 1H), 1.96-2.08 (m, 2H), 2.12-2.23 (m, 4H), 3.01 (d, J=12.9Hz, 2H), 3.16 (s, 2H), 3.49 (d, J=13.2Hz, 2H), 5.46 (s, 1H), 7.16 (dd, J=6.8,3.0Hz, 6H), and 7.29-7.38 (m, 9H), 7.87 (s, 1H), 7.95 (s, 1H).MS(DCI/NH
3)m/z＝546(M+H)
+。
Embodiment 54B
(4s)-and 4-[5-(pyrazoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Two (tosilate)
According to method L by the product of embodiment 54A (operation of application method H is translated into tosilate then for 100mg, the 0.18mmol) title compound of preparation free alkali:
1H NMR (300MHz, and the δ ppm 1.99 of methyl alcohol-D4) (d, J=13.6Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=8.1Hz, 2H), 7.71 (d, J=8.1Hz, 2H), 8.09 (br.s, 2H).MS(DCI/NH
3)m/z＝304(M+H)
+。C
14H
17N
5OSC
7H
8O
3The analytical calculation value of S: C, 53.03; H, 5.30; N, 14.73; Measured value: C, 52.48; H, 5.03; N, 14.46.
(4s)-4-(5-phenoxy group-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 55A
2-bromo-5-phenoxy group-1,3, the 4-thiadiazoles
With 2,5-two bromos-1,3,4-thiadiazoles (1.00g, 4.10mmol; Preparation is described in Yasuda, T.; Imase, T.; Sasaki, S.; Yamamoto, T.Macromolecules 2005,38, and 1500) and phenol (188mg, 2.00mmol; Aldrich) (2.0g 6.0mmol) handles reflux 5 hours to the solution in anhydrous tetrahydro furan (4mL) with cesium carbonate.Mixture is cooled to room temperature, and with the chloroform dilution, by diatomite filtration, residuum obtains title compound through flash chromatography (Analogix 40x120mm 80g silicagel column, chloroform) purifying:
1H NMR (300MHz, and the δ ppm7.28-7.35 of chloroform-D) (m, 3H), 7.41-7.49 (m, 2H).MS(+ESI)m/z＝257/259(M+H)
+。
Embodiment 55B
(4s)-4-(5-phenoxy group-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method A, carry out embodiment 10A product (100mg, 0.599mmol) and embodiment 55A product (operation of application method C is the operation of application method H subsequently for 180mg, linked reaction 0.700mmol), and the product that generates is converted into title compound:
1H NMR (300MHz, and the δ ppm 1.95 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.18 (s, 1H), 2.29 (d, J=13.9Hz, 2H), 2.36 (s, 3H), 2.66 (s, 2H), 3.56 (s, 2H), 3.58-3.74 (m, 4H), 5.41 (t, J=3.4Hz, 1H), 7.19-7.26 (m, 2H), 7.28-7.36 (m, 3H), 7.43-7.51 (m, 2H), 7.68-7.73 (m, 2H).MS(+ESI)m/z＝330(M+H)
+。C
17H
19N
3O
2SC
7H
8O
3S0.5H
2The analytical calculation value of O: C, 56.45; H, 5.53; N, 8.23; Measured value: C, 56.11; H, 5.38; N, 8.02.
Embodiment 56
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 56A
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-boron
The alkane complex compound
According to method A by the product of embodiment 10A (515mg, 3.1mmol) and 2-bromo-tertiary butyl-1,3,4-thiadiazoles (682mg, 3.1mmol; Referring to JP 58140084) make:
1H NMR (300MHz, the δ ppm 1.26 of methyl alcohol-D4) (s, 1H), 1.42 (s, 9H), 1.74 (d, J=12.2Hz, 2H), 2.05 (s, 1H), 2.22 (d, J=13.2Hz, 1H), 2.54 (s, 2H), 3.17-3.33 (m, 6H), 5.33-5.47 (m, 1H).MS(DCI/NH
3)m/z＝308(M+H)
+。
Embodiment 56B
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method C by the product of embodiment 56A (operation of application method H is translated into tosilate then for 929mg, the 3.02mmol) title compound of preparation free alkali:
1H NMR (300MHz, δ ppm 1.42 (s, 9H) 1.99 (d, the J=13.6Hz of methyl alcohol-D4), 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), and 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=7.8Hz, 2H), 7.70 (d, J=8.1Hz, 2H).MS(DCI/NH
3)m/z＝294(M+H)
+。C
15H
23N
3OSC
7H
8O
3The analytical calculation value of S: C, 56.75; H, 6.71; N, 9.02; Measured value: C, 56.62; H, 6.81; N, 8.98.
Embodiment 57
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
Embodiment 57A
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-boron
The alkane complex compound
According to method A by the product of embodiment 9D (200mg, 1.2mmol) and 2-bromo-tertiary butyl-1,3,4-thiadiazoles (270mg, 1.2mmol; Referring to JP 58140084) make:
1H NMR (300MHz, the δ ppm 1.42 of chloroform-D) (s, 9H), 1.70 (s, 1H), 1.96-2.08 (m, 2H), 2.12-2.23 (m, 4H), 3.01 (d, J=12.9Hz, 2H), 3.16 (s, 2H), 3.49 (d, J=13.2Hz, 2H), 5.46 (s, 1H).MS(DCI/NH
3)m/z＝308(M+H)
+。
Embodiment 57B
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane right
Tosylate
According to method C by the product of embodiment 57A (operation of application method H is translated into tosilate then for 106mg, the 0.34mmol) title compound of preparation free alkali:
1H NMR (300MHz, the δ ppm 1.42 of methyl alcohol-D4) (s, 9H), 2.05-2.32 (m, 5H), 2.36 (s, 3H), 2.71 (s, 2H), 3.42-3.63 (m, 4H), 3.81 (d, J=12.5Hz, 2H), 5.41 (s, 1H), 7.23 (d, J=7.8Hz, 2H), 7.70 (d, J=8.1Hz, 2H).MS(DCI/NH
3)m/z＝294(M+H)
+。C
15H
23N
3OSC
7H
8O
3The analytical calculation value of S: C, 56.75; H, 6.71; N, 9.02; Measured value: C, 54.04; H, 6.43; N, 8.41.
Embodiment 58
(4s)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to first
Benzene sulfonate
Embodiment 58A
(4s)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
According to method A by the product of embodiment 10A (100mg, 0.599mmol) and 2-bromo-5-phenyl-1,3,4-oxadiazole (148mg, 0.658mmol; Vachl, P.; Toth, L.M.TetrahedronLett 2004,45, and 7157) preparation, the operation of application method C subsequently is translated into unhindered amina:
1HNMR (300MHz, the δ ppm 1.71 of methyl alcohol-D4) (s, 1H), 1.94 (d, J=13.6Hz, 2H), 2.25-2.37 (m, 4H), 3.09-3.21 (m, 4H), 5.25 (t, J=3.2Hz, 1H), 7.49-7.59 (m, 3H), 7.90-7.99 (m, 2H).MS(+ESI)m/z＝298(M+H)
+。
Embodiment 58B
(4s)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to first
Benzene sulfonate
According to method H by the product of embodiment 58A (77mg 1.77mmol) makes:
1H NMR (300MHz, and the δ ppm 2.00 of methyl alcohol-D4) (d, J=13.6Hz, 2H), 2.23 (s, 1H), and 2.30-2.41 (m, 5H), 2.73 (s, 2H), 3.60 (s, 2H), 3.63-3.80 (m, 4H), 5.36 (t, J=3.4Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.51-7.63 (m, 3H), and 7.67-7.74 (m, 2H), 7.92-7.99.(m，2H)。MS(+ESI)m/z＝298(M+H)
+。
Embodiment 59
(4r)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to first
Benzene sulfonate
Embodiment 59A
(4r)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
According to method A by the product of embodiment 9D (100mg, 0.599mmol) and 2-bromo-5-phenyl-1,3,4-oxadiazole (148mg, 0.658mmol; Vachl, P.; Toth, L.M.TetrahedronLett.2004,45,7157) preparation, the operation of application method C subsequently is translated into unhindered amina:
1HNMR (300MHz, and the δ ppm 1.76 of methyl alcohol-D4) (s, 1H), 2.05 (d, J=11.9Hz, 2H), 2.19-2.30 (m, 4H), 3.05 (d, J=12.9Hz, 2H), 3.17 (s, 2H), 3.46 (d, J=13.2Hz, 2H), 5.27 (s, 1H), 7.49-7.59 (m, 3H), and 7.91-7.97 (m, 2H).MS(+ESI)m/z＝298(M+H)
+。
Embodiment 59B
(4r)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to first
Benzene sulfonate
According to method H by the product of embodiment 59A (45mg 0.15mmol) makes:
1H NMR (300MHz, and the δ ppm 2.05-2.17 of methyl alcohol-D4) (m, 2H), 2.21-2.34 (m, 3H), 2.36 (s, 3H), 2.73 (s, 2H), 3.53 (d, J=12.5Hz, 2H), 3.59 (s, 2H), 3.82 (d, J=12.5Hz, 2H), 5.27 (t, J=3.6Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.50-7.63 (m, 3H), 7.70 (d, J=8.5Hz, 2H), 7.90-7.98 (m, 2H).MS(+ESI)m/z＝298(M+H)
+。C
17H
19N
3O
2The analytical calculation value: C, 61.39; H, 5.80; N, 8.95; Measured value: C, 61.11; H, 5.83; N, 8.91.
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 60A
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 10A (100mg, 0.599mmol) and 2-chloro benzothiazole (102mg, 0.599mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm1.71 of chloroform-D) (d, J=12.9Hz, 2H), 2.00-2.07 (m, 1H), 2.25 (d, J=13.2Hz, 2H), 2.50 (s, 2H), 3.18-3.35 (m, 6H), 5.43 (t, J=3.4Hz, 1H), 7.21-7.28 (m, 1H), 7.34-7.41 (m, 1H), and 7.63-7.68 (m, 2H).MS(+ESI)m/z＝301(M+H)
+。
Embodiment 60B
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 60A (180mg 0.60mmol) makes:
1H NMR (300MHz, and the δ ppm 1.70 of methyl alcohol-D4) (s, 1H), 1.86-1.95 (m, 2H), 2.23-2.35 (m, 4H), 3.13-3.22 (m, 4H), 5.43 (t, J=3.1Hz, 1H), 7.25 (ddd, J=8.3,7.0,1.0Hz, 1H), 7.37 (td, J=7.7,1.2Hz, 1H), 7.59-7.64 (m, 1H), 7.70-7.75 (m, 1H).MS(+ESI)m/z＝287(M+H)
+。
Embodiment 60C
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 60B (131mg 0.457mmol) makes:
1H NMR (300MHz, the δ ppm 1.97 of methyl alcohol-D4) (d, J=12.5Hz, 2H), 2.21 (s, 1H), 2.28-2.39 (m, 5H), 2.71 (s, 2H), 3.59 (s, 2H), 3.64-3.78 (m, 4H), 5.57 (t, J=3.6Hz, 1H), 7.22 (d, J=8.1Hz, 2H), 7.28 (td, J=7.6,1.4Hz, 1H), 7.40 (td, J=7.6,1.4Hz, 1H), 7.61-7.65 (m, 1H), 7.71 (dt, J=8.4,1.9Hz, 2H), 7.74-7.78 (m, 1H).MS (+ESI)m/z＝287(M+H)
+。C
16H
18N
2OSC
7H
8O
3S0.2H
2The analytical calculation value of O: C, 59.77; H, 5.76; N, 6.06; Measured value: C, 59.63; H, 5.81; N, 5.76.
Embodiment 61
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 61A
(4r)-4-(benzene thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 9D (100mg, 0.599mmol) and 2-chloro benzothiazole (102mg, 0.599mmol; Aldrich) make:
1H NMR (300MHz, the δ ppm1.90-2.09 of chloroform-D) (m, 5H), 2.46 (s, 2H), 2.99 (d, J=12.9Hz, 2H), 3.14 (s, 2H), 3.48 (d, J=13.2Hz, 2H), 5.33 (t, J=3.2Hz, 1H), 7.24 (ddd, J=8.3,7.0,1.0Hz, 1H), 7.33-7.41 (m, 1H), 7.62-7.69 (m, 2H).MS(+ESI)m/z＝287(M+H)
+。
Embodiment 61B
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 61A (180mg 0.60mmol) makes:
1H NMR (300MHz, and the δ ppm 1.72-1.80 of methyl alcohol-D4) (m, 1H), 2.02-2.14 (m, 2H), 2.15-2.29 (m, 4H), 3.03 (dd, J=13.1,1.2Hz, 2H), 3.16 (s, 2H), 3.46 (d, J=13.2Hz, 2H), 5.41-5.48 (m, 1H), 7.25 (td, J=7.7,1.2Hz, 1H), 7.37 (td, J=7.8,1.4Hz, 1H), 7.62 (dt, J=8.1,0.7Hz, 1H), 7.72 (dd, J=7.6,1.2Hz, 1H) MS (+ESI) m/z=287 (M+H)
+
Embodiment 61C
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 61B (123mg 0.429mmol) makes:
1H NMR (300MHz, and the δ ppm 2.07-2.19 of methyl alcohol-D4) (m, 2H), 2.20-2.31 (m, 3H), 2.36 (s, 3H), 2.69 (s, 2H), 3.50 (d, J=12.5Hz, 2H), 3.57 (s, 2H), 3.80 (d, J=12.5Hz, 2H), 5.49 (t, J=3.4Hz, 1H), 7.22 (d, J=8.1Hz, 2H), 7.28 (td, J=7.6,1.0Hz, 1H), 7.40 (td, J=7.8,1.4Hz, 1H), 7.63-7.79 (m, 4H) MS (+ESI) m/z=287 (M+H)
+C
16H
18N
2OSC
7H
8O
3The analytical calculation value of S: C, 60.24; H, 5.71; N, 6.11; Measured value: C, 60.36; H, 5.73; N, 6.18.
Embodiment 62
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosic acid of decane
Salt
Embodiment 62A
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 10A (102mg, 0.610mmol) and 2,6-dichlorobenzothiazole (122mg, 0.599mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.72 of chloroform-D) (d, J=12.2Hz, 2H), 2.04 (s, 1H), 2.24 (d, J=12.9Hz, 2H), 2.48 (s, 2H), and 3.17-3.34 (m, 6H), 5.41 (t, J=3.6Hz, 1H), 7.33 (dd, J=9.0,2.2Hz, 1H), 7.56 (d, J=8.5Hz, 1H), 7.63 (d, J=2.0Hz, 1H).MS(+ESI)m/z＝335/337(M+H)
+。
Embodiment 62B
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 62A (184mg 0.55mmol) makes:
1H NMR (300MHz, and the δ ppm 1.65 of chloroform-D) (s, 1H), 1.79-1.89 (m, 2H), and 2.19-2.35 (m, 4H), 3.12-3.22 (m, 4H), and 3.27-3.36 (m, 2H), 5.43 (t, J=3.2Hz, 1H), 7.31 (dd, J=8.6,2.2Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.61 (d, J=2.0Hz, 1H).
Embodiment 62C
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosic acid of decane
Salt
According to method H by the product of embodiment 62B (138mg 0.430mmol) makes:
1H NMR (300MHz, the δ ppm 1.97 of methyl alcohol-D4) (d, J=12.9Hz, 2H), 2.21 (s, 1H), 2.27-2.39 (m, 5H), 2.71 (s, 2H), 3.58 (s, 2H), 3.63-3.78 (m, 4H), 5.58 (t, J=3.4Hz, 1H), 7.22 (d, J=8.5Hz, 2H), 7.39 (dd, J=8.6,2.2Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.70 (d, J=8.1Hz, 2H), 7.82 (d, J=2.0Hz, 1H).MS(+ESI)m/z＝321/323(M+H)
+。C
16H
17ClN
2OSC
7H
8O
3The analytical calculation value of S: C, 56.03; H, 5.11; N, 5.68; Measured value: C, 56.12; H, 5.14; N, 5.65.
Embodiment 63
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosic acid of decane
Salt
Embodiment 63A
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 9D (102mg, 0.610mmol) and 2,6-dichlorobenzothiazole (122mg, 0.599mmol; Aldrich) make:
1H NMR (300MHz, the δ ppm 1.88-2.10 of chloroform-D) (m, 5H), 2.45 (s, 2H), 2.99 (dd, J=13.2,1.4Hz, 2H), 3.14 (s, 2H), 3.46 (d, J=13.2Hz, 2H), 5.31 (t, J=3.4Hz, 1H), 7.33 (dd, J=8.5,2.0Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.64 (d, J=2.0Hz, 1H).MS(+ESI)m/z＝321/323(M+H-BH
3)
+。
Embodiment 63B
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 63A (190mg 0.57mmol) makes:
1H NMR (300MHz, and the δ ppm 1.67-1.78 of chloroform-D) (m, 2H), 1.98-2.23 (m, 5H), 3.00 (dd, J=13.2,1.0Hz, 2H), 3.16 (s, 2H), 3.51 (d, J=132Hz, 2H), 5.46 (s, 1H), 7.28-7.34 (m, 1H), 7.56 (d, J=8.8Hz, 1H), 7.62 (d, J=2.7Hz, 1H).MS(+ESI)m/z＝321/323(M+H)
+。
Embodiment 63C
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane to toluene sulphur
Hydrochlorate
According to method H by the product of embodiment 63B (152mg 0.474mmol) makes:
1H NMR (300MHz, the δ ppm 2.07-2.19 of methyl alcohol-D4) (m, 2H), 2.20-2.31 (m, 3H), 2.36 (s, 3H), 2.68 (s, 2H), 3.50 (d, J=11.9Hz, 2H), 3.57 (s, 2H), 3.79 (d, J=12.5Hz, 2H), 5.50 (t, J=3.4Hz, 1H), 7..22 (d, J=7.8Hz, 2H), 7.39 (dd, J=8.6,2.2Hz, 1H), 7.61 (d, J=8.8Hz, 1H), 7.70 (ddd, J=8.3,2.0,1.9Hz, 2H), 7.81 (d, J=24Hz, 1H).MS(+ESI)m/z＝321/323(M+H)
+。C
16H
17ClN
2OSC
7H
8O
3S0.4H
2The analytical calculation value of O: C, 55.22; H, 5.20; N, 5.60; Measured value: C, 55.00; H, 5.19; N, 5.64.
Embodiment 64
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
Embodiment 64A
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method A by the product of embodiment 10A (103mg, 0.616mmol) and 2-Lv benzoxazole (100mg, 0.86mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm1.74 of chloroform-D) (d, J=12.2Hz, 2H), 2.06 (s, 1H), 2.27 (d, J=12.9Hz, 2H), 2.50 (s, 2H), 3.19-3.34 (m, 6H), 5.29 (t, J=3.4Hz, 1H), 7.17-7.30 (m, 2H), 7.35-7.40 (m, 1H), 7.48 (dd, J=7.5,1.7Hz, 1H).
Embodiment 64B
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method D by the product of embodiment 64A (141mg 0.496mmol) makes:
1H NMR (300MHz, and the δ ppm 1.71 of methyl alcohol-D4) (s, 1H), 1.87-1.98 (m, 2H), 2.23-2.36 (m, 4H), and 3.11-3.22 (m, 4H), 3.32-3.39 (m, 2H), 5.32 (t, J=2.9Hz, 1H), 7.17-7.31 (m, 2H), 7.39-7.46 (m, 2H).MS(+ESI)m/z＝271(M+H)
+。
Embodiment 64C
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] tosilate of decane
According to method H by the product of embodiment 64B (124mg, 0.459mmol) and tosic acid monohydrate (87mg, 0.46mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 2.00 of methyl alcohol-D4) (d, J=13.2Hz, 2H), 2.23 (s, 1H), 2.29-2.41 (m, 5H), 2.72 (s, 2H), 3.60 (s, 2H), 3.63-3.80 (m, 4H), 5.43 (t, J=3.4Hz, 1H), 7.18-7.34 (m, 4H), 7.45 (dd, J=7.5,1.4Hz, 2H), 7.71 (ddd, J=8.3,2.0,1.9Hz, 2H) .MS (+ESI) m/z=271 (M+H)
+C
16H
18N
2O
2C
7H
8O
3SH
2The analytical calculation value of O: C, 59.98; H, 6.13; N, 6.08; Measured value: C, 59.77; H, 6.18; N, 6.33.
(4s)-4-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine hydrochlorate
Embodiment 65A
(4s)-4-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
Embodiment 65B
(4r)-4-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
With 1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-ketone (1.51g, 10mmol; Referring to Becker, D.P.; Flynn, D.L.Synthesis 1992,1080) HOAc (50mL) solution with 3-amino-6-chloro-pyridine (1.90g, 15mmol; Aldrich), anhydrous Na
2SO
4(18.5g, 0.13mol; Aldrich) and NaBH (OAc)
3(4.22g, 20mmol; Aldrich) handle, stirred 10 hours in envrionment temperature.After reacting completely, solid is leached concentrated filtrate.Residuum is carefully used saturated Na
2CO
3CHCl is used in the aqueous solution (pH 10) alkalization
3(3x100mL) extraction, the extract after the merging obtains title compound through flash chromatography [silica gel, ammonium hydroxide-methyl alcohol-chloroform (2: 10: 90)] purifying:
Embodiment 65A(4s) steric isomer:
1H NMR (300MHz, the δ ppm1.74-1.94 of methyl alcohol-D4) (m, 4H), 1.97-2.10 (m, 2H), 2.18-2.43 (m, 2H), 3.23-3.28 (m, 2H), 3.33-3.45 (m, 4H), 3.78 (s, 1H), 6.84-7.36 (m, 2H), 7.69-7.94 (m, 1H).MS(DCI/NH
3)m/z＝264/266(M+H)
+。
Embodiment 65B(4r) steric isomer:
1H NMR (300MHz, and the δ ppm 1.71-1.93 of methyl alcohol-D4) (m, 4H), 2.02-2.26 (m, 4H), and 2.90-3.03 (m, 2H), 3.08-3.16 (m, 2H), 3.35-3.46 (m, 2H) 3.67 (s, 1H), 7.03-7.10 (m, 1H), and 7.11-7.17 (m, 1H), 7.74 (d, J=3.05Hz, 1H).MS(DCI/NH
3)m/z＝264(M+H)
+.266(M+H)
+。
Embodiment 65C
(4s)-4-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine hydrochlorate
According to method H by the product of embodiment 65A (100mg 0.38mmol) makes:
1H NMR (300MHz, and the δ ppm 1.81-2.10 of methyl alcohol-D4) (m, 2H), 2.11-2.23 (m, 1H), 2.23-2.48 (m, 4H), and 3.50-3.60 (m, 2H), 3.64-3.81 (m, 4H), 3.98 (s, 1H), 7.36-7.56 (m, 2H), 7.98 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝264/266(M+H)
+。C
14H
18ClN
31.15HCl1.65H
2The analytical calculation value of O: C, 50.13; H, 6.75; N, 12.53; Measured value: C, 50.01; H, 6.35; N, 12.15.
Embodiment 66
(4r)-4-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine tri hydrochloride
According to method H by the product of embodiment 65B (100mg 0.38mmol) makes:
1H NMR (300MHz, the δ ppm 2.08-2.52 of methyl alcohol-D4) (m, 7H), 3.40-3.61 (m, 4H), 3.75-3.90 (m, 3H), 7.54-7.68 (m, 2H), 8.03 (d, J=3.0Hz, 1H).MS(DCI/NH
3)m/z＝264/266(M+H)
+。C
14H
18ClN
33.15HCl1.2H
2The analytical calculation value of O: C, 42.01; H, 5.93; N, 10.50; Measured value: C, 42.29; H, 5.56; N, 10.10.
Embodiment 67
(4s)-4-N-(6-phenylpyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine dihydrochloride
Embodiment 67A
(4s)-4-N-(6-phenylpyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
According to method E by the product of embodiment 65A (200mg, 0.76mmol) and phenyl-boron dihydroxide (121mg, 1.0mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.58-1.77 of methyl alcohol-D4) (m, 1H), 1.78-1.92 (m, 2H), 1.90-2.02 (m, 2H), 2.16-2.42 (m, 3H), 3.06-3.41 (m, 7H), 3.75 (s, 1H), 7.17 (dd, J=8.6,2.8Hz, 1H), 7.26-7.34 (m, 1H), and 7.59-7.70 (m, 3H), 7.73-7.83 (m, 2H), 8.09 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝306(M+H)
+。
Embodiment 67B
(4s)-4-N-(6-phenylpyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine dihydrochloride
According to method H by the product of embodiment 67A (150mg 0.49mmol) makes:
1H NMR (300MHz, and the δ ppm 1.93-2.08 of methyl alcohol-D4) (m, 2H), 2.15-2.26 (m, 1H), 2.26-2.51 (m, 4H), 3.55-3.63 (m, 2H), 3.66-3.82 (m, 4H), and 4.12-4.19 (m, 1H), 7.52-7.70 (m, 3H), 7.76-7.85 (m, 2H), 7.99 (dd, J=9.2,2.7Hz, 1H), 8.08 (d, J=9.2Hz, 1H), 8.20 (d, J=2.7Hz, 1H).MS (DCI/NH
3) m/z=306 (M+H)
+C
20H
23N
32HCl0.9H
2The analytical calculation value of O: C, 60.25; H, 7.08; N, 9.58; Measured value: C, 60.24; H, 6.92; N, 9.47.
Embodiment 68
(4s)-4-N-[6-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine disalt
Hydrochlorate
Embodiment 68A
(4s)-4-N-[6-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
According to method E by the product of embodiment 65A (200mg, 0.76mmol) and 5-indyl boric acid (160mg, 10mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm1.62-1.76 of methyl alcohol-D4) (m, 1H), 1.80-1.90 (m, 2H), 1.93-2.02 (m, 2H), and 2.21-2.39 (m, 2H), 3.13-3.17 (m, 2H), 3.18-3.30 (m, 4H), 3.77-3.86 (m, 1H), 6.49 (d, J=4.0Hz, 1H), 7.18 (dd, J=8.6,2.8Hz, 1H), 7.24 (d, J=3.4Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.52-7.62 (m, 2H), 7.95 (s, 1H), 8.06 (d, J=2.4Hz, 1H).MS(DCI/NH
3)m/z＝345(M+H)
+。
Embodiment 68B
(4s)-4-N-[6-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine disalt
Hydrochlorate
According to method H by the product of embodiment 68A (110mg 0.32mmol) makes:
1H NMR (300MHz, and the δ ppm 1.88-2.07 of methyl alcohol-D4) (m, 2H), 2.13-2.28 (m, 1H), 2.28-2.51 (m, 4H), 3.55-3.63 (m, 2H), 3.68-3.83 (m, 4H), and 4.09-4.14 (m, 1H), 6.62 (d, J=3.0Hz, 1H), 7.40 (d, J=3.0Hz, 1H), 7.54 (dd, J=8.8,2.1Hz 1H), 7.60-7.65 (m, 1H), 7.97 (dd, J=9.2,2.7Hz, 1H), 8.03-8.16 (m, 2H).MS(DCI/NH
3)m/z＝345(M+H)
+。C
20H
23N
32HCl2.5H
2The analytical calculation value of O: C, 57.14; H, 6.76; N, 12.12; Measured value: C, 57.22; H, 6.63; N, 11.77.
Embodiment 69
(4s)-4-N-(5-pyridine bromide-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine dihydrochloride
Embodiment 69A
(4s)-4-N-(5-pyridine bromide-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
According to the operation described in the embodiment 65A, by 1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-ketone (1.51g, 10mmol; Referring to Becker, D.P.; Flynn, D.L.Synthesis 1992,1080) and 3-amino-5-pyridine bromide (2.06g, 12mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.81-1.99 of methyl alcohol-D4) (m, 2H), 2.02-2.15 (m, 1H), and 2.17-2.40 (m, 4H), 3.44-3.51 (m, 2H), and 3.53-3.66 (m, 4H), 3.91 (s, 1H), and 7.26-7.41 (m, 1H), 7.84 (d, J=1.7Hz, 1H), 8.01 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝308/310(M+H)
+。
Embodiment 69B
(4s)-4-N-(5-pyridine bromide-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine dihydrochloride
According to method H by the product of embodiment 69A (50mg 0.16mmol) makes:
1H NMR (300MHz, and the δ ppm 1.89-2.04 of methyl alcohol-D4) (m, 2H), 2.15-2.49 (m, 5H), and 3.53-3.61 (m, 2H), 3.64-3.81 (m, 4H), 4.08[s (br.), 1H], 8.03 (dd, J=2.37,1.70Hz, 1H), 8.20 (d, J=1.36Hz, 1H), 8.28 (d, J=2.37Hz, 1H).MS(DCI/NH
3)m/z＝308/310(M+H)
+。C
14H
18BrN
32HCl1.1H
2The analytical calculation value of O: C, 41.94; H, 5.58; N, 10.48; Measured value: C, 42.13; H, 5,26; N, 10.13.
