CN101501040A - Amino-imidazolones and their use as a medicament for treating cognitive impairment, Alzheimer disease, neurodegeneration and dementia - Google Patents
Amino-imidazolones and their use as a medicament for treating cognitive impairment, Alzheimer disease, neurodegeneration and dementia Download PDFInfo
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- CN101501040A CN101501040A CNA2007800301257A CN200780030125A CN101501040A CN 101501040 A CN101501040 A CN 101501040A CN A2007800301257 A CNA2007800301257 A CN A2007800301257A CN 200780030125 A CN200780030125 A CN 200780030125A CN 101501040 A CN101501040 A CN 101501040A
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Abstract
This invention relates to novel compounds having the structural formula I below: and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.
Description
Technical field
The present invention relates to novel compound and pharmaceutical composition thereof.In addition, the present invention relates to be used for the treatment of and/or prevent following treatment of diseases method: A beta-related pathologies (A β-related pathology), for example mongolism (Downs syndrome) and beta amyloid vascular disease are such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease (Alzheimer Disease), the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease (Parkinson ' s disease) are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
Background technology
Several groups have identified and have isolated and had the active aspartate protease of beta-secretase (Hussain et al., 1999, Lin et.al, 2000, Yan et.al, 1999, Sinha et.al., 1999 and Vassar et.al., 1999).Beta-secretase is also referred to as Asp2 (Yan et.al, 1999), β position APP lyase (BACE) (Vassar et.al., 1999) or memapsin-2 (Lin et al., 2000) in pertinent literature.The kinds of experiments means have been adopted in the evaluation of BACE, for example est database analysis (Hussain et al.1999), cloning by expression (Vassar et.al., 1999), come purifying to be derived from the albumen (Sinha et al.1999) of human brain from the proteic public database identifier of the C.elegans that is predicted homologue (Yan et al.1999) and the final inhibitor that uses.Thereby five groups adopt three kinds of different laboratory facilities to identify identical enzyme, thereby believe firmly that BACE is a beta-secretase.Also mention following patent documentation: WO96/40885, EP871720, United States Patent (USP) 5,942,400 and 5,744,346, EP855444, US6,319,689, WO99/64587, WO99/31236, EP1037977, WO00/17369, WO01/23533, WO0047618, WO00/58479, WO00/69262, WO01/00663, WO01/00665 and US6,313,268.
What found is, BACE is a stomach en-sample aspartate protease, and this sophisticated enzyme is made up of the terminal catalyst structure domain of N-, membrane spaning domain and utricle matter structural domain.BACE has optimum activity (Vassar et al, 1999) during for 4.0-5.0 at pH, and is suppressed by the pepstatin of standard (for example pepstatin) is slight.What shown is that the catalyst structure domain that removes membrane spaning domain and cytoplasmic structure territory has activity (Lin et al, 2000) to peptide substrate.BACE is membrane-bound 1 type albumen, and it is as the active proenzyme of part and synthetic, and in cerebral tissue great expression.It is considered to represent main beta-secretase activity, and is considered to produce the rate-limiting step of amyloid-beta-protein (A β).Thereby BACE is in the pathology of alzheimer's disease and be used for the treatment of in the drug development of alzheimer's disease and be subjected to special concern.
A β or amyloid-beta-protein are the main components of brain spot, and the brain spot is an alzheimer's disease peculiar (De Strooper et al, 1999).A β is the peptide by the formed 39-42 of a specificity cracking residue of I class transmembrane protein (being called APP or amyloid precursor protein).A beta-secretase activity makes this albumen between residue Met671 and Asp672 (the 770aa isoform to APP is numbered) cracking take place, thereby forms the N-end of A β.The second pyrolysis of described peptide is relevant with gamma-secretase, thereby forms the C-end of A β peptide.
Alzheimer's disease (AD) torments the people more than 20,000,000 in the world according to estimates, and believes that it is the most general dull-witted form.Alzheimer's disease is a kind of progressive dementia, is that amyloid plaque and neurofibrillary tangles accumulate in the brain by the formed bulk deposition thing of the protein degradation production that gathers wherein.Amyloid plaque is considered to cause the reason of finding dementia in the Alzheimer patient.
The possibility that develops into alzheimer's disease increased with the age, and along with the aged's of developed country increase, this disease becomes serious day by day problem.In addition, there is the familial association in alzheimer's disease, therefore have dual APP sudden change and (be called the Swedish sudden change, wherein the APP of sudden change constitutes the quite big improved substrate of BACE) any individual development become the possibility of AD much bigger, and also much bigger (in addition referring to US 6,245 in the possibility that develops into AD at an early age, 964 and US 5,877,399, it relates to the transgenosis rodent that comprises APP-Swedish).Therefore, also need develop strongly and can be used for these individual compounds in preventative mode.
The gene of finding coding APP is positioned on No. 21 karyomit(e), the karyomit(e) as additional copies that described No. 21 karyomit(e)s also are in mongolism to be found.The mongolism patient is tending towards suffering from alzheimer's disease at an early age, and the mongolism patient more than 40 years old nearly all demonstrates Alzheimer type pathology (Oyama et al., 1994).This is considered to the additional copies owing to the app gene of being found in these patients, it has caused the overexpression of APP, has therefore increased APP β level, thereby has caused the high incidence of alzheimer's disease in this class crowd.Thereby the inhibitor of BACE can be used for reducing mongolism patient's Alzheimer type pathology.
Therefore, reduce or block the active medicine of BACE and should or deposit A β or its segmental other local A β level and segmental level of A β of reducing in brain, thereby delay the formation and the AD of amyloid plaque or involve A β or progress (Yankner, 1996 of sedimentary other sufferer of its fragment; DeStrooper and Konig, 1999).Therefore, BACE is used for the treatment of with regard to exploitation and/or prevents with regard to the medicine of following disease is important candidate's target: the A beta-related pathologies, for example mongolism and beta amyloid vascular disease are such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
Therefore, by suppressing BACE, be useful to the deposition that suppresses A β and part thereof with inhibitor (for example compound that the application provided).
Suppress the sedimentary treatment potentiality of A β impelled many research groups to separate and the potential inhibitor that characterizes Secretases and identify them (for example referring to WO01/23533 A2, EP0855444, WO00/17369, WO00/58479, WO00/47618, WO00/77030, WO01/00665, WO01/00663, WO01/29563, WO02/25276, US5,942,400, US6,245,884, US6,221,667, US6,211,235, WO02/02505, WO02/02506, WO02/02512, WO02/02518, WO02/02520, WO02/14264, WO05/058311, WO05/097767, WO06/041404, WO06/041405, WO06/0065204, WO06/0065277, US2006287294, WO06/138265, US20050282826, US20050282825, US20060281729, WO06/138217, WO06/138230, WO06/138264, WO06/138265, WO06/138266, WO06/099379, WO06/076284, US20070004786, US20070004730, WO07/011833, WO07/011810, US20070099875, US20070099898, WO07/049532).
Compare with potential inhibitor known in the art, compound exhibits of the present invention goes out useful character, for example the hERG selectivity of Ti Gaoing.
Summary of the invention
The application provides the compounds of structural formula I of free alkali form or the solvate of its pharmacologically acceptable salt, solvate or its salt:
A independently is selected from optional by one or more R
15,6 or 7 yuan of heterocycles that replace;
B independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
2Replace;
C independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
1Independently be selected from halogen, cyano group, nitro, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, NR
6R
7, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6(SO
2) R
7, SOR
6, SO
2R
6, OSO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl C
3-6Heterocyclic radical is optional to be replaced by one or more group E; Or
Two R
1Substituting group can form optional ring or the heterocycle that is replaced by one or more group E with the atom that they linked to each other;
R
2, R
3Or R
4Be selected from aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical, C
3-6Heterocyclic radical, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6(SO
2) R
7, SOR
6, SO
2R
6, OSO
2R
6And SO
3R
6, wherein said aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical and C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace;
R
5Independently be selected from hydrogen, cyano group OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, CONR
6R
7, CO
2R
6, COR
6, SO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace;
E independently is selected from halogen, nitro, CN, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl heterocyclic, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, NR
6R
7, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6SO
2R
7, SO
2R
6, SOR
6, OSO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl heterocyclic can be chosen wantonly by one or more substituting groups and replace, and described substituting group independently is selected from halogen, nitro, cyano group, OR
6, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy and trifluoromethoxy;
R
6And R
7Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic, or
R
6And R
7Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
R
8Independently be selected from halogen, cyano group, nitro, OR
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, NR
9R
10, CONR
9R
10, NR
9(CO) R
10, O (CO) R
9, CO
2R
9, COR
9, (SO
2) NR
9R
10, NR
9(SO
2) R
10, SO
2R
9, SOR
9, OSO
2R
9And SO
3R
9, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace; Or
Two R
8Can form optional ring or the heterocycle that is replaced by one or more group E with the atom that they linked to each other;
R
9And R
10Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic; Or
R
9And R
10Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
M=0,1 or 2;
N=0,1,2 or 3;
P=0,1,2 or 3;
Q=0,1,2 or 3;
T=0,1,2 or 3;
Wherein among n, p or the q is at least 1.
The present invention also provides pharmaceutical composition, and described pharmaceutical composition comprises the formula I compound as the treatment significant quantity of activeconstituents, and is combined with pharmaceutically acceptable vehicle, carrier or thinner.
The present invention also provides and regulates the active method of BACE, and it comprises makes the BACE enzyme contact with formula I compound.
The present invention also provides the method for treatment or prevention patient's A beta-related pathologies, and it comprises that the formula I compound with the treatment significant quantity gives described patient.
The compound that the present invention also provides the application to describe, it is as medicine.
In one aspect of the invention, provide the compound of formula I, wherein
A independently is selected from 5 or 6 yuan of heterocycles;
B independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
2Replace;
C independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
2, R
3Or R
4Independently be selected from aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical, C
3-6Heterocyclic radical, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6(SO
2) R
7, SOR
6, SO
2R
6, OSO
2R
6And SO
3R
6, wherein said aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical and C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace;
R
5Be hydrogen;
E independently is selected from halogen, nitro, CN, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl heterocyclic, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, NR
6R
7, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6SO
2R
7, SO
2R
6, SOR
6, OSO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl heterocyclic can be chosen wantonly by one or more substituting groups and replace, and described substituting group independently is selected from halogen, nitro, cyano group, OR
6, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy and trifluoromethoxy;
R
6And R
7Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic, or
R
6And R
7Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
R
8Independently be selected from halogen, cyano group, nitro, OR
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, NR
9R
10, CONR
9R
10, NR
9(CO) R
10, O (CO) R
9, CO
2R
9, COR
9, (SO
2) NR
9R
10, NR
9(SO
2) R
10, SO
2R
9, SOR
9, OSO
2R
9And SO
3R
9, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace; Or
Two R
8Can form optional ring or the heterocycle that is replaced by one or more group E with the atom that they linked to each other;
R
9And R
10Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic; Or
R
9And R
10Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
m＝0
N=0 or 1;
P=0 or 1;
Q=0,1,2 or 3;
T=0,1,2 or 3;
Wherein among n, p or the q is at least 1.
In another aspect of this invention, provide the compound of formula I, wherein B independently is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by a R
2Replace.
In another aspect of this invention, provide the compound of formula I, wherein B independently is selected from phenyl or pyridyl, and described phenyl or pyridyl are optional by a R
2Replace.
In another aspect of this invention, provide the compound of formula I, wherein C independently is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by a R
3Replace.
In another aspect of this invention, provide the compound of formula I, wherein n is 1 and R
2Be OSO
2R
6
In another aspect of this invention, provide the compound of formula I, wherein B independently is selected from phenyl and pyridyl; N is 1 and R
2Be OSO
2R
6
In another aspect of this invention, provide the compound of formula I, wherein R
3Be OSO
2R
6
In another aspect of this invention, provide the compound of formula I, wherein C independently is selected from phenyl or 6 yuan of heteroaromatic rings; P is 1 and R
3Be OSO
2R
6
In another aspect of this invention, provide the compound of formula I, wherein R
6Be C
1-6Alkyl.
In another aspect of this invention, provide the compound of formula I, wherein R
6Be trifluoromethyl.
In another aspect of this invention, provide the compound of formula I, wherein m is 0; N is 0; P is 0; And q is 1.
In another aspect of this invention, provide the compound of formula I, wherein m is 0; N is 1; P is 0; And q is 0.
In another aspect of this invention, provide the compound of formula I, wherein m is 0; N is 0; P is 1; And q is 0.
In another aspect of this invention, provide the compound of formula I, wherein t is 1 or 2.
In an embodiment aspect this, R
8Be positioned on the C, and independently be selected from halogen, cyano group, nitro and OR
9
In another embodiment aspect this, R
8Be positioned on the C, and independently be selected from halogen, cyano group, nitro and OR
9, R wherein
9Be selected from C
1-6Alkyl and trifluoromethyl.
In another embodiment aspect this, R
8Be positioned on the C, and be the optional C that is replaced by one or more group E
1-6Alkyl.
In another embodiment aspect this, R
8Be positioned on the C, and be the optional C that is replaced by one or more group E
1-6Alkyl, wherein group E is a halogen.
In another aspect of this invention, provide the compound of formula I, wherein
A is selected from 5 or 6 yuan of heterocycles;
B is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by a R
2Replace;
C is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
2Or R
3Be OSO
2R
6
R
5Be hydrogen;
R
6Be C
1-6Alkyl;
R
8Be selected from halogen, cyano group, nitro and OR
9
R
9Be selected from C
1-6Alkyl and trifluoromethyl;
m＝0；
N=0 or 1;
p＝0；
Q=0,1 or 2;
T=0 or 1;
Wherein among n or the q is at least 1.
In another aspect of this invention, provide the compound of formula I, wherein
A independently is selected from 5 or 6 yuan of heterocycles;
B is for choosing wantonly by a R
2The phenyl that replaces;
C independently is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
2Or R
3Be OSO
2R
6
R
5Be hydrogen;
E is a halogen;
R
6Independently be selected from C
1-6Alkyl and trifluoromethyl;
R
8Independently be selected from halogen, OR
9And C
1-6Alkyl, wherein said C
1-6Alkyl is optional to be replaced by one or more group E;
R
9Independently be selected from hydrogen and C
1-6Alkyl;
m＝0；
N=0 or 1;
P=0 or 1;
q＝0；
T=0,1 or 2;
Wherein among n or the p is at least 1.
In another aspect of this invention, provide the compound of formula I, wherein
A is by two R
16 yuan of heterocycles that replace;
B is by a R
2The phenyl that replaces;
C is 6 yuan of heteroaromatic rings;
R
1Be halogen;
R
2Be CONR
6R
7
R
5Be hydrogen;
R
6And R
7Be C
1-6Alkyl;
R
8Be halogen;
m＝2；
n＝1；
p＝0；
Q=0; And
T=0 or 1.
In another aspect of this invention, provide the compound of formula I, described compound is selected from:
Methylsulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-[6-amino-8-(3-pyrazine-2-base phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(5-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } the phenyl ester acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(5-methoxypyridine-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } the phenyl ester acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-cyanobiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(6-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.25 acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(2,6-difluoro pyridine-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.25 acetate;
Methylsulfonic acid 4-{6-amino-8-[3 '-(trifluoromethoxy) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(2 '-fluoro-3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(2 '-fluoro-5 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-ethoxybiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-nitrobiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(2 ', 5 '-dimethoxy-biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-cyano group-4 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(5 '-cyano group-2 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Methylsulfonic acid 4-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Methylsulfonic acid 3 '-[6-amino-8-(4-p-methoxy-phenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also]-5-methoxyl biphenyl-3-base ester acetate;
Methylsulfonic acid 3 '-[6-amino-8-(4-p-methoxy-phenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also]-5-chlordiphenyl-3-base ester acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3-pyrazine-2-base phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Third-1-sulfonic acid 4-{6-amino-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } the phenyl ester acetate;
Third-1-sulfonic acid 4-{6-amino-8-[3 '-(trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.5 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(4 '-fluoro-3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 '-chloro-2 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(2 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-{6-amino-8-[3-(5-methoxypyridine-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-{6-amino-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-{6-amino-8-[3 '-(trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 '-chloro-2 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(2 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 3 '-[5-amino-7-(4-p-methoxy-phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl]-5-methoxyl biphenyl-3-base ester acetate;
Methylsulfonic acid 4-[5-amino-7-(3 '-methoxyl biphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[5-amino-7-(3 ', 5 '-DCBP-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[5-amino-7-(3-(pyridin-3-yl) phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-{5-amino-7-[3-(2-fluorine pyridin-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.5 acetate;
Methylsulfonic acid 4-{5-amino-7-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3 '-methoxyl biphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3 ', 5 '-DCBP-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3-(pyridin-3-yl) phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.75 acetate;
Third-2-sulfonic acid 4-{5-amino-7-[3-(2-fluorine pyridin-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.75 acetate;
Third-2-sulfonic acid 4-{5-amino-7-[3-(5-methoxypyridine-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.5 acetate;
Methylsulfonic acid 3 '-(6-amino-8-(pyridin-4-yl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also)-5-chlordiphenyl-3-base ester 0.5 acetate; And
Methylsulfonic acid 3 '-(6-amino-8-(pyridin-4-yl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also)-5-methoxyl biphenyl-3-base ester 0.25 acetate.
In another aspect of this invention, provide the compound of formula I, described compound is selected from:
Trifluoromethanesulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.75 acetate;
Trifluoromethanesulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 3 '-(6-amino-8-phenyl-2,3,4,8-imidazolidine is [1,5-a] pyrimidine-8-yl also)-5-methoxyl biphenyl-3-base ester hydrochloride;
Methylsulfonic acid 3-{6-amino-8-[3 ', 5 '-two (trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-{6-amino-8-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 ', 5 '-dimethyl diphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Third-1-sulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Third-1-sulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Third-1-sulfonic acid 3-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Cyclopropyl sulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Cyclopropyl sulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-{6-amino-8-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester; And
Methylsulfonic acid 3 '-[6-amino-8-(3-p-methoxy-phenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also]-5-methoxyl biphenyl-3-base ester.
In another aspect of this invention, provide the compound of formula I, described compound is selected from:
3-{6-amino-3,3-two fluoro-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also }-N, the N-dimethyl benzamide; With
4-{6-amino-3,3-two fluoro-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also }-N, the N-dimethyl benzamide.
Some formula I compounds can have stereogenic centres and/or rotamerism center (E-and Z-isomer), and are to be understood that and the present invention includes all such optically active isomers, enantiomer, diastereomer, atropisomer and geometrical isomer.
The present invention relates to the purposes of formula I compound as defined above and salt thereof.The salt that is used for pharmaceutical composition can be pharmacologically acceptable salt, but other salt also can be used for preparation I compound.
Should be appreciated that any and all tautomeric forms that the invention still further relates to formula I compound.
Compound useful as drug of the present invention.In some embodiments, the invention provides hydrolyzable precursor in formula I compound or pharmaceutically acceptable salt thereof, tautomer or the body, it is as medicine.In some embodiments, the invention provides the described compound of the application, it is used for the treatment of or prevents the medicine of A beta-related pathologies.In some other embodiment, the A beta-related pathologies is mongolism, beta amyloid vascular disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment, MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, relevant attention deficit symptom, dementia, presenile dementia, senile dementia, the paralysis or the sex change of cortex matrix on relevant dementia, the carrying out property nuclear with Parkinson's disease of dementia, the sex change origin of relevant neurodegeneration, mixed type blood vessel origin with alzheimer's disease with alzheimer's disease.
In some embodiments, the invention provides hydrolyzable precursor in formula I compound or pharmaceutically acceptable salt thereof, tautomer or the body, be used for the treatment of or prevent purposes in the medicine of A beta-related pathologies in preparation.In some other embodiment, the A beta-related pathologies comprises for example mongolism and beta amyloid vascular disease, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
In some embodiments, the invention provides and suppress the active method of BACE, it comprises makes BACE contact with compound of the present invention.BACE is considered to represent main beta-secretase activity, and is considered to produce the rate-limiting step of amyloid-beta-protein (A β).Thereby, suppressing BACE with inhibitor (for example compound that the application provided), this can be used for suppressing the deposition of A β and part thereof.Because the deposition of A β and part thereof and the such disease association of for example alzheimer's disease, so BACE is used for the treatment of with regard to exploitation and/or prevents with regard to the medicine of following disease is important candidate's target: the A beta-related pathologies, for example mongolism and beta amyloid vascular disease are such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
In some embodiments, the invention provides the method that is used for the treatment of following disease: the A beta-related pathologies, for example mongolism and beta amyloid vascular disease, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear, described method comprises the formula I compound or pharmaceutically acceptable salt thereof with the treatment significant quantity, hydrolyzable precursor gives Mammals (comprising the people) in tautomer or the body.
In some embodiments, the invention provides the method that is used to prevent following disease: the A beta-related pathologies, for example mongolism and beta amyloid vascular disease, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear, described method comprises the formula I compound or pharmaceutically acceptable salt thereof with the treatment significant quantity, hydrolyzable precursor gives Mammals (comprising the people) in tautomer or the body.
In some embodiments, the invention provides by with formula I compound or pharmaceutically acceptable salt thereof, hydrolyzable precursor and cognition and/or hypermnesia medicine give the method that following disease (being comprised the people) was treated or prevented to Mammals in tautomer or the body: the A beta-related pathologies, for example mongolism and beta amyloid vascular disease are such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear.Cognition enhancer thing, hypermnesia medicine and anticholinesterase include but not limited to bright (Exelon), tacrine (Cognex) and the memantine (Namenda, Axura or Ebixa) of E2020 (Aricept), lycoremine (Reminyl or Razadyne), Li Fansi.