(4s)-4-N-[5-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
According to method E by the product of embodiment 69A (150mg, 0.50mmol) and 5-indyl boric acid (160mg, 1.0mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm1.59-1.77 of methyl alcohol-D4) (m, 1H), 1.79-1.93 (m, 2H), 1.93-2.07 (m, 2H), 2.28-2.32 (m, 2H), 3.10-3.32 (m, 6H), 3.88 (s, 1H), 6.51 (dd, J=3.0,0.7Hz, 1H), 7.27 (d, J=3.4Hz, 1H), 7.30-7.34 (m, 1H), 7.36 (d, J=1.7Hz, 1H), 7.47 (d, J=8.3Hz, 1H), 7.78 (d, J=1.0Hz, 1H), 7.93 (d, J=2.4Hz, 1H), 8.03 (d, J=1.7Hz, 1H).MS(DCI/NH3)m/z＝345(M+H)
+。
Embodiment 71
(4s)-4-N-[5-(indoles-6-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine two
(trifluoroacetate)
According to method F, by the product of embodiment 69AP (100mg, 0.325mmol) and 6-indyl boric acid (130mg, 0.807mmol; Frontier) preparation, the HPLC purifying of application acidic conditions obtains its trifluoroacetate:
1H NMR (300MHz, and the δ ppm 1.95-2.04 of methyl alcohol-D4) (m, 2H), 2.18-2.45 (m, 5H), 3.59 (m, 2H), 3.72 (m, 4H), 4.15 (s, 1H), 6.53 (dd, J=3.2,0.8Hz, 1H), 7.33-7.41 (m, 2H), 7.68-7.77 (m, 2H), 8.03-8.07 (m, 1H), 8.10 (d, J=2.4Hz, 1H), 8.32 (d, J=1.0Hz, 1H).MS(DCI/NH
3)m/z＝345(M+H)
+。C
22H
24N
42.3C
2HF
3O
2H
2The analytical calculation value of O: C, 51.22; H, 4.41; N, 8.98; Measured value: C, 51.17; H, 4.75; N, 8.98.
Embodiment 72
(4s)-4-N-[5-(indoles-4-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] the rich horse of decane-4-amine
Hydrochlorate
According to method F, by the product of embodiment 69A (100mg, 0.325mmol) and 4-indyl boric acid (130mg, 0.807mmol; Frontier) title compound of preparation free alkali, the operation of application method H subsequently is translated into fumarate:
1H NMR (300MHz, and the δ ppm1.90-1.95 of methyl alcohol-D4) (m, 2H), 2.15-2.19 (m, 1H), 2.32-2.45 (m, 4H), and 3.50-3.58 (m, 2H), 3.62-3.73 (m, 4H), 4.04 (s, 1H), 6.56 (dd, J=3.2,0.8Hz, 1H), 6.69 (s, 2H), 7.09 (dd, J=7.1,1.0Hz, 1H), 7.16-7.24 (m, 1H), 7.32 (d, J=3.4Hz, 1H), 7.41-7.45 (m, 2H), 8.04 (d, J=2.7Hz, 1H), 8.12 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝345(M+H)
+。C
22H
24N
41.5C
4H
4O
40.7H
2The analytical calculation value of O: C, 63.31; H, 5.96; N, 10.55; Measured value: C, 63.05; H, 5.95; N, 10.74.
Embodiment 73
(4s)-4-N-[5-(3-aminomethyl phenyl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] the rich horse of decane-4-amine
Hydrochlorate
According to method F, by the product of embodiment 69A (100mg, 0.325mmol) and tolyl boric acid (110mg, 0.808mmol; Aldrich) title compound of preparation free alkali, the operation of application method H subsequently is translated into fumarate:
1H NMR (300MHz, and the δ ppm1.83-1.98 of methyl alcohol-D4) (m, 2H), 2.08-2.26 (m, 1H), and 2.27-2.40 (m, 4H), 2.41 (s, 3H), and 3.50-3.59 (m, 2H), 3.60-3.80 (m, 4H), and 3.97-4.08 (m, 1H), 6.70 (s, 2H), 7.17-7.59 (m, 5H), and 7.93-8.18 (m, 2H).MS(DCI/NH
3)m/z＝320(M+H)
+。C
21H
25N
32C
4H
4O
41.6H
2The analytical calculation value of O: C, 60.01; H, 6.29; N, 7.24; Measured value: C, 59.88; H, 6.55; N, 7.54.
Embodiment 74
(4s)-4-N-[5-(3-chloro-phenyl-)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine two
(trifluoroacetate)
According to the operation of method F, by the product of embodiment 69A (100mg, 0.325mmol) and-chlorophenylboronic acid (101mg, 0.650mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.86-2.06 of methyl alcohol-D4) (m, 2H), 2.15-2.26 (m, 1H), and 2.26-2.54 (m, 4H), 3.53-3.65 (m, 2H), and 3.64-3.83 (m, 4H), 4.14 (s, 1H), and 7.48-7.58 (m, 2H), 7.60-7.70 (m, 1H), and 7.74-7.80 (m, 1H), 7.89 (s, 1H), and 8.10-8.24 (m, 2H).MS(DCI/NH
3)m/z＝340/342(M+H)
+。C
20H
22N
3Cl2.5C
2F
3O
2H1.2H
2The analytical calculation value of O: C, 46.44; H, 4.19; N, 6.50; Measured value: C, 46.23; H, 4.17; N, 6.67.
(4s)-4-N-[5-(3-chloro-phenyl-benzene-3-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-
Two (trifluoroacetates) of amine
According to the operation of method F, by the product of embodiment 69A (100mg, 0.325mmol) and-chlorophenylboronic acid (101mg, 0.650mmol; Aldrich) make:
1H NMR (300MHz, and the δ ppm 1.88-2.11 of methyl alcohol-D4) (m, 2H), 2.15-2.28 (m, 1H), 2.27-2.49 (m, 4H), and 3.54-3.64 (m, 2H), 3.65-3.87 (m, 4H), 4.07-4.28 (m, 1H), 7.36-7.44 (m, 1H), 7.48 (t, J=7.8Hz, 1H), 7.61-7.70 (m, 2H), 7.71-7.76 (m, 2H), 7.78 (dt, J=7.7,1.6Hz, 1H), 7.94 (t, J=1,7Hz, 1H), 8.00 (s, 1H), 8.19 (s, 1H), 8.37 (s, 1H).MS(DCI/NH
3)m/z＝416/418(M+H)
+。C
26H
26N
3O2.2C
2HF
3O
2The analytical calculation value: C, 54.76; H, 4,26; N, 6.30; Measured value: C, 54.75; H, 4.15; N, 6.12.
Embodiment 76
(4s)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 76A
(4s)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (84.2mg, 0.51mmol) and the 3-fluorinated pyridine (66 μ L 0.77mmol) make:
1H NMR (300MHz, the δ ppm 1.65-1.69 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.26-2.31 (m, 4H), 3.19-3.27 (m, 6H), 4.58 (t, J=3.2Hz, 1H), 7.23-7.24 (m, 2H), 8.25-8.27 (m, 1H), 8.34-8.36 (m, 1H).MS(DCI/NH
3)m/z＝245(M+H)
+。
Embodiment 76B
(4s)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 76A (69.8mg 0.27mmol) makes:
1H NMR (300MHz, the δ ppm 1.94-1.99 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), 2.35-2.38 (m, 2H), 2.55 (br s, 2H), 3.60 (s, 2H), and 3.64-3.77 (m, 4H), 5.15 (t, J=3.2Hz, 1H), 8.02 (dd, J=9.0,5.6Hz, 1H), 8.34-8.38 (m, 1H), 8.50 (d, J=5.4Hz, 1H), 8.77 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝231(M+H)
+。C
14H
18N
2The analytical calculation value of O2.05HCl: C, 55.12; H, 6.62; N, 9.18; Cl, 23.82.Measured value: C, 54.91; H, 6.79; N, 9.04; Cl, 23.59.
Embodiment 77
(4s)-and 4-[(1-pyridine oxide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 77A
(4s)-and 4-[(1-pyridine oxide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (85.2mg, 0.51mmol) and 3-fluorinated pyridine N-oxide compound (87.2mg 0.77mmol) makes:
1H NMR (300MHz, the δ ppm1.67-1.71 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.19-2.26 (m, 4H), 3.15-3.27 (m, 6H), 4.54 (t, J=3.4Hz, 1H), 6.88 (dd, J=8.7,2.4Hz, 1H), 7.19 (dd, J=8.7,6.4Hz, 1H), 7.91-7.93 (m, 1H), 8.00 (t, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝261(M+H)
+。
Embodiment 77B
(4s)-and 4-[(1-pyridine oxide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 77A (100.4mg 0.39mmol) makes:
1H NMR (300MHz, the δ ppm 1.93-1.97 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.33-2.38 (m, 2H), 2.53 (br s, 2H), 3.58 (s, 2H), 3.64-3.76 (m, 4H), 5.08 (t, J=3,4Hz, 1H), 7.78 (dd, J=8.8,6.1Hz, 1H), 7.88 (ddd, J=8.8,2.4,1.0Hz, 1H), 8.37 (ddd, J=6.1,1.9,1.0Hz, 1H), 8.66 (app t, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝247(M+H)
+。C
14H
18N
2O
22HCl0.6H
2The analytical calculation value of O: C, 50.95; H, 6.47; N, 8.49; Cl, 21.48.Measured value: C, 51.18; H, 6.39; N, 8.48; Cl, 21.27.
Embodiment 78
(4r)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 78A
(4r)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product (85.0mg, 0Sl mmol) of embodiment 9D and 3-fluorinated pyridine (66 μ L 0.77mmol) make:
1H NMR (300MHz, and the δ ppm 1.83-1.87 of chloroform-D) (m, 2H), 1.99-2.14 (m, 3H), 2.26 (br s, 2H), 2.29-2.96 (m, 2H), 3.12 (s, 2H), 3.49-3.53 (m, 2H), 4.44 (t, J=3.2Hz, 1H), 7.23-7.24 (m, 2H), 8.26 (t, J=3.0Hz, 1H), and 8.33-8.34 (m, 1H).MS(DCI/NH
3)m/z＝245(M+H)
+。
Embodiment 78B
(4r)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 78A (81.0mg 0.33mmol) makes:
1H NMR (300MHz, and the δ ppm 2.12-2.16 of methyl alcohol-D4) (m, 2H), 2.25-2.29 (m, 2H), 2.54 (br s, 2H), 3.47-3.51 (m, 2H), 3.58 (s, 2H), and 3.83-3.87 (m, 2H), 5.07 (t, J=3.4Hz, 1H), 8.05 (dd, J=8.72,5.55Hz, 1H), and 8.37-8.41 (m, 1H), 8.50-8.52 (m, 1H), 8.79 (d, J=2.78Hz, 1H).MS(DCI/NH
3)m/z＝231(M+H)
+。C
14H
18N
2The analytical calculation value of O2.1HCl: C, 54.80; H, 6.60; N, 9.13; Cl, 24.26.Measured value: C, 54.72; H, 6.87; N, 9.06; Cl, 24.37.
Embodiment 79
(4s)-and 4-[(2-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 79A
(4s)-and 4-[(2-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (85.1mg, 0.51mmol) and 2-chloro-3-fluorinated pyridine (141.6mg 1.08mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.06 (br s, 1H), 2.26 (br s, 2H), and 2.35-2.40 (m, 2H), 3.16-3.28 (m, 6H), 4.62 (t, J=3.4Hz, 1H), 7.20-7.21 (m, 2H), 8.04-8.06 (m, 1H).MS(DCI/NH
3)m/z＝294(M+NH
3-H)
+。
Embodiment 79B
(4s)-and 4-[(2-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 79A (110.6mg 0.40mmol) makes:
1H NMR (300MHz, the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), 2.41-2.48 (m, 4H), 3.58 (s, 2H), 3.62-3.74 (m, 4H), 5.02 (t, J=3.2Hz, 1H), 7.38 (dd, J=8.3,4.8Hz, 1H), 7.69 (dd, J=8.1,1.4Hz, 1H), 8.01 (dd, J=4.8,1.6Hz, 1H).MS(DCI/NH
3)m/z＝265(M+H)
+。C
14H
17ClN
2O1.65HCl0.4H
2The analytical calculation value of O: C, 50.63; H, 5.90; N, 8.43; Cl, 28.29.Measured value: C, 50.80; H.5.66; N, 8.43; Cl, 28.29.
(4s)-and 4-[(2-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 80A
(4s)-and 4-[(2-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (88.0mg, 0.53mmol) and 2-bromo-3-fluorinated pyridine (146.3mg 0.83mmol) makes:
1H NMR (300MHz, and the δ ppm1.67-1.71 of chloroform-D) (m, 2H), 2.06 (br s, 1H), 2.27 (br s, 2H), 2.38-2.42 (m, 2H), and 3.17-3.29 (m, 6H), 4.64 (t, J=3.4Hz, 1H), 7.13-7.16 (m, 1H), 7.20-7.24 (m, 1H), 8.04 (dd, J=4.4,1.6Hz, 1H).MS(DCI/NH
3)m/z＝323(M+H)
+。
Embodiment 80B
(4s)-and 4-[(2-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 80A (92.7mg 0.29mmol) makes:
1HNMR (300MHz, the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), 2.44-2.49 (m, 4H), 3.58 (s, 2H), 3.63-3.75 (m, 4H), 5.05 (t, J=3.2Hz, 1H), 7.43 (dd, J=8.5,4.8Hz, 1H), 7.67 (dd, J=8.3,1.5Hz, 1H), 8.02 (dd, J=4.8,1.4Hz, 1H).MS?(DCI/NH
3)m/z＝309(M+H)
+。C
14H
17BrN
2The analytical calculation value of O2HCl: C, 44.00; H, 5.01; N, 7.33.Measured value: C, 44.00; H, 5.16; N, 7.23.
Embodiment 81
(4s)-and 4-[(4-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 81A
(4s)-and 4-[(4-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (81.0mg, 0.49mmol) and 4-chloro-3-fluorinated pyridine (131.7mg 1.00mmol) makes:
1H NMR (300MHz, the δ ppm1.67-1.71 of chloroform-D) (m, 2H), 2.05 (br s, 1H), 2.31-2.38 (m, 4H), 3.16-3.28 (m, 6H), 4.69 (t, J==3.4Hz, 1H), 7.36 (d, J=5.1Hz, 1H), 7.19 (d, J=5.1Hz, 1H), 8.29 (s, 1H).MS(DCI/NH
3)m/z＝294(M+NH
3-H)
+。
Embodiment 81B
(4s)-and 4-[(4-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 81A (88.6mg 0.32mmol) makes:
1H NMR (300MHz, and the δ ppm 1.96-2.00 of methyl alcohol-D4) (m, 2H), 2.24 (br s, 1H), and 2.40-2.44 (m, 2H), 2.57 (br s, 2H), 3.60 (s, 2H), 3.66-3.77 (m, 4H), 5.21 (t, J=3.4Hz, 1H), 7.98 (d, J=5.9Hz, 1H), 8.40 (d, J=5.6Hz, 1H), 8.80 (s, 1H).MS(DCI/NH
3)m/z＝265(M+H)
+。C
14H
17ClN
2O1.75HCl1.65H
2The analytical calculation value of O: C, 46.93; H, 6.20; N, 7.82; Cl, 27.21.Measured value: C, 47.03; H, 5.90; N, 7.82; Cl, 26.92.
Embodiment 82
(4s)-and 4-[(4-picoline-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 82A
(4s)-and 4-[(4-picoline-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (82.7mg, 0.50mmol) and 3-fluoro-4-picoline (117.7mg 1.06mmol) makes:
1H NMR (300MHz, the δ ppm1.67-1.71 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.24-2.31 (m, 7H), 3.19-3.28 (m, 6H), 4.65 (t, J=3.2Hz, 1H), 7.11 (d, J=4.8Hz, 1H), 8.13-8.14 (m, 2H).MS(DCI/NH
3)m/z＝259(M+H)
+。
Embodiment 82B
(4s)-and 4-[(4-picoline-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 82A (46.0mg 0.18mmol) makes:
1H NMR (300MHz, and the δ ppm 1.97-2.02 of methyl alcohol-D4) (m, 2H), 2.24 (br s, 1H), and 2.34-2.38 (m, 2H), 2.58-2.60 (m, 5H), 3.60 (s, 2H), 3.69-3.79 (m, 4H), 5.18 (t, J=3.4Hz, 1H), 7.93 (d, J=5.6Hz, 1H), 8.40 (d, J=5.6Hz, 1H), 8.73 (s, 1H).MS(DCI/NH
3)m/z＝245(M+H)
+。C
15H
20N
2O2HCl1.15H
2The analytical calculation value of O: C, 53.31; H, 7.25; N, 8.29; Cl, 20.98.Measured value: C, 53.34; H, 7.27; N, 8.31; Cl, 20.81.
Embodiment 83
(4s)-and 4-{[4-(trifluoromethyl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 83A
(4s)-and 4-{[4-(trifluoromethyl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
According to method I by the product of embodiment 10A (86.0mg, 0.52mmol) and 3-fluoro-4-(trifluoromethyl) pyridine (139.1mg 0.84mmol) makes:
1H NMR (300MHz, the δ ppm 1.67-1.71 of chloroform-D) (m, 2H), 2.04 (br s, 1H), 2.26-2.35 (m, 4H), 3.20-3.31 (m, 6H), 4.82 (t, J=3.2Hz, 1H), 7.50 (d, J=4.8Hz, 1H), 8.39-8.43 (m, 2H).MS(DCI/NH
3)m/z＝313(M+H)
+。
Embodiment 83B
(4s)-and 4-{[4-(trifluoromethyl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 83A (76.3mg 0.24mmol) makes:
1H NMR (300MHz, and the δ ppm 1.93-1.97 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), and 2.33-2.38 (m, 2H), 2.57 (br s, 2H), 3.59 (s, 2H), 3.65-3.71 (m, 4H), 5.22 (t, J=3.2Hz, 1H), 7.69 (d, J=4.8Hz, 1H), 8.42 (d, J=4.8Hz, 1H), 8.70 (s, 1H).MS(DCI/NH
3)m/z＝299(M+H)
+。C
15H
17F
3N
2O1.15HCl0.55H
2The analytical calculation value of O: C, 51.45; H, 5.54; N, 8.00; Cl, 11.64.Measured value: C, 51.60; H, 5.72; N, 8.03; Cl, 11.59.
Embodiment 84
(4s)-and 4-[(5-fluorinated pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 84A
(4s)-and 4-[(5-fluorinated pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (84.2mg, 0.50mmol) and 3,5-two fluoro pyridines (100.2mg 0.87mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.71 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.24-2.27 (m, 4H), 3.19-3.28 (m, 6H), 4.58 (t, J=3.2Hz, 1H), 6.98 (dt, J=10.2,2.4Hz, 1H), 8.15 (d, J=2.4Hz, 1H), 8.18-8.19 (m, 1H).MS(DCI/NH
3)m/z＝263(M+H)
+。
Embodiment 84B
(4s)-and 4-[(5-fluorinated pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 84A (105.8mg 0.40mmol) makes:
1H NMR (300MHz, the δ ppm 1.93-1.97 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.34-2.39 (m, 2H), 2.54 (br s, 2H), 3.59 (s, 2H), and 3.65-3.76 (m, 4H), 5.10 (t, J=3.2Hz, 1H), 8.09 (dt, J=10.2,2.4Hz, 1H), 8.48 (dd, J=2.3,1.4Hz, 1H), 8.58 (d, J=2.3Hz, 1H).MS(DCI/NH
3)m/z＝249(M+H)
+。C
14H
17FN
2The analytical calculation value of O1.85HCl: C, 53.25; H, 6.02; N, 8.87; Cl, 20.77. measured value: C, 53.03; H, 5.97; N, 8.87; Cl, 20.48.
(4s)-and 4-[(5-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 85A
(4s)-and 4-[(5-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (85.9mg, 0.51mmol) and 3, the 5-dichloropyridin (108.0mg 0.73mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.23-2.27 (m, 4H), 3.19-3.28 (m, 6H), 4.58 (t, J=3.2Hz, 1H), 7.23-7.25 (m, 1H), 8.23-8.24 (m, 2H).MS(DCI/NH
3)m/z＝279(M+H)
+。
Embodiment 85B
(4s)-and 4-[(5-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 85A (57.7mg 0.21mmol) makes:
1H NMR (300MHz, and the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), and 2.34-2.39 (m, 2H), 2.51 (br s, 2H), 3.58 (s, 2H), 3.63-3.75 (m, 4H), 5.06 (t, J=3.4Hz, 1H), 8.09-8.10 (m, 1H), 8.45 (d, J=1.98Hz, 1H), 8.54 (d, J=2.38Hz, 1H).MS(DCI/NH
3)m/z＝265(MH+H)
+。C
14H
17ClN
2The analytical calculation value of O2HCl: C, 49.80; H, 5.67; N, 8.30; Cl, 31.50.Measured value: C, 49.64; H, 5.82; N, 8.15; Cl, 31.30.
Embodiment 86
(4s)-and 4-[(5-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 86A
(4s)-and 4-[(5-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (85.3mg, 0.51mmol) and 3-bromo-5-fluorinated pyridine (141.8mg 0.81mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.23-2.26 (m, 4H), 3.19-3.28 (m, 6H), 4.57 (t, J=3.2Hz, 1H), 7.39-7.40 (m, 1H), 8.26 (d, J=2.7Hz, 1H), 8.23 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝323(M+H)
+。
Embodiment 86B
(4s)-and 4-[(5-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 86A (105.1mg 0.33mmol) makes:
1H NMR (300MHz, the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.34-2.38 (m, 2H), 2.51 (br s, 2H), 3.58 (s, 2H), 3.64-3.75 (m, 4H), 5.07 (t, J=3.6Hz, 1H), 8.26-8.27 (m, 1H), 8.55-8.62 (m, 2H).MS(DCI/NH
3)m/z＝309(M+H)
+。C
14H
17BrN
2The analytical calculation value of O1.85HCl: C, 44.54; H, 5.06; N, 7.42.Measured value: C, 44.51; H, 4.99; N, 7.36.
Embodiment 87
(4s)-and 4-[(5-iodo pyridin-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 87A
(4s)-and 4-[(5-iodo pyridin-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (86.3mg, 0.52mmol) and 3-fluoro-5-iodo pyridine (186.1mg 0.84mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.23-2.26 (m, 4H), 3.19-3.28 (m, 6H), 4.56 (t, J=3.2Hz, 1H), 7.57-7.57 (m, 1H), 8.28 (d, J=2.7Hz, 1H), 8.46 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝371(M+H)
+。
Embodiment 87B
(4s)-and 4-[(5-iodo pyridin-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 87A (67.3mg 0.18mmol) makes:
1H NMR (300MHz, and the δ ppm 1.91-1.95 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), and 2.34-2.38 (m, 2H), 2.50 (br s, 2H), 3.56 (s, 2H), 3.64-3.75 (m, 4H), 5.07 (t, J=3.2Hz, 1H), 8.43-8.45 (m, 1H), 8.62 (d, J=2.4Hz, 1H), 8.66 (d, J=1.6Hz, 1H).MS(DCI/NH
3)m/z＝357(M+H)
+。C
14H
17IN
2The analytical calculation value of O2.25HCl: C, 38.30; H, 4.62; N, 6.34.Measured value: C, 38.37; H, 4.43; N, 6.39.
Embodiment 88
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] niacinamide
Embodiment 88A
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] niacinamide N-borane complex
According to method I by the product of embodiment 10A (86.0mg, 0.52mmol) and 5-fluoro niacinamide (102.0mg 0.73mmol) makes:
1H NMR (300MHz, the δ ppm 1.66-1.70 of chloroform-D) (m, 2H), 2.04 (br s, 1H), 2.23-2.26 (m, 4H), 3.19-3.23 (m, 6H), 4.58 (t, J=3.2Hz, 1H), 7.54-7.56 (m, 1H), 8.49 (d, J=2.7Hz, 1H), 8.59 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝288(M+H)
+。
Embodiment 88B
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] the niacinamide hydrochloride
According to method J by the product of embodiment 88A (16.9mg 0.059mmol) makes:
1H NMR (300MHz, the δ ppm 1.94-1.99 of methyl alcohol-D4) (m, 2H), 2.23 (br s, 1H), 2.37-2.41 (m, 2H), 2.57 (br s, 2H), 3.60 (s, 2H), and 3.67-3.77 (m, 4H), 5.19 (t, J=3.39Hz, 1H), 8.53 (dd, J=2.7,1.4Hz, 1H), 8.83 (d, J=2.7Hz, 1H), 8.85 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝274(M+H)
+。C
15H
19N
3O
22.65HCl the analytical calculation value: C, 48.70; H, 5.90; N, 11.36.Measured value: C, 48.45; H, 6.17; N, 11.44.
Embodiment 89
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane salt
Hydrochlorate
Embodiment 89A
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane N-borane complex
According to method K by the product of embodiment 86A (83.6mg, 0.26mmol) and 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (1553mg 0.36mmol) makes:
1H NMR (300MHz, the δ ppm 1.76-1.81 of chloroform-D) (m, 2H), 1.90 (br s, 1H), 2.23-2.26 (m, 4H), 3.22-3.26 (m, 4H), 3.34-3.39 (m, 2H), 4.65 (t, J=3.2Hz, 1H), 7.17-7.22 (m, 6H), 7.32-7.37 (m, 9H), 7.66 (s, 1H), 7.94 (s, 1H), 8.16 (d, J=2.7Hz, 1H), 8.32 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝539(M-BH
3H+H)
+。
Embodiment 89B
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane salt
Hydrochlorate
According to method J by the product of embodiment 89A (47.0mg 0.085mmol) makes:
1H NMR (300MHz, the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H), 2.23 (br s, 1H), 2.39-2.43 (m, 2H), 2.57 (br s, 2H), 3.60 (s, 2H), and 3.68-3.78 (m, 4H), 5.24 (t, J=3.2Hz, 1H), 8.34 (s, 2H), 8.47-8.48 (m, 1H), 8.55 (d, J=2.4Hz, 1H), 8.77 (d, J=1.4Hz, 1H).MS(DCI/NH
3)m/z＝297(M+H)
+。C
nH
20N
4O2HCl2H
2The analytical calculation value of O: C, 50.38; H, 6.47; N, 13.82.Measured value: C, 50.51; H, 6.57; N, 13.76.
(4s)-and 4-{[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
]
The decane hydrochloride
Embodiment 90A
(4s)-and 4-{[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
]
Decane N-borane complex
According to method K by the product of embodiment 86A (102.7mg, 0.32mmol) and 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles (94.7mg 0.46mmol) makes:
1H NMR (300MHz, the δ ppm 1.66-1.70 of chloroform-D) (m, 2H), 2.04 (br s, 1H), 2.28-2.32 (m, 4H), 3.19-3.28 (m, 6H), 3.97 (s, 3H), 4.63 (t, J=3.2Hz, 1H), 7.26-7.28 (m, 1H), 7.66 (s, 1H), 7.76 (s, 1H), 8.18 (d, J=2.8Hz, 1H), 8.39 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝325(M+H)
+。
Embodiment 90B
(4s)-and 4-{[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 90A (92.2mg 0.28mmol) makes:
1H NMR (300MHz, the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H), 2.23 (br s, 1H), 2.38-2.42 (m, 2H), 2.57 (br s, 2H), 3.60 (s, 2H), 3.70-3.79 (m, 4H), 3.98 (s, 3H), 5.26 (t, J=3.2Hz, 1H), 8.13 (s, 1H), 8.39 (s, 1H), 8.46-8.47 (m, 1H), 8.57 (d, J=2.4Hz, 1H), 8.73 (d, J=1.6Hz, 1H).MS(DCI/NH
3)m/z＝311(M+H)
+。C
18H
22N
4O2HCl1.55H
2The analytical calculation value of O: C, 52.57; H, 6.67; N, 13.62; Cl, 17.24.Measured value: C, 52.79; H, 6.62; N, 13.44; Cl, 17.03.
Embodiment 91
(4s)-and 4-{[5-(1H-pyrazol-1-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 91A
3-fluoro-5-(1H-pyrazol-1-yl) pyridine
With 3-bromo-5-fluorine pyridine (300mg, 1.705mmol), the 1H-pyrazoles (180mg, 2.64mmol), ferric acetyl acetonade (181mg, 0.511mmol), cupric oxide (II) (13.6mg, 0.170mmol) and cesium carbonate (1.11g 3.41mmol) is suspended in DMF (2.0mL).Reaction mixture was stirred 60 hours at 90 ℃.After being cooled to room temperature, allow reaction mixture between ethyl acetate (3x30mL) and water (100mL), distribute.Organic layer is merged, with salt solution (50mL) washing, dry (sodium sulfate).Then it is concentrated, residuum obtains title compound through flash chromatography on silica gel method purifying:
1H NMR (400MHz, the δ ppm 6.55-6.65 of methyl alcohol-D4) (m, 1H), 7.80 (d, J=1.2Hz, 1H), 8.10 (dt, J=9.9,2.3Hz, 1H), 8.38 (d, J=2.5Hz, 1H), 8.42 (d, J=1.5Hz, 1H), 8.93 (s, 1H).MS(ESI)m/z＝163(M+H)
+。C
8H
6FN30.15CH
3The analytical calculation value of OH: C, 61.99; H, 4.48; N, 32.42; Measured value: C, 62.30; H, 4.12; N, 32.21.
Embodiment 91B
(4s)-and 4-{[5-(1H-pyrazol-1-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane two
Hydrochloride
With the product of embodiment 10A (23.7mg, 0.142mmol) and potassium tert.-butoxide (18.2mg 0.162mmol) is dissolved in dimethyl sulfoxide (DMSO) (0.3mL), and stirs 1 hour at 25 ℃.(22mg, DMSO 0.135mmol) (0.3mL) solution adds dropwise with embodiment 91A product.Reaction mixture was stirred 18 hours at 25 ℃.Mixture is dissolved in DMF (2mL), filters, through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required compound, concentrate under the vacuum, carry out the process described in the method C then.The mixture that will form in 3N HCl is concentrated into dried, stirs among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains title compound:
1H NMR (400MHz, the δ ppm 1.98 of methyl alcohol-D4) (m, 2H), 2.24 (br s, 1H), 2.41 (m, 2H), 2.60 (br s, 2H), 3.61 (br s, 2H), 3.70-3.80 (m, 4H), 5.33 (t, J=3.2Hz, 1H), 6.65-6.71 (m, 1H), 7.88 (d, J=1.5Hz, 1H), 8.56-8.77 (m, 3H), 9.04 (s, 1H).MS(ESI)m/z＝297(M+H)
+。C
17H
20N
4O2HCl1.6H
2The analytical calculation value of O: C, 51.29; H, 6.38; N, 14.07; Cl, 17.81; Measured value: C, 51.21; H, 6.18; N, 13.87; Cl, 17.96.
(4s)-and 4-{[5-(4-chloro-phenyl-) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 92A
(4s)-and 4-{[5-(4-chloro-phenyl-) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine
Complex compound
According to method K by the product of embodiment 86A (82.6mg, 0.26mmol) and the 4-chlorophenylboronic acid (66.3mg 0.42mmol) makes:
1H NMR (300MHE, and the δ ppm1.67-1.71 of chloroform-D) (m, 2H), 2.03 (br s, 1H), and 2.28-2.32 (m, 4H), 3.19-3.28 (m, 6H), 4.66 (t, J=3.2Hz, 1H), 7.35-7.37 (m, 1H), 7.44-7.51 (m, 4H), 8.32 (d, J=2.8Hz, 1H), 8.46 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝355(MH+H)
+。
Embodiment 92B
(4s)-and 4-{[5-(4-chloro-phenyl-) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 92A (52.4mg 0.15mmol) makes:
1H NMR (300MHz, the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H), 2.24 (br s, 1H), 2.40-2.44 (m, 2H), 2.59 (br s, 2H), 3.60 (s, 2H), and 3.68-3.78 (m, 4H), 5.26 (t, J=3.2Hz, 1H), and 7.58-7.62 (m, 2H), 7.81-7.85 (m, 2H), 8.51 (dd, J=2.7,1.4Hz, 1H), 8.74 (d, J=2.7Hz, 1H), 8.79 (d, J=1.4Hz, 1H).MS(DCI/NH
3)m/z＝341(M+H)
+。C
20H
21ClN
2O2HCM1.5H
2The analytical calculation value of O: C, 54.50; H, 5.95; N, 6.36; Cl, 24.13.Measured value: C, 54.80; H, 5.86; N, 6.31; Cl, 23.79.
(4s)-4-(3,4 '-dipyridyl-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 93A
5-fluoro-3,4 '-dipyridyl
According to method K, except using silica gel column chromatography (ethyl acetate, R
f=0.21) replace outside the HPLC purified product of preparation, by 3-bromo-5-fluorinated pyridine (439.0mg, 2.50mmol) and pyridin-4-yl boric acid (509.9mg 3.73mmol) makes:
1H NMR (300MHz, the δ ppm7.50-7.51 of chloroform-D) (m, 2H), 7.65 (dt, J=9.1,2.4Hz, 1H), 8.56 (d, J=2.8Hz, 1H), 8.73-8.76 (m, 3H).MS(DCI/NH
3)m/z＝175(M+H)
+。
Embodiment 93B
(4s)-4-(3,4 '-dipyridyl-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (84.0mg, 0.50mmol) and the product of embodiment 93A (111.3mg 0.64mmol) makes:
1H NMR (300MHz, and the δ ppm1.68-1.72 of chloroform-D) (m, 2H), 2.05 (br s, 1H), and 2.30-2.32 (m, 4H), 3.20-3.30 (m, 6H), 4.68 (t, J=3.1Hz, 1H), 7.43-7.44 (m, 1H), 7.48-7.50 (m, 2H), 8.40 (d, J=2.7Hz, 1H), 8.53 (d, J=1.7Hz, 1H), 8.72-8.74 (m, 2H).MS(DCI/NH
3)m/z＝322(M+H)
+。
Embodiment 93C
(4s)-4-(34 '-dipyridyl-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 93B (141.8mg 0.44mmol) makes:
1H NMR (300MHz, the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H), 2.24 (br s, 1H), 2.41-2.45 (m, 2H), 2.59 (br s, 2H), 3.60 (s, 2H), and 3.70-3.78 (m, 4H), 5.31 (t, J=3.39Hz, 1H), and 8.52-8.54 (m, 1H), 8.57-8.60 (m, 2H), 8.82 (d, J=2.71Hz, 1H), 8.95 (d, J=1.36Hz, 1H), 9.00-9.02 (m, 2H).MS(DCI/NH
3)m/z＝308(M+H)
+。C
19H
21N
3O3HCl2H
2The analytical calculation value of O: C, 50.40; H, 6.23; N, 9.28.Measured value: C, 50.70; H, 6.23; N, 9.23.
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 94A
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine network
Compound
According to method K by the product of embodiment 86A (101.0mg, 0.31mmol) and pyrimidine-5-ylboronic acid (53.1mg 043mmol) makes:
1H NMR (300MHz, and the δ ppm 1.68-1.73 of chloroform-D) (m, 2H), 2.06 (br s, 1H), and 2.30-2.32 (m, 4H), 3.20-3.30 (m, 6H), 4.70 (t, J=3.1Hz, 1H), 7.40-7.41 (m, 1H), 8.44 (d, J=2.7Hz, 1H), 8.49 (d, J=2.0Hz, 1H), 8.98 (s, 2H), 9.29 (s, 1H).MS(DCI/NH
3)m/z＝323(M+H)
+。
Embodiment 94B
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 94A (24.0mg 0.074mmol) makes:
1H NMR (300MHz, the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H), 2.24 (br s, 1H), 2.41-2.45 (m, 2H), 2.59 (br s, 2H), 3.60 (s, 2H), and 3.70-3.78 (m, 4H), 5.31 (t, J=3.4Hz, 1H), and 8.66-8.68 (m, 1H), 8.88 (d, J=2.4Hz, 1H), 8.94 (d, J=1.6Hz, 1H), 9.26 (s, 2H), 9.32 (s, 1H).MS(DCI/NH
3)m/z＝309(M+H)
+。
(4r)-4-(6-chloro-pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 95A1,95A2,95A3 and 95A4
(4s)-4-(6-chloro-pyridin-3-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane N-borane complex
(95Al),
(4r)-4-(6-chloro-pyridin-3-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane N-borane complex
(95A2),
(4s)-4-(5-fluoro-pyridin-3-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane N-borane complex
(95A3) and
(4r)-4-(5-fluoro-pyridin-3-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane N-borane complex
(95A4)
With embodiment 9A product (2.4: 1 non-enantiomer mixture; 3.34g, the 20mmol) solution in anhydrous THF (40mL), with two (trimethyl silyl) potassium amides (4.0g 20mmol) handles, and with mixture stirring at room 1 hour.(2.6g 20mmol), heats mixture 2 hours at 60 ℃ to add 2-chloro-5-fluorinated pyridine.With mixture through flash chromatography [200g silica gel, with hexane-eluent ethyl acetate (with 100%～60% gradient of 40mL/ minute flow velocity)] purifying through 72 minutes.Collect four kinds of products: (4s)-4-(6-chloro-pyridin-3-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7] decane N-borane complex (95Al); (4r)-4-(6-chloro-pyridin-3-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7] decane N-borane complex (95A2); (4s)-4-(5-fluoro-pyridine-2-base oxygen base)-1-azepine-three ring [3.3.1.1
3,7] decane N-borane complex (95A3); (4r)-4-(5-fluoro-pyridine-2-base oxygen base)-1-azepine-three ring [3.3.1.1
3,7] decane N-borane complex (95A4).
Embodiment 95B
(4r)-4-(6-chloro-pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 95A2 (750mg, 2.69mmol) preparation obtains title compound:
1H NMR (300MHz, and the δ ppm 1.75 of methyl alcohol-D4) (s, 1H), 1.97-2.08 (m, 4H), 2.14-2.25 (m, 2H), 2.95 (s, 1H), 2.99 (s, 1H), 3.14 (s, 2H), 3.45 (s, 1H), 3.49 (s, 1H), 4.74 (s, 1H), and 7.33-7.38 (m, 1H), 7.45-7.52 (m, 1H), 8.09 (d, J=3.1Hz, 1H).MS(DCI/NH
3)m/e＝265/267(M+H)
+。
Embodiment 95C
(4r)-4-(6-chloro-pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method H by the product of embodiment 95B (120mg, 0.453mmol) preparation obtains title compound:
1H NMR (300MHz, the δ ppm 2.04-2.29 of methyl alcohol-D4) (m, 5H), 2.47 (s, 2H), 3.43 (s, 1H), 3.46 (s, 1H), 3.55 (s, 2H), 3.80 (s, 1H), 3.84 (s, 1H), 4.81 (t, J=3.4Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 7.57 (dd, J=8.8,3.4Hz, 1H), 8.18 (d, J=3.1Hz, 1H).MS(DCI/NH
3)m/e＝265，267(M+H)
+。C
14H
17N
2The analytical calculation value of ClO1.5HCl: C, 52.64; H, 5.84; N, 8.77; Measured value C, 52.44; H, 5.86; N, 8.68.
(4s)-and 4-[(6-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 96A
(4s)-and 4-[(6-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (81.6mg, 0.49mmol) and 2-bromo-5-fluorinated pyridine (160.8mg 0.91mmol) makes:
1H NMR (300MHz, and the δ ppm1.65-1.69 of chloroform-D) (m, 2H), 2.03 (br s, 1H), and 2.20-2.26 (m, 4H), 3.15-3.27 (m, 6H), 4.54 (t, J=3.1Hz, 1H), 7.13 (dd, J=8.8,3.1Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 8.09 (d, J=3.4Hz, 1H).MS(DCI/NH
3)m/z＝323(M+H)
+。
Embodiment 96B
(4s)-and 4-[(6-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 96A (111.3mg 0.35mmol) makes:
1H NMR (300MHz, and the δ ppm 1.89-1.93 of methyl alcohol-D4) (m, 2H), 2.19 (br s, 1H), and 2.34-2.38 (m, 2H), 2.47 (br s, 2H), and 3.56-3.72 (m, 6H), 4.90 (t, J=3.4Hz, 1H), 7.47 (dd, J=8.7,3.2Hz, 1H), 7.54 (d, J=9.1Hz, 1H), 8.18 (d, J=3.2Hz, 1H).MS(DCI/NH
3)m/z＝309(M+H)
+。C
14H
17BrN
2The analytical calculation value of O1.2HCl: C, 47.62; H, 5.17; N, 7.94.Measured value: C, 47.62; H, 5.17; N, 7.90.
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-formonitrile HCN hydrochloride
Embodiment 97A
5-[(4s)-and the 1-aza-tricycle] 3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-formonitrile HCN N-borane complex
According to method I by the product of embodiment 10A (88.1mg, 0.53mmol) and 5-fluoro-2-cyanopyridine (5-fluoropicolinonitrile) (61.5mg 0.50mmol) makes:
1H NMR (300MHz, the δ ppm 1.69-1.73 of chloroform-D) (m, 2H), 2.06 (br s, 1H), 2.22-2.27 (m, 4H), 3.21-3.30 (m, 6H), 4.68 (t, J=3.1Hz, 1H), 7.24-7.28 (m, 1H), 7.66 (d, J=8.7Hz, 1H), 8.41 (d, J=3.6Hz, 1H).MS(DCI/NH
3)m/z＝287(M+NH
4)
+。
Embodiment 97B
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-formonitrile HCN hydrochloride
According to method J by the product of embodiment 97A (54.8mg 0.20mmol) makes:
1H NMR (300MHz, the δ ppm 1.91-1.95 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.34-2.39 (m, 2H), 2.50 (br s, 2H), 3.57 (s, 2H), and 3.61-3.74 (m, 4H), 5.04 (t, J=3.4Hz, 1H), 7.64 (dd, J=8.8,3.1Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 8.49 (d, J=3.1Hz, 1H).MS(DCI/NH
3)m/z＝256(M+H)
+。C
15H
17N
3OHClH
2The analytical calculation value of O: C, 61.75; H, 6.22; N, 14.40; Cl, 12.15.Measured value: C, 61.64; H, 6.41; N, 14.36; Cl, 12.24.
(4s)-and 4-[(5-thiophene-2-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method G, by the product of embodiment 10C (50mg, 0.16mmol) and 2-thienyl boric acid (29mg, 0.23mmol; Al drich) title compound of preparation free alkali, the operation of application method H is translated into tosilate:
1H NMR (300MHz, the δ ppm 1.92 of methyl alcohol-D4) (d, J=13.6Hz, 2H), 2.19 (s, 1H), 2.32-2.46 (m, 6H), 2.55 (s, 2H), 3.57 (s, 2H), 3.68 (s, 4H), 5.46 (s, 1H), 6.93 (d, J=8.5Hz, 1H), 7.10 (dd, J=5.1,3.4Hz, 1H), 7.22 (d, J=8.5Hz, 2H), 7.37 (dd, J=15.3,4.4Hz, 2H), 7.70 (d, J=8.1Hz, 2H), 7.97 (dd, J=8.6,2.5Hz, 1H), 8.38 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝313(M+H)
+。
(4s)-and 4-{[6-(1H-indoles-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane two
Hydrochloride
The formation method H of applied microwave Suzuki coupling method G and salt, by the product of embodiment 15B (165mg 0.623mmol) and 1H-indoles-5-ylboronic acid preparation, obtains title compound:
1HNMR (300MHz, the δ ppm 1.96 of methyl alcohol-D4) (s, 1H), 2.00 (s, 1H), 2.24 (s, 1H), 2.40 (s, 1H), 2.44 (s, 1H), 2.59 (s, 2H), 3.61 (s, 2H), 3.74 (s, 4H), 5.19 (t, J=3.2Hz, 1H), 6.66 (dd, J=3.2,0.8Hz, 1H), 7.43 (d, J=3.4Hz, 1H), and 7.59-7.64 (m, 1H), 7.64-7.68 (m, 1H), 8.16 (dd, J=1.9,0.8Hz, 1H), and 8.31-8.35 (m, 1H), 8.36-8.41 (m, 1H), 8.61 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/e＝346(M+H)
+。C
22H
23N
3O2HClH
2The analytical calculation value of O: C, 60.55; H, 6.24; N, 9.63; Measured value C, 60.71; H, 6.38; N, 9.39.
(4r)-and 4-{[6-(1H-indoles-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane three
Fluoroacetate
The formation method H of applied microwave Suzuki coupling method G and salt, by the product of embodiment 95B (135mg 0.510mmol) and 1H-indoles-5-ylboronic acid preparation, obtains title compound:
1HNMR (300MHz, the δ ppm 2.06-2.30 of methyl alcohol-D4) (m, 5H), 2.52 (s, 2H), 3.44 (s, 1H), 3.49 (s, 1H), 3.57 (s, 2H), 3.86 (s, 1H), 3.90 (s, 1H), 4.84-4.86 (m, 1H), 6.52 (d, J=3.1Hz, 1H), 7.26-7.30 (m, 1H), 7.46 (d, J=8.5Hz, 1H), 7.59-7.67 (m, 2H), 7.83 (d, J=8.8Hz, 1H), 8.06 (s, 1H), 8.37 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/e＝346(M+H)
+。C
22H
23N
3O1.17C
2HF
3O
2The analytical calculation value: C, 61.05; H, 5.09; N, 8.78; Measured value C, 60.98; H, 4.98; N, 8.75.
(4s)-and 4-{[6-(1H-indoles-6-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane three
Hydrochloride
The formation method H of applied microwave Suzuki coupling method G and salt, by the product of embodiment 15B (115mg 0.434mmol) and 1H-indoles-6-ylboronic acid preparation, obtains title compound:
1HNMR (300MHz, the δ ppm 1.93-2.05 of methyl alcohol-D4) (m, 2H), 2.24 (s, 1H), 2.40 (s, 1H), 2.44 (s, 1H), 2.59 (s, 2H), 3.61 (s, 2H), 3.67-3.81 (m, 4H), 5.19 (t, J=3.2Hz, 1H), 6.61 (d, J=3.1Hz, 1H), 7.48-7.55 (m, 2H), 7.82 (d, J=8.5Hz, 1H), 7.97 (s, 1H), 8.31-8.36 (m, 1H), 8.36-8.42 (m, 1H), 8.62 (d, J=2.4Hz, 1H).MS(DCI/NH
3)m/e＝346(M+H)
+。C
22H
23N
3O3HCl0.3H
2The analytical calculation value of O: C, 57.42; H, 5.83; N, 9.13; Measured value C, 57.46; H, 5.98; N, 9.01.
(4r)-and 4-{[6-(1H-indoles-6-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane two
Hydrochloride
The formation method H of applied microwave Suzuki coupling method G and salt, by the product of embodiment 95B (125mg 0.472mmol) and 1H-indoles-6-ylboronic acid preparation, obtains title compound:
1HNMR (300MHz, the δ ppm 2.11-2.34 of methyl alcohol-D4) (m, 5H), 2.58 (s, 2H), 3.49 (s, 1H), 3.54 (s, 1H), 3.60 (s, 2H), 3.87 (s, 1H), 3.92 (s, 1H), 5.09 (t, J=3.4Hz, 1H), 6.61 (dd, J=3.2,0.8Hz, 1H), 7.49-7.54 (m, 2H), 7.83 (d, J=8.5Hz, 1H), 7.98 (s, 1H), 8.32-8.38 (m, 1H), 8.38-8.43 (m, 1H), 8.61 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/e＝346(M+H)
+。C
22H
23N
3O2HCl2.2H
2The analytical calculation value of O: C, 57.69; H, 6.47; N, 9.17; Measured value C, 57.35; H, 6.26; N, 8.95.
Embodiment 103
5-{5-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-yl }-1,3-dihydro-2H-Yin
Diindyl-2-ketone dihydrochloride
The formation method H of applied microwave Suzuki coupling method G and salt, by the product of embodiment 15B (185mg 0.699mmol) and the preparation of 5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) Indolin-2-one, obtains title compound:
1H NMR (300MHz, the δ ppm1.93-2.00 of methyl alcohol-D4) (m, 2H), 2.23 (s, 1H), 2.39 (s, 1H), 2.43 (s, 1H), 2.56 (s, 2H), 3.58-3.78 (m, 8H), 5.09-5.16 (m, 1H), 7.10 (d, J=8.5Hz, 1H), and 7.73-7.82 (m, 2H), 8.10-8.23 (m, 2H), 8.57 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/e＝362(M+H)
+。C
22H
23N
3O
22HClH
2The analytical calculation value of O: C, 58.64.; H, 6.02; N, 9.29; Measured value C, 58.64; H, 5.99; N, 9.11.
Embodiment 104
(4r)-and 4-{[6-(1-cumarone-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane
Trifluoroacetate
The formation method H of applied microwave Suzuki coupling method G and salt, by the product of embodiment 95B (165mg, 0.623mmol) and 2-(cumarone-5-yl)-4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane (dioxaborolane) preparation obtains title compound:
1H NMR (300MHz, the δ ppm 2.07-2.30 of methyl alcohol-D4) (m, 5H), 2.52 (s, 2H), 3.45 (s, 1H), 3.49 (s, 1H), 3.57 (s, 2H), 3.86 (s, 1H), 3.90 (s, 1H), 4.87 (t, J=3.2Hz, 1H), 6.91 (d, J=3.1Hz, 1H), 7.58 (d, J=8.8Hz, 1H), 7.63 (dd, J=8.8,3.1Hz, 1H), 7.79-7.88 (m, 3H), 8.13 (d, J=1.4Hz, 1H), 8.42 (d, J=2.4Hz, 1H).MS(DCI/NH
3)m/e＝347(M+H)
+。C
22H
22N
2O
21.15C
2HF
3O
2The analytical calculation value: C, 61.12; H, 4.89; N, 5.87; Measured value C, 60.98; H, 4.74; N, 5.87.
Embodiment 105
(4s)-and 4-[(5,6-two bromo pyridin-3-yls) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 105A
(4s)-and 4-[(5,6-two bromo pyridin-3-yls) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine network
Compound
According to method I by the product of embodiment 10A (108.6mg, 0.65mmol) and 2,3-two bromos-5-fluorinated pyridine (24.5mg 0.96mmol) makes:
1H NMR (300MHz, the δ ppm1.67-1.70 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.22-2.24 (m, 4H), 3.19-3.28 (m, 6H), 4.55 (t, J=3.1Hz, 1H), 7.49 (d, J=2.7Hz, 1H), 8.06 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝401(M+H)
+。
Embodiment 105B
(4s)-and 4-[(5,6-two bromo pyridin-3-yls) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 105A (142.3mg 0.35mmol) makes:
1HNMR (300MHz, the δ ppm 1.89-1.93 of methyl alcohol-D4) (m, 2H), 2.18 (br s, 1H), 2.33-2.37 (m, 2H), 2.46 (br s, 2H), 3.56-3.71 (m, 6H), 4.92 (t, J=3.2Hz, 1H), 7.91 (d, J=2.8Hz, 1H), 8.19 (d, J=2.8Hz, 1H).MS(DCI/NH
3)m/z＝387(MH+H)
+。C
14H
16Br
2N
2The analytical calculation value of O1.5HCl: C, 37.98; H, 3.98; N, 6.33.Measured value: C, 37.98; H, 4.07; N, 6.30.
Embodiment 106
(4s)-4-(pyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 106A
(4s)-4-(pyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (101.3mg, 0.61mmol) and the 2-fluorinated pyridine (120mg, 1.06mmol):
1H NMR (300MHz, and the δ ppm 1.63-1.67 of chloroform-D) (m, 2H), 2.01 (br s, 1H), and 2.23-2.29 (m, 4H), 3.17-3.30 (m, 6H), 5.29 (t, J=3.1Hz, 1H), 6.77 (d, J=8.3Hz, 1H), 6.85-6.89 (m, 1H), and 7.56-7.62 (m, 1H), 8.11 (dd, J=5.2,2.0Hz, 1H).MS(DCI/NH
3)m/z＝260(M+NH
3-H)
+。
Embodiment 106B
(4s)-4-(pyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 106A (53.7mg 0.22mmol) makes:
1H NMR (300MHz, the δ ppm 1.96-2.00 of methyl alcohol-D4) (m, 2H), 2.23 (br s, 1H), 2.34-2.39 (m, 2H), 2.58 (br s, 2H), 3.59 (s, 2H), 3.67-3.71 (m, 4H), 5.44 (t, J=3.4Hz, 1H), 7.30-7.34 (m, 1H), 7.42 (d, J=8.7Hz, 1H), 8.16-8.22 (m, 1H), 8.30-8.32 (m, 1H).MS(DCI/NH
3)m/z＝231(M+H)
+。C
14H
18N
2The analytical calculation value of O2HCl: C, 55.45; H, 6.65; N, 9.24; Cl, 23.38.Measured value: C, 55.43; H, 6.67; N, 9.10; Cl, 23.49.
Embodiment 107
(4s)-and 4-[(5-fluoro-pyridine-2-yl) the oxygen base]-1-azepine-three ring [3.3.1.1
3,7
] the decane dihydrochloride
Use the formation method H that boronation method C and salt are taken off in acid, by product (4s)-4-(5-fluoro-pyridine-2-base oxygen base)-1-azepine-three ring [3.3.1.1 of embodiment 95A3
3,7] decane N-borane complex (200mg, 0.763mmol) preparation obtains title compound:
1H NMR (300MHz, the δ ppm 1.89 of methyl alcohol-D4) (s, 1H), 1.94 (s, 1H), 2.18 (s, 1H), 2.33 (s, 1H), 2.37 (s, 1H), 2.52 (s, 2H), 3.56 (s, 2H), 3.61-3.72 (m, 4H), 5.38 (t, J=3.2Hz, 1H), 6.94 (dd, J=9.3,3.9Hz, 1H), 7.58 (ddd, J=9.2,7.8,3.1Hz, 1H), 8.01 (d, J=3.1Hz, 1H).MS(DCI/NH
3)m/e＝249(M+H)
+。C
14H
17N
2FO2.9HClH
2The analytical calculation value of O: C, 45.20; H, 5.93; N, 7.53; Measured value C, 45.29; H, 6.11; N, 7.48.
Embodiment 108
(4s)-and 4-[(5-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 108A
(4s)-and 4-[(5-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I, except using silica gel column chromatography (2.5% ethyl acetate/dichloromethane, R
f=0.39) replace outside the HPLC purified product of preparation, by the product of embodiment 10A (419.0mg, 2.51mmol) and 5-bromo-2-chloropyridine (592.4mg 3.08mmol) makes:
1H NMR (300MHz, and the δ ppm 1.63-1.67 of chloroform-D) (m, 2H), 1.99 (br s, 1H), and 2.23-2.29 (m, 4H), 3.17-3.28 (m, 6H), 5.22 (t, J=3.1Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 7.67 (dd, J=8.8,2.0Hz, 1H), 8.15 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝338(M+NH
3-H)
+。
Embodiment 108B
(4s)-and 4-[(5-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 108A (151.9mg 0.47mmol) makes:
1HNMR (300MHz, and the δ ppm 1.90-1.94 of methyl alcohol-D4) (m, 2H), 2.18 (br s, 1H), and 2.33-2.37 (m, 2H), 2.52 (br s, 2H), and 3.54-3.71 (m, 6H), 5.41 (t, J=3.2Hz, 1H), 6.85 (d, J=8.8Hz, 1H), 7.84 (dd, J=8.8,2.7Hz, 1H), 8.19 (d, J=2.7Hz, 1H).MS(DCI/NH
3)m/z＝309(M+H)
+。C
14H
17BrN
2The analytical calculation value of O1.15HCl: C, 47.89; H, 5.21; N, 7.98.Measured value: C, 47.91; H, 5.14; N, 7.84.
Embodiment 109
(4s)-and 4-[(4-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 109A
(4s)-and 4-[(4-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (86.7mg, 0.51mmol) and 4-bromo-2-fluorinated pyridine (166.3mg 0.95mmol) makes:
1H NMR (300MHz, and the δ ppm1.63-1.67 of chloroform-D) (m, 2H), 2.00 (br s, 1H), and 2.20-2.28 (m, 4H), 3.17-3.28 (m, 6H), 5.27 (t, J=3.4Hz, 1H), 7.00 (d, J=1.6Hz, 1H), 7.04 (dd, J=4.8,1.6Hz, 1H), 7.94 (d, J=4.8Hz, 1H).MS(DCI/NH
3)m/z＝338(M+NH
3-H)
+。
Embodiment 109B
(4s)-and 4-[(4-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 109A (41.8mg 0.13mmol) makes:
1H NMR (300MHz, and the δ ppm 1.90-1.94 of methyl alcohol-D4) (m, 2H), 2.19 (br s, 1H), and 2.33-2.38 (m, 2H), 2.53 (br s, 2H), 3.57 (br s, 2H), 3.62-3.72 (m, 4H), 5.44 (t, J=3.4Hz, 1H), and 7.17-7.21 (m, 2H), 8.01 (d, J=5.4Hz, 1H).MS(DCI/NH
3)m/z＝309(M+H)
+。C
14H
17BrN
2The analytical calculation value of O1.15HCl; C, 47.89; H, 5.21; N, 7.98.Measured value: C, 47.99; H, 5.06; N, 7.82.