In some embodiments, the invention provides by with formula I compound or pharmaceutically acceptable salt thereof, hydrolyzable precursor (wherein each material is all provided by the application) and anticholinesterase or anti-inflammatory drug give the method that following disease (being comprised the people) was treated or prevented to Mammals in tautomer or the body: the A beta-related pathologies, for example mongolism and beta amyloid vascular disease are such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
In some embodiments, the invention provides by giving the method that following disease (being comprised the people) was treated or prevented to Mammals: the A beta-related pathologies compound of the present invention and atypical antipsychotic, for example mongolism and beta amyloid vascular disease are such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment is such as but not limited to MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, with the neurodegeneration of the such disease-related of for example alzheimer's disease or comprise the dementia that mixed type blood vessel origin and sex change originate from, presenile dementia, senile dementia and the dementia relevant with Parkinson's disease are in interior dementia, described other disease arbitrarily of paralysis or the sex change of cortex matrix or the application on the carrying out property nuclear, obstacle or illness.Atypical antipsychotic includes but not limited to olanzapine (Olanzapine) (the commercially available Zyprexa of being), Aripiprazole (Aripiprazole) (commercially available is Abilify), risperidone (Risperidone) (commercially available is Risperdal), Quetiapine (Quetiapine) (commercially available is Seroquel), leoponex (Clozapine) (commercially available is Clozaril), Ziprasidone (Ziprasidone) (commercially available is Geodon) and olanzapine/fluoxetine (Olanzapine/Fluoxetine) (commercially available is Symbyax).
In some embodiments, with the Mammals of The compounds of this invention treatment or humanly suffered from concrete disease or obstacle by diagnosis, for example the application described those.In these cases, this treatment of Mammals of being treated or human needs.Yet diagnosis need not before just to carry out.
The present invention also comprises pharmaceutical composition, and described pharmaceutical composition comprises as one or more The compounds of this invention of activeconstituents and at least a pharmaceutically acceptable carrier, thinner or vehicle.
The given definition of the application is intended to be illustrated in the employed term of the application everywhere.Term " the application " refers to whole application.
Multiple compound of the present invention can exist by specific rotamerism form or stereoisomeric forms in any ratio.The present invention includes all these compounds, comprise cis and trans-isomer(ide), R and S enantiomer, diastereomer, (D)-isomer, (L)-isomer, their racemic mixture and their other mixture, these are all contained within the scope of the invention.Extra unsymmetrical carbon can be present in the substituting group (for example alkyl).All these isomer and their mixture all are intended to comprise in the present invention.The described compound of the application can have asymmetric center.The The compounds of this invention that comprises asymmetric replacement atom can be separated into optical activity form or racemic form.It is well-known in the art how preparing the optical activity form, for example by the resolution of racemic form, by synthetic from having optically active starting raw material, or use optical activity reagent synthetic.If desired, the separation of racemize material can realize by method known in the art.The multiple geometrical isomer of alkene, the two keys of C=N etc. also can be present in the described compound of the application, and all these stable isomer all are expected among the present invention.Cis and trans geometrical isomer to The compounds of this invention are described, and they can be separated into mixture of isomers, or are separated into isomeric form separately.All chirality forms of structure, diastereo-isomerism form, racemic form and all rotamerism forms all are intended to comprise in the present invention, unless specifically indicated specific stereochemistry or isomeric form.
When will connect substituent key be shown as with shack in the key of two atoms when intersecting, described substituting group can be gone up arbitrary atom with ring and be connected.When not indicating described substituting group when listing substituting group and by which atom coming to be connected with the rest part of the compound of given structural formula, described substituting group can connect by the arbitrary atom in the described substituting group.As long as the combination of substituting group, substituent position and/or variable can obtain stable compound, so this combination allows.
The employed term of the application " the optional replacement " refers to replace and chooses wantonly, can be unsubstituted with regard to specified atom or group therefore.Under the situation that expectation replaces; this replacement refers to that the hydrogen of the arbitrary number on specified atom or the group is selected from the group replacement of designated groups; condition is the normal valency that can not surpass specified atom or group, and the result who replaces obtains stable compound.For example, (be CH if substituting group is a methyl
3), 3 hydrogen on the carbon atom can be replaced so.Described substituent example includes but not limited to: halogen, CN, NH
2, OH, SO, SO
2, COOH, OC
1-6Alkyl, CH
2OH, SO
2H, C
1-6Alkyl, OC
1-6Alkyl, C (=O) C
1-6Alkyl, C (=O) OC
1-6Alkyl, C (=O) NH
2, C (=O) NHC
1-6Alkyl, C (=O) N (C
1-6Alkyl)
2, SO
2C
1-6Alkyl, SO
2NHC
1-6Alkyl, SO
2N (C
1-6Alkyl)
2, NH (C
1-6Alkyl), N (C
1-6Alkyl)
2, NHC (=O) C
1-6Alkyl, NC (=O) (C
1-6Alkyl)
2, C
5-6Aryl, OC
5-6Aryl, C (=O) C
5-6Aryl, C (=O) OC
5-6Aryl, C (=O) NHC
5-6Aryl, C (=O) N (C
5-6Aryl)
2, SO
2C
5-6Aryl, SO
2NHC
5-6Aryl, SO
2N (C
5-6Aryl)
2, NH (C
5-6Aryl), N (C
5-6Aryl)
2, NC (=O) C
5-6Aryl, NC (=O) (C
5-6Aryl)
2, C
5-6Heterocyclic radical, OC
5-6Heterocyclic radical, C (=O) C
5-6Heterocyclic radical, C (=O) OC
5-6Heterocyclic radical, C (=O) NHC
5-6Heterocyclic radical, C (=O) N (C
5-6Heterocyclic radical)
2, SO
2C
5-6Heterocyclic radical, SO
2NHC
5-6Heterocyclic radical, SO
2N (C
5-6Heterocyclic radical)
2, NH (C
5-6Heterocyclic radical), N (C
5-6Heterocyclic radical)
2, NC (=O) C
5-6Heterocyclic radical, NC (=O) (C
5-6Heterocyclic radical)
2
The application uses separately or is intended to comprise and has 1 to 12 carbon atom as " alkyl " of suffix or prefix the side chain and the straight chain representative examples of saturated aliphatic alkyl of (if or the concrete number of carbon atom is provided, refer to described concrete number so).For example, " C
0-6Alkyl " expression has the alkyl of 0,1,2,3,4,5 or 6 carbon atom.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group and hexyl.In subscript is in the situation of integer 0 (0), and the group of subscript indication indicates described group and can not exist, and promptly has direct key to link to each other between group.
The application uses separately or is intended to comprise and has 2 to 12 carbon atoms as " thiazolinyl " of suffix or prefix the side chain and the straight chain aliphatic alkyl that contain alkene (alkene) or alkene (olefin) of (if or the concrete number of carbon atom is provided, refer to described concrete number so).For example, " C
2-6Thiazolinyl " expression has the thiazolinyl of 2,3,4,5 or 6 carbon atoms.The example of thiazolinyl includes but not limited to vinyl, allyl group, 1-propenyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl but-2-ene base, 3-methyl but-1-ene base, 1-pentenyl, 3-pentenyl and 4-hexenyl etc.
The application uses separately or is intended to comprise and has 2 to 12 carbon atoms as " alkynyl " of suffix or prefix the side chain that contains alkynes and the straight chain aliphatic alkyl of (if or the concrete number of carbon atom is provided, refer to described concrete number so).For example, " C
2-6Alkynyl " expression has the alkynyl of 2,3,4,5 or 6 carbon atoms.The example of alkynyl include but not limited to ethynyl, 1-proyl, 2-propynyl, 3-butynyl ,-pentynyl, hexin base and 1-methylpent-2-alkynyl.
The application's employed " aromatics " refers to have one or more alkyl that have the unsaturated carbocyclic of aromatic character (for example 4n+2 delocalized electron) and comprise about at the most 14 carbon atoms.In addition, " heteroaromatic " refers to have one or more unsaturated rings that have aromatic character (for example 4n+2 delocalized electron), contain carbon and one or more heteroatoms (as nitrogen, oxygen and sulphur).
The employed term of the application " aryl " refers to 5 to 14 aromatic ring structures that carbon atom is formed.The ring structure that contains 5,6,7 and 8 carbon atoms can be mono-cyclic aromatic group, for example phenyl.The ring structure that contains 8,9,10,11,12,13 or 14 carbon atoms can be many cyclic groups, for example naphthyl.Aromatic ring can be substituted with substituting group described above at one or more ring positions.Term " aryl " also comprises the many rings ring system with two or more rings, wherein two or more carbon are two adjacent ring common (ring is " condensed ring "), wherein at least one ring is an aromatics, and other ring for example can be cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical.Term " neighbour ", " " and " to " be applied to 1 respectively, 2-, 1,3-and 1, the dibasic benzene of 4-.For example, title " 1, the 2-dimethyl benzene " has identical meaning with " neighbour-dimethyl benzene ".
The application's employed " cycloalkyl " refers to have the saturated cyclic group of given number carbon atom.These can comprise the multi-loop system of condensed ring or bridge joint.Preferred cycloalkyl has 3 to 10 carbon atoms in its ring structure, more preferably have 3,4,5 and 6 carbon in its ring structure." C for example
3-6Cycloalkyl " represent for example such group of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Have at least one carbon-to-carbon double bond and have the cyclic hydrocarbon radical that contains of 4 to 12 carbon atoms in the application's employed " cycloalkenyl group " finger ring.
Have at least one carbon-to-carbon triple bond and have the cyclic hydrocarbon radical that contains of 7 to 12 carbon atoms in the application's employed " cycloalkynyl radical " finger ring.
The application's employed " halo " or " halogen " refer to fluorine, chlorine, bromine and iodine." counter ion " are used to represent the material of little electronegative or positively charged, for example chlorion, bromide anion, hydroxide ion, acetate ion, sulfate ion, toluenesulphonic acids radical ion, Phenylsulfonic acid radical ion etc.
The employed term of the application " heterocyclic radical " or " heterocyclic " or " heterocycle " refer to contain monocyclic, bicyclic or tricyclic (except as otherwise noted) of saturated, the undersaturated or fractional saturation of 3 to 20 atoms, wherein 1,2,3,4 or 5 annular atoms is selected from nitrogen, sulphur or oxygen, except as otherwise noted, it can link to each other by carbon or nitrogen, wherein-and CH
2-Ji chooses quilt-C (O)-replacement wantonly; Unless and there have opposite explanation, ring nitrogen or sulphur atom to choose oxidation formation N-oxide compound or S-oxide compound or ring nitrogen wantonly to be optional quaternized; Wherein ring-NH is optional is replaced by ethanoyl, formyl radical, methyl or methylsulfonyl; And ring is optional is replaced by one or more halogens.It should be understood that these heteroatomss can not be adjacent one another are when the sum of S atom in the heterocyclic radical and O atom surpasses 1.If described heterocyclic radical is two ring or three rings, then at least one ring may optionally be heteroaromatic rings or aromatic ring, and condition is that at least one ring is non-heteroaromatic.If described heterocyclic radical is a monocycle, then it is aromatics scarcely.The example of heterocyclic radical includes but not limited to piperidyl, N-ethanoyl piperidyl, N-methyl piperidine base, N-formyl piperazine base, N-methylsulfonyl piperazinyl, high piperazinyl, piperazinyl, azetidinyl (azetidinyl), oxetanyl (oxetanyl), morpholinyl, tetrahydro isoquinolyl, tetrahydric quinoline group, indolinyl, THP trtrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuran base and 2,5-dioxo alkyl imidazole base.