(4s)-4-(3,3 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 110A
(4s)-4-(3,3 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method K by the product of embodiment 108A (118.8mg, 0.37mmol) and pyridin-3-yl boric acid (69.3mg 0.56mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.02 (br s, 1H), 2.26-2.34 (m, 4H), 3.19-3.32 (m, 6H), 5.35 (t, J=3.2Hz, 1H), 6.88-6.91 (m, 1H), 7.38 (dd, J=7.9,4.8Hz, 1H), 7.80-7.83 (m, 2H), 8.34 (d, J=2.0Hz, 1H), 8.61 (dd, J=4.8.1.6Hz, 1H), 8.79 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝322(M+H)
+。
Embodiment 110B
(4s)-4-(3,3 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 110A (58.5mg 0.18mmol) makes:
1H NMR (300MHz, the δ ppm 1.94-1.98 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), 2.37-2.41 (m, 2H), 2.59 (br s, 2H), 3.59 (br s, 2H), 3.66-3.75 (m, 4H), 5.56 (t, J=3.4Hz, 1H), 7.12 (d, J=8.7Hz, 1H), 8.14-8.22 (m, 2H), 8.61 (d, J=2.8Hz, 1H), 8.83 (d, J=6.0Hz, 1H), 8.88-8.92 (m, 1H), 9.19 (d, J=2.4Hz, 1H).MS(DCI/NH
3)m/z＝308(M+H)
+。C
19H
21N
3O2HClH
2The analytical calculation value of O: C, 57.29; H, 6.33; N, 10.55; Cl, 17.80.Measured value: C, 57.21; H, 6.42; N, 10.46; Cl, 17.63.
Embodiment 111
(4s)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 110A
6-fluoro-3,4 '-dipyridyl
According to method K, except using silica gel column chromatography (10% ethanol/ethyl acetate, R
f=0.32) replace outside the HPLC purified product of preparation, by 5-bromo-2-fluorinated pyridine (881mg, 5.00mmol) and pyridin-4-yl boric acid (979mg 7.96mmol) makes:
1H NMR (300MHz, the δ ppm7.08 of chloroform-D) (dd, J=8.5,3.0Hz, 1H), 7.48-7.50 (m, 2H), 8.01-8.07 (m, 1H), 8.51 (d, J=2.7Hz, 1H), 8.72-8.74 (m, 2H).MS(DCI/NH
3)m/z＝175(M+H)
+。
Embodiment 111B
(4s)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (101.1mg, 0.62mmol) and the product of embodiment 111A (107.3mg 0.62mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.02 (br s, 1H), 2.25-2.34 (m, 4H), 3.19-3.32 (m, 6H), 5.35 (t, J=3.2Hz, 1H), 6.90 (d, J=8.5Hz, 1H), and 7.47-7.49 (m, 2H), 7.88 (dd, J=8.6,2.5Hz, 1H), 8.43 (d, J=2.4Hz, 1H), 8.67-8.68 (m, 2H).MS(DCI/NH
3)m/z＝(M+H)
+。
Embodiment 111C
(4s)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 111B (134.6mg 0.42mmol) makes:
1HNMR (300MHz, and the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H); 2.22 (br s, 1H); 2.37-2.41 (m, 2H), 2.60 (br s, 2H); 3.36 (br s, 2H); 3.71 (br s, 4H); 5.61 (t, J=3.2Hz, 1H); 7.15 (d, J=8.8Hz, 1H); 8.36-8.42 (m, 3H); 8.83-8.87 (m, 3H).MS(DCI/NH
3)m/z＝308(M+H)
+。C
19H
21N
3O1.8HCl1.45H
2The analytical calculation value of O: C, 57.17; H, 6.49; N, 10.53; Cl, 15.99.Measured value: C, 57.43; H, 6.85; N, 10.17; Cl, 16.12.
Embodiment 112
(4r)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 112A
(4r)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 9D (100.1mg, 0.60mmol) and the product of embodiment 111A (109.6mg 0.63mmol) makes:
1H NMR (300MHz, the δ ppm1.97-2.03 of chloroform-D) (m, 5H), 2.31 (br s, 2H), 2.94-2.99 (m, 2H), 3.13 (s, 2H), 3.49-3.53 (m, 2H), 5.24 (t, J=2.8Hz, 1H), 6.92 (d, J=8.5Hz, 1H), 7.46-7.48 (m, 2H), 7.88 (dd, J=8.8,2.7Hz, 1H), 8.42 (d, J=2.4Hz, 1H), 8.67-8.68 (m, 2H).MS(DCI/NH
3)m/z＝322(M+H)
+。
Embodiment 112B
(4r)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 112A (123.8mg 0.39mmol) makes:
1HNMR (300MHz, the δ ppm 2.11-2.17 of methyl alcohol-D4) (m, 2H), 2.24-2.28 (m, 3H), 2.57 (br s, 2H), 3.46-3.52 (m, 2H), 3.58 (br s, 2H), 3.83-3.87 (m, 2H), 5.52 (t, J=2.8Hz, 1H); 7.15 (d, J=8.8Hz, 1H); 8.35-8.42 (m, 3H); 8.85-8.86 (m, 3H).MS(DCI/NH
3)m/z＝308(M+H)
+。C
19H
21N
3O2.4HCl2.25H
2The analytical calculation value of O: C, 52.41; H, 6.46; N, 9.65; Cl, 19.54.Measured value: C, 52.28; H, 6.33; N, 9.54; Cl, 19.69.
Embodiment 113
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 113A
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine network
Compound
According to method K by the product of embodiment 108A (102.3mg, 0.32mmol) and pyridin-3-yl boric acid (61.1mg 0.49mmol) makes:
1H NMR (300MHz, the δ ppm1.67-1.71 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.25-2.34 (m, 4H), 3.19-3.32 (m, 6H), 5.36 (t, J=3.1Hz, 1H), 6.94 (d, J=8.7Hz, 1H), 7.82 (dd, J=8.7,2.8Hz, 1H), 8.35 (d, J=2.8Hz, 1H), 8.91 (s, 2H), 9.22 (s, 1H).MS(DCI/NH
3)m/z＝323(M+H)
+。
Embodiment 113B
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 113A (58.5mg 0.18mmol) makes:
1H NMR (300MHz, the δ ppm 1.94-1.98 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), 2.37-2.41 (m, 2H), 2.59 (br s, 2H), 3.59 (br s, 2H), and 3.66-3.75 (m, 4H), 5.56 (t, J=3.4Hz, 1H), 7.07 (d, J=8.7Hz, 1H), 8.12-8.17 (m, 2H), 8.56 (d, J=2.8Hz, 1H), 9.06 (S, 2H), 9.15 (s, 1H).MS(DCI/NH
3)m/z＝309(M+H)
+。
Embodiment 114
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridine-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane salt
Hydrochlorate
Embodiment 114A
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl) pyridine-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] the decane complex compound
According to method K by the product of embodiment 108A (48.5mg, 0.15mmol) and 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (109.9mg 0.25mmol) makes:
1H NMR (300MHz, the δ ppm 1.76-1.81 of chloroform-D) (m, 2H), 1.99 (br s, 1H), 2.25-2.30 (m, 4H), 3.16-3.25 (m, 6H), 5.27 (t, J=3.2Hz, 1H), 6.77 (d, J=9.2Hz, 1H), 7.17-7.21 (m, 6H), 7.32-7.37 (m, 9H), 7.56 (s, 1H), 7.67 (dd, J=8.7,2.5Hz, 1H), 7.88 (s, 1H), 8.19 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/z＝568(M+NH
3-H)
+。
Embodiment 114B
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridine-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane salt
Hydrochlorate
According to method J by the product of embodiment 114A (44.4mg 0.080mmol) makes:
1HNMR (300MHz, the δ ppm 1.93-1.97 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.36-2.41 (m, 2H), 2.57 (br s, 2H), 3.58 (br s, 2H), and 3.66-3.75 (m, 4H), 5.45 (t, J=3.2Hz, 1H), 7.12 (d, J=9.1Hz, 1H), 8.13 (dd, J=8.6,2.5Hz, 1H), 8.25 (s, 2H), 8.47 (d, J=1.7Hz, 1H).MS(DCI/NH
3)m/z＝297(M+H)
+。C
17H
20N
4O2HCM1.15H
2The analytical calculation value of O: C, 52.11; H, 6.30; N, 14.30.Measured value: C, 52.14; H, 6.33; N, 14.24.
Embodiment 115
6-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl pyridine-2-carboxamide
Embodiment 115A
6-chloro-N-(pyridin-4-yl) picolinamide
(0.50g 3.17mmol) is dissolved in thionyl chloride (5.0mL), stirs 1 hour at 25 ℃ with 6-chloropyridine-2-carboxylic acid (6-Chloropicolinic acid).The evaporation thionyl chloride, add 4-aminopyridine (0.28g, 2.98mmol), triethylamine (0.415mL, 2.98mmol) and methylene dichloride (50mL).Solution was stirred 18 hours at 25 ℃.Allow reaction mixture between methylene dichloride (50mL) and saturated sodium hydrogen carbonate solution (100mL), distribute.With organic layer drying (sodium sulfate) and concentrated, residuum obtains title compound through flash chromatography on silica gel method purifying:
1H NMR (500MHz, the δ ppm 7.71 of methyl alcohol-D4) (dd, J=7.9,0.9Hz, 1H), 7.91-7.95 (m, 2H), 8.05 (t, J=7.8Hz, 1H), 8.20 (dd, J=7.6,0.6Hz, 1H), 8.43-8.52 (m, 2H).MS(ESI)m/z＝335(M+H)
+。
Embodiment 115B
6-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl pyridine-2-carboxamide richness
The horse hydrochlorate
According to method B, by the product of embodiment 115A (134mg, 0.574mmol) and the product of embodiment 10B (80mg, 0.522mmol) preparation obtains free alkali.According to method H itself and fumaric acid are reacted then, obtain title compound:
1H NMR (500MHz, the δ ppm1.91-2.01 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.37-2.46 (m, 2H), 2.58 (br s, 2H), 3.58 (s, 2H), 3.67-3.81 (m, 4H), 5.80 (t, J=3.2Hz, 1H), 6.69 (s, 2H, C
4H
4O
4), 7.18 (dd, J=8.2,0.6Hz, 1H), 7.86-7.90 (m, 3H), 7.97 (dd, J=8.2,7.3Hz, 1H), 8.48 (d, J=6.1Hz, 2H).MS(ESI)m/z＝351(M+H)
+。C
20H
22N
4O
21.05C
4H
4O
4The analytical calculation value: C, 61.54; H, 5.59; N, 11.86; Measured value: C, 61.40; H, 5.76; N, 11.78.
Embodiment 116
(4s)-and 4-[(2-chloro-pyridine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 116A
(4s)-and 4-[(2-chloro-pyridine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (82.8mg, 0.50mmol) and 4-bromo-2-chloro-pyridine (85 μ L 0.77mmol) make:
1H NMR (300MHz, and the δ ppm 1.67-1.71 of chloroform-D) (m, 2H), 2.03 (br s, 1H), and 2.19-2.27 (m, 4H), 3.19-3.25 (m, 6H), 4.64 (t, J=3.4Hz, 1H), 6.76 (dd, J=5.8,2.4Hz, 1H), 6.85 (d, J=2.4Hz, 1H), 8.22 (d, J=5.8Hz, 1H).MS(DCI/NH
3)m/z＝279(M+H)
+。
Embodiment 116B
(4s)-and 4-[(2-chloro-pyridine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 116A (86.6mg, 0.31mmol) preparation:
1H NMR (300MHz, the δ ppm 1.93-1.97 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.31-2.35 (m, 2H), 2.52 (br s, 2H), 3.59 (br s, 2H), and 3.66-3.76 (m, 4H), 5.17 (t, J=3.4Hz, 1H), 7.32 (dd, J=6.4,2.4Hz, 1H), 7.50 (d, J=2.4Hz, 1H), 8.38 (d, J=6.4Hz, 1H).MS(DCI/NH
3)m/z＝265(M+H)
+。C
14H
17ClN
2O2HCl0.3H
2The analytical calculation value of O: C, 49.01; H, 5.76; N, 8.17.Measured value: C, 49.18; H, 5.85; N, 7.92.
Embodiment 117
(4s)-and 4-[(6-methyl pyridazine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 117A
(4s)-and 4-[(6-methyl pyridazine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (83.7mg, 050mmol) and 3-chloro-methyl pyridazine (100.6mg 0.78mmol) makes:
1H NMR (300MHz, the δ ppm 1.65-1.69 of chloroform-D) (m, 2H), 2.00 (br s, 1H), 2.20-2.24 (m, 2H), 2.42 (br s, 2H), 3.18-3.30 (m, 6H), 5.50 (t, J=3.6Hz, 1H), 6.92 (d, J=8.8Hz, 1H), 7.25 (d, J=8.8Hz, 1H).MS(DCI/NH
3)m/z＝260(M+H)
+。
Embodiment 117B
(4s)-and 4-[(6-methyl pyridazine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 117A (28.2mg 0.11mmol) makes:
1H NMR (300MHz, and the δ ppm 1.97-2.01 of methyl alcohol-D4) (m, 2H), 2.23 (br s, 1H), and 2.35-2.39 (m, 2H), 2.64 (br s, 2H), 2.81 (s, 3H), 3.60 (br s, 2H), and 3.68-3.78 (m, 4H), 5.58 (t, J=3.4Hz, 1H), 7.98 (d, J=9.1Hz, 1H), 8.22 (d, J=9.1Hz, 1H).MS(DCI/NH
3)m/z＝246(M+H)
+。C
14H
19N
3The analytical calculation value of O2.25HCl: C, 51.37; H, 6.54; N, 12.84.Measured value: C, 51.37; H, 6.70; N, 12.90.
Embodiment 118
(4s)-4-(pyrimidine-2-yloxy)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 118A
(4s)-4-(pyrimidine-2-yloxy)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (86.3mg, 0.S2mmol) and the 2-chloropyrimide (99.2mg 0.87mmol) makes:
1H NMR (300MHz, the δ ppm 1.65-1.70 of chloroform-D) (m, 2H), 2.02 (br s, 1H), 2.30-2.40 (m, 4H), 3.19-3.29 (m, 6H), 5.27 (t, J=3.4Hz, 1H), 6.96 (t, J=4.8Hz, 1H), 8.52 (d, J=4.8Hz, 2H).MS(DCI/NH
3)m/z＝246(M+H)
+。
Embodiment 118B
(4s)-4-(pyrimidine-2-yloxy)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to the product 61.6mg of method J, 0.25mmol) make by embodiment 118A:
1H NMR (300MHz, and the δ ppm 1.92-1.97 of methyl alcohol-D4) (m, 2H); 2.21 (br s, 1H); 2.38-2.41 (m, 2H), 2.57 (br s, 2H); 3.58 (br s, 2H); 3.64-3.74 (m, 4H); 5.48 (t, J=3.2Hz, 1H); 7.15 (t, J=4.9Hz, 1H); 8.60 (d, J=4.8Hz, 2H).MS(DCI/NH
3)m/z＝232(M+H)
+。C
13H
17N
3OHCl0.1H
2The analytical calculation value of O: C, 57.93; H, 6.81; N, 15.59; Cl, 13.15.Measured value: C, 57.74; H, 6.60; N, 15.55; Cl, 13.38.
Embodiment 119
(4s)-and 4-[(5-brominated pyrimidine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 119A
(4s)-and 4-[(5-brominated pyrimidine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (81.5mg, 0.49mmol) and 5-bromo-2-chloropyrimide (135.6mg 0.70mmol) makes:
1H NMR (300MHz, the δ ppm1.66-1.70 of chloroform-D) (m, 2H), 2.02 (br s, 1H), 2.29-2.33 (m, 4H), 3.19-3.29 (m, 6H), 5.21 (t, J=3.2Hz, 1H), 8.53 (s, 2H).MS(DCI/NH
3)m/z＝339(M+NH
3-H)
+。
Embodiment 119B
(4s)-and 4-[(5-brominated pyrimidine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 119A (20.4mg 0.063mmol) makes:
1HNMR (300MHz, the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.36-2.40 (m, 2H), 2.56 (br s, 2H), 3.58-3.73 (m, 6H), 5.42 (t, J=3.4Hz, 1H), 8.68 (s, 2H).MS(DCI/NH
3)m/z＝310(M+H)
+。C
13H
16BrN
3The analytical calculation value of OHCl: C, 45.04; H, 4.94; N, 12.12.Measured value: C, 45.22; H, 5.24; N, 11.90.
(4s)-4-(pyrimidine-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 120A
(4s)-4-(pyrimidine-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 10A (88.4mg, 0.53mmol) and 5-fluorine pyrimidine (92.0mg 0.94mmol) makes:
1H NMR (300MHz, the δ ppm 1.68-1.73 of chloroform-D) (m, 2H), 2.05 (br s, 1H), 2.24-2.29 (m, 4H), 3.18-3.29 (m, 6H), 4.65 (t, J=3.2Hz, 1H), 8.46 (s, 2H), 8.89 (s, 1H).MS(DCI/NH
3)m/z＝261(M+NH
3-H)
+。
Embodiment 120B
(4s)-4-(pyrimidine-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 120A (91.5mg 0.37mmol) makes:
1H NMR (300MHz, the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.36-2.41 (m, 2H), 2.53 (br s, 2H), 3.58 (s, 2H), 3.63-3.75 (m, 4H), 5.08 (t, J=3.2Hz, 1H), 8.79 (s, 2H), 8.93 (s, 1H).MS(DCI/NH
3)m/z＝232(MH+H)
+。C
13H
17N
3The analytical calculation value of O2HCl: C, 51.33; H, 6.30; N, 13.81.Measured value: C, 51.59; H, 6.70; N, 13.80.
Embodiment 121
(4s)-4-(pyrimidine-4-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method B by the product of embodiment 10B (89mg, 0.581mmol) and 4-chloropyrimide hydrochloride (98mg, 0.651mmol) preparation obtains free alkali.According to method H itself and fumaric acid are reacted then, obtain the title compound of fumarate:
1H NMR (500M Hz, the δ ppm 1.90-1.99 of methyl alcohol-D4) (m, 2H), 2.19 (br s, 1H), 2.30-2.38 (m, 2H), 2.55 (br s, 2H), 3.56 (br s, 2H), 3.61-3.72 (m, 4H), 5.59 (t, J=3.2Hz, 1H), 6.69 (s, 2H, C
4H
4O
4), 7.01 (dd, J=6.0,1.1Hz, 1H), 8.51 (d, J=5.8Hz, 1H), 8.74 (s, 1H).MS(ESI)m/z＝232(M+H)
+。
Embodiment 122
(4s)-and 4-[(6-Chloropyrimide-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
With the product of embodiment 10B (73mg, 0.437mmol) and potassium tert.-butoxide (51mg 0.454mmol) is dissolved in dimethyl sulfoxide (DMSO) (2.5mL), and stirs 1 hour at 25 ℃.Add 4, and 6-dichloro-pyrimidine (111mg, 0.743mmol).Reaction mixture was stirred 18 hours at 25 ℃.Mixture is dissolved in DMF (2mL), filters, through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required compound, concentrate under the vacuum, carry out the process described in the method C then, obtain free alkali.According to method H itself and fumaric acid are reacted then, obtain title compound:
1H NMR (400MHz, the δ ppm 1.89-2.01 of methyl alcohol-D4) (m, 2H), 2.18 (br s, 1H), 2.27-2.39 (m, 2H), 2.53 (br s, 2H), 3.55 (br s, 2H), 3.59-3.72 (m, 4H), 5.58 (t, J=3.1Hz, 1H), 6.68 (s, 2H, C
4H
4O
4), 7.10 (d, J=0.9Hz, 1H), 8.58 (s, 1H).MS(ESI)m/z＝266(M+H)
+。
Embodiment 123
(4s)-and 4-{[6-(1-trityl-1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
Embodiment 123A
4-chloro-6-(1-trityl-1H-pyrazoles-4-yl) pyrimidine
In the microwave reaction pipe, add 4, and the 6-dichloro pyrimidine (480mg, 3.22mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (1.28g, 2.93mmol; JP 2005232071), two (triphenylphosphine) palladium chloride (II) (82mg, 0.117mmol), (776mg 7.32mmol), adds solvent 2-propyl alcohol (90mL) and water (3.0mL) to yellow soda ash subsequently.With the seal of tube, will be reflected at and be heated to 108 ℃ of maintenances 30 minutes in the microwave reactor.After being cooled to room temperature, allow mixture between ethyl acetate (2x 100mL) and water (200mL), distribute.With the organic extraction salt water washing that merges, dry (sodium sulfate) under reduced pressure concentrates, and the material of generation through silica gel flash column chromatography purifying, is obtained title compound:
1H NMR (300MHz, the δ ppm 7.11-7.22 of methyl alcohol-D4) (m, 6H), 7.28-7.41 (m, 9H), 7.81-7.83 (m, 1H), 8.23-8.26 (m, 1H), 8.30 (s, 1H), 8.75-8.78 (m, 1H).MS(DCI/NH
3)m/z＝423(M+H)
+。
Embodiment 123B
(4s)-and 4-{[6-(1-trityl-1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
According to method B by the product of embodiment 10B (80mg, 0.522mmol) and the product of embodiment 123A (243mg 0.574mmol) makes:
1H NMR (500MHz, and the δ ppm 1.63 of chloroform-D) (br s, 1H), 1.76-1.85 (m, 2H), 2.05 (br s, 2H), 2.23-2.32 (m, 2H), 3.11-3.21 (m, 4H), and 3.24-3.34 (m, 2H), 5.41 (t, J=3.1Hz, 1H), 6.81 (d, J=0.9Hz, 1H), 7.14-7.21 (m, 6H), 7.29-7.36 (m, 9H), 8.05 (s, 1H), 8.15 (s, 1H), 8.62 (d, J=0.9Hz, 1H).MS(ESI)m/z＝540(M+H)
+。
Embodiment 124
(4s)-and 4-{[6-(1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane
(76mg, 0.141mmol) suspension in THF (10mL) was handled with 3N HCl (5mL), stirring at room 18 hours with embodiment 123 products.Allow mixture aqueous sodium carbonate (1.0M, 100mL) and chloroform-Virahol (4: 1, distribute between 200mL).With organic extraction salt water washing, dry (sodium sulfate) under reduced pressure concentrates, at Waters Nova-Pak HR Cl8 6 μ m
On the Prep-Pak cylinder (40x100mm), used 10%～100% gradient of acetonitrile in the 10mM ammonium acetate solution in 12 minutes, flow velocity 70mL/ minute, the HPLC purifying of material through preparing with generating obtained title compound:
1H NMR (500MHz, and the δ ppm 1.70 of methyl alcohol-D4) (br s, 1H), 1.88 (m, 2H), 2.12 (br s, 2H), 2.29-2.36 (m, 2H), and 3.12-3.20 (m, 4H), 3.27-3.35 (m, 2H), 5.47 (t, J=3.1Hz, 1H), 7.17 (d, J=0.9Hz, 1H), 8.26 (s, 2H), 8.62 (d, J=0.9Hz, 1H).MS(APCI)m/z＝298(M+H)
+。C
16H
19N
5O0.5H
2The analytical calculation value of O: C, 62.73; H, 6.58; N, 22.86; Measured value: C, 62.66; H, 6.53; N, 22.76.
Embodiment 125
(4s)-and 4-[(6-pyridin-4-yl pyrimidine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 125A
4-chloro-6-(pyridin-4-yl) pyrimidine
Pack 4 in the sealed tube into, the 6-dichloro pyrimidine (252mg, 1.690mmol), trimethylammonium (phenyl) tin (stannane) (345mg, 1.432mmol), toluene (10mL) and tetrakis triphenylphosphine palladium (0) (66.2mg, 0.057mmol).With reaction mixture nitrogen degasification, then 120 ℃ of heating 4 hours.After being cooled to room temperature, add gac, reaction mixture filters by the frit filter plate, under reduced pressure concentrates.The material that generates through flash chromatography on silica gel method purifying, is obtained title compound:
1HNMR (500MHz, the δ ppm 8.16-8.21 of methyl alcohol-D4) (m, 2H), 8.27 (d, J=0.9Hz, 1H), 8.71-8.79 (m, 2H), 9.11 (d, J=0.9Hz, 1H).MS(ESI)m/z＝192(M+H)
+。
Embodiment 125B
(4s)-and 4-[(6-pyridin-4-yl pyrimidine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method B, by the product of embodiment 10A (48mg, 0.287mmol) and the product of embodiment 125A (55mg, 0.287mmol) borane complex of preparation title compound.Carry out the process described in the method C then, obtain title compound:
1H NMR (400MHz, and the δ ppm 1.74 of methyl alcohol-D4) (br s, 1H), 1.85-1.96 (m, 2H), 2.18 (br s, 2H), 2.29-2.44 (m, 2H), 3.15-3.24 (m, 4H), and 3.32-3.37 (m, 2H), 5.55 (t, J=2.7Hz, 1H), 7.54 (d, J=1.2Hz, 1H), and 8.09-8.13 (m, 2H), 8.68-8.72 (m, 2H), 8.83 (d, J=0.9Hz, 1H).MS(ESI)m/z＝309(M+H)
+。
Embodiment 126
(4s)-4-(pyrazine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 126A
(4s)-4-(pyrazine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
(82.5mg, 0.49mmol) (80 μ L 0.91mmol) make: MS (DCI/NH with the 2-chloropyrazine by the product of embodiment 10A according to method I
3) m/z=261 (M+NH
3-H)
+
Embodiment 126B
(4s)-4-(pyrazine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 126A (18.2mg 0.074mmol) makes:
1HNMR (300MHz, the δ ppm 1.92-1.96 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.36-2.40 (m, 2H), 2.56 (br s, 2H), 3.58 (br s, 2H), 3.64-3.74 (m, 4H), 5.49 (t, J=3.2Hz, 1H), 8.15-8.18 (m, 2H); 8.32 (d, J=1.4Hz, 1H).MS(DCI/NH
3)m/z＝232(M+H)
+。C
13H
17N
3The analytical calculation value of O1.32HCl: C, 55.88; H, 6.61; N, 15.04.Measured value: C, 56.22; H, 6.43; N, 14.68.
Embodiment 127
4-[(6-methylpyrazine-2-yl) oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 127A
4-[(6-methylpyrazine-2-yl) oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
(101.4mg, 0.61mmol) (100.7mg 0.78mmol) makes: MS (DCyNH with 2-chloro-6-methylpyrazine by the product of embodiment 9A according to method I
3) m/z=275 (M+NH
3-H)
+
Embodiment 127B
4-[(6-methylpyrazine-2-yl) oxygen base]-1-aza-tricycle [3.3.11
3,7
] the decane hydrochloride
According to method J by the product of embodiment 127A (18.2mg 0.074mmol) makes: 3.1: 1.0 mixture isomer [according to
1H NMR (300MHz, the integration of the δ ppm 5.53 of methyl alcohol-D4) (t, J=3.22, main) and 5.42 (t, J=3.39, accessory)].MS(DCI/NH
3)m/z＝246(M+H)
+。C
14H
18N
2O1.5HCl0.65H
2The analytical calculation value of O: C, 53.94; H, 7.05; N, 13.48; Cl, 17.06.Measured value: C, 54.17; H, 7.26; N, 13.52; Cl, 16.80.
Embodiment 128
(4r)-and 4-[(6-phenyl pyrazines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 128A
2-chloro-6-phenyl pyrazines
According to method K, except using silica gel chromatography (DCM, R
f=0.37) replace outside the HPLC purified product of preparation, by 2, the 6-dichloropyrazine (1.01g, 6.78mmol) and phenyl-boron dihydroxide (946.7mg 7.76mmol) makes:
1H NMR (300MHz, the δ ppm 7.46-7.53 of chloroform-D) (m, 3H), 7.94-7.98 (m, 2H), 8.22 (s, 1H), 8.63 (s, 1H).MS(DCI/NH
3)m/z＝191(M+H)
+。
Embodiment 128B
(4r)-and 4-[(6-phenyl pyrazines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 9D (163.6mg, 0.98mmol) and the product of embodiment 128A (99.0mg 0.52mmol) makes:
1H NMR (300MHz, and the δ ppm1.89-2.06 of chloroform-D) (m, 5H), 2.37 (br s, 1H), and 2.97-3.01 (m, 2H), 3.15 (s, 2H), and 3.51-3.55 (m, 2H), 5.33 (t, J=3.2Hz, 1H), 7.50-7.56 (m, 3H), 8.00-8.05 (m, 2H), 8.53 (s, 1H), 8.94 (s, 1H).MS(DCI/NH
3)m/z＝322(M+H)
+。
Embodiment 128C
(4r)-and 4-[(6-phenyl pyrazines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method I by the product of embodiment 128B (45.1mg 0.14mmol) makes:
1H NMR (300MHz, the δ ppm 2.20-2.31 of methyl alcohol-D4) (m, 5H), 2.62 (br s, 2H), 3.34-3.54 (m, 2H), 2.59 (br s, 2H), 3.86-3.91 (m, 4H), 5.56 (t, J=3.4Hz, 1H), 7.47-4.55 (m, 3H); 8.04-8.08 (m, 2H), 8.25 (s, 1H), 8.73 (s, 1H).MS(DCI/NH
3)m/z＝308(M+H)
+。C
19H
21N
3O1.25HClH
2The analytical calculation value of O: C, 61.51; H, 659; N, 11.33; Cl, 11.95.Measured value: C, 61.36; H, 6.49; N, 11.30; Cl, 11.93.