The application's employed " heteroaryl " or " heteroaromatic " refer to have at least one ring hetero atom aromatic heterocycle of (for example sulphur, oxygen or nitrogen).Heteroaryl comprises single-loop system and (for example having 2,3 or 4 the condensed rings) system that encircles more.The example of heteroaryl includes but not limited to pyridyl (being pyridinyl), pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazyl, indazolyl, 1; 2,4-thiadiazolyl group, isothiazolyl, benzothienyl, purine radicals, carbazyl, fluorenes acyl group (fluorenonyl), benzimidazolyl-, indolinyl etc.In some embodiments, heteroaryl has 1 to about 20 carbon atoms, is about 3 to about 20 carbon atoms in other embodiments.In some embodiments, heteroaryl comprises 3 to about 14,4 to about 14,3 to about 7 or 5 to 6 one-tenth annular atomses.In some embodiments, heteroaryl or heteroaromatic group have 1 to about 4,1 to about 3 or 1 to 2 heteroatoms.In some embodiments, heteroaryl or heteroaromatic group have 1 heteroatoms.
The employed phrase of the application " protecting group " refers to interim substituting group, and its protection has the functional group of potential reaction, makes it the chemical conversion that can not take place not expect.The example of described protecting group comprises the ester of carboxylic acid, the silyl ether of alcohol and the corresponding acetal and the ketal of aldehyde and ketone.The protecting group chemical field (Greene, T.W. have been carried out summarizing; Wuts, P.G.M.Protective Groups in OrganicSynthesis, 3
RdEd.; Wiley:New York, 1999).
The application employed " halo (halo) " or " halogen (halogen) " refer to fluorine, chlorine, bromine and iodine.
The application's employed " pharmaceutically acceptable " refers to such compound, material, composition and/or formulation, they are applicable to human tissue in rational medical determination range and contact with animal tissues, and not having over-drastic toxicity, pungency, transformation reactions or other problem or complication, this matches with rational interests/risk ratio.
The application's employed " pharmacologically acceptable salt " refers to the derivative of disclosed compound, and wherein parent compound is modified by preparing its hydrochlorate or alkali salt.The example of pharmacologically acceptable salt includes but not limited to the inorganic base salts of the inorganic acid salt of alkaline residue (for example amine) or organic acid salt, acidic residues (for example carboxylic acid) or organic alkali salt etc.Pharmacologically acceptable salt comprises the conventional non-toxic salts or the quaternary ammonium salt of parent compound, and it for example prepares from nontoxicity mineral acid or organic acid.For example, described conventional non-toxic salts comprises from those salt of mineral acid (for example hydrochloric acid) deutero-.
Pharmacologically acceptable salt of the present invention can synthesize from the parent compound that comprises alkalescence or acidic moiety by the chemical process of routine.Usually, these salt can prepare by the following method: these compounds of free acid form or free alkali form and stoichiometric suitable alkali or acid are reacted in water or organic solvent or the mixture of the two; Usually use non-aqueous media, as ether, ethyl acetate, ethanol, Virahol or acetonitrile.
The application's employed " tautomer " refers to other constitutional isomer that balance exists because hydrogen atom moves, for example keto-enol change, and wherein resulting compound has the character of ketone and unsaturated alcohol.
The application's employed " stable compound " and " stable structure " refer to that compound is enough stable, are separated to useful purity and are mixed with effective therapeutical agent thereby hold out against from reaction mixture.
Compound of the present invention also comprises hydrate and solvate.
The present invention also comprises isotope-labeled The compounds of this invention.The compound of " isotopic labeling " or " radio-labeling " is the The compounds of this invention with following feature: wherein one or more atoms are different from the replacement of (promptly naturally occurring) atom or the replacement of common atomic mass of occurring in nature or total mass number by atomic mass or total mass number.The suitable radionuclide that can be combined in the The compounds of this invention includes but not limited to
2H (also writing D, the expression deuterium),
3H (also writing T, the expression tritium),
11C,
13C,
14C,
13N,
15N,
15O,
17O,
18O,
18F,
35S,
36Cl,
82Br,
75Br,
76Br,
77Br,
123I,
124I,
125I and
131I.Be combined in radionuclide in these radiolabeled compounds and depend on the concrete application of described radiolabeled compound.For example, with regard to extracorporeal receptor mark and competition assay, be combined with
3H,
14C,
82Br,
125I,
131I or
35The compound of S is normally the most useful.With regard to radiological imaging is used,
11C,
18F,
125I,
123I,
124I,
131I,
75Br,
76Br or
77Br is normally the most useful.
It should be understood that " radiolabeled compound " is the compound that is combined with at least one radionuclide.In some embodiments, radionuclide is selected from
3H,
14C,
125I,
35S and
82Br.
The defined dementia resisting treatment of the application is applicable as independent therapy, perhaps is applied as the conventional chemical therapy that comprises The compounds of this invention.These chemotherapy comprise the medicament of one or more following kinds: acetylcholinesterase depressant, anti-inflammatory agent, cognition and/or hypermnesia agent or atypical antipsychotic agents (atypical antipsychotic agent).
When this combination therapy can be by each therapeutic component, carry out successively or separately.These combined prods use compound of the present invention.
Compound of the present invention can give in the following manner: oral, parenteral, oral cavity, vagina, rectum, suck, be blown into, in hypogloeeis, intramuscular, subcutaneous, local, the nose, in the intraperitoneal, intrathoracic, intravenously, epidural, sheath, Intraventricular and being expelled in the joint.
When determining only individual dosage regimen and dosage level at concrete patient, dosage depend on severity, patient's age and the body weight of route of administration, disease and attending doctor the other factors considered usually.
The compounds of this invention is used for the treatment of dull-witted significant quantity for being enough to alleviate warm-blooded animal (particularly people) dementia symptom to the ill, slowing down dull-witted progress or reduce the dementia symptom patient and worsen dangerous amount.
For from compound pharmaceutical composition of the present invention, inertia pharmaceutically acceptable carrier can be solid or liquid.But solid formulation comprises pulvis, tablet dispersible granule, capsule, cachet and suppository.
Solid carrier can be one or more materials, and it also can be used as thinner, correctives, solubilizing agent, lubricant, suspending agent, tackiness agent or tablet disintegrant, and it also can be into capsule material.
In pulvis, carrier is the solid of fine pulverizing, and it mixes with the activeconstituents of fine pulverizing.In tablet, activeconstituents and carrier with necessary bond property are pressed into desired shape and size then by suitable mixed.
In order to prepare suppository composition,, for example by stirring, activeconstituents is scattered in wherein then at first with low melt wax (for example mixture of glycerin fatty acid ester and theobroma oil) fusing.Then, the homogenizing mixture that melts is poured in the mould of suitable dimension, make its cooling and curing then.
Suitable carriers comprises magnesiumcarbonate, Magnesium Stearate, talcum, lactose, sucrose, pectin, dextrin, starch, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.
In some embodiments, the invention provides formula I compound or pharmaceutically acceptable salt thereof, it is used for that Mammals (comprising the people) is carried out therapeutic and disposes (comprising preventive disposal), and it is mixed with pharmaceutical composition according to the pharmacy practice of standard usually.
Except that compound of the present invention, pharmaceutical composition of the present invention also can comprise one or more has the pharmaceutical component of therapeutic value to the described illness of one or more the application, or the described illness of one or more the application is had the pharmaceutical component coupling (simultaneously or give successively) of therapeutic value with one or more.
Term " composition " is intended to comprise the preparation of activeconstituents or its pharmacologically acceptable salt and pharmaceutically acceptable carrier.For example, the present invention can be mixed with following form by methods known in the art: pulvis or the aerosol or the propellant of for example tablet, capsule, aqueous solution agent or oily solution agent, suspensoid, emulsion, paste, ointment, gelifying agent, nasal spray, suppository, the fine pulverizing that is used to suck and be used for parenteral and use aseptic aqueous solution agent or the oily solution agent or the suspensoid of (comprising intravenously, intramuscular or infusion) or do not have bacterial emulsion.
Fluid composition comprises solution, suspensoid and emulsion.As the example of the liquid preparation that is suitable for administered parenterally, can mention the aseptic aqueous solution or the sterilized water-propylene glycol solution of active compound.Also liquid composition can be mixed with the water-based polyglycol solution.The aqueous solution agent that oral administration is used can prepare by the following method: activeconstituents is dissolved in the water, and adds suitable tinting material, correctives, stablizer and thickening material as required.Aqueous suspension for oral use can prepare by the following method: the activeconstituents of fine pulverizing is dispersed in the water with viscous substance (for example natural/synthetic gum, resin, methylcellulose gum, Xylo-Mucine and known other suspending agent of pharmacy field).
Pharmaceutical composition can be a unit dosage.With regard to this form, composition is divided into the unitary dose that contains an amount of activeconstituents.Unit dosage can be a packaged preparation, and described packing comprises the separately preparation of amount, for example is packaged in tablet, capsule and pulvis in bottle or the ampoule.Unit dosage also can be capsule, cachet or a tablet itself, maybe can be any these packaged forms of suitable number.
Composition can be prepared, be used for any suitable route of administration and method.Pharmaceutically acceptable carrier or thinner are included in employed those materials in the preparation that is suitable for following administration: oral administration, rectal administration, nasal administration, part (comprising oral cavity and hypogloeeis) administration, vagina administration or parenteral (comprising in subcutaneous, intramuscular, intravenously, intracutaneous, the sheath and epidural) administration.Reason for convenience, preparation can be unit dosage, and can prepare by the known any means of pharmaceutical field.
With regard to solids composition, can use conventional nontoxicity solid carrier to comprise N.F,USP MANNITOL, lactose, Mierocrystalline cellulose, derivatived cellulose, starch, Magnesium Stearate, soluble saccharin, talcum, glucose, sucrose, magnesiumcarbonate of pharmaceutical grade for example etc.The liquid composition that can be used for administration can for example prepare by the following method: active compound defined above is reached optional excipient substance dissolving in carrier (for example water, salt solution, D/W, glycerine, ethanol etc.), dispersion etc., form solution or suspension thus.If desired, the pharmaceutical composition for the treatment of administration also can comprise a small amount of nontoxicity auxiliary substance, for example wetting agent or emulsifying agent, pH buffer reagent etc., for example sodium acetate, Arlacel-20, trolamine sodium acetate, Arlacel-20, triethanolamine oleate etc.The practical methods for preparing these formulations is well known by persons skilled in the art, or is conspicuous for those skilled in the art; For example referring to Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975.
Can come according to various methods compound of the present invention is derived." derivative " of the employed compound of the application comprise salt (for example pharmacologically acceptable salt), arbitrarily mixture (for example with the inclusion compound (inclusion complex) or the inner complex of compound formation such as cyclodextrin, or with for example Mn
2+And Zn
2+Title complex Deng metal ion formation), polymorphic, solvate (for example hydrate), prodrug or liposome, coupling companion (coupling partner) and the protecting group of free acid or free alkali, compound.For example, " prodrug " refers to change in vivo any compound of bioactive compounds.
The salt of The compounds of this invention is preferably on the physiology and fully tolerates and avirulent salt.Many examples of salt are well known by persons skilled in the art.All these salt all within the scope of the invention, and related compound comprises the salt form of compound.