Embodiment 129
(4r)-4-(1,3-thiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
Embodiment 129A
(4r)-4-(1,3-thiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane N-borane complex
According to method I by the product of embodiment 9D (168.7mg, 1.01mmol) and 2-diuril azoles (162.5mg 136mmol) makes:
1H NMR (300MHz, the δ ppm 1.87-2.01 of chloroform-D) (m, 5H), 2.39 (br s, 1H), 2.94-2.98 (m, 2H), 3.12 (s, 2H), 3.43-3.48 (m, 2H), 5.12 (t, J=3.4Hz, 1H), 6.70 (d, J=3.6Hz, 1H), 7.11 (d, J=4.0Hz, 1H).MS(DCI/NH
3)m/z＝251(M+H)
+。
Embodiment 129B
(4r)-4-(1,3-thiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 129A (125.7mg 0.50mmol) makes:
1HNMR (300MHz, the δ ppm 2.07-2.11 of methyl alcohol-D4) (m, 2H), 2.22-2.28 (m, 3H), 2.62 (br s, 1H), 3.46-3.57 (m, 4H), 3.75-3.79 (m, 4H), 5.25 (t, J=3.4Hz, 1H), 6.99 (d, J=3.73Hz, 1H), 7.20 (d, J=3.73Hz, 1H).MS(DCI/NH
3)m/z＝237(M+H)
+。C
12H
16N
2The analytical calculation value of OS1.91HCl: C, 47.11; H, 5.90; N, 9.16.Measured value: C, 47.47; H, 5.51; N, 9.10.
(4r)-4-(5-bromo-thiazol-2-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] the decane tosylate
Embodiment 130Al and 130A2
(4r)-4-(5-bromo-thiazol-2-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane (130Al) and
(4s)-4-(5-bromo-thiazol-2-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane (130A2)
Product (2.4: 1 non-enantiomer mixtures with embodiment 9A; 334mg, 2.0mmol) with 2, the solution of 5-two bromo thiazoles reacts according to etherification method B, obtains the non-enantiomer mixture of N-borane complex.Diastereomer separates with the hexane/ethyl acetate wash-out through silica gel chromatography, obtains auxiliary product 4r isomer and main products 4s isomer.Then each isomer is stood acid and take off boronation method C, obtain title compound 130Al and 130A2.Auxiliary product 130Al:
1H NMR (300MHz, and the δ ppm 1.70-1.75 of methyl alcohol-D4) (m, 1H), 1.95-2.13 (m, 4H), 2.17 (d, J=2.7Hz, 1H), 2.21 (d, J=2.4Hz, 1H), 2.97 (d, J=1.4Hz, 1H), 3.01 (d, J=1.4Hz, 1H), 3.13 (s, 2H), 3.37 (s, 1H), 3.41 (s, 1H), 5.23 (t, J=3.4Hz, 1H), 7.11 (s, 1H).MS(DCI/NH
3)m/e＝315，317(M+H)
+。Main products 130A2: main products 130A2:
1H NMR (300MHz, the δ ppm 1.67 of methyl alcohol-D4) (s, 1H), 1.85 (s, 1H), 1.89 (s, 1H), 2.13-2.30 (m, 4H), 3.05-3.16 (m, 4H), 3.26 (s, 1H), 5.22 (t, J=3.4Hz, 1H), 7.11 (s, 1H).MS(DCI/NH
3)m/e＝315，317(M+H)
+。
Embodiment 130B
(4r)-and 4-[(5-bromo-thiazol-2-yl) the oxygen base]-1-azepine-three ring [3.3.1.1
3,7
] the decane tosylate
According to the formation method H of salt by the product of embodiment 130Al (32mg, 0.101mmol) preparation obtains title compound:
1H NMR (300MHz, the δ ppm 2.00-2.28 of methyl alcohol-D4) (m, 5H), 2.37 (s, 3H), 2.59 (s, 2H), 3.46 (d, J=12.2Hz, 2H), 3.55 (s, 2H), 3.73 (s, 1H), 3.77 (s, 1H), 5.28 (t, J=3.6Hz, 1H), 7.16 (s, 1H), 7.23 (d, J=7.8Hz, 2H), 7.70 (d, J=8.1Hz, 2H).MS(DCI/NH
3)m/e＝315，317(M+H)
+。C
12H
15N
2BrOSC
7H
8O
3The analytical calculation value of S: C, 46.82; H, 4.76; N, 5.75; Measured value C, 46.72; H, 4.42; N, 5.68.
Embodiment 131
(4s)-4-(5-[4-(trifluoromethoxy) phenyl]-1,3-thiazoles-2-yl } the oxygen base)-the 1-aza-tricycle
[3.3.1.1
3,7
] the decane hydrochloride
Embodiment 131A
(4s)-4-(5-[4-(trifluoromethoxy) phenyl]-1,3-thiazoles-2-yl } the oxygen base)-the 1-aza-tricycle
[3.3.1.1
3,7
] decane N-borane complex
According to method K by the product of embodiment 20A (65.0mg, 0.20mmol) and 4-(trifluoromethoxy) phenyl-boron dihydroxide (74.8mg 0.36mmol) makes:
1H NMR (300MHz, the δ ppm 1.69-1.73 of chloroform-D) (m, 2H), 2.03 (br s, 1H), 2.22-2.26 (m, 2H), 2.43 (s, 2H), 3.19-3.24 (m, 6H), 5,42 (t, J=3.4Hz, 1H), 6.81-6.84 (m, 2H), 7.27 (s, 1H), 7.43-7.47 (m, 2H).MS(DCI/NH
3)m/z＝411(M+H)
+。
Embodiment 131B
(4s)-4-(5-[4-(trifluoromethoxy) phenyl]-the 13-thiazol-2-yl } the oxygen base)-the 1-aza-tricycle
[3.3.1.1
3,7
] the decane hydrochloride
According to method J by the product of embodiment 131A (45.7mg 0.11mmol) makes:
1H NMR (300MHz, and the δ ppm 1.95-1.99 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), and 2.31-2.35 (m, 2H), 2.66 (br s, 2H), 3.58 (br s, 2H), 3.63-3.73 (m, 4H), 5.41 (t, J=3.4Hz, 1H), 7.30-7.32 (m, 2H), 7.48 (s, 1H), and 7.59-7.64 (m, 2H).MS(DCI/NH
3)m/z＝397(M+H)
+。C
19H
19F
3N
2O
2The analytical calculation value of S1.15HCl0.35HCl: C, 51.32; H, 4.73; N, 6.30; Cl, 9.17.Measured value: C, 51.42; H, 4.77; N, 6.29; Cl, 9.05.
Embodiment 132
(4s)-and 4-{[5-(4-chloro-phenyl-)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.11
3,7
] decane
(50mg, 0.152mmol) (30.9mg 0.198mmol) handles described in embodiment 123A, obtains the N-borane complex of title compound with the 4-chlorophenylboronic acid with the product of embodiment 20A.Then it is handled described in method C.The mixture that forms among the 3N HCl is concentrated into dried, stirred among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (500MHz, and the δ ppm 1.91-2.03 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), and 2.27-2.38 (m, 2H), 2.66 (br s, 2H), 3.58 (br s, 2H), 3.62-3.76 (m, 4H), 5.40 (t, J=3.2Hz, 1H), 7.37-7.42 (m, 2H), 7.47 (s, 1H), and 7.48-7.53 (m, 2H).MS(ESI)m/z＝347(M+H)
+。
Embodiment 133
4-{2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-1,3-thiazoles-5-yl } aniline
Product (the 50mg that in sealed tube, adds embodiment 20A, 0.152mmol), 4-(tert-butoxycarbonyl amino) phenyl-boron dihydroxide (46.8mg, 0.198mmol), two (triphenylphosphine) palladium chloride (II) (4.3mg, 6.08 μ mol) and aqueous sodium carbonate (1.0M, 0.38mL), add solvent 2-propyl alcohol (1.2mL) subsequently.Pipe is heated to 93 ℃ to be kept 90 minutes.After being cooled to room temperature, allow mixture between ethyl acetate (2x50mL) and water (50mL), distribute.With the organic extraction salt water washing that merges, dry (sodium sulfate) under reduced pressure concentrates.At Waters Nova-Pak HR Cl8 6 μ m
On the Prep-Pak cylinder (40x100mm), in 12 minutes, use 10%～100% gradient of acetonitrile in the 10mM ammonium acetate solution, flow velocity 70mL/ minute,, obtain white solid generating the HPLC purifying of material through preparation.Described in solid such as method C, handle then, obtain free alkali.According to method H itself and HCl-diox are reacted then, obtain title compound:
1H NMR (500MHz, and the δ ppm 1.91-2.04 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), and 2.28-2.39 (m, 2H), 2.66 (br s, 2H), 3.59 (br s, 2H), 3.62-3.75 (m, 4H), 5.40 (t, J=3.3Hz, 1H), 7.17-7.30 (m, 2H), 7.45 (s, 1H), and 7.52-7.63 (m, 2H).MS(ESI)m/z＝328(M+H)
+。
Embodiment 134
(4s)-4-(5-(pyridin-3-yl)-thiazol-2-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane toluene sulphur
Hydrochlorate
Applied microwave Suzuki coupling method G by main products embodiment 130A2 (31mg 0.098mmol) and pyridin-3-yl boric acid preparation, uses the formation method H of salt then, obtains title compound:
1H NMR (300MHz, the δ ppm 1.95 of methyl alcohol-D4) (s, 1H), 1.99 (s, 1H), 2.20 (s, 1H), 2.31 (s, 1H), 2.36 (s, 3H), 2.66 (s, 2H), 3.55-3.75 (m, 6H), 5.43 (t, J=3.4Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.47 (dd, J=85,5.4Hz, 1H), 7.60 (s, 1H), 7.70 (d, J=7.8Hz, 2H), 7.96-8.02 (m, 1H), 8.45-8.49 (m, 1H), 8.72 (d, J=2.0Hz, 1H).MS(DCI/NH
3)m/e＝314(M+H)
+。
Embodiment 135
(4r)-4-(5-(pyridin-3-yl)-thiazol-2-yl oxygen base)-1-azepine-three ring [3.3.1.1
3,7
] decane toluene sulphur
Hydrochlorate
Applied microwave Suzuki coupling method G by auxiliary product embodiment 130Al (40mg 0.127mmol) and pyridin-3-yl boric acid preparation, uses the formation method H of salt then, obtains title compound:
1H NMR (300MHz, the δ ppm 2.04-2.30 of methyl alcohol-D4) (m, 5H), 2.36 (s, 3H), 2.65 (s, 2H), 3.43-3.84 (m, 6H), 5.35 (t, J=3.6Hz, 1H), 7.23 (d, J=8.5Hz, 2H), 7.47 (dd, J=8.1,4.7Hz, 1H), 7.61 (s, 1H), 7.70 (d, J=8.5Hz, 2H), 7.99 (dt, J=8.1,1.9Hz, 1H), 8.47 (dd, J=5.1,1.4Hz, 1H), 8.71 (d, J=2.4Hz, 1H).MS(DCI/NH
3)m/e＝314(M+H)
+。C
17H
19N
3OS1.05C
7H
8O
3The analytical calculation value of S: C, 59.18; H, 5.59; N, 8.50; Measured value C, 59.02; H, 5.43; N, 8.55.
Embodiment 136
(4s)-and 4-[(5-pyrimidine-5-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane hydrochloric acid
Salt
Embodiment 136A
(4s)-and 4-[(5-pyrimidine-5-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-boron
The alkane complex compound
According to method K by the product of embodiment 20A (95.2mg, 0.29mmol) and pyrimidine-5-ylboronic acid (59.2mg 0.48mmol) makes:
1H NMR (300MHz, the δ ppm 1.70-1.74 of chloroform-D) (m, 2H), 2.05 (br s, 1H), 2.21-2.25 (m, 2H), 2.45 (s, 2H), 3.20-3.25 (m, 6H), 5.29 (t, J=34Hz, 1H), 7.41 (s, 1H), 8.81 (s, 2H), 9.13 (s, 1H).MS(DCI/NH
3)m/z＝329(M+H)
+。
Embodiment 136B
(4s)-and 4-[(5-pyrimidine-5-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane hydrochloric acid
Salt
According to method J by the product of embodiment 136A (17.3mg 0.053mmol) makes:
1HNMR (300MHz, the δ ppm 1.95-2.00 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.31-2.36 (m, 2H), 2.68 (br s, 2H), 3.59 (s, 2H), 3.63-3.75 (m, 4H), 5.47 (t, J=3.6Hz, 1H), 7.72 (s, 1H), 8.98 (s, 2H), 9.07 (s, 1H).MS(DCI/NH
3)m/z＝315(M+H)
+。C
16H
18N
4The analytical calculation value of OS2HCl: C, 49.62; H, 5.20; N, 14.46.Measured value: C, 49.86; H, 5.23; N, 14.26.
Embodiment 137
(4s)-and 4-{[5-(2-methoxy pyrimidine-5-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
To embodiment 20A product (80mg, 0.243mmol) in the solution in DMF (2.5mL), add 2-methoxy pyrimidine-5-ylboronic acid (70.4mg, 0.457mmol), two (triphenylphosphine) palladium chloride (II) (8.5mg, 0.012mmol) and cesium carbonate (206mg, 0.632mmol).Reaction mixture was stirred 18 hours at 65 ℃.After being cooled to room temperature, reaction mixture distributes between ethyl acetate (2x30mL) and water (30mL) then with ethyl acetate (30mL) dilution.Organic layer is merged, with salt solution (200mL) washing, dry (sodium sulfate), vacuum concentration.Residuum obtains the N-borane complex through flash chromatography on silica gel method purifying, then it is handled described in method C.The mixture that forms among the 3N HCl is concentrated into dried, stirred among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (500MHz, and the δ ppm 1.94-2.02 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), and 2.28-2.38 (m, 2H), 2.62-2.71 (m, 2H), 3.59 (br s, 2H), 3.62-3.79 (m, 4H), 4.04 (s, 3H), 5.43 (t, J=3.2Hz, 1H), 7.51 (s, 1H), and 8.71-8.75 (m, 2H).MS(ESI)m/z＝345(M+H)
+。C
17H
20N
4O
2The analytical calculation value of S1.3HCl: C, 52.11; H, 5.48; N, 14.30; Measured value: C, 52.08; H, 5.52; N, 14.33.
Embodiment 138
(4s)-and 4-{[5-(2-tetramethyleneimine-1-yl pyrimidines-5-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
To embodiment 20A product (62mg, 0.188mmol) in the solution in DMF (2.0mL), add 2-(tetramethyleneimine-1-yl)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyrimidine (78mg, 0.283mmol), two (triphenylphosphine) palladium chloride (II) (6.6mg, 9.42 μ mol) and cesium carbonate (153mg 0.471mmol), stirs reaction mixture 4 hours at 65 ℃.After being cooled to room temperature, reaction mixture filters with methyl alcohol (4.0mL) dilution, through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required N-borane complex, concentrate the processing described in the row method C of going forward side by side under the vacuum.Operation by method H is converted into tosylate with the free alkali that generates:
1H NMR (400MHz, and the δ ppm 1.93-2.01 of methyl alcohol-D4) (m, 2H), 2.11-2.17 (m, 4H), 2.18-2.23 (m, 1H), 2.27-2.34 (m, 2H), 2.36 (s, 12H), 2.65 (br s, 2H), 3.56-3.60 (m, 2H), 3.62-3.75 (m, 8H), 5.43 (t, J=3.5Hz, 1H), 7.19-7.26 (m, 8H), 7.55 (s, 1H), 7.67-7.73 (m, 8H), 8.72 (s, 2H).MS(APCI)m/z＝384(M+H)
+。
Embodiment 139
(4s)-and 4-{[5-(6-piperazine-1-yl pyridines-3-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
To embodiment 20A product (75mg, 0.228mmol) in the solution in DMF (2.0mL), (5-(4,4 to add 1-, 5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-yl) piperazine (99mg, 0.342mmol), two (triphenylphosphine) palladium chloride (II) (8.0mg, 0.011mmol) and cesium carbonate (186mg 0.570mmol), stirs reaction mixture 18 hours at 65 ℃.After being cooled to room temperature, reaction mixture filters with methyl alcohol (2.0mL) dilution, through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of free alkali, concentrate under the vacuum, carry out the processing described in the method H then, obtain tosylate:
1H NMR (400MHz, and the δ ppm 1.92-2.00 of methyl alcohol-D4) (m, 2H), 2.14-2.23 (m, 1H), and 2.27-2.34 (m, 2H), 2.36 (s, 9H), 2.65 (br s, 2H), 3.39-3.45 (m, 4H), 3.58 (s, 2H), 3.61-3.76 (m, 4H), and 3.91-3.97 (m, 4H), 5.41 (t, J=3.2Hz, 1H), 7.18-7.24 (m, 6H), 7.26 (d, J=9.2Hz, 1H), 7.46 (s, 1H), and 7.66-7.73 (m, 6H), 8.04 (dd, J=9.2,2.5Hz, 1H), 8.18 (d, J=2.1Hz, 1H).MS(ESI)m/z＝398(M+H)
+。C
21H
27N
5The analytical calculation value of OS2.75TsOH: C, 55.50; H, 5.67; N, 8.04; Measured value: C, 55.31; H, 5.88; N, 7.93.
Embodiment 140
(4s)-and 4-{[5-(1H-pyrazol-1-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
Alkane
Product (100mg with embodiment 20B, 0.304mmol), 1H-pyrazoles (32.1mg, 0.471mmol), ferric acetyl acetonade (32.2mg, 0.091mmol), cupric oxide (II) (2.4mg, 0.030mmol) and cesium carbonate (198mg, 0.608mmol) be suspended in DMF (0.5mL), and stirred 60 hours at 90 ℃.After being cooled to room temperature, reaction mixture with methyl alcohol (3.0mL) dilution, is filtered, through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of free alkali, and concentrate under the vacuum, (0.5M 3mL) handles to use methyl alcohol (0.3mL) and HCl-diethyl ether then.In stirring at room after 10 minutes, with sedimentation and filtration, vacuum-drying obtains the hydrochloride of title compound:
1HNMR (500MHz, the δ ppm 1.90-2.01 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.27-2.38 (m, 2H), 2.66 (br s, 2H), 3.58 (br s, 2H), and 3.61-3.75 (m, 4H), 5.42 (t, J=3.3Hz, 1H), 6.50 (t, J=2.1Hz, 1H), 7.32 (s, 1H), 7.68 (d, J=1.5Hz, 1H), 8.05 (d, J=2.4Hz, 1H).MS(ESI)m/z＝303(M+H)
+。C
15H
18N
4The analytical calculation value of OS1.2HCl: C, 52.05; H, 5.59; N, 16.19; Measured value: C, 52.14; H, 5.79; N, 15.83.
Embodiment 141
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
Embodiment 141A
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane N-borane complex
(1.06g 3.23mmol) in the solution in DMF (32mL), adds 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (1.83g, 4.20mmol to product embodiments 20B; JP 2005232071), two (triphenylphosphine) palladium chloride (II) (113mg, 0.161mmol) and cesium carbonate (2.57g 7.87mmol), stirs reaction mixture 6 hours at 65 ℃.After being cooled to room temperature, allow reaction mixture between water (250mL) and ethyl acetate (3x 200mL), distribute.With the organic extraction salt water washing that merges, dry (sodium sulfate) under reduced pressure concentrates, and the material of generation through silica gel flash column chromatography purifying, is obtained title compound:
1HNMR (400MHz, and the δ ppm 1.62-1.72 of chloroform-D) (m, 2H), 1.96-2.03 (m, 1H), 2.16-2.24 (m, 2H), 2.39 (br s, 2H), 3.11-3.24 (m, 6H), 5.17 (t, J=2.9Hz, 1H), 7.00 (s, 1H), 7.11-7.22 (m, 6H), 7.29-7.36 (m, 9H), 7.43 (d, J=0.6Hz, 1H), 7.73 (d, J=0.6Hz, 1H).MS(APCI)m/z＝545(M-BH
3+H)
+。
Embodiment 141B
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
((3N 1.0mL) handles, and reaction mixture was stirring at room 10 minutes with HCl for 60mg, the 0.107mmol) suspension in acetone (3.0mL) with embodiment 141A product.(2.5M 2.0mL), allows reaction mixture distribute between water (50mL) and chloroform (3x30mL) to add sodium hydroxide.With the organic extraction drying (sodium sulfate) that merges, under reduced pressure concentrate, the material that generates through silica gel flash column chromatography purifying, is obtained title compound:
1H NMR (400MHz, and the δ ppm 1.79-1.88 of chloroform-D) (m, 2H), 2.21 (br s, 1H), and 2.32-2.39 (m, 2H), 2.65 (br s, 2H), and 3.43-3.59 (m, 6H), 5.25 (t, J=3.1Hz, 1H), 7.00 (s, 1H), 7.12-7.20 (m, 6H), 7.29-7.36 (m, 9H), 7.45 (s, 1H), 7.73 (s, 1H).MS(APCI)m/z＝545(M+H)
+。
Embodiment 142
(4s)-and 4-{[5-(1-propyl group-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
With embodiment 20A product (120mg, 0.365mmol) 2-propyl alcohol (2.5mL) solution and 1-propyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazoles (103mg, 0.438mmol), two (triphenylphosphine) palladium chloride (II) chloride (12.8mg, 0.018mmol) and aqueous sodium carbonate (1.0M 0.91mL) merges.With reaction mixture nitrogen degasification, stirred 1 hour at 100 ℃ then.After being cooled to room temperature, reaction mixture is filtered by the glass microfiber filter plate, concentrate, be dissolved in DMF (2mL), through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required free alkali and N-borane complex, concentrate under the vacuum.Carry out the process described in the method C then.The mixture that will form in 3N HCl is concentrated into dried, stirs among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the tri hydrochloride of title compound:
1H NMR (400MHz, and the δ ppm 0.93 of methyl alcohol-D4) (t, J=7.5Hz, 3H), 1.91 (hex, 7.4Hz, 2H), 1.96-2.02 (m, 2H), 2.22 (br s, 1H), 2.27-2.37 (m, 2H), 2.66 (br s, 2H), 3.59 (br s, 2H), and 3.63-3.75 (m, 4H), 4.19 (t, J=7.1Hz, 2H), 5.38 (t, J=3.2Hz, 1H), 7.31 (s, 1H), 7.89 (s, 1H), 8.08 (s, 1H).MS(ESI)m/z＝345(M+H)
+。C
18H
24N
4OS2.75HCl0.7H
2The analytical calculation value of O: C, 47.27; H, 6.20; N, 12.25; Cl, 21.32; Measured value: C, 46.98; H, 6.21; N, 12.60; Cl, 21.18.
Embodiment 143
(4s)-and 4-{[5-(1-isobutyl--1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
To embodiment 20A product (95mg, 0.289mmol) in the solution in DMF (2.5mL), add 1-isobutyl--4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-and the 1H-pyrazoles (87mg, 0.346mmol), two (triphenylphosphine) palladium chloride (II) (10.1mg, 0.014mmol) and cesium carbonate (235mg, 0.722mmol).With the reaction mixture nitrogen purge, stirred 18 hours at 65 ℃ then.After being cooled to room temperature, add methyl alcohol (2.0mL), reaction mixture filters by the glass microfiber filter plate, through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of N-borane complex, concentrate under the vacuum.Carry out the process described in the method C then.The mixture that will form in 3N HCl is concentrated into dried, stirs among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (400MHz, and the δ ppm 0.91 of methyl alcohol-D4) (d, J=6.8Hz, 6H), 1.90-2.01 (m, 2H), and 2.10-2.24 (m, 2H), 2.28-2.36 (m, 2H), 2.64 (br s, 2H), 3.58 (br s, 2H), 3.61-3.75 (m, 4H), 3.95 (d, J=7.4Hz, 2H), 5.34 (t, J=3.4Hz, 1H), 7.19 (s, 1H), 7.65 (d, J=0.9Hz, 1H), 7.85 (d, J=0.9Hz, 1H).MS(ESI)m/z＝359(M+H)
+。C
19H
26N
4OS1HC10.25H
2The analytical calculation value of O: C, 57.13; H, 6.94; N, 14.03; Cl, 8.88; Measured value: C, 57.08; H, 7.07; N, 14.13; Cl, 8.92.
Embodiment 144
(4s)-and 4-{[5-(1-ethanoyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
Embodiment 144A
(4s)-and 4-{[5-(pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] decane two
Hydrochloride
According to the product of method L Processing Example 141A (128mg, 0.229mmol).The mixture that will form in 3NHCl is concentrated into dried, stirs among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the dihydrochloride of title compound:
1H NMR (400MHz, the δ ppm 1.93-2.01 of methyl alcohol-D4) (m, 2H), 2.22 (s, 1H), 2.27-2.37 (m, 2H), 2.66 (s, 2H), 3.59 (s, 2H), 3.62-3.75 (m, 4H), 5.40 (t, J=3.1Hz, 1H), 7.37 (s, 1H), 8.22 (s, 2H).MS(APCI)m/z＝303(M+H)
+。C
15H
18N
4The analytical calculation value of OS2HCl: C, 48.00; H, 5.37; N, 14.93; Cl, 18.89; Measured value: C, 47.86; H, 5.64; N, 14.57; Cl, 18.58.
Embodiment 144B
(4s)-and 4-{[5-(1-ethanoyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
(80mg, 0.213mmol) (1.00g 9.80mmol) handles the suspension in acetate (1.0mL), and reaction mixture was stirring at room 1 hour with diacetyl oxide with embodiment 144A product.Reaction mixture is concentrated into dried, adds methyl alcohol (1.0mL).In stirring at room after 10 minutes, filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (500MHz, and the δ ppm 1.93-2.01 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), and 2.27-2.35 (m, 2H), 2.65 (br s, 2H), 2.67 (s, 3H), 3.58 (br s, 2H), and 3.62-3.75 (m, 4H), 5.39 (t, J=3.2Hz, 1H), 7.40 (s, 1H), 8.01 (s, 1H), 8.47 (s, 1H).MS(APCI)m/z＝345(M+H)
+。C
17H
20N
4O
2The analytical calculation value of S1.5HCl: C, 51.16; H, 5.43; N, 14.04; Measured value: C, 51.42; H, 5.19; N, 13.81.
Embodiment 145
(4s)-and 4-{[5-(5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-azepine three
Ring [3.3.1.1
3,7
] decane
To embodiment 20A product (139mg, 0.422mmol) 2-propyl alcohol (2.7mL) solution in, add 5-methyl isophthalic acid-phenyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-and the 1H-pyrazoles (100mg, 0.352mmol), two (triphenylphosphine) palladium chloride (II) (12.4mg, 0.018mmol) and aqueous sodium carbonate (1.0M, 0.88mL).With reaction mixture nitrogen degasification, and 100 ℃ of stirrings 1 hour.After being cooled to room temperature, reaction mixture is filtered by the glass microfiber filter plate, concentrate, be dissolved in MeOH (2.0mL), through the HPLC[of preparation
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required free alkali and N-borane complex, concentrate under the vacuum, carry out the processing described in method C then.The mixture that will form in 3N HCl is concentrated into dried, stirs among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (400MHz, the δ ppm 1.93-2.02 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.27-2.36 (m, 2H), 2.37-2.43 (m, 3H), 2.66 (br s, 2H), 3.58 (br s, 2H), 3.60-3.77 (m, 4H), 5.38 (br s, 1H), 7.15-7.21 (m, 1H), 7.45-7.53 (m, 3H), 7.53-7.60 (m, 2H), 7.71-7.78 (m, 1H).MS(ESI)m/z＝393(M+H)
+。
Embodiment 146
(4s)-and 4-[(5-isoxazole-4-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
To embodiment 20A product (100mg, 0.304mmol) 2-propyl alcohol (2.0mL) solution in, add 4-(4,4,5,5-tetramethyl--1,3, and 2-dioxane pentaborane-2-base) isoxazole (71.1mg, 0.365mmol), two (triphenylphosphine) palladium chloride (II) (10.7mg, 0.015mmol) and aqueous sodium carbonate (1.0M, 0.76mL).With reaction mixture nitrogen degasification, and 100 ℃ of stirrings 2 hours.After being cooled to room temperature, reaction mixture is filtered by the glass microfiber filter plate, concentrate, be dissolved in MeOH (2.0mL), and the HPLC[through preparing
XTerra RPl8 5 μ m posts, 30x100mm, flow velocity 40mL/ minute, the 5-95% gradient of acetonitrile in damping fluid (0.1M ammonium bicarbonate aqueous solution, regulating pH with ammonium hydroxide is 10) in 22 minutes, UV detects at 254nm] purifying.To contain the part set of required free alkali and N-borane complex, concentrate under the vacuum, carry out the processing described in method C then.To generate material and be absorbed among the 3N HCl, be concentrated into driedly, stir among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the tri hydrochloride of title compound:
1H NMR (400MHz, the δ ppm 1.90-2.02 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.25-2.39 (m, 2H), 2.64 (br s, 2H), 3.58 (br s, 2H), 3.60-3.75 (m, 4H), 5.36 (t, J=3.3Hz, 1H), 7.19 (s, 1H), 7.43 (s, 1H).MS(ESI)m/z＝304(M+H)
+。C
15H
17N
3O
2S2.95HCl0.45NH
4The analytical calculation value of Cl: C, 41.42; H, 5.04; N, 11.11; Measured value: C, 41.35; H, 4.99; N, 11.05.