Comprise at compound under the situation of amine functional group, these compounds can for example form quaternary ammonium salt by the following method: according to technician's known method, make the reaction of described compound and alkylating agent.These quaternary ammonium compounds within the scope of the invention.
The compound that contains amine functional group also can form the N-oxide compound.The compound that contains amine functional group that the application is related also comprises the N-oxide compound.
Comprise at compound under the situation of some amine functional groups, one or more nitrogen-atoms oxidations can be formed the N-oxide compound.The specific examples of N-oxide compound is the N-oxide compound of tertiary amine or the N-oxide compound of nitrogenous heterocyclic nitrogen-atoms.
The N-oxide compound can prepare by the following method: handle corresponding amine with oxygenant (for example hydrogen peroxide or peracid (for example peroxycarboxylic acid)), referring to for example Advanced Organic Chemistry, by JerryMarch, 4th Edition, Wiley Interscience, pages.More specifically, can pass through L.W.Deady (Syn.Comm.1977,7, method 509-514) prepares the N-oxide compound, in described method, make amine compound and metachloroperbenzoic acid (MCPBA) for example in inert solvent (for example methylene dichloride) reaction.
Contain at compound under the situation of chiral centre, the various optical form of compound (for example enantiomer, epimer and diastereomer and racemic mixture) all within the scope of the invention.
Compound can exist by multiple different rotamerism form and tautomeric form, and related compound comprises all these forms.For fear of query, can exist and only specifically describe or shown under a kind of situation of form that all other forms all still comprise within the scope of the invention by one of several rotamerism forms or tautomeric form at compound.
The dosage of compound changes with the patient who is treated, and the dosage of compound be every day about 100ng/kg body weight to the 100mg/kg body weight, be preferably 10pg/kg to 10mg/kg every day.For example, dosage can easily be determined according to the knowledge of the disclosed content of the application and this area by those skilled in the art.Thereby the technician can easily determine the amount of compound and optional additives, vehicle and/or carrier in the composition, also can easily determine the amount of institute's administration in the method for the invention.
Compound of the present invention has demonstrated vitro inhibition beta-secretase (comprising BACE) activity.What shown is that the inhibitor of beta-secretase can be used for blocking the formation of A β peptide or gathering, and therefore has useful effect at the treatment alzheimer's disease with depositing in other relevant neurodegenerative disease with raising of A β peptide level and/or A β peptide.Therefore, believe that compound of the present invention can be used for treating alzheimer's disease and the disease relevant with dementia.Therefore, expect that compound of the present invention and salt thereof have the activity of antagonism age-related disease (for example alzheimer's disease and other A beta-related pathologies, for example mongolism and beta amyloid vascular disease).Expect that compound of the present invention most possibly uses as single medicine, but also can strengthen drug combination with a variety of cognitive defects.
The preparation method
The invention still further relates to the preparation method of formula (I) compound or pharmaceutically acceptable salt thereof of free alkali form.Below in the description to these methods, should be appreciated that to add suitable protecting group according to the mode that the those of ordinary skill in organic synthesis field is understood easily, and from each reactant and intermediate, remove protecting group subsequently suitable the time.Use the routine operation of these protecting groups and the case description of suitable protecting group to exist for example " Protective Groups in Organic Synthesis ", T.W.Greene, P.G.M.Wutz, 3
RdEdition, Wiley-Interscience, New York is in (1999).Should be appreciated that microwave can be used for reaction mixture is heated.
The preparation of intermediate
Described method (A, B, C, D, E, R wherein except as otherwise noted,
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Comprising as hereinbefore defined):
(i) compound (wherein C the is an aryl) diazotization that makes formula II is to obtain the compound of formula III, and wherein halogen (halo) is represented halogen such as bromine or chlorine.
Reaction can be carried out in the following manner: handle suitable amine with nitrous acid, follow formed diazonium salt (diazonium) with suitable cuprous halide (as cuprous bromide (I) or cuprous chloride (I)), perhaps use copper and Hydrogen bromide or salt acid treatment.Reaction can be in suitable solvent (as water), carries out to the temperature between refluxing at-20 ℃.
(ii) the compound (wherein halogen is represented halogen such as bromine or chlorine) to formula III carries out borylization (borylation), to obtain the compound of formula IV, wherein R
11Expression hydrogen, alkyl or aryl, or two R
11Can form the ring-type boric acid ester.
Reaction can be carried out in the following manner:
A) reaction is undertaken by using lithium alkylide (as butyllithium) or magnesium and suitable boron compound (as trimethyl borate or triisopropyl borate ester).Reaction can be in suitable solvent (as tetrahydrofuran (THF), hexane or methylene dichloride), and the temperature between-78 ℃ to+20 ℃ is carried out; Or
B) can be at the suitable palladium catalyst that contains or do not contain suitable ligand (as tricyclohexyl phosphine or 2-(dicyclohexyl phosphino-) biphenyl) (as three (dibenzalacetones), two palladiums (0), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II), tetrakis triphenylphosphine palladium (0), diphenylphosphine ferrocene palladium chloride or palladium) and the existence of suitable alkali (as tertiary amine (as triethylamine or diisopropylethylamine) or potassium acetate) under, use suitable boron substance (as 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-Lian-1,3,2-two oxa-boron heterocycle pentanes, two catechol ester groups, two boron (biscatecholatodiboron) or tetramethyl ethylene ketone borine (pinacolborane)) react.Reaction can be in suitable solvent (as dioxane, toluene, acetonitrile, water, ethanol or 1,2-glycol dimethyl ether) or their mixture, and the temperature between 20 ℃ to 160 ℃ is carried out.
(wherein halogen is represented for example bromine of halogen, R (iii) to make the compound of formula V
12Be aryl or heteroaryl) with the compound of formula VI (R wherein
13Be aryl or heteroaryl) react, to obtain the compound of formula VII.
Reaction can be carried out in the following manner: with the compound of lithium alkylide (as butyllithium) or magnesium processing formula V, then add the compound of formula VI.Reaction can be in suitable solvent (as ether or tetrahydrofuran (THF)), carries out to the temperature between refluxing at-78 ℃.
The compound reaction that (iv) makes formula VII is to obtain the compound of formula VIII.
Reaction can be carried out in the following manner: use suitable reductive agent (as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride) to reduce.Reaction can be in suitable solvent (as methyl alcohol, ethanol, ether or tetrahydrofuran (THF)), carries out to the temperature between refluxing at-78 ℃.
(the compound reaction that v) makes formula VIII is to obtain the compound of formula IX.
Reaction can be carried out in the following manner: the compound of handling formula VIII with suitable thiocarbonyl transfering reagent (thiocarbonyltransfer agent) (as thiocarbonic acid SOH O, O-two (pyridine-2-base ester) or thiophosgene).Reaction can be in suitable solvent (as methylene dichloride or chloroform), carries out to the temperature between refluxing at-78 ℃.
(the compound reaction that vi) makes formula IX is to obtain the compound of formula X.
Reaction can be carried out in the following manner: with suitable alkali (as potassium tert.-butoxide) in suitable solvent (as tetrahydrofuran (THF) or ether), at-78 ℃ to suitable lsothiocyanates (suc as formula the compound of IX) and the dithiocarbonic anhydride of Temperature Treatment between refluxing.
(the compound reaction that vii) makes formula X is to obtain the compound of formula XI.
Reaction can be carried out in the following manner: the compound of handling formula X with suitable diamines (as 1,3-diaminopropanes or quadrol).Reaction can be in suitable solvent (as ethanol or methyl alcohol), carries out to the temperature between refluxing at 0 ℃.
(viii) make compound (wherein F is ring B, C or the phenyl among the formula I) reaction of formula XII, to obtain the compound of formula XIII.
Reaction can be carried out in the following manner: with suitable Lewis acid (Lewis acid) (as boron tribromide) in suitable solvent (as methylene dichloride), at-78 ℃ to the described methyl ether of Temperature Treatment between refluxing.
(ix) compound (wherein F is ring B, C or the phenyl among the formula I) of formula XIII is reacted, to obtain the compound of formula XIV, wherein R
14Be alkyl.
Reaction can be carried out in the following manner: handle suitable alcohol with suitable SULPHURYL CHLORIDE or acid anhydrides (as methylsulfonyl chloride, 1-third SULPHURYL CHLORIDE, cyclopropyl SULPHURYL CHLORIDE or methylsulfonic acid acid anhydride) in the presence of suitable alkali (as triethylamine).Reaction can be in suitable solvent (as methylene dichloride), carries out to the temperature between refluxing at 0 ℃.Perhaps reaction can be carried out in the following manner: alkylsulfonyl with 1,1,1-three fluoro-N-phenyl-N-[(trifluoromethyls)] Toluidrin handles suitable alcohol in the presence of suitable alkali (as salt of wormwood or N-ethyl diisopropylamine).Reaction can be in suitable solvent (as methylene dichloride or tetrahydrofuran (THF)), and the temperature between 0 ℃ to 160 ℃ is carried out.
(x) compound of formula XI is reacted, to obtain the compound of formula XV.
Reaction can be carried out in the following manner: with suitable oxygenant (as tert-butyl hydroperoxide) and the suitable thioketones (suc as formula the compound of XI) of ammonia treatment.Reaction can be in suitable solvent (as methyl alcohol), carries out to the temperature between refluxing at 0 ℃.
The preparation method of end product
Another object of the present invention is the compound of preparation general formula (I) and the method for salt thereof, wherein except as otherwise noted, and A, B, C, D, E, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Define as mentioned.When expectation obtains acid salt, usable acid is (as hydrogen halide, example hydrochloric acid) handle free alkali in suitable solvent (as tetrahydrofuran (THF), ether, methyl alcohol, ethanol, chloroform or methylene dichloride or their mixture), reaction can take place between-30 ℃ to+50 ℃.
(a) make compound (wherein halogen is represented halogen such as the bromine) reaction of formula XVI to obtain the compound of formula I.
The reaction of method (a) can be carried out in the following manner: make suitable compound suc as formula the compound of XVI and suitable formula IV aryl boric acid or aryl-boric acid ester (R wherein
11Expression hydrogen, alkyl or aryl, or two R
11Can form the ring-type boric acid ester) coupling.Can use the suitable palladium catalyst that contains or do not contain suitable ligand (as triphenylphosphine, tri-butyl phosphine or 2-(dicyclohexyl phosphino-) biphenyl) (as [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II), tetrakis triphenylphosphine palladium (0), diphenylphosphine ferrocene palladium chloride, palladium (II) or two (dibenzalacetone) palladium (0)) react, or use nickel catalyzator (as nickel/carbon or 1,2-two (diphenylphosphino) ethane Nickel Chloride) and zinc and triphenylphosphine three (sodium sulfonate) to react.In reaction, can use suitable alkali, as cesium fluoride, alkanamine (as triethylamine), or alkaline carbonate or oxyhydroxide or alkaline earth metal carbonate or oxyhydroxide (as salt of wormwood, yellow soda ash, cesium carbonate or sodium hydroxide), reaction can be in the temperature between+20 ℃ to+160 ℃, in suitable solvent (as toluene, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, water, ethanol or N, dinethylformamide or their mixture), carry out.
(b) make compound (wherein halogen is represented halogen such as the bromine) reaction of formula XVI to obtain the compound of formula I.
The reaction of method (b) can be carried out in the following manner: make suitable compound suc as formula the aryl stannane of the compound of XVI and suitable formula XVII (R wherein
15Be the trialkyl tinbase) coupling.Can use the suitable palladium catalyst (as two (triphenylphosphine) palladium chloride (II), tetrakis triphenylphosphine palladium (0) or two (dibenzalacetone) palladium (0)) that contains or do not contain suitable ligand (as triphenylarsine), at suitable solvent (as N, dinethylformamide, tetrahydrofuran (THF), toluene, 1-Methyl-2-Pyrrolidone or dioxane) in, react to the temperature between refluxing at+20 ℃.
General method
Used raw material obtains from commercial source, or according to document operation preparation.
In Creator, Initiaror or Smith synthesizer monotype microwave cavity, carry out microwave heating, produce continuous gamma radiation at 2450MHz.
In specified deuterated solvent, be recorded in 300MHz, 400MHz, 500MHz or 600MHz record
1H NMR spectrum.Except as otherwise noted, use outfit to have the 3mm flow injection SEI of Z gradient
1H/D-
13The Bruker av400NMR spectrograph of C probe (use BEST215 liquid processor be used for sample injection) or use the Bruker DPX400NMR spectrograph that is equipped with the 4-nuclear probe that has the Z gradient obtains 400MHz spectrum.Use the BrukerDRX600NMR spectrograph record 600MH that is equipped with the 5mm TXI probe that has the Z gradient
1H NMR.Use Varian INOVA (magnet is Oxford AS500) 500NMR spectrograph record 500MHz
1H NMR.Chemical shift provides with the downfield of relative TMS and the ppm form of upfield.The resonance diversity (Resonance multiplicities) of unimodal, doublet, triplet, quartet, multiplet and broad peak is expressed as s, d, t, q, m and br respectively.
Be equipped with Waters X-Terra MS, record LC-MS analyzes on the Waters LCMS of C8-post (3.5 μ m, 100mm x 3.0mm i.d.).Flow phase system is grouped into by following one-tenth: the aqueous solution/acetonitrile of A:10mM ammonium acetate (95:5) and B: acetonitrile.Last 4-5 minute and use from the linear gradient of 0% to 100%B operation, flow velocity is 1.0mL/min.Mass spectrograph is equipped with the electric spray ion source (ESI) with positive ion mode or negative ion mode operation.Capillary voltage is 3kV, and mass spectrograph scans between m/z100-700 usually.Alternatively, LC-MS HPLC condition is as follows: post: Agilent ZorbaxSB-C82mm ID X 50mm; Flow velocity: 1.4mL/min; Gradient: last 3 minutes from 95%A to 90%B, kept 1 minute, last 1 minute and become 95%A, kept then 1 minute.Wherein A=contains the aqueous solution of 2% acetonitrile of 0.1% formic acid, and B=contains the acetonitrile solution of 2% water of 0.1% formic acid.UV-DAD 210-400nm, or
Carrying out LC-MS in the LC-MS system that single quadrupole mass spectrometer is formed by Waters Alliance 2795HPLC, Waters PDA 2996 diode-array detectors, Sedex75ELS detector and ZMD analyzes.Mass spectrograph is equipped with the electric spray ion source (ES) with positive ion mode or negative ion mode operation.Capillary voltage and awl voltage are set at 3.2kV and 30V respectively.Mass spectrograph scans between m/z100-600, and be 0.7s sweep time.Diode-array detector scans between 200-400nm.With the temperature regulation to 40 of ELS detector ℃, and pressure is made as 1.9 crust.For separation, use linear gradient, originate in 100%A (A:10mM ammonium acetate/5% acetonitrile), end at 100%B (B: acetonitrile).Employed post is X-Terra MS C8,3.0 * 50mm, and 3.5 μ m (Waters) are with the flow velocity operation of 1.0mL/min.The column oven temperature is set at 40 ℃, or
Carrying out LC-MS in the LC-MS system that single quadrupole mass spectrometer is formed by Waters Alliance 2795HPLC, Waters PDA 2996 diode-array detectors, Sedex75ELS detector and ZQ analyzes.Mass spectrograph is equipped with the electric spray ion source (ES) with positive ion mode or negative ion mode operation.Capillary voltage and awl voltage are set at 3.2kV and 30V respectively.Mass spectrograph scans between m/z 100-700, and be 0.3s sweep time.Diode-array detector scans between 200-400nm.With the temperature regulation to 40 of ELS detector ℃, and pressure is made as 1.9 crust.At X-Terra MS C8,3.0 * 50mm on the 3.5 μ m (Waters), separates with the flow velocity of 1mL/min.Use linear gradient, originate in 100%A (A:10mM ammonium acetate/5% acetonitrile, or 8mM formic acid/5% acetonitrile), end at 100%B (B: acetonitrile).The column oven temperature is set at 40 ℃, or
Carrying out LC-MS on the LC-MS that is made up of Waters sample processor 2777C, Waters 1525 μ binary pump, Waters 1500 column ovens, the single quadrupole mass spectrometer of Waters ZQ, Waters PDA2996 diode-array detector and Sedex85ELS detector analyzes.Mass spectrograph is equipped with the electric spray ion source (ES) with positive ion mode or negative ion mode operation.Mass spectrograph scans between m/z 100-700, and be 0.3s sweep time.Capillary voltage and awl voltage are set at 3.4kV and 30V respectively.Diode-array detector scans between 200-400nm.With the temperature regulation to 40 of ELS detector ℃, and pressure is made as 1.9 crust.Use linear gradient and separate, originate in 100%A (A:10mM ammonium acetate/5% acetonitrile, or 8mM formic acid/5% acetonitrile), end at 100%B (B: acetonitrile).Employed post is Gemini C18,3.0mm x 50mm, and 3 μ m, (Phenomenex), with the flow velocity operation of 1ml/min.The column oven temperature is set at 40 ℃, or
Carrying out LC-MS in the LC-MS system that single quadrupole mass spectrometer is formed by Waters Alliance 2795HPLC, Waters PDA 2996 diode-array detectors, Sedex 85ELS detector and ZQ analyzes.Mass spectrograph is equipped with the electric spray ion source (ES) with positive ion mode or negative ion mode operation.Capillary voltage and awl voltage are set at 3.2kV and 30V respectively.Mass spectrograph scans between m/z100-700, and be 0.3s sweep time.Diode-array detector scans between 200-400nm.With the temperature regulation to 40 of ELS detector ℃, and pressure is made as 1.9 crust.At X-Terra MS C8,3.0 * 50mm on the 3.5 μ m (Waters), separates with the flow velocity of 1mL/min.Use linear gradient, originate in 100%A (A:10mM ammonium acetate/5% acetonitrile, or 8mM formic acid/5% acetonitrile), end at 100%B (B: acetonitrile).The column oven temperature is set at 40 ℃, or carries out LC-MS and analyze on the LC-MS that is made up of Waters sample processor 2777C, Waters1525 μ binary pump, Waters1500 column oven, the single quadrupole mass spectrometer of Waters ZQ, Waters PDA2996 diode-array detector and Sedex85ELS detector.Mass spectrograph is equipped with atmospheric pressure chemical ionization (APCI) ion source, and described ion source also is equipped with normal atmosphere photo-ionisation (APPI) device.Mass spectrograph scans with positive ion mode (switching between APCI and APPI).Mass range is set at m/z 120-800, uses the sweep time of 0.3s.APPI reverberator (repeller) and APCI corona (corona) are set at 0.86kV and 0.80 μ A respectively.In addition, desolvation temperature (300 ℃), desolvation gas (400L/Hr) and awl gas (5L/Hr) all are consistent for APCI with the APPI pattern.Use Gemini post C18,3.0mm x 50mm, 3 μ m (Phenomenex) separate, and move with the flow velocity of 1ml/min.Use linear gradient, originate in 100%A (A:10mM ammonium acetate/5% methyl alcohol), end at 100%B (methyl alcohol).The column oven temperature is set at 40 ℃.
GC-MS: (GC 6890, carry out compound identification on 5973NMSD) in the GC-MS system that is provided by Agilent Technologies.Employed post is VF-5MS, ID0.25mm * 30m, 0.25 μ m (Varian Inc.).Use the linear temperature gradient, originate in 40 ℃ (keeping 1 minute) and end at 300 ℃ (keeping 1 minute), 25 ℃/minute.Mass spectrograph is equipped with chemi-ionization (CI) ion source, and reactant gas is a methane.Mass spectrograph is equipped with electron-bombardment (EI) ion source, and electronic voltage is made as 70eV.Mass spectrograph scans between m/z 50-500, and sweep velocity was made as for 3.25 scanning/seconds, or
(GC 6890, carry out compound identification on 5973NMSD) in the GC/DIP-MS system that is provided by Agilent Technologies.Direct probe (Direct Inlet Probe, DIP) interface that mass spectrograph is equipped with SIM GmbH to make.Mass spectrograph is equipped with chemi-ionization (CI) ion source, and reactant gas is a methane.Mass spectrograph is equipped with electron-bombardment (EI) ion source, and electronic voltage is made as 70eV.Mass spectrograph scans between m/z 50-500, and sweep velocity was made as for 3.25 scanning/seconds.When introducing sample by the direct injection mouth, 1 μ l sample solution is added to probe tip, and thermograde is applied to probe, originate in 40 ℃, and end at 400 ℃, 2 ℃/s.When introducing sample by GC, use the linear temperature gradient, originate in 40 ℃ (keeping 1 minute), and end at 300 ℃ (keeping 1 minute), 25 ℃/minute.Employed post is VF-5MS, ID0.25mm x 30m, 0.25 μ m (Varian Inc.).
Preparation property HPLC: being prepared property chromatogram on the automatic purifying HPLC of the Waters with diode-array detector.Post: XTerra MS C8,19 x 300mm, 10 μ m.Use the gradient of 5% acetonitrile solution of the 0.1M ammonium acetate of acetonitrile/in MilliQWater, the acetonitrile from 20% moves to 60% acetonitrile, lasts 13 minutes.Flow velocity: 20mL/min.Alternatively, partly carrying out purifying on the preparation property ShimadzuLC-8A HPLC, it has the Waters of being equipped with
Post (C18,5 μ m, the Shimadzu SPD-10A UV-visible light detector of 100mm * 19mm).Use the gradient of 0.1% trifluoroacetic acid of acetonitrile/in MilliQ Water.Acetonitrile from 35% moves to 60% acetonitrile, lasts 20 minutes.Flow velocity: 10ml/min.