Embodiment 147
(4s)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 147A
(4s)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine network
Compound
According to method B by the product of embodiment 10A (600mg, 3.59mmol) and 2,4-two bromo thiazoles (1047mg 4.31mmol) makes:
1H NMR (500MHz, the δ ppm 1.70-1.78 of methyl alcohol-D4) (m, 2H), 1.96 (br s, 1H), 2.11-2.19 (m, 2H), 2.36 (br s, 2H), 3.14 (br s, 2H), 3.15-3.24 (m, 4H), 5.21 (t, J=3.4Hz, 1H), 6.88 (s, 1H).MS(APCI)m/z＝329(M+H)
+。
Embodiment 147B
(4s)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method C by the product of embodiment 147A (455mg 1.38mmol) makes:
1H NMR (500MHz, the δ ppm 1.68 of methyl alcohol-D4) (br s, 1H), 1.83-1.93 (m, 2H), 2.19 (brs, 2H), 2.21-2.30 (m, 2H), 3.10-3.16 (m, 4H), 3.25-3.29 (m, 2H), 5.22 (t, J=3.2Hz, 1H), 6.86 (s, 1H).MS(ESI)m/z＝315/317(M+H)
+。C
12H
15BrN
2OS0.3H
2The analytical calculation value of O: C, 44.95; H, 4.90; N, 8.74; Measured value: C, 44.78; H, 4.62; N, 8.60.
Embodiment 148
(4r)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
According to method B by the product of embodiment 9D (117mg, 0.700mmol) and 2,4-two bromo thiazoles (191mg, 0.784mmol) the N-borane complex of preparation title compound.Then it is handled described in method C, obtain free alkali, the operation by method H subsequently is translated into fumarate:
1H NMR (500MHz, the δ ppm 2.05-2.12 of methyl alcohol-D4) (m, 2H), 2.18-2.28 (m, 3H), 2.60 (br s, 2H), 3.46 (m, 2H), 3.54 (br s, 2H), 3.70-3.80 (m, 2H), 5.28 (t, J=3.4Hz, 1H), 6.69 (s, 2H; C
4H
4O
4), 6.93 (s, 1H).MS(ESI)m/z＝315/317(M+H)
+。C
12H
15BrN
2OS1.15C
4H
4O
4The analytical calculation value: C, 44.43; H, 4.40; N, 6.24; Measured value: C, 44.62; H, 4.36; N, 6.12.
Embodiment 149
(4s)-and 4-[(4-chloro-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Embodiment 149A
(4s)-and 4-[(4-chloro-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane N-borine network
Compound
According to method B by the product of embodiment 10A (66mg, 0.395mmol) and 2,4-dichloro-thiazole (66.9mg 0.435mmol) makes:
1H NMR (500MHz, the δ ppm 1.64-1.86 of methyl alcohol-D4) (m, 2H), 1.96 (br s, 1H), 2.06-2.22 (m, 2H), 2.36 (br s, 2H), 3.10-3.25 (m, 6H), 5.20 (t, J=3.4Hz, 1H), 6.74 (s, 1H).MS(DCI/NH
3)m/z＝300(M+NH
2)
+。
Embodiment 149B
(4s)-and 4-[(4-chloro-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
(80mg 0.281mmol) prepares free alkali by product embodiments 149A according to method C.To generate material and be absorbed among the 3N HCl, be concentrated into driedly, stir among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (500MHz, the δ ppm 1.91-2.02 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.24-2.33 (m, 2H), 2.63 (br s, 2H), 3.57 (br s, 2H), 3.61-3.81 (m, 4H), 5.37 (t, J=3.2Hz, 1H), 6.80 (s, 1H).MS(ESI)m/z-271(M+H)
+。C
12H
15ClN
2The analytical calculation value of OS1.0HCl: C, 46.91; H, 5.25; N, 9.12; Cl, 23.08; Measured value: C, 46.64; H, 5.01; N, 8.92; Cl, 23.06.
Embodiment 150
(4s)-and 4-{[4-(1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems
Alkane
In sealed tube, add embodiment 147A product (50mg, 0.152mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1-trityl-1H-pyrazoles (86mg, 0.198mmol; JP 2005232071), two (triphenylphosphine) palladium chloride (II) (5.3mg, 7.60 μ mol), cesium carbonate (121mg, 0.371mmol) and DMF (1.5mL).Pipe was heated 6 hours at 65 ℃.After being cooled to room temperature, allow mixture between ethyl acetate (3x10mL) and water (100mL), distribute.The organic extraction that merges is washed with salt solution (100mL), and dry (sodium sulfate) under reduced pressure concentrates.Residuum obtains the N-borane complex of the trityl as protecting group of white solid through flash chromatography on silica gel method purifying.Described in solid such as method L, handle then, obtain free alkali.According to method H itself and tosic acid monohydrate are reacted then, obtain the xylenesulfonate of title compound:
1H NMR (400MHz, the δ ppm 1.91-2.01 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.27-2.34 (m, 2H), 2.36 (s, 6H; TsOH), 2.68 (br s, 2H), 3.58 (br s, 2H), 3.63-3.77 (m, 4H), 5.46 (t, J=3.4Hz, 1H), 7.13 (s, 1H), 7.22 (d, J=8.0Hz, 4H; TsOH), 7.70 (d, J=8.3Hz, 4H; TsOH), 8.35 (s, 2H).MS(ESI)m/z＝303(M+H)
+。C
15H
18N
4OS2.2TsOH0.7H
2The analytical calculation value of O: C, 52.63; H, 5.37; N, 8.07; Measured value: C, 52.46; H, 5.19; N, 8.21.
Embodiment 151
(4s)-and 4-[(4-phenyl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Product (71mg to embodiment 147A, 0.216mmol) in the solution of 2-propyl alcohol (3.0mL) and water (1.0mL), add phenyl-boron dihydroxide (34.2mg, 0.280mmol), two (triphenylphosphine) palladium chloride (II) (6.1mg, 8.6 μ mol) and aqueous sodium carbonate (2.5M, 0.54mL).With reaction mixture nitrogen degasification, under 90 ℃ of stirrings, heated 2 hours then.After being cooled to room temperature, reaction mixture with ethyl acetate (5.0mL) dilution, is filtered by the glass microfiber filter plate, concentrate,, obtain the N-borane complex through flash chromatography on silica gel method purifying.Carry out the processing described in method C then.To generate material and be absorbed among the 3N HCl, be concentrated into driedly, stir among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (500MHz, and the δ ppm 1.93-2.03 of methyl alcohol-D4) (m, 2H), 2.22 (br s, 1H), and 2.31-2.41 (m, 2H), 2.73 (br s, 2H), 3.59 (br s, 2H), 3.67-3.77 (m, 4H), 5.51 (t, J=3.2Hz, 1H), 7.20 (s, 1H), 7.27-7.32 (m, 1H), 7.33-7.47 (m, 2H), 7.77-7.90 (m, 2H).MS(ESI)m/z＝313(M+H)
+。
Embodiment 152
(4s)-and 4-[(4-pyridin-4-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
Product (65mg with embodiment 147A, 0.198mmol) be dissolved in 2-propyl alcohol (1.5mL), add pyridine-4-boric acid (31.6mg, 0.257mmol), two (triphenylphosphine) palladium chloride (II) (5.6mg, 7.90 μ mol) and aqueous sodium carbonate (1.0M, 0.49mL), with reaction mixture nitrogen degasification, under 90 ℃ of stirrings, heated 1.5 hours then.After being cooled to room temperature, reaction mixture with ethyl acetate (5.0mL) dilution, is filtered by the glass microfiber filter plate, concentrate,, obtain the N-borane complex through flash chromatography on silica gel method purifying.Carry out the processing described in method C then.To generate material and be absorbed among the 3N HCl, be concentrated into driedly, stir among diethyl ether/MeOH at 10: 1.Filtering precipitate, vacuum-drying obtains the hydrochloride of title compound:
1H NMR (500MHz, and the δ ppm 1.92-2.08 of methyl alcohol-D4) (m, 2H), 2.23 (br s, 1H), and 2.28-2.40 (m, 2H), 2.75 (br s, 2H), 3.61 (br s, 2H), 3.75 (br s, 4H), 5.62 (t, J=3.3Hz, 1H), 8.23 (s, 1H), 8.50 (d, J=6.4Hz, 2H), 8.80 (d, J=6.4Hz, 2H).MS(APCI)m/z＝314(M+H)
+。C
17H
19N
3OS2.15HC12.35H
2The analytical calculation value of O: C, 47.03; H, 6.00; N, 9.68; Cl, 17.56; Measured value: C, 47.20; H, 6.25; N, 9.62; Cl, 17.56.
Embodiment 153
(4s)-and 4-[(4-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7
] decane
At the product (70mg of microwave reaction pipe adding with embodiment 147A, 0.213mmol), pyridin-3-yl boric acid (26.1mg, 0.213mmol), two (triphenylphosphine) palladium chloride (II) (5.2mg, 7.45 μ mol) and yellow soda ash (56.4mg, 0.532mmol), add solvent 2-propyl alcohol (2.5mL) and water (0.83mL) subsequently.With the seal of tube, will be reflected at and be heated to 105 ℃ of maintenances 10 minutes in the microwave reactor.After being cooled to room temperature, reaction mixture filters by the glass microfiber filter plate with 2-propyl alcohol (5.0mL) dilution, concentrates, and through flash chromatography on silica gel method purifying, obtains the N-borane complex.Carry out the processing described in method C then, obtain title compound:
1H NMR (500MHz, and the δ ppm 1.71 of methyl alcohol-D4) (br s, 1H), 1.86-1.93 (m, 2H), 2.24-2.34 (m, 4H), and 3.14-3.22 (m, 4H), 3.31-3.35 (m, 2H), 5.37 (t, J=2.9Hz, 1H), 7.38 (s, 1H), 7.46 (ddd, J=8.1,4.9,0.8Hz, 1H), 8.25 (ddd, J=8.2,2.1,1.5Hz, 1H), 8.45 (dd, J=4.9,1.5Hz, 1H), 9.00 (dd, J=2.3,0.8Hz, 1H).MS(APCI)m/z＝314(M+H)
+。
Embodiment 154
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl-1,3-thiazoles-4-formyl
Amine
Embodiment 154A
2-bromo-N-(pyridin-4-yl) thiazole-4-carboxamide
(97mg 0.409mmol) is dissolved in the solvent mixture of ethanol (15mL) and water (7.5mL), and (2.50M 2.54mL) handles with aqueous sodium hydroxide solution with 2-bromethiazole-4-carboxylic acid, ethyl ester.Mixture was stirred 30 minutes at 35 ℃, then ethyl acetate (100mL) and HCl (1.0M, 100mL) between distribution.With organic phase drying (sodium sulfate) and concentrated, obtain the carboxylic acid white solid.In pyridine (5mL) solution of this material, add 4-aminopyridine (46.1mg, 0.490mmol), HOBt (78mg, 0.511mmol), DMAP (10.0mg, 0.082mmol) and EDAC (117mg, 0.613mmol).Reaction mixture stirring at room 18 hours, is filtered by the frit filter plate then.Vacuum concentrated filtrate, and HPLC[Waters Nova-Pak HR Cl8 6 μ m through preparing
Prep-Pak cylinder (40x100mm), 10%～100% gradient of acetonitrile in the 10mM ammonium acetate solution in 12 minutes, flow velocity 70mL/ minute] purifying, obtain title compound:
1H NMR (400MHz, the δ ppm 7.83-7.90 of methyl alcohol-D4) (m, 2H), 8.40 (s, 1H), 8.43-8.46 (m, 2H).MS(ESI)m/z＝284/286(M+H)
+。
Embodiment 154B
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl-1,3-thiazoles-4-formyl
Amine
According to method B by the product of embodiment 10A (32.3mg, 0.194mmol) and the product of embodiment 154A (50mg, 0.176mmol) the N-borane complex of preparation title compound.Then it is handled described in method C, obtain free alkali, the operation by method H subsequently is translated into fumarate:
1H NMR (500MHz, the δ ppm 1.92-2.04 of methyl alcohol-D4) (m, 2H), 2.21 (br s, 1H), 2.29-2.38 (m, 2H), 2.70 (br s, 2H), 3.59 (br s, 2H), 3.64-3.82 (m, 4H), 5.62 (t, J=3.1Hz, 1H), 6.71 (s, 2H; C
4H
4O
4), 7.85-7.87 (m, 2H), 7.88 (s, 1H), 8.46 (d, J=4.6Hz, 2H).MS(ESI)m/z＝357(M+H)
+。C
18H
20N
4O
2S1.55C
4H
4O
41.65H
2The analytical calculation value of O: C, 51.35; H, 5.25; N, 9.90; Measured value: C, 51.52; H, 5.47; N, 9.75.
Embodiment 155
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-(4-chloro-phenyl-)-1,3-oxazole-4-formyl
Amine
Embodiment 155A
2-chloro-N-(4-chloro-phenyl-) oxazole-4-methane amide
Described in embodiment 154A, by 2-chlorine for oxazole-4-carboxylic acid, ethyl ester (83.5mg, 0.475mmol) and the 4-chloroaniline (60.5mg 0.475mmol) makes:
1H NMR (500MHz, DMSO-D6) δ ppm 7.37-7.45 (m, 2H), 7.81-7.89 (m, 2H), 8.91 (s, 1H), 10.45 (s, 1H).MS(DCI/NH
3)m/z＝274(M+NH
4)
+。
Embodiment 155B
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-(4-chloro-phenyl-)-1,3-oxazole-4-formyl
Amine
Method described in the Application Example 122, by the product of embodiment 10A (38.9mg, 0.233mmol) and the product of embodiment 155A (57mg, 0.222mmol) the N-borane complex of preparation title compound.Described in method C, it at first is converted into free alkali then, is converted into fumarate according to method H then:
1H NMR (400MHz, the δ ppm 1.93-2.05 of methyl alcohol-D4) (m, 2H), 2.20 (br s, 1H), 2.26-2.36 (m, 2H), 2.70 (br s, 2H), 3.57 (br s, 2H), 3.59-3.77 (m, 4H), 5.36 (br s, 1H), 6.66-6.75 (m, 2H), 7.31-7.40 (s, 2H; C
4H
4O
4), 7.64-7.72 (m, 2H), 8.05-8.15 (s, 1H).MS(APCI)m/z＝374(M+H)
+。
Embodiment 156
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-phenyl-1,3-oxazole-4-methane amide
Embodiment 156A
2-chloro-N-Ben Ji oxazole-4-methane amide
Described in embodiment 154A, by 2-chlorine for oxazole-4-carboxylic acid, ethyl ester (45.4mg, 0.258mmol) and aniline (24mg 0.258mmol) makes:
1H NMR (500MHz, the δ ppm 7.13-7.18 of methyl alcohol-D4) (m, 1H), 7.32-7.38 (m, 2H), 7.65-7.71 (m, 2H), 8.53 (s, 1H).MS(APCI)m/z＝223(M+H)
+。
Embodiment 156B
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-N-phenyl-1,3-oxazole-4-methane amide
Method described in the Application Example 122, by the product of embodiment 10A (33mg, 0.198mmol) and the product of embodiment 156A (42mg, 0.189mmol) the N-borane complex of preparation title compound.Then it is handled described in method C, obtains title compound:
1H NMR (500MHz, and the δ ppm 1.70 of methyl alcohol-D4) (br s, 1H), 1.86-1.95 (m, 2H), and 2.23-2.32 (m, 4H), 3.13-3.19 (m, 4H), and 3.32-3.36 (m, 2H), 5.30 (t, J=2.9Hz, 1H), 7.12-7.17 (m, 1H), 7.32-7.38 (m, 2H), 7.65-7.69 (m, 2H), 8.04 (s, 1H).MS(ESI)m/z＝340(M+H)
+。C
19H
21N
3O
30.05H
2The analytical calculation value of O: C, 67.06; H, 6.25; N, 12.35; Measured value: C, 66.77; H, 6.04; N, 12.73.
Embodiment 157
(4s)-and 4-{[5-(3-bromo phenyl)-1,3,4-thiadiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7
]
Decane
According to product and 2-(3-bromo the phenyl)-5-chloro-1,3 of method B by embodiment 10B, 4-thiadiazoles (Zubets, I.V.; Boikov, Yu.A.; Viktorovskii, I.V.; V ' yunov, K.A.Khimiya Geterotsiklicheskikh Soedinenii, 1986,10,1416-1419) make:
1H-NMR (DMSO-d6) δ 8.02 (m, 1H), 7.86 (d, J=9Hz, 1H), 7.73 (d, J=9Hz, 1H), 7.49 (t, J=9Hz, 1H), 5.28 (m, 1H), 3.2-3.15 (m, 3H), 3.02-3.0 (m, 5H), 2.16-2.13 (m, 5H), 1.84-1.79 (2H), 1.56 (m, 1).MS(ESI)m/z＝394，392(M+H)
+(4％)；136(100％)。
Embodiment 158
(4s)-4-{5-[1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-1,3,4-thiadiazoles-2-yl } phenol
Embodiment 158A
2-(4-(benzyloxy) phenyl)-5-bromo-1,3,4-thiadiazoles benzyloxy
Use Vachal, P.; Toth, L.M.Tetrahedron Lett.2004,45, the method described in the 7157-7161 prepares title compound by 4-(benzyloxy) Benzoyl chloride.
Embodiment 158B
(4s)-4-(5-[4-(benzyloxy) phenyl] and-1,3,4-thiadiazoles-2-yl } the oxygen base)-the 1-aza-tricycle
[3.3.1.1
3,7
] decane N-borane complex
Method described in the application method A is with embodiment 158A and embodiment 10A coupling.
Embodiment 158C
(4s)-4-(5-[4-(benzyloxy) phenyl] and-1,3,4-thiadiazoles-2-yl } the oxygen base)-the 1-aza-tricycle
[3.3.1.1
3,7
] decane
According to method C embodiment 158B is converted into title compound.
Embodiment 158D
(4s)-4-{5-[1-aza-tricycle [3.3.1.1
3,7
] last of the ten Heavenly stems-4-base oxygen base]-1,3,4-thiadiazoles-2-yl } phenol
Palladium/carbon (～10%, by weight) exist down with embodiment 158C hydrogenation in ethanol (～15psi).By removing by filter solvent, concentrate in a vacuum, obtain title compound.
Embodiment 159
(4s)-N-pyridin-3-yl-1-aza-tricycle [3.3.1.1
3,7
] two (the 4-tosylates) half of decane-4-amine
Hydrate
To 1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-ketone (151mg, in acetate 1.00mmol) (5mL) solution, adding pyridine-3-amine (143mg, 1.52mmol).Add anhydrous sodium sulphate (1.82g, 12.8mmol), with mixture in stirring at room.After 10 minutes, add sodium triacetoxy borohydride (412mg, 1.94mmol), with mixture stirring at room 10 hours.Reaction mixture by diatomite filtration, is cleaned with chloroform (5mL).Vacuum concentrated filtrate by flash chromatography on silica gel method purifying (with chloroform-methanol-dense ammonium hydroxide, 90: 10: 1 wash-outs), obtains colourless colloid with residuum.With itself and 4-toluene sulfonic acide monohydrate (29mg) chemical combination in the boiling mixture of ethyl acetate (5mL) and EtOH (0.5mL), be cooled to room temperature.After 30 hours, collect product by filtering, with ethyl acetate (2mL) washing, vacuum-drying obtains title compound:
1H NMR (300MHz, and the δ 1.91-2.00 of methyl alcohol-D4) (m, 3H), 2.14-2.33 (m, 5H), 2.36 (s, 6H), 3.57 (s, 2H), 3.69 (s, 4H), 4.03 (s, 1H), 7.23 (d, J=7.9Hz, 4H), 7.70 (d, J=8.3Hz, 4H), 7.72-7.77 (m, 1H), and 7.81-7.87 (m, 1H), 8.01 (d, J=5.6Hz, 1H), and 8.18ppm (d, J=2.8Hz, 1H): MS (DCI/NH
3) m/z 230 (M+H)
+C
14H
19N
32C
7H
8O
3S0.5H
2The analytical calculation value of O: C, 57.71; H, 6.23; N, 7.21.Measured value: C, 57.78; H, 6.03; N, 7.19.
Embodiment 160
(4s)-N-(5-bromo-6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7
] the 4-first of decane-4-amine
Benzene sulfonate
To 1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-ketone (151mg, in acetate 1.00mmol) (5mL) solution, add sal epsom (1.80g, 15mmol) and 5-bromo-6-chloro-pyridine-3-amine (310mg, 1.49mmol).The suspension that forms was stirred 0 minute, add then sodium triacetoxy borohydride (412mg, 1.94mmol).Stirring at room 14 hours, vacuum concentration was to doing then with mixture.With white solid residuum furnishing mud in ethyl acetate (3mL), add to the silicagel column upper end, with chloroform-methanol-dense ammonium hydroxide, 90: 10: 1 wash-outs obtain pink solid.This material adds hot ethyl acetate (1mL) solution of 4-toluene sulfonic acide monohydrate (40mg, 1 equivalent) with ethyl acetate (3mL) heating.Add other ethyl acetate (3mL) and EtOH (3mL) during heating so that mixture is even.After being cooled to room temperature and finally cooling off-10 ℃, mixture is filtered, the solid of collecting ethyl acetate (3mL) washing, vacuum-drying obtains title compound:
1H NMR (300MHz, and the δ 1.91 of methyl alcohol-D4) (br d, J=13.1Hz, 2H), 2.11-2.21 (m, 1H), 2.22-2.32 (m, 4H), 2.36 (s, 3H), 3.54 (s, 2H), 3.59-3.72 (m, 4H), 3.91 (s, 1H), 7.23 (d, J=7.9Hz, 2H), 7.47 (d, J=2.8Hz, 1H), 7.70 (d, J=8.3Hz, 2H), and 7.85ppm (d, J=2.8Hz, 1H); MS DCI/NH
3M/z 342/344/346 (M+H)
+C
14H
17N
3ClBrC
7H
8O
3The analytical calculation value of S: C, 48.99; H, 4.89; N, 8.16.Measured value: C, 48.95; H, 4.66; N, 8.02.
Embodiment 161
(4s)-N-[6-(1H-indoles-6-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
According to method E by the product of embodiment 65A (150mg, 0.57mmol) and indoles-6-boric acid (190mg, 1.2mmol; Aldrich) free alkali of preparation title compound:
1H NMR (300MHz, and the δ ppm 1.70 of methyl alcohol-D4) (s, 1H), 1.82-1.92 (m, 2H), 1.97 (s, 2H), 2.28 (d, J=11.2Hz, 2H), 3.13-3.29 (m, 4H), 3.31-3.44 (m, 4H), 3.84 (s, 1H), 7.18 (dd, J=8.6,2.9Hz, 1H), 7.51 (d, J=8.5Hz, 1H), 7.54-7.68 (m, 1H), 7.97 (d, J=6.8Hz, 2H), 8.03 (d, J=9.2Hz, 2H), 8.13 (d, J=3.1Hz, 1H).MS(DCI/NH
3)m/z＝345(M+H)
+。
Embodiment 162
(4s)-N-[6-(1H-indol-3-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
Embodiment 162A
(4s)-N-[6-(1-benzene sulfonyl-1H-indol-3-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane
-4-amine
According to method E by the product of embodiment 65A (150mg, 0.569mmol) and 1-benzene sulfonyl-1H-indol-3-yl boric acid (350mg, 1.2mmol; Aldrich) make: MS (DCI/NH
3) m/z=485 (M+H)
+
Embodiment 162B
(4s)-N-[6-(1H-indol-3-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7
] decane-4-amine
With the product of embodiment 162A (50mg, 0.103mmol) and salt of wormwood (34mg, 0.25mmol) the solution reflux in methyl alcohol (3mL) is 90 minutes.After the cooling, remove and desolvate, residuum is water-soluble, and mixture extracts with ethyl acetate (3x).The extract salt water washing that merges, dry (Na
2SO
4), filter, concentrate the free alkali that obtains title compound:
1H NMR (300MHz, and the δ ppm 1.68 of methyl alcohol-D4) (s, 1H), 1.86 (d, J=14.9Hz, 2H), 1.96 (s, 2H), 2.29 (d, J=12.2Hz, 2H), 3.09-3.29 (m, 8H), 3.81 (s, 1H), 7.01-7.24 (m, 3H), 7.40 (d, J=7.1Hz, 1H), 7.50-7.61 (m, 2H), 7.98 (d, J=7.5Hz, 1H), 8.07 (d, J=2.4Hz, 1H).MS(DCI/NH
3)m/z＝345(M+H)
+。
Composition of the present invention
The present invention also provides the pharmaceutical composition that comprises with pharmaceutically acceptable carrier-bound treatment significant quantity formula (I) compound.Described composition comprises the The compounds of this invention of preparing with the pharmaceutically acceptable carrier of one or more non-toxicity.Pharmaceutical composition can make be made into solid or liquid form is for oral administration, for parenteral injection or for rectal administration.
Term " pharmaceutically acceptable carrier " refers to the preparation assistant agent of weighting agent, thinner, encapsulating material or any kind of non-toxicity, non-activity solid, semisolid or liquid when being used for this paper.Some examples that can serve as the material of pharmaceutically acceptable carrier are carbohydrates, as lactose, dextrose plus saccharose; Starch is as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and rhodia; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum; Cocoa butter and bolt wax; Oils is as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycols is as propylene glycol; The ester class is as ethyl oleate and Laurate ethyl; Agar; Buffer reagent is as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol and phosphate buffered saline buffer, and the compatible lubricant of other non-toxicity, as Sodium Lauryl Sulphate BP/USP and Magnesium Stearate, with the judgement according to the formulation art technician, tinting material, releasing agent, Drug coating, sweeting agent, correctives and perfume compound, sanitas and antioxidant also can appear in the described composition.
Can with in pharmaceutical composition per os of the present invention, rectum, parenteral, the brain pond, intravaginal, intraperitoneal, part (as by pulvis, ointment or drops), cheek (bucally) or per os or intranasal spray to people and other administration.Term " parenteral " is showed the prescription formula when being used for this paper, comprises that intravenously, intramuscular, intraperitoneal, breastbone are interior, subcutaneous, intraarticular injection and infusion.
The pharmaceutical composition of parenteral injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion, and the sterile powder that is used for being formulated as again aseptic parenteral solution or dispersion liquid.The suitable example of water-based and non-aqueous carrier, thinner, solvent or solvent comprises water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc. and their suitable mixture), vegetables oil (as sweet oil) and injectable organic ester such as ethyl oleate, or its suitable mixture.For example be coated with as Yelkin TTS, under the situation of dispersion liquid, use tensio-active agent, can keep the suitable flowability of composition by keeping desired particle size and passing through by using.
These compositions also can comprise adjuvant such as sanitas, wetting agent, emulsifying agent and dispersion agent.For example metagin, butylene-chlorohydrin, phenol, Sorbic Acid etc. can be guaranteed prophylactic effect to microorganism by multiple antibacterial agent and anti-mycotic agent.Also can expectedly comprise isotonic agent, for example carbohydrate, sodium-chlor etc.By can prolong the absorption of injectable drug form with the reagent of delayed absorption such as aluminum monostearate and gelatin.
In some cases, for the effect of prolong drug, the usually expectation absorption of medicine of subcutaneous or intramuscular injection of slowing down.This can be by realizing with the crystallization of low water solubility or the liquid suspension of amorphous material.The specific absorption of medicine can be depending on its solubility rate, and it can be depending on grain size and crystalline form again.Alternative ground, the medicament forms of parenteral admin can be by with medicine dissolution or be suspended in the oiliness solvent and use.
Except active compound, suspension can comprise suspension agent, for example ethoxylation isooctadecanol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar, tragakanta and composition thereof.
If desired, in order more effectively to distribute, The compounds of this invention can be incorporated in slowly-releasing or targeted delivery system such as polymeric matrix, liposome and the microballoon.They can be sterilized, for example, it is dissolved in sterilized water or some other aseptic injection media by fungi-proofing filter filtration or by in the aseptic solid composite form, adding disinfectant.
Can prepare injection storage storehouse (depot) form by the micro-capsule matrix that in biodegradable polymer such as polylactide-poly-glycollide class, forms medicine.According to the character of medicine and polymer ratio and used concrete polymkeric substance, may command rate of drug release.The example of other biodegradable polymer comprises poly-(ortho ester) and poly-(acid anhydride).Also can be by pharmaceutical pack being embedded in preparation storage storehouse injection formulations in liposome compatible or the microemulsion with body tissue.
Injection formulations can be sterilized, for example, it is dissolved in sterilized water or some other aseptic injection media by fungi-proofing filter filtration or by in the aseptic solid composite form, adding disinfectant.
Injection formulations for example aseptic injection water-based or oil-based suspension can be according to known technology with suitable dispersion agent or wetting agent and suspension agent preparation.Aseptic injection preparation also can be aseptic injectable solution, suspension or the emulsion in non-toxicity, parenteral acceptable diluent or solvent, as the solution in 1,3 butylene glycol.In acceptable solvent and solvent, can make water, ringer's solution, American Pharmacopeia (U.S.P.) and isotonic sodium chlorrde solution.In addition, aseptic expressed oil is commonly used for solvent or suspension medium.Any nonirritant expressed oil that comprises synthetic glycerine monoesters or triglyceride all can be used for this purpose.In addition, lipid acid such as oleic acid can be used for preparing injection.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule.In this type of solid dosage, the pharmaceutically acceptable carrier of one or more The compounds of this invention and at least a non-activity such as Trisodium Citrate or Lin Suanergai and/or following ingredients are mixed: a) weighting agent or swelling agent, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and Whitfield's ointment; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent is as paraffin; F) absorption enhancer is as quaternary ammonium compound; G) wetting agent is as hexadecanol and glyceryl monostearate; H) absorption agent is as kaolin and wilkinite; And i) lubricant, as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP, and composition thereof.Under the situation of capsule, tablet and nine doses, formulation also can comprise buffer reagent.
Also available lactose (lactose) or toffee (milk sugar) and high molecular weight polyethylene glycol are used in the solids composition of similar type in soft-filled gelatin capsule agent and the hard-filled gelatin capsule agent as weighting material.
The solid dosage of tablet, lozenge, capsule, pill and granule can prepare with dressing and shell such as enteric coating and well-known other dressing of pharmacy formulation art.They can be chosen wantonly and comprise opalizer, also can be a release of active ingredients or the preferred composition that discharges in the enteron aisle part in the mode that postpones.The examples of materials that is used for promoting agent delay release can comprise polymeric material and wax.
The composition of rectum or vagina administration is preferably suppository, described suppository can be by being mixed with The compounds of this invention and suitable non-irritating carrier such as cocoa butter, polyoxyethylene glycol or bolt wax, suppository is solid at ambient temperature, but under body temperature liquid, so in rectum or vaginal canal, melt release of active compounds.
The liquid dosage form of oral administration comprises pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active compound, liquid dosage form can comprise this area inert diluent commonly used, for example water or other solvent, the fatty acid ester of solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and anhydro sorbitol, and composition thereof.
Except inert diluent, oral compositions also can comprise adjuvant such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and perfume compound.
The formulation of The compounds of this invention part or percutaneous dosing comprises ointment, paste, creme, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Under aseptic condition that required The compounds of this invention and pharmaceutically acceptable carrier and possibility is essential any required sanitas or buffer reagent mix.Eye preparation, ear drop, eye ointment, pulvis and solution are also included within the scope of the invention.
Except active compound of the present invention, ointment, paste, creme and gelifying agent can comprise animal and plant fat, grease, wax, paraffin, starch, tragakanta, derivatived cellulose, polyoxyethylene glycol, silicone, wilkinite, silicic acid, talcum and zinc oxide, or its mixture.
Except The compounds of this invention, pulvis and sprays can comprise lactose, talcum, silicic acid, aluminium hydroxide, Calucium Silicate powder and Silon, or the mixture of these materials.Sprays can comprise propellent commonly used such as Chlorofluorocarbons (CFCs) in addition.
The compounds of this invention can also the liposome form administration.As known in the art, liposome is usually derived from phosphatide or other lipid material.List in the aqueous medium-or multilayer is liquid, aqueous crystal formation by being dispersed in for liposome.Can use on any non-toxicity that can form liposome, the physiology and can accept and metabolizable lipid.Except The compounds of this invention, adopt the present composition of liposome form can comprise stablizer, sanitas etc.Preferred lipid is natural and synthetic phosphatide and the phosphatidylcholine (Yelkin TTS) that uses separately or together.
The method that forms liposome is known in the art.For example consult Prescott and compile, Methods inCell Biology, XIV volume, Academic Press, New York, N.Y., (1976), the 33rd page and following or the like.
The formulation of The compounds of this invention topical comprises pulvis, sprays, ointment and inhalation.Under aseptic condition, active compound is mixed with pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellent.Eye preparation, eye ointment, pulvis and solution are also included within the scope of the invention.Aqueous liquid composition of the present invention also is useful especially.
The compounds of this invention can use the form of its pharmacy acceptable salt.Term " pharmacy acceptable salt " is meant those salt, and described salt is applicable to contact people and zootic tissue and does not have undue toxicity, pungency, atopic reaction etc. in the rational medicine determination range, and matches with rational benefit/risk-benefit risks.Pharmacy acceptable salt is well-known in the art.Thereby described salt can be in the final separation of The compounds of this invention and purge process made acid-stable in situ or by making free alkali functional group and appropriate organic reaction preparation separately in position.
Representative acid salt can make by using multiple acid, and described acid includes but not limited to acetate, hexanodioic acid, Lalgine, citric acid, aspartic acid, phenylformic acid, Phenylsulfonic acid, butyric acid, dextrocamphoric acid, camphorsulfonic acid, carbonic acid, glucosulfone acid, Phosphoric acid glycerol esters, enanthic acid, caproic acid, fumaric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, 2-isethionate (hydroxyethylsulfonic acid), lactic acid, toxilic acid, methylsulfonic acid, nicotinic acid, the 2-naphthene sulfonic acid, oxalic acid, pounce on acid, pectic acid, persulfuric acid, the 3-phenylpropionic acid, picric acid, trimethylacetic acid, propionic acid, Succinic Acid, sulfuric acid, tartrate, thiocyanic acid, phosphoric acid, L-glutamic acid, tosic acid, and undeeanoic acid.
The example that is particularly useful for forming the acid of pharmaceutically-acceptable acid addition comprises this type of mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and this type of organic acid such as oxalic acid, toxilic acid, Succinic Acid, tartrate and citric acid.
Base addition salt can by will contain carboxylic moiety and suitable alkali (as oxyhydroxide, carbonate or the supercarbonate of pharmaceutically acceptable metallic cation) or with ammonia or organic primary, second month in a season or reactive tertiary amine, in the final separation and the purge process made acid-stable in situ of The compounds of this invention.Pharmacy acceptable salt includes but not limited to based on salt of the positively charged ion of basic metal or alkaline-earth metal such as lithium, sodium, potassium, calcium, magnesium and aluminium etc., with non-toxicity quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethylammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine etc.Other the representative organic amine that is used to form base addition salt comprises quadrol, thanomin, diethanolamine, piperidines and piperazine.
And, can alkaline nitrogen-containing group is quaternized with reagent, the muriate of described reagent such as elementary alkyl halide such as methyl, ethyl, propyl group and butyl, bromide and iodide; The sulfuric ester of dialkylsulfates such as dimethyl, diethyl, dibutyl and diamyl; Long-chain halogenide is as muriate, bromide and the iodide of decyl, lauryl, myristyl and stearyl-; Arylalkyl halogenide is as bromide of benzyl and styroyl etc.Thereby obtain solubilized and maybe can be dispersed in product in water or the oil.
Term " pharmaceutically acceptable prodrug " or " prodrug " are when being used for this paper, represent those prodrugs of The compounds of this invention, described prodrug is in the scope that rational medicine is judged, be applicable to contact people and zootic tissue and do not have undue toxicity, pungency, atopic reaction etc., and match with rational benefit/risk-benefit risks, and be effective in its desired use.Prodrug of the present invention can be converted into parent formula (I) compound, for example hydrolysis in blood in vivo rapidly.Comprehensively discuss and be provided in T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S.Symposium Series, with Edward B.Roche, compile, Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press (1987).
The present invention also considers to comprise pharmaceutically acceptable compound, described compound give when having the patient who needs to use can be by body in bio-transformation change an accepted way of doing sth (I) compound
The mensuration of biologic activity
In order to measure the effect of representative compounds of the present invention as α 7 nAChR parts, according to [
3H]-methyllycaconitine (MLA) in conjunction with measure or [
3H]-DPPB in conjunction with measuring, estimated The compounds of this invention.In order to measure the effect of representative compounds of the present invention as α 4 β 2 nAChR parts, according to following description carry out [
3H]-Cytisine is in conjunction with mensuration, estimated The compounds of this invention.
[
3
H]-the Cytisine combination
According to Pabreza LA, Dhawan, S, Kellar KJ, [
3H]-Cytisine Binding toNicotinic Cholinergic Receptors in Brain, Mol.Pharm 39:9-12, the modification condition of operation described in 1991, mensuration combines with α 4 β 2 nAChR hypotypes.Be rich in the rat brain part of decerebellation film (ABS Inc., Wilmington DE) slowly thaw at 4 ℃, washing, resuspending is in 30 times of volume BSS-Tris damping fluids (120mM NaCl/5mM KCl/2mM CaCl
2/ 2mMMgCl
2/ 50mM Tris-Cl, 7.4,4 ℃ of pH) in.To comprise 100-200 μ g protein and 0.75nM[
3H]-Cytisine (30C
i/ mmol; Perkin Elmer/NEN Life Science Products, Boston, sample MA) was hatched 75 minutes at 4 ℃ with final volume 500 μ L.Every kind of compound is carried out the double test with seven kinds of log10 dilution concentration.In the presence of 10 μ M (-)-nicotine, measure non-specific binding.With 96 hole filtration unit (Packard Instruments, Meriden, CT) glass fibre filter filter plate (Millipore, the Bedford that is prewetting, MA) go up vacuum filtration, use the ice-cold BSS damping fluid of 2mL (120mM NaCl/5mM KCl/2mM CaCl then rapidly
2/ 2mM MgCl
2) rinsing, the separation and combination radioactivity.With Packard MicroScint-
Flicker mixture (40 μ L) adds in each hole, uses Packard
The Instrument measuring radioactivity.Pass through Microsoft
The non-linear regression of software is determined IC
50Value.Use Cheng-Prusoff formula week by IC
50Calculating K
iValue, wherein K
i=IC
50/ (the 1+[part]/K
D).
[
3
H]-methyllycaconitine (MLA) combination
According to [
3H]-Cytisine is in conjunction with measuring the conditions of similarity of using, and mensuration combines with α 7 nAChR hypotypes.Be rich in the rat brain part of decerebellation film (ABS Inc., Wilmington DE) slowly thaw at 4 ℃, washing, resuspending is in 30 times of volume BSS-Tris damping fluids (120mM NaCl, 5mMKCl, 2mM CaCl
2, 2mM MgCl
2And 50mM Tris-Cl, 7.4,22 ℃ of pH) in.To comprise 100-200 μ g protein, 5nM[
3H]-MLA (25C
i/ mmol; Perkin Elmer/NEN LifeScience Products, Boston, MA) and 0.1% bovine serum albumin (BSA, Millipore, Bedford, sample MA) was hatched 60 minutes at 22 ℃ with final volume 500 μ L.Every kind of compound is carried out the double test with seven kinds of log10 dilution concentration.In the presence of 10 μ M MLA, measure non-specific binding.(CT) (Millipore, Bedford MA) go up vacuum filtration, use the ice-cold BSS rinsing of 2mL then rapidly, the separation and combination radioactivity at the glass fibre filter filter plate of prewetting with 2%BSA for Packard Instruments, Meriden with 96 hole filtration units.With Packard MicroScint-
Flicker mixture (40 μ L) adds in each hole, uses Packard
The Instrument measuring radioactivity.Pass through Microsoft
The non-linear regression of software is determined IC
50Value.Use Cheng-Prusoff formula week by IC
50Calculating K
iValue, wherein K
i=IC
50/ (the 1+[part]/K
D).
[
3
H]-the DPPB combination
Application be rich in rat brain part or people's cortex part of decerebellation film (ABS Inc., Wilmington DE), measure [
3H]-DPPB, [
3H]-(S, S)-2,2-dimethyl-5-(6-phenyl-pyridazine-3-yl)-5-azepine-2-nitrogen-dicyclo (azonia-bicyclo) [2.2.1] heptane iodide combine with α 7 nAChR hypotypes.Pellet is slowly thawed at 4 ℃, and washing is overlapped 7 resuspending in 30 times of volume BSS-Tris damping fluids (120mM NaCl, 5mM KCl, 2mMCaCl with Polytron with one
2, 2mM MgCl
2And 50mM Tris-Cl, 7.4,4 ℃ of pH) in.Comprise 100-200 μ g protein and 0.5nM [
3H]-DPPB (62.8C
i/ mmol; The test compounds of seven kinds of log10 dilution concentration of double R46V, Abbott Labs) was hatched 75 minutes at 4 ℃ with final volume 500 μ L.In the presence of 10 μ M methyllycaconitines (methyllycaconitine), measure non-specific binding.Use the Packard cell harvestor, using 0.3%PEI preimpregnation Millipore
Collecting board FB goes up and collects binding radioactivity, with the washing of 2.5mL ice-cold buffer, uses Packard TopCountMicroplate β counter and measures radioactivity.By
The non-linear regression of Excel or Assay Explorer is determined IC
50Value.Use Cheng-Prusoff formula week by IC
50Calculating K
iValue, wherein K
i=IC
50/ (the 1+[part]/K
D).According to the preparation manipulation of the following stated obtain [
3H]-DPPB.
[methyl-
3
H] 2,2-dimethyl-5-(6-phenyl-pyridazine-3-yl)-5-azepine-2-nitrogen dicyclo [2.2.1] heptane;
The preparation of iodide
According to the following stated operation preparation be used for above [
3H]-DPPB in conjunction with measure [methyl-
3H] 2,2-dimethyl-5-(6-phenyl-pyridazine-3-yl)-5-azepine-2-nitrogen-dicyclo [2.2.1] heptane; Iodide.
Step 1:(S, S)-5-(6-phenyl-pyridazine-3-yl)-2,5-diaza-dicyclo [2.2.1] heptane-2-carboxylic acid uncle
The preparation of butyl ester
To (S, S)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (3.43g, 17.3mmol, Aldrich Chemical Company) and in the suspension of 3-chloro-6-phenyl pyridazine (3.30g, 17.3mmol, Aldrich Chemical Company) in toluene (50mL), add triethylamine (20mL), under 100 ℃ and nitrogen with mixture heating up 7 days.Black mixture is cooled to room temperature, and the precipitation that will form is by filtering separation, with toluene (15mL) washing, vacuum-drying obtains pale solid title compound (3.00g).Concentrated filtrate by the silica gel column chromatography purifying, is used eluent ethyl acetate with residuum, obtains other product (0.41g, ultimate production 3.41g, 56%): MS (DCI/NH
3) m/z 353 (M+H)
+
Step 2:(S, S)-2-methyl 5-(6-phenyl-pyridazine-3-yl)-2,5-diaza-dicyclo [2.2.1] heptane
Preparation
(3.41g 9.7mmol) is dissolved in formic acid (20mL), and (37% by weight, and 1.0g 12.3mmol) handles with formalin with the product of step 1 gained.100 ℃ of heating 1 hour, allow brown solution be cooled to room temperature, vacuum concentration in mixture.Residuum is used CH by the silica gel column chromatography purifying
2Cl
2-CH
3OH-NH
4OH (95: 5: 1) wash-out obtains pale solid title compound (2.50g, 96%): MS (DCI/NH
3) m/z 267 (M+H)
+
Step 3:[
3
H]-(S, S)-2,2-dimethyl-5-(6-phenyl-pyridazine-3-yl)-5-azepine-2-nitrogen-dicyclo
The preparation of [2.2.1] heptane iodide ([
3
H]-DPPB)
With in the toluene [
3H] methyl iodide (250mC
i, 0.1mL, 85Ci/mmol, AmericanRadiolabeled Chemicals, Inc.) (0.788mg, 2.96 μ mole 0.45mL) merge with the dichloromethane solution of step 2 products obtained therefrom.On bottle cap, allow mixture spend the night at room temperature reaction.Add methyl alcohol, evaporating solvent obtains 42mC
iAbsorb product with methyl alcohol, to carry out the HPLC purifying.
Step 4: high performance liquid chromatography purifying (HPLC)
Will about 7mC
i[
3H]-DPPB is evaporated to driedly, residuum is dissolved in the acetonitrile of about 4.5ml altogether: among water: the TFA (15: 85: 0.1).Use Agilent HPLC system, on about 0.9mL to the Phenomenex Luna of per injection C18 (2) post (5 microns, 250mmx4.6mm ID).By in 20 minutes from the moving phase wash-out of 10%B to 20%B gradient [
3H]-DPPB, wherein mobile phase A=0.1% trifluoroacetic acid aqueous solution, and Mobile phase B=0.1% trifluoroacetic acid acetonitrile solution, the about 1mL/min of flow velocity.Be fixed on 275nm with Agilent wavelengthtunable UV detector and obtain peak value detection and color atlas.Collect at about 14 minutes with the Agilent fraction collector and to comprise [
3H]-the DPPB part.Merge flow point, evaporating solvent in a vacuum.Residuum is dissolved in 200 degree (proof) ethanol (2mL), obtains 7mC
i
Step 5: the mensuration of purity and intrinsic specific activity
With Agilent 1100 serial HPLC systems measurements [
3H]-DPPB, this system comprises quaternary pump, automatic sampler and photodiode arrangement UV detector.Packard Radiomatic A 500 radioactive detectors are connected to the HPLC system.During radioassay, with the Ultima-Flo M flicker mixture of 500 μ L wandering cellss and 3: 1 ratios: HPLC moving phase.Analyze with Phenomenex Luna Cl8 (2) post (5 microns, 250mmx4.6mm ID).Eluent gradient is: begin with 10%B, internal oblique line rose to 20%B in 20 minutes, and then 1 minute internal oblique line rises to 90%B, and kept 9 minutes at 90%B, wherein mobile phase A=0.1% trifluoroacetic acid aqueous solution, and Mobile phase B=0.1% trifluoroacetic acid acetonitrile solution.Flow velocity is set at about 1mL/min, and UV detects and is set in 275nm.
When with [
3H]-during the MLA determination experiment, the preferred compound of the present invention has about 0.1 nmole to about 10 micromolar K
iValue, many preferred compounds have less than 1 micromolar K
iValue.Other preferred compound confirmation The compounds of this invention [
3H]-the Cytisine associated value is in about 0.1 nmole～be no less than 10 micromolar scopes.Some preferred compound exhibits and α 4 beta 2 receptors compare the bigger usefulness of α 7 acceptors.Usually, in view of [
3H]-Cytisine is in conjunction with the K that measures
iValue considers that MLA measures the K that measures
iValue is so that at formula D '=K
i 3 The H-Cytisine/ K
I MLAIn, D ' is defined as above-mentioned preferred compound greater than about 50.Alternative ground, [
3H]-K that DPPB measure to measure
iValue can be used for replacing K
I MLA, so that at formula D '=K
i 3 The H-Cytisine/ K
I[3H]-DPPBIn, D ' is greater than about 50.
Compound of the present invention is α 7 nAChR parts and/or α 4 β 2 parts, regulates the function of α 7 nAChR and/or α 4 β 2 parts by the activity that changes acceptor or signaling.These compounds can be the inverse agonist of inhibition acceptor primary activity, or block the antagonist of agonist activated receptor effect fully.These compounds also can block or partly activate the partial agonist of α 7 nAChR acceptors for part, or the agonist of activated receptor.Also trigger the key signal process that relates to multiple kinases and Phosphoric acid esterase and protein-protein interaction in conjunction with the alpha 7 nicotinic acceptor, this is important to the influence that memory, cytoprotection, genetic transcription and disease change.
Inventive method
Compound of the present invention and composition are useful on nAChR, the more especially effect of α 7 nAChR regulated.Especially, compound of the present invention and the composition illness that can be used for treating or prevent to regulate by α 7nAChR.Usually, this type of illness can be regulated mammiferous α 7nAChR by selectivity and be improved, preferably by for example giving compound of the present invention or composition as the part of treatment plan separately or with another kind of promoting agent combination.In addition, some compounds of the present invention are except to also having affinity to α 4 β 2 nAChR α 7 nAChR, and the alternative cpd that two kinds of receptor subtypes are had an amphipathic properties is also expected useful effect.
Include but not limited to specified The compounds of this invention among the embodiment, have the nAChR affinity, more especially α 7 nAChR affinities.As α 7 nAChR parts, The compounds of this invention can be useful on treatment and prevent many disease or illnesss by α 7 nAChR mediation.
For example, α 7 nAChR have shown remarkable effect (Levin, E.D., J.Neurobiol.53:633-640,2002) on enhancing comprises cognitive function aspect study, memory and the attention.Like this, α 7 parts are applicable to the treatment cognitive disorder, comprise for example attention deficit disorder, attention deficit move obstacle (ADHD), alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, Pick's disease, Louis body dependency dementia and mongolism dependency dementia and the cognitive defect relevant with schizophrenia more.
In addition, the nAChR that comprises α 7 has been presented at and has related to nicotine external (Jonnala, R.B. and Buccafusco; J.J., J.Neurosci.Res.66:565-572,2001) and the interior (Shimohama of body; S. etc., Brain Res.779:359-363,1998) neuroprotective.More specifically, neurodegeneration is the basis of several carrying out property CNS illnesss (including but not limited to the CNS hypofunction that alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington Chorea, Louis body dependency dementia and traumatic brain injury cause).For example, the amyloid-beta peptide relevant with alzheimer's disease causes that the functional defect of α 7 nAChR has been regarded as key factor (Liu, the Q.-S. of the cognitive defect morbidity relevant with disease, Kawai, H., Berg, D.K., PNAS 98:4734-4739,2001).The activation that has shown α 7nAChR can be blocked this neurotoxicity (Kihara, T. etc., J.Biol.Chem.276:13541-13546,2001).Like this, improve the defective that α 7 active selective ligands can be resisted alzheimer's disease and other neurodegenerative disease.
Schizophrenia is a kind of disease of complexity, it is characterized in that perception, cognition and emotion are unusual.There are important evidence prompting α 7 nAChR to relate to this disease, are included in the shortage (Leonard, S.Eur.J.Pharmacol.393:237-242,2000) that measures these acceptors among the necrotomy patient.The shortage of sensation course (gate) is one of schizoid sign.These shortages can be by the stdn of nicotine part (Adler L.E. etc., Schizophrenia Bull.24:189-202,1998 that act on α 7nAChR; Stevens, K.E. etc., Psychopharmacology 136:320-327,1998).Therefore, α 7 parts confirm potential in treatment schizophrenia.
The blood vessel generation, a kind of process that relates to the neovascularity growth is important to useful system function, the circulation around described system function such as wound healing, skin graft vascularization and promotion circulation as the increase vascular occlusion.Non-selective nicotine sample nAChR agonist shown can stimulate blood vessel take place (Heeschen, C. etc., Nature Medicine 7:833-839,2001).Shown that the blood vessel of improvement relates to the activation of α 7 nAChR (Heeschen, C. etc., J.Clin.Invest.110:527-536,2002).Therefore, α 7 subtype-selective nAChR parts provide stimulates the improvement potential that blood vessel takes place and side effect improves.
A group α 7 nAChR in the spinal cord regulate the serotonergic transmission (Cordero-Erausquin, M. and Changeux, J.-P.PNAS98:2803-2807,2001) relevant with the effect of nicotine compound alleviating pain.α 7 nAChR parts confirm to have the treatment pain status to comprise acute pain, post-operative pain and the chronic pain state treatment potential of (comprising inflammatory pain and neuropathic pain).And α 7 nAChR are expressed in the surface that relates to the main scavenger cell of inflammatory reaction, and activation α 7 is known from experience the release (Wang, H. etc., Nature421:384-388,2003) of the cytokine that suppresses TNF and other triggering inflammatory reaction.Therefore, selectivity α 7 parts confirm to have the potential of treatment disease, described disease relates to the disease of TNF-mediation, for example rheumatoid arthritis, Crohn disease, ulcerative colitis, inflammatory bowel, organ-graft refection, the acute immunological disease relevant with organ transplantation, chronic immunity disease, septic shock, toxic shock syndrome, serious poisonous disease syndrome, depression and the poker back relevant with organ transplantation.
The mammalian sperm acrosomal reaction is important exocytosis in the fertilization process of sperm to ovum.The activation that has shown α 7 nAChR on the spermoblast is the basis (S.Biol.Reproduct.68:1348-1353 2003 for Son, J.H. and Meizel) of acrosomal reaction.Therefore, 7 doses of confirmations of selectivity α have the effect of treatment Infertility.
The compounds of this invention is particularly useful in treatment and prevention influence memory, cognition, neurodegeneration, neurodevelopment and schizoid disease or illness.
Schizophrenia dependency cognitive impairment limits the ability of patient's normal function usually, and conventional available treatment (as using atypical antipsychotic agents) can not fully be treated symptom.(Rowley, M. etc., J.Med.Chem.44:477-501,2001).This type of cognitive defect and nicotine cholinergic system dysfunction, particularly α 7 receptor actives declines relevant (Friedman, J.I. etc., Biol Psychiatry, 51:349-357,2002).Therefore, α 7 receptor activators can provide effective treatment, to be used to improve the cognitive function with the schizophreniac of atypical antipsychotic agents treatment.Therefore, the combination of α 7nAChR part and atypical antipsychotic agents can provide the therapeutic efficiency of improvement.The specific examples of suitable atypical antipsychotic agents includes but not limited to leoponex, risperidone, olanzapine, Quetiapine, Ziprasidone, zotepine and Zomaril etc.
The actual dose level of activeconstituents in pharmaceutical composition of the present invention is transformable, so that obtain the amount of active compound for the effective realization expection of concrete patient, composition and administering mode therapeutic response.The dosage level of selecting will depend on particular compound activity, route of administration, to treat the severity of disease and will treat disease of patient and medical history previously.Yet, in the art technology scope, begin to be lower than the compound dosage of realizing expection therapeutic action desired level, increase dosage then gradually, until the effect that realizes expection.
When being used for above or other when treatment, a kind of The compounds of this invention of treatment significant quantity can be used with the form (when this type of form exists) of pure form or pharmacy acceptable salt, ester, acid amides or prodrug.Alternative ground can be with compound with the pharmaceutical composition administration, and described pharmaceutical composition comprises the compound of interest with one or more pharmaceutically acceptable carrier combinations.The The compounds of this invention of phrase " treatment significant quantity " refers to the compound of sanatory q.s, is applicable to therapeutic treatment with rational benefit/risk-benefit risks.Yet the total usage that should understand The compounds of this invention and composition every day will be determined in the scope that rational medicine is judged by the doctor in charge.For any concrete patient, concrete treatment effective dose level will depend on multiple factor, comprise the illness that will treat and the severity of illness; The activity of used particular compound; Used concrete composition; Patient's age, body weight, general situation, sex and diet; The administration time of used particular compound, route of administration and excretion rate; The course of treatment; With combination of used particular compound or the medicine that uses simultaneously; And the well-known similar factor of medical field.For example, in the scope that art technology is known, begin, increase dosage then gradually, until the effect that realizes expection to be lower than the compound dosage of realizing expection therapeutic action desired level.
Total dose every day of administration of human or zootic The compounds of this invention is that about 0.010mg/kg body weight is to about 1g/kg body weight.More preferred dose can be about 0.010mg/kg body weight to about 100mg/kg body weight.If desired, effective per daily dose can be divided into multidose and be used for administration.Therefore, unit-dose composition can comprise such amount or its approximate number to form per daily dose.