Alternatively, using another kind of post is Atlantis C18 19 x 100mm, 5 μ m chromatographic columns.Use the gradient of 5% acetonitrile solution of the 0.1M ammonium acetate of acetonitrile/in MilliQ Water.Move to the 35-50% acetonitrile from 0% acetonitrile, last 15 minutes.Flow velocity: 15mL/min, or
Is being furnished with being prepared property chromatogram in automatic sampler and automatization run tank (Waters 2767), gradient pump (Waters2525), regenerative pump (Waters 600), make-up pump (Waters 515), Waters Active Splitter, post switching (Waters CFO), PDA (Waters 2996) and the mass spectrometric WatersFractionLynx of the Waters ZQ system.Post: XBridge
TMPrep C85 μ m OBD
TM19x100mm has guard column XTerra
Prep MS C8 10 μ m 19 x 10mm cylinders.Separate for LC, to the gradient of 100%B (100% acetonitrile), flow velocity is 25mL/min from 100% A (the MilliQ Water and 5% acetonitrile that contain 95% 0.1M ammonium acetate) in application.PDA scans between 210-350nm.The ZQ mass spectrograph uses the ESI operation of positive ion mode.Capillary voltage is 3kV, and awl voltage is 30V.By mixing triggering is that UV and MS signal are determined fraction collection.
At Merch TLC plate (silica gel 60F
254) on carry out thin-layer chromatography (TLC), spot is manifested by UV.Use Merck silica gel 60 (0.040-0.063mm) or utilize Combi Flash
Companion
TMSystem (uses RediSep
TMThe quick post of positive) carries out flash chromatography.
Use software ACD/Name, 8.0 or 9.0 versions (Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004 and 2005) are named compound.
Embodiment
Next be a plurality of non-limiting examples of The compounds of this invention.
Embodiment 1
4-bromo-1-fluoro-2-anisole
(48%, (1.0g, the 7.1mmol) solution in water (10mL) is cooled to 0 ℃ with the mixture that obtains then in ice bath 2.41mL) to be added to 4-fluoro-3-anisidine with hydrobromic acid aqueous solution.(holding temperature is between 0-5 ℃ simultaneously for 538mg, the 7.8mmol) solution in water (5mL) to last 15 minutes dropping Sodium Nitrites.The diazonium salt solution that obtains is added to the cuprous bromide (I) that preheats to 75 ℃, and (1.12g is 7.8mmol) in the suspension in water (5mL).Fully shake mixture, and the adding hydrobromic acid aqueous solution (48%, 12.07mL), then solution is stirred 16h in envrionment temperature.Add excessive water, the product extracted with diethyl ether, the organic extract liquid of merging washs with saturated sodium-chloride water solution, through dried over mgso, filters, and vacuum evaporating solvent then obtains 1.02g (70% yield) title compound:
1H-NMR(DMSO-d
6)：δ?7.36(dd，J＝7.78，2.26Hz，1H)，7.23-7.17(m，1H)，7.14-7.09(m，1H)，3.86(s，H)；MS(EI)m/z?204，206[M+1]。
Embodiment 2
2-(4-fluoro-3-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentanes
With anhydrous 1,2-glycol dimethyl ether (12mL) be added to 4-bromo-1-fluoro-2-anisole (1.02g, 5.0mmol), three (dibenzalacetones), two palladiums (0) (228mg, 0.25mmol), tricyclohexyl phosphine (209mg, 0.75mmol), salt of wormwood (732mg, 7.5mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-Lian-1,3,2-two oxa-boron heterocycle pentanes (1.14g, 4.5mmol) in, then with the mixture that obtains in microwave at 150 ℃ of irradiation 1h.When being cooled to envrionment temperature, mixture is filtered, vacuum evaporating solvent obtains crude product: MS (EI) m/z 252[M+1 then].
Embodiment 3
3-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenol
Title compound is as described in example 2 above, begins synthetic, 48% yield from 3-chloro-5-methoxyphenol.Carry out purifying through column chromatography (gradient of using methylene dichloride/acetonitrile (100/0 to 90/10) is as eluent):
1H-NMR (DMSO-d
6): δ 9.36 (s, 1H), 6.69 (d, J=2.3Hz, 1H), 6.61 (d, J=2.0Hz, 1H), 6.41 (t, J=2.4Hz, 1H), 3.69 (s, 3H), 1.27 (s, 12H); MS (ES) m/z251[M+1]
+
Embodiment 4
Methylsulfonic acid 3-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl ester
At 0 ℃ of 3-methoxyl group-5-(4 under argon gas atmosphere to stirring, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenol (0.12g, 0.48mmol) add triethylamine (0.058g in the solution in methylene dichloride (3mL), 0.58mmol), then add methylsulfonyl chloride (0.071g, 0.62mmol).Make reaction mixture reach envrionment temperature and stir 18h, then with the mixture vacuum concentration that obtains to doing.Carry out purifying through column chromatography (gradient of using methylene dichloride/acetonitrile (100/0 to 90/10) is as eluent), obtain 0.050g (32% yield) title compound:
1H-NMR (CDCl
3): δ 7.30 (d, J=2.3Hz, 1H), 7.28 (d, J=2.0Hz, 1H), 6.96 (t, J=2.4Hz, 1H), 3.86 (s, 3H), 3.16 (s, 3H), 1.35 (s, 12H); MS (ES) m/z 329[M+1]
+
Embodiment 5
3-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenol
(5g, 19.9mmol are described in Maleczka R.E.et.al.J.Am.Chem.Soc.2003 with 3-bromo-5-chlorophenol, 125, among the 7792-7793), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-Lian-1,3,2-two oxa-boron heterocycle pentane (6.06g, 23.9mmol), [1,1 '-two (diphenylphosphino) ferrocene] and palladium chloride (II) methylene dichloride adducts (487mg, 0.6mmol), potassium acetate (5.86g, 59.7mmol), 1,2-glycol dimethyl ether (60mL) and water (4mL) divide in four the microwave bottles of packing into, shine 15 minutes at 150 ℃ in each comfortable microwave then.When being cooled to envrionment temperature, combined mixture with the salt solution dilution, is used extracted with diethyl ether then.The organic phase that merges is through dried over sodium sulfate, then vacuum concentration.Carry out purifying through column chromatography (gradient of using 0-5% acetonitrile/methylene dichloride is as eluent), obtain 1.43g (28% yield) title compound:
1H NMR (DMSO-d
6) δ 9.89 (s, 1H), 7.02 (s, 2H), 6.91 (s, 1H), 1.28 (s, 12H); MS (ES) m/z 253[M-1]
-
Embodiment 6
Methylsulfonic acid 3-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl ester
(122 μ L 0.79mmol) are added drop-wise to 3-chloro-5-(4,4 with methylsulfonyl chloride at 0 ℃, 5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenol (200mg, 0.79mmol) and triethylamine (0.4mL is 3.14mmol) in the mixture in anhydrous methylene chloride (1.5mL).Reaction mixture stirs 1h in envrionment temperature, with methylene dichloride (10mL) dilution, washes with water, and through dried over sodium sulfate, vacuum concentration then obtains the rough title compound of 0.200g (86% yield):
1H NMR (CDCl
3) δ 7.75 (d, J=1.52Hz, 2H), 7.57 (d, J=1.77Hz, 2H), 7.41 (t, J=2.15Hz, 1H), 3.18 (s, 3H), 1.35 (s, 12H); MS (EI) m/z 332[M+1].
Embodiment 7
1-(3-bromophenyl)-1-(4-p-methoxy-phenyl) methylamine
50 ℃ with 4-bromine phenylmethylether (5.3g, anhydrous tetrahydro furan 28.4mmol) (25mL) drips of solution be added to magnesium (0.69g, 28.4mmol) and the mixture of iodine crystal in anhydrous tetrahydro furan (25mL) in.Mixture is stirred 5h, be cooled to room temperature then.(3.5g, the 19mmol) solution in anhydrous tetrahydro furan (30mL) heat 16h with mixture at 60 ℃ then to last 30 minutes dropping 3-bromobenzylcyanides.Mixture is cooled to room temperature, adds anhydrous methanol (25mL), then mixture restir 45 minutes just.Mixture is cooled to 0 ℃, and (1.4g 38mmol), makes mixture reach room temperature then and stirs 4h to last 15 minutes and add in batches sodium borohydride.Add saturated aqueous ammonium chloride, vacuum is removed most of organic solvent then.The resistates dichloromethane extraction.Organic phase is filtered and evaporation through dried over sodium sulfate.Carry out purifying through column chromatography (using ethyl acetate (10-35%)/normal heptane), obtain 4.5g (81% yield) title compound as eluent:
1H NMR (DMSO-d
6) δ 7.59-7.57 (m, 1H), 7.37-7.33 (m, 2H), 7.30-7.26 (m, 2H), 7.25-7.20 (m, 1H), 6.86-6.82 (m, 2H), 5.03 (s, 1H), 3.70 (s, 3H), 2.31 (br s, 2H); MS m/z (CI) 291,293[M+1]
+
Embodiment 8
1-(3-bromophenyl)-1-pyridin-4-yl methylamine
(hexane solution of 2.5M, 10.20mL 25.40mmol) are added to refrigerative (78 ℃) 1, and (6g is 25.40mmol) in the solution in anhydrous diethyl ether (60mL) for the 3-dibromobenzene with butyllithium under argon gas atmosphere.The mixture that obtains is stirred 1h at-78 ℃.(2.64g, the 25.40mmol) solution in anhydrous diethyl ether (45mL) continue to stir 20 minutes at-78 ℃ then to add the 4-cyanopyridine.Make reaction mixture reach envrionment temperature, add anhydrous methanol (30mL), then with the mixture restir that obtains 45 minutes.Solution is cooled to 0 ℃, and (1.3g 34.0mmol), stirs reaction mixture then and spends the night in envrionment temperature to add sodium borohydride.The careful saturated aqueous ammonium chloride (40mL) that adds concentrates mixture then.Water is with methylene dichloride (40mL) extracting twice, and organic layer is through dried over sodium sulfate, vacuum concentration.Product through column chromatography (use chloroform: the gradient elution of methyl alcohol 0-10%) carry out purifying, obtain 4.22g (63% yield) title compound:
1H NMR (CDCl
3) δ 8.56 (dd, J=4.55,1.52Hz, 2H), 7.54 (t, J=1.77Hz, 1H), 7.40 (dt, J=7.83,1.52Hz, 1H), 7.33-7.24 (m, 3H), 7.20 (t, J=7.83Hz, 1H), 5.15 (s, 1H), 1.78 (br s, 2H); MS (ESI) m/z 264,266[M+1]
+
Embodiment 9
1-bromo-3-[isothiocyano (4-p-methoxy-phenyl) methyl] benzene
At 0 ℃ with thiophosgene (1.3mL, 17mmol) be added to 1-(3-bromophenyl)-1-(4-p-methoxy-phenyl) methylamine (4.5g of stirring in batches, 15.4mmol) in the solution and saturated sodium bicarbonate aqueous solution (40mL) in methylene dichloride (70mL), then mixture is stirred 2h at 0 ℃.Collect organic phase, the water dichloromethane extraction.The organic extract liquid salt water washing that merges, through dried over sodium sulfate, filtering also, vacuum concentration obtains 5.02g (98% yield) title compound:
1H NMR (DMSO-d
6) δ 7.57-7.52 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.30 (m, 2H), 6.99-6.95 (m, 2H), 6.48 (s, 1H), 3.75 (s, 3H).