The compounds of this invention is α 7 nAChR parts, and it regulates the function of α 7 nAChR by the activity that changes acceptor or signaling.These compounds can be the inverse agonist of inhibition acceptor primary activity, or block the antagonist of agonist activated receptor effect fully.These compounds also can block or partly activate the partial agonist of α 7 nAChR acceptors for part, or the agonist of activated receptor.Also trigger the key signal process that relates to multiple kinases and Phosphoric acid esterase and protein-protein interaction in conjunction with α 7 acceptors, this is important to the influence that memory, cytoprotection, genetic transcription and disease change.Therefore, to formula (I) compound of administration treatment significant quantity, provide selectivity to regulate the method for α 4 β 2, α 7 or α 4 β 2 and the effect of alpha 7 nicotinic acetylcholine receptor.
Further, formula (I) compound to administration treatment significant quantity, the method of treatment or preventing disease or illness is provided, and described disease or illness are selected from attention deficit disorder, attention deficit moves obstacle (ADHD) more, alzheimer's disease (AD), mild cognitive impairment, senile dementia, the AIDS dementia, Pick's disease, Louis body dependency dementia, mongolism dependency dementia, amyotrophic lateral sclerosis, Huntington Chorea, smoking cessation, nicotine abstinence syndrome, traumatic brain injury dependency CNS hypofunction, acute pain, post-operative pain, chronic pain, inflammatory pain, Infertility, the growth of wound healing dependency neovascularity lacks, the growth of skin graft vascularization dependency neovascularity lacks, and circulation (the more especially circulation around the vascular occlusion) deficiency, rheumatoid arthritis, Crohn disease, ulcerative colitis, inflammatory bowel, the organ-graft refection, the acute immunological disease relevant with organ transplantation, the chronic immunity disease relevant with organ transplantation, septic shock, toxic shock syndrome, serious poisonous disease syndrome, depressed, and poker back.More preferably, to formula (I) compound of administration treatment significant quantity, provide treatment cognitive disorder, neurodegeneration and schizoid method.Further, formula (I) compound also can with the atypical antipsychotic combined administration.
The preparation of salt
Embodiment A
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane anhydrous
The L-bitartrate
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (21.5mg 0.07mmol) is dissolved in 200 of 1.0mL and spends ethanol the decane free alkali.Simultaneously, 11.75mgL-tartrate (0.08mmol) is dissolved in the 200 degree ethanol of 250 μ L.Stir down, the L-tartaric acid solution is added drop-wise to (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] in the decane free base solution.After adding, bottle is removed from agitating plate.Place, crystallization goes out anhydrous L-bitartrate.
Embodiment B
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the L-wine of decane
Stone acid hydrogen salt hydrate
In envrionment temperature with anhydrous (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the L-bitartrate solid (60mg) of decane is suspended in the water (500 μ L).Along with the mistake of time (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that decrystallizes out
3,7] the L-hydrogen tartrate salt hydrate of decane.
Embodiment C
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane
The anhydrous phosphoric acid dihydric salt
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (20mg 0.064mmol) is dissolved in the 1.0mL methyl alcohol decane free alkali.Simultaneously, 5 μ L, 85% phosphoric acid (0.073mmol) are diluted in the 245 μ L methyl alcohol.Stir then down, phosphoric acid solution is added drop-wise to (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] in the decane free base solution.After adding, bottle is removed from agitating plate.Place crystallization water outlet dihydrogen phosphate.
Embodiment D
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] phosphoric acid of decane
The dihydric salt hydrate
With anhydrous (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the dihydrogen phosphate hydrate solids of decane is exposed in the high humidity.Along with the mistake of time (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that decrystallizes out
3,7] the biphosphate salt hydrate of decane.
Embodiment E
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] decane anhydrous
Disuccinate
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (20mg 0.064mmol) is dissolved in the 2-propyl alcohol (or tetrahydrofuran (THF)) of 1.0mL the decane free alkali.Simultaneously, (8.25mg 0.07mmol) is dissolved in the 2-propyl alcohol (or tetrahydrofuran (THF)) of 500 μ L with Succinic Acid.Two kinds of solution are heated to 50 ℃.Under 50 ℃ of stirrings, the Succinic Acid drips of solution is added to (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 then
3,7] in the decane free base solution.Then bottle is removed from heat/agitating plate.Placement also naturally cools to envrionment temperature, and crystallization goes out anhydrous disuccinate.
Embodiment F
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] fourth two of decane
Acid hydrogen salt hydrate
In envrionment temperature with anhydrous (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane disuccinate solid (25mg) is suspended in the 100 μ L water.Along with the mistake of time (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that decrystallizes out
3,7] the disuccinate hydrate of decane.
Embodiment G
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] hydrochloric acid of decane
Salt four/monohydrate (1 salt: 0.25 water)
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (40mg 0.13mmol) is dissolved in 200 of 2.0mL and spends ethanol the decane free alkali.(5N, 30 μ L are 0.15mmol) with 220 μ L200 degree alcohol dilutions with dense HCl solution.Stir down, the HCl solution that dilutes is joined (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] in the decane free base solution.Bottle is removed from agitating plate, allowed solvent evaporation.Along with the mistake of the time hydrochloride four/monohydrate that decrystallizes out.
In order to prepare (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] hydrochloride four/monohydrate monocrystalline of decane, the supernatant liquor that above experiment is obtained is used for this experiment.Allow solvent evaporate at leisure.Past formation monocrystalline hydrochloride four/monohydrate along with the time.
Embodiment H
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] hydrochloric acid of decane
Salt sesquialter hydrate (1 salt: 1.5 water)
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] hydrochloride four/monohydrate solid 50mg of decane is suspended in the 200 μ L water.Along with the mistake of time (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that decrystallizes out
3,7] the hydrochloride sesquialter hydrate of decane.
Example I
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] lemon of decane
Acid dihydride salt
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (63mg 0.2mmol) is dissolved in the 1.0mL methyl alcohol decane free alkali.(41mg 0.21mmol) is dissolved in the 0.5mL methyl alcohol with citric acid.Stir down, citric acid solution is added drop-wise to (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] in the decane free base solution.After the adding, bottle is removed from agitating plate, and allowed solvent evaporate at leisure.Along with the mistake of time (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that decrystallizes out
3,7] the dihydrogen citrate salt of decane.
In order to prepare (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the dihydrogen citrate single-crystal of salt of decane, at 50 ℃ with (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the dihydrogen citrate salt (20mg) of decane be dissolved in 0.8mL water/2-propyl alcohol (1: 6, V/V).With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the dihydrogen citrate salt solid of decane plants seed crystal, and in air-tight bottle it is cooled to envrionment temperature in solution.Past formation monocrystalline along with the time.
Embodiment J
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] lemon of decane
The acid hydrogen salt
With (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] (62mg 0.2mmol) is dissolved in the 1.5mL methyl alcohol decane free alkali.(19mg 0.1mmol) is dissolved in the 0.5mL methyl alcohol with citric acid.Stir down, citric acid solution is added drop-wise to (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] in the decane free base solution.In the stirring, along with the mistake of time (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen the base)-1-aza-tricycle [3.3.1.1 that decrystallizes out
3,7] the citric acid hydrogen salt of decane.
Embodiment K
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7
] the decane free alkali
In order to prepare (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the free alkali monocrystalline of decane, with (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane free alkali (13mg) is dissolved in the 1.0mL 2-propyl alcohol.Allow solvent evaporate at leisure.Past formation (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 along with the time
3,7] the free alkali monocrystalline of decane.
Also consider to comprise preparation (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] method of decane Citrate trianion, it is by will (4s)-4-(5-phenyl-1,3, the basic oxygen base of 4-thiadiazoles-2-)-1-aza-tricycle [3.3.1.1 in citric acid and methyl alcohol
3,7] the decane recrystallize.
Should understand above detailed description and attached embodiment and only be used to illustrate, should not be considered as limiting the scope of the invention, described scope is limited separately by affiliated claims and equivalent thereof.It will be appreciated by one of skill in the art that various changes and modification to disclosed embodiment.Can carry out such change and modification not breaking away under spirit of the present invention and the scope thereof, it includes but not limited to and chemical structure of the present invention, substituting group, derivative, intermediates, synthetic, preparation and/or relevant change and the modification of using method.
Claims (34)
1. formula (I) compound
Or its pharmacy acceptable salt or prodrug, wherein
L
1For-O-or-NR
a-;
A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5
Ar
1Be aryl or heteroaryl;
Ar
2Be aryl or bicyclic heteroaryl;
Ar
3Be aryl or heteroaryl;
Ar
4Be bicyclic heteroaryl;
Ar
5Be aryl or heteroaryl;
L
2For key ,-O-,-NR
a-,-CH
2-or-C (O) NR
a-;
L
3For key ,-O-,-NR
a-or-CH
2-; With
R
aBe hydrogen or alkyl.
2. according to the compound of claim 1, wherein A is Ar
1
3. according to the compound of claim 2, Ar wherein
1Be selected from
D wherein
1, E
1, F
1, J
1, K
1, X
8, X
9, X
10, and X
11Independently be-CR separately
1Or N;
X
12, X
13, X
14, X
15, M
1And M
2Independently be-CR separately
1, N or C;
G
1For O ,-NR
1a, or S;
Y
1For-CR
1Or N;
Y
2For-CR
1Or N;
Y
3Be NH, O or S;
R
1For hydrogen, alkyl, alkoxyl group, alkoxy carbonyl, cyano group, halogen, nitro ,-NR
bR
c, haloalkyl or-C (O) NR
bR
c
R
1aBe hydrogen or alkyl;
R
bAnd R
cIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl;
X
12-X
15One of be C; With
M
1Or M
2Be C.
4. according to the compound of claim 3, L wherein
1For-O-.
5. according to the compound of claim 3, L wherein
1For-NR
a-.
6. according to the compound of claim 1, wherein A is-Ar
2-L
2-Ar
3
7. according to the compound of claim 6, Ar wherein
2Be selected from following group:
D
2, E
2, F
2, J
2, and K
2Independently be-CT separately
2Or N;
G
2For O ,-NR
2a, or S;
At (i), (ii) and in each group (iii), one by T
2Or R
2a(R wherein
2aBe T
2) expression substituting group be-L
2-Ar
3And other is by T
2The substituting group of expression be hydrogen, alkyl, alkoxyl group, alkoxy carbonyl, cyano group, halogen, nitro or-NR
bR
c
R
2aBe hydrogen, alkyl or T
2With
R
bAnd R
cIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl.
8. according to the compound of claim 6, Ar wherein
3Be selected from following group:
D wherein
3, E
3, F
3, J
3, K
3, X
8, X
9, X
10, and X
11Independently be-CR separately
3Or N;
X
16, X
17, X
18, X
19, M
1, and M
2Independently be-CR separately
3, N or C;
G
3For O ,-NR
3a, or S;
Y
1For-CR
3Or N;
Y
2For-CR
3Or N;
Y
3Be NH, O or S;
R
3Be hydrogen, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl, cyano group, halogen, halogenated alkoxy, haloalkyl, hydroxyl, nitro, R
eR
fN-or aryl; Wherein aryl is preferably the optional phenyl that is replaced by halogen, alkyl or cyano group;
R
3aBe hydrogen, alkyl, alkyl-carbonyl, trityl or aryl, wherein aryl is preferably phenyl;
R
eAnd R
fIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl, or R
eAnd R
fThe nitrogen-atoms that connects with them forms heterocycle separately, and wherein said heterocycle is preferably pyrrolidyl, piperidyl or piperazinyl;
X
16, X
17, X
18, and X
19One of be C; With
M
1Or M
2Be C.
9. according to the compound of claim 6, wherein
L
1For-NR
a-; With
L
2Be key.
10. according to the compound of claim 6, wherein
L
1For-O-; With
L
2Be key.
11. according to the compound of claim 1, wherein A is-Ar
4-L
3-Ar
5
12. according to the compound of claim 1, wherein-Ar
4-L
3-Ar
5For
Y
4For-NR
4a, O or S;
Y
5For N, C or-CR
4
Y
6For N, C or-CR
4
Condition is Y
5Or Y
6One of be C;
R
4Be hydrogen, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl, cyano group, halogen, halogenated alkoxy, haloalkyl, hydroxyl, nitro, oxo or R
eR
fN-;
R
4aBe hydrogen or alkyl;
R
eAnd R
fIndependent separately is hydrogen, alkyl, alkoxy carbonyl or alkyl-carbonyl, or R
eAnd R
fThe nitrogen-atoms that connects with them forms heterocycle separately, and wherein said heterocycle is preferably pyrrolidyl, piperidyl or piperazinyl;
X
4For N, C or-CRx
4
X
5For N, C or-CRx
5
X
6For N, C or-CR
X6
X
7For N, C or-CR
X7
Condition is X
4, X
5, X
6, or X
7Have only one to can be N, have only one to be C, and remaining must be different from N; With
R
X4, R
X5, R
X6And R
X7Independent separately is hydrogen or alkyl.
13. the compound of claim 1, wherein compound is
(4s)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-chlorine pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-phenyl pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-phenyl pyridazine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[6-(1H-indoles-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[6-(1H-indoles-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[6-(1-thionaphthene-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[6-(1-thionaphthene-5-yl) pyridazine-3-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(5-phenylpyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(1H-indoles-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(thionaphthene-5-yl) pyridine-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-aminopyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl thiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(3-chloro-phenyl-)-thiazol-2-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(3-chloro-4-p-methoxy-phenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(4-fluorophenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(3, the 5-difluorophenyl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound; 5-[2-(1-aza-tricycle [3.3.1.1
3,7] decane-(4s)-and Ji oxygen base) thiazole-5-yl]-Indolin-2-one;
5-[2-(1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound-(4s)-and Ji oxygen base) thiazole-5-yl]-Indolin-2-one;
(4s)-4-[5-(2-Trifluoromethyl-1 H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-6-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indol-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(pyridin-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(furans-2-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(furans-3-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(thiene-3-yl-)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(pyrazoles-4-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-bromo-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound;
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(1H-indoles-6-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(1H-indoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(thionaphthene-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[5-(pyrazoles-4-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenoxy group-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(5-phenyl-1,3,4-oxadiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4r)-N-(6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-(6-phenylpyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[6-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-(5-pyridine bromide-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(indoles-5-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(indoles-6-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(indoles-4-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(3-aminomethyl phenyl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[5-(3-chloro-phenyl-)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine; (4s)-4 N-[5-(3-chloro-phenyl-benzene-3-yl)-pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(1-pyridine oxide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(pyridin-3-yl oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(2-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(2-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-picoline-3-yl) the oxygen base]-1-aza-tricycle [3.3.11
3,7] decane;
(4s)-and 4-{[4-(trifluoromethyl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-fluorinated pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-iodo pyridin-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] niacinamide;
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1H-pyrazol-1-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(4-chloro-phenyl-) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(3,4 '-dipyridyl-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(6-chloro-pyridine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-pyridine bromide-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-formonitrile HCN;
(4s)-and 4-[(5-thiophene-2-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1H-indoles-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-{[6-(1H-indoles-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1H-indoles-6-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-{[6-(1H-indoles-6-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
5-{5-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base] pyridine-2-yl }-1,3-dihydro-2H-indol-2-one;
(4r)-and 4-{[6-(1-cumarone-5-yl) pyridin-3-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5,6-two bromo pyridin-3-yls) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyridine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-fluorinated pyridine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-pyridine bromide-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(3,3 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(3,4 '-dipyridyl-6-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyrimidine-5-yl pyridines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1H-pyrazoles-4-yl) pyridine-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
6-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl pyridine-2-carboxamide;
(4s)-and 4-[(2-chloro-pyridine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-methyl pyridazine-3-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrimidine-2-yloxy)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-brominated pyrimidine-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrimidine-5-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrimidine-4-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-Chloropyrimide-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1-trityl-1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[6-(1H-pyrazoles-4-yl) pyrimidine-4-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(6-pyridin-4-yl pyrimidine-4-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(pyrazine-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
4-[(6-methylpyrazine-2-yl) oxygen base]-1-aza-tricycle [3.3.11
3,7] decane;
(4r)-and 4-[(6-phenyl pyrazines-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-(1,3-thiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(5-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-(5-[4-(trifluoromethoxy) phenyl]-1,3-thiazoles-2-yl } the oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(4-chloro-phenyl-)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
4-{2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-1,3-thiazoles-5-yl } aniline;
(4s)-and 4-[(5-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(5-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-pyrimidine-5-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(2-methoxy pyrimidine-5-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(2-tetramethyleneimine-1-yl pyrimidines-5-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(6-piperazine-1-yl pyridines-3-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1H-pyrazol-1-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-trityl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-propyl group-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-isobutyl--1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(1-ethanoyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[5-(5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(5-isoxazole-4-base-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-and 4-[(4-bromo-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-chloro-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-{[4-(1H-pyrazoles-4-yl)-1,3-thiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-phenyl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-pyridin-4-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-and 4-[(4-pyridin-3-yl-1,3-thiazoles-2-yl) the oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-pyridin-4-yl-1,3-thiazoles-4-methane amide;
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-(4-chloro-phenyl-)-1,3-oxazole-4-methane amide;
2-[(4s)-1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-N-phenyl-1,3-oxazole-4-methane amide;
(4s)-and 4-{[5-(3-bromo phenyl)-1,3,4-thiadiazoles-2-yl] the oxygen base }-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-{5-[1-aza-tricycle [3.3.1.1
3,7] last of the ten Heavenly stems-4-base oxygen base]-1,3,4-thiadiazoles-2-yl } phenol;
(4s)-N-pyridin-3-yl-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-(5-bromo-6-chloro-pyridine-3-yl)-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[6-(1H-indoles-6-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-N-[6-(1H-indol-3-yl) pyridin-3-yl]-1-aza-tricycle [3.3.1.1
3,7] decane-4-amine;
(4s)-4-[5-(1H-indoles-5-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4s)-4-[5-(1H-indoles-6-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(1H-indoles-5-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane;
(4r)-4-[5-(1H-indoles-6-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane; Or
(4r)-4-[5-(1-cumarone-5-yl) pyridin-3-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane.
14. treatment or prevention are by the method for disease, illness or the defective of alpha 7 nicotinic acetylcholine receptor, α 4 β, 2 nAChRs or α 7 and 2 two kinds of nAChRs adjustings of α 4 β, wherein said disease, illness or damaged dysmnesia, cognitive disorder, neurodegeneration or the neurodevelopment obstacle of being selected from, this method comprises formula (I) compound of administering therapeutic appropriate amount.
15. according to the method for claim 14, wherein disease or illness are selected from attention deficit disorder, attention deficit moves obstacle (ADHD) more, alzheimer's disease (AD), mild cognitive impairment, schizophrenia, age related memory defects (AAMI), senile dementia, the AIDS dementia, Pick's disease, Louis body dependency dementia, mongolism dependency dementia, amyotrophic lateral sclerosis, Huntington Chorea, smoking cessation, nicotine abstinence syndrome, schizoaffective disorder, two-phase obstacle and mania, traumatic brain injury dependency CNS hypofunction, acute pain, post-operative pain, chronic pain, inflammatory pain, and neuropathic pain.
16. according to the method for claim 14, wherein disease or illness are attention deficit cognitive defect, alzheimer's disease, mild cognitive impairment, age related memory defects and schizoid cognitive defect that how moving obstacle is correlated with.
17., further comprise and atypical antipsychotic combined administration formula (I) compound according to the method for claim 14.
18. according to the method for claim 14, wherein disease or illness are selected from Infertility, circulation is not enough, the growth of wound healing dependency neovascularity lacks, skin graft vascularization dependency neovascularity is grown shortage, ischemic, inflammation, sacroiliitis and dependency illness, wound healing and diabetes associated complication.
19. use the formula V compound
The method of formula (I) compound of preparation claim 1.
20. the compound of formula (VI)
Or its pharmacy acceptable salt or prodrug, wherein
L
1For-O-or-NR
a-;
A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5
Ar
1Be aryl or heteroaryl;
Ar
2Be aryl or bicyclic heteroaryl;
Ar
3Be aryl or heteroaryl;
Ar
4Be bicyclic heteroaryl;
Ar
5Be aryl or heteroaryl;
L
2For key ,-O-,-NR
a-,-CH
2-or-C (O) NR
a-;
L
3For key ,-O-,-NR
a-or-CH
2-; With
R
aBe hydrogen or alkyl.
21. the compound of claim 20, wherein said compound are the prodrug of formula (I) compound of claim 1.
22. the compound of claim 20, wherein compound is
(4r)-4-(5-pyridine bromide-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(6-chloro-pyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(6-nitropyridine-3-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(5-bromethiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-and 4-[5-(4-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-and 4-[5-(3-fluorophenyl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-and 4-[5-(1H-indoles-5-yl)-1,3,4-thiadiazoles-2-base oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(the 5-tertiary butyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4s)-4-(6-chloro benzothiazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex;
(4r)-4-(6-chloro benzothiazole-Ji oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex; Or
(4s)-4-(benzoxazole-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane N-borane complex.
23. the compound of formula (VII)
Or its pharmacy acceptable salt or prodrug, wherein
L
1For-O-or-NR
a-;
A is-Ar
1,-Ar
2-L
2-Ar
3Or-Ar
4-L
3-Ar
5
Ar
1Be aryl or heteroaryl;
Ar
2Be aryl or bicyclic heteroaryl;
Ar
3Be aryl or heteroaryl;
Ar
4Be bicyclic heteroaryl;
Ar
5Be aryl or heteroaryl;
L
2For key ,-O-,-NR
a-,-CH
2-or-C (O) NR
a-;
L
3For key ,-O-,-NR
a-or-CH
2-; With
R
aBe hydrogen or alkyl.
24. the compound of claim 23, wherein said compound are the prodrug of formula (I) compound of claim 1.
25. the compound of claim 23, wherein compound is
(4s)-4-[5-(1H-indoles-5-yl)-thiazol-2-yl oxygen base]-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound;
(4s)-5-4-[2-(1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound-Ji oxygen base) thiazole-5-yl]-Indolin-2-one; Or
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane-1-oxide compound.
26. compound, it is
(4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] anhydrous L-bitartrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] L-hydrogen tartrate salt hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] anhydrous phosphoric acid dihydric salt, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] biphosphate salt hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] anhydrous disuccinate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] disuccinate hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] hydrochloride four/monohydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] hydrochloride sesquialter hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] decane dihydrogen citrate salt or (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the citric acid hydrogen salt of decane.
27. (4s)-4-(5-phenyl-1,3,4-thiazol-2-yl oxygen the base)-1-aza-tricycle [3.3.1.1 that spreads out and identify by powder X-ray-ray
3,7] crystalline salt of decane, wherein said salt is:
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the anhydrous L-bitartrate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 4.96 ± 0.20,9.99 ± 0.20,11.77 ± 0.20,14.62 ± 0.20,14.99 ± 0.20,18.14 ± 0.20,18.44 ± 0.20,19.48 ± 0.20,20.05 ± 0.20,21.02 ± 0.20,21.38 ± 0.20,22.76 ± 0.20,24.74 ± 0.20,26.65 ± 0.20 and 32.19 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the L-hydrogen tartrate salt hydrate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 4.63 ± 0.20,9.26 ± 0.20,13.43 ± 0.20,13.91 ± 0.20,15.98 ± 0.20,17.86 ± 0.20,21.36 ± 0.20 and 22.33 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the anhydrous phosphoric acid dihydric salt of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 5.14 ± 0.20,10.31 ± 0.20,11.20 ± 0.20,13.17 ± 0.20,13.47 ± 0.20,15.61 ± 0.20,16.69 ± 0.20,17.27 ± 0.20,17.5O ± 0.20,18.56 ± 0.20,18.90 ± 0.20,19.41 ± 0.20,20.93 ± 0.20,21.80 ± 0.20,22.53 ± 0.20,23.96 ± 0.20,26.01 ± 0.20 and 26.44 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the biphosphate salt hydrate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 5.28 ± 0.20,9.82 ± 0.20,10.61 ± 0.20,13.79 ± 0.20,14.24 ± 0.20,15.13 ± 0.20,16.65 ± 0.20,16.95 ± 0.20,18.35 ± 0.20,19.52 ± 0.20,19.84 ± 0.20,21.55 ± 0.20,23.85 ± 0.20,24,26 ± 0.20 and 25.80 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the anhydrous disuccinate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 12.53 ± 0.20,13.50 ± 0.20,14.76 ± 0.20,16.98 ± 0.20,18.07 ± 0.20,18.34 ± 0.20,18.35 ± 0.20,18.88 ± 0.20,19.62 ± 0.20,19.67 ± 0.20,20.00 ± 0.20,20.71 ± 0.20,23.64 ± 0.20,23.96 ± 0.20,25.61 ± 0.20 and 36.29 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the disuccinate hydrate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 8.92 ± 0.20,10.94 ± 0.20,11.71 ± 0.20,13.41 ± 0.20,14.90 ± 0.20,17.61 ± 0.20,17.92 ± 0.20,18.19 ± 0.20,19.60 ± 0.20,22 58 ± 0.20,26.19 ± 0.20 and 27.07 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the hydrochloride four/monohydrate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 5.19 ± 0.20,12.96 ± 020,13.00 ± 0.20,14.88 ± 0.20,14.98 ± 0.20,15.61 ± 0.20,17.79 ± 0.20,18.26 ± 0.20,18.93 ± 0.20,20.02 ± 0.20,20.67 ± 0.20,20.86 ± 0.20,21.72 ± 0.20,22.38 ± 0.20,22.55 ± 0.20,24.09 ± 0.20 and 26.10 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the hydrochloride sesquialter hydrate of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 4.94 ± 0.20,9.93 ± 0.20,14.09 ± 0.20,14.9 ± 0.20,17.85 ± 0.20,19.92 ± 0.20,21.72 ± 0.20,22.43 ± 0.20,22.63 ± 0.20 and 23.95 ± 0.20;
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the dihydrogen citrate salt of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 7.98 ± 0.20,11.98 ± 0.20,12.45 ± 0.20,15.76 ± 0.20,16.00 ± 0.20,17.75 ± 0.20,18.79 ± 0.20,18.82 ± 0.20,20.59 ± 0.20,22,25 ± 0.20,22.61 ± 0.20,24.16 ± 0.20,24.79 ± 0.20,25.06 ± 0.20,26.21 ± 0.20 and 29.43 ± 0.20; Or
Crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the citric acid hydrogen salt of decane, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 9.37 ± 0.20,9.62 ± 0.20,10.30 ± 0.20,11.24 ± 0.20,12.18 ± 0.20,13.73 ± 0.20,15.55 ± 0.20,16.17 ± 0.20,16.37 ± 0.20,16.76 ± 0.20,18.35 ± 0.20,18.67 ± 0.20,18.89 ± 0.20,19.98 ± 0.20,20.48 ± 0.20,20.94 ± 0.20,21.54 ± 0.20 and 22.02 ± 0.20.
28. crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the decane free alkali, it shows at least one characteristic peak in powder x-ray diffraction figure, 2 θ angle values of characteristic peak are 7.18 ± 0.20,10.19 ± 0.20,13.90 ± 0.20,14.37 ± 0.20,14.40 ± 0.20,14.66 ± 0.20,15.09 ± 0.20,15.21 ± 0.20,18.13 ± 0.20,18.43 ± 0.20,19.41 ± 0.20,19.88 ± 0.20 (two peaks), 20.09 ± 0.20,20.46 ± 0.20,21.66 ± 0.20,23.08 ± 0.20,26.84 ± 0.20,28.71 ± 0.20 and 30.90 ± 0.20.
29. pure basically crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] anhydrous L-bitartrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] L-hydrogen tartrate salt hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] anhydrous phosphoric acid dihydric salt, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] biphosphate salt hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] anhydrous disuccinate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] disuccinate hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] hydrochloride four/monohydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] hydrochloride sesquialter hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] dihydrogen citrate salt, (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1 of decane
3,7] decane the citric acid hydrogen salt or (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane.
30. crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the anhydrous disuccinate of decane, it has wherein that a is 12.958 (17)
, b is 7.561 (10)
, c is 39.66 (5)
And β is 94.54 (2) ° a unit cell parameters.
31. crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane hydrochloride four/monohydrate, it has wherein that a is 19.440 (7)
, b is 9.969 (4)
, c is 35.322 (13)
And β is 105.325 (17) ° a unit cell parameters.
32. crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the dihydrogen citrate salt of decane, it has wherein that a is 22.651 (8)
, b is 9.992 (3)
, c is 10.338 (4)
And β is 101.961 (5) ° a unit cell parameters.
33. crystal (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] the decane free alkali, it has wherein that a is 6.4427 (17)
, b is 9.895 (3)
, c is 13.102 (4)
And α is 70.145 (4) °, and β is that 81.691 (4) ° and γ are 73.391 (4) ° unit cell parameters.
34. preparation (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] method of decane Citrate trianion, comprise (4s)-4-(5-phenyl-1,3,4-thiadiazoles-2-base oxygen base)-1-aza-tricycle [3.3.1.1
3,7] decane recrystallize in citric acid and methyl alcohol.
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