Embodiment 10
The 4-[(3-bromophenyl) (isothiocyano) methyl] pyridine
With thiocarbonic acid SOH O, O-two (pyridine-2-base ester) (183mg, 0.79mmol; Be described in Kim S.et al.Tetrahedron Lett.1985,26 (13), among the 1661-1664) disposablely be added to 1-(3-bromophenyl)-1-pyridin-4-yl methylamine (100mg is 0.38mmol) in the solution in methylene dichloride (2mL).Mixture was stirred 30 minutes, use methylene dichloride (15mL) dilution then, use the salt water washing, obtain 0.100g (86% yield) crude product: MS (ES) m/z 305,307[M+1] through dried over sodium sulfate and vacuum concentration
+
Embodiment 11
4-(3-bromophenyl)-4-(4-p-methoxy-phenyl)-1,3-thiazoles alkane-2, the 5-dithione
At-78 ℃ with 1-bromo-3-[isothiocyano (4-p-methoxy-phenyl) methyl] benzene (8.7g, 26mmol) and dithiocarbonic anhydride (3.1mL, 52mmol) drips of solution in anhydrous tetrahydro furan (30mL) is added to the potassium tert.-butoxide of stirring (4.2g is 37mmol) in the mixture in anhydrous tetrahydro furan (80mL).After the adding, make mixture reach room temperature and spend the night.Add entry, salt solution and ethyl acetate, collect organic phase then.The water ethyl acetate extraction, the salt water washing of the organic extract liquid of merging obtains 10.5g (98% yield) title product through dried over sodium sulfate and evaporation:
1H NMR (DMSO-d
6) δ 7.48-7.43 (m, 1H), 7.41-7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.22-7.18 (m, 2H), 6.89-6.85 (m, 2H), 3.74 (s, 3H).
Embodiment 12
4-(3-bromophenyl)-4-pyridin-4-yl-thiazolidine-2, the 5-dithione
At-78 ℃ with the 4-[(3-bromophenyl) (isothiocyano) methyl] pyridine (4.63g, 15.19mmol) and dithiocarbonic anhydride (1.82mL, 30.38mmol) drips of solution in anhydrous tetrahydro furan (30mL) is added to the potassium tert.-butoxide of stirring (2.56g is 22.79mmol) in the solution in anhydrous tetrahydro furan (60mL).Make mixture reach envrionment temperature, stir simultaneously and spend the night.Evaporating solvent is dissolved in resistates in the ethyl acetate (100mL) then, uses the salt water washing, through dried over sodium sulfate and vacuum concentration.Through column chromatography (use chloroform: the gradient elution of methyl alcohol 0-10%) carry out purifying, obtain 4.95g (85% yield) title compound: MS (ES) m/z 382,383[M+1]
+
Embodiment 13
8-(3-bromophenyl)-8-(4-p-methoxy-phenyl)-3,4,7, the 8-imidazolidine is [1,5-a] pyrimidine-6 (2H)-thioketones also
With 4-(3-bromophenyl)-4-(4-p-methoxy-phenyl)-1,3-thiazoles alkane-2, (7g, 15mmol) with 1, (3.3g, 44mmol) solution in ethanol (70mL) is at 70 ℃ of heating 1.5h for the 3-diaminopropanes for the 5-dithione.Mixture is cooled to room temperature and concentrated, and resistates dilutes with ethyl acetate, with saturated sodium bicarbonate aqueous solution and salt water washing, through dried over sodium sulfate and evaporation.Carry out purifying through column chromatography (using ethyl acetate (5-25%)/normal heptane), obtain 5.1g (83% yield) title compound as eluent:
1HNMR (DMSO-d
6) δ 10.82 (s, 1H), 7.54-7.51 (m, 2H), 7.44-7.41 (m, 1H), 7.37-7.33 (m, 1H), 7.27-7.23 (m, 2H), 6.96-6.92 (m, 2H), 3.74 (s, 3H), 3.74-3.70 (m, 2H), 3.49-3.44 (m, 2H), 1.80-1.73 (m, 2H).
Embodiment 14
8-(3-bromophenyl)-8-(4-hydroxy phenyl)-3,4,7, the 8-imidazolidine is [1,5-a] pyrimidine-6 (2H)-thioketones also
With 8-(3-bromophenyl)-8-(4-p-methoxy-phenyl)-3,4,7, the 8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones (4.5g 10.9mmol) is dissolved in the methylene dichloride (100mL), is cooled to 0 ℃ then.(1.5mL 16mmol), is warmed to mixture room temperature then and stirs 2h to add boron tribromide.Mixture is cooled to 0 ℃, and (1.5mL 16mmol), makes mixture reach room temperature and stirs 1h to add more boron tribromide then.Add entry, salt solution and ethyl acetate, collect organic phase then.Water is handled with dense ammonium hydroxide, uses ethyl acetate extraction then.The organic phase salt water washing that merges obtains 3.6g (82% yield) title compound through dried over sodium sulfate and evaporation:
1H NMR (DMSO-d
6) δ 10.77 (s, 1H), 9.58 (s, 1H), 7.55-7.51 (m, 2H), 7.44-7.40 (m, 1H), and 7.38-7.32 (m, 1H), 7.13-7.09 (m, 2H), 6.76-6.72 (m, 2H), 3.74-3.69 (m, 2H), 3.48-3.43 (m, 2H), 1.80-1.73 (m, 2H).
Embodiment 15
Methylsulfonic acid 4-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester
To 8-(3-bromophenyl)-8-(4-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones (3.6g, 8.9mmol) and triethylamine (1.7mL 12mmol) adds methylsulfonyl chloride (0.78mL in the mixture in methylene dichloride (50mL), 10mmol), then the mixture stirring is spent the night.(0.85mL 6mmol), heats 4h with mixture at 30 ℃ then to add more triethylamine.Evaporating solvent distributes resistates then between ethyl acetate and saturated sodium bicarbonate aqueous solution.Organic phase salt water washing is through dried over sodium sulfate and concentrated.Carry out purifying through column chromatography (using ethyl acetate (10-50%)/normal heptane), obtain 2.4g (56% yield) title compound as eluent:
1H NMR (DMSO-d
6) δ 10.93 (brs, 1H), 7.59-7.51 (m, 2H), 7.48-7.43 (m, 3H), 7.40-7.35 (m, 3H), 3.76-3.71 (m, 2H), 3.51-3.47 (m, 2H), 3.40 (s, 3H), 1.82-1.75 (m, 2H).
Embodiment 16
Third-1-sulfonic acid 4-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester
Title compound is as described in the embodiment 15, and from 8-(3-bromophenyl)-8-(4-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones and 1-third SULPHURYL CHLORIDE begins to prepare, 68% yield:
1H NMR (DMSO-d
6) δ 10.93 (br s, 1H), 7.58-7.54 (m, 2H), 7.46-7.43 (m, 3H), 7.40-7.33 (m, 3H), 3.73 (t, J=5.90Hz, 2H), 3.53-3.47 (m, 4H), 1.87-1.81 (m, 2H), 1.81-1.75 (m, 2H), 1.03 (t, J=7.53Hz, 3H).
Embodiment 17
Cyclopropyl sulfonic acid 4-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester
Title compound is as described in the embodiment 15, and from 8-(3-bromophenyl)-8-(4-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones and cyclopropyl SULPHURYL CHLORIDE begins to prepare, 65% yield:
1H NMR (DMSO-d
6) δ 10.93 (br s, 1H), 7.57-7.54 (m, 2H), 7.48-7.44 (m, 2H), 7.43-7.36 (m, 4H), 3.74 (t, J=6.15Hz, 2H), 3.49 (t, J=5.27Hz, 2H), 3.09-3.02 (m, 1H), 1.82-1.76 (m, 2H), 1.20-1.16 (m, 2H), and 1.06-1.01 (m, 2H).
Embodiment 18
7-(3-bromophenyl)-7-(4-p-methoxy-phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones
Title compound is as described in the embodiment 13, and from 4-(3-bromophenyl)-4-(4-p-methoxy-phenyl)-1,3-thiazoles alkane-2,5-dithione and quadrol (but heating 36h) begin to prepare, 55% yield:
1HNMR (DMSO-d
6) δ 10.62 (s, 1H), 7.62 (t, J=1.88Hz, 1H), and 7.57-7.54 (m, 1H), 7.49-7.46 (m, 1H), 7.38 (t, J=7.91Hz, 1H), 7.33-7.29 (m, 2H), 6.99-6.95 (m, 2H), 4.31 (t, J=8.78Hz, 2H), 3.74 (s, 3H), 3.71 (t, J=8.78Hz, 2H).
Embodiment 19
7-(3-bromophenyl)-7-(4-hydroxy phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones
This compound is that from 7-(3-bromophenyl)-7-(4-p-methoxy-phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones begins to prepare 98% yield as described in the embodiment 14:
1HNMR (DMSO-d
6) δ 10.56 (s, 1H), 9.64 (s, 1H), 7.63-7.61 (m, 1H), 7.56-7.53 (m, 1H), 7.49-7.45 (m, 1H), 7.38 (t, J=7.91Hz, 1H), and 7.20-7.16 (m, 2H), 6.79-6.75 (m, 2H), 4.30 (t, J=8.78Hz, 2H), 3.70 (t, J=8.78Hz, 2H).
Embodiment 20
Methylsulfonic acid 4-[7-(3-bromophenyl)-5-sulfo--2,5,6,7-tetrahydrochysene-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester
This compound is that from 7-(3-bromophenyl)-7-(4-hydroxy phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones begins to prepare 58% yield as described in the embodiment 15:
1HNMR (DMSO-d
6) δ 10.74 (s, 1H), 7.68 (t, J=1.88Hz, 1H), 7.60-7.57 (m, 1H), 7.56-7.49 (m, 3H), 7.44-7.38 (m, 3H), 4.33 (t, J=9.03Hz, 2H), 3.72 (t, J=8.91Hz, 2H), 3.40 (s, 3H); MS (ES) m/z 464,466[M-1]
-
Embodiment 21
Third-2-sulfonic acid 4-[7-(3-bromophenyl)-5-sulfo--2,5,6,7-tetrahydrochysene-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester
This compound is that from 7-(3-bromophenyl)-7-(4-hydroxy phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones and sec.-propyl SULPHURYL CHLORIDE begin to prepare, 40% yield as described in the embodiment 15:
1H NMR (DMSO-d
6) δ 10.73 (s, 1H), 7.67 (t, J=1.76Hz, 1H), 7.56-7.67 (m, 1H), 7.54-7.49 (m, 3H), 7.43-7.37 (m, 3H), 4.36-4.29 (m, 2H), 3.77-3.69 (m, 3H), 1.42 (s, 3H), 1.41 (s, 3H).
Embodiment 22
8-(3-bromophenyl)-8-(pyridin-4-yl)-3,4,7, the 8-imidazolidine is [1,5-a] pyrimidine-6 (2H)-thioketones also
With 4-(3-bromo-phenyl)-4-pyridin-4-yl-thiazolidine-2, (1.99g, 5.22mmol) with 1, (1.31mL, 15.66mmol) mixture in ethanol (40mL) is 70 ℃ of heated overnight for the 3-diaminopropanes for the 5-dithione.Mixture is cooled to envrionment temperature and vacuum concentration.Resistates is dissolved in the methylene dichloride (40mL), and water and salt water washing are through dried over sodium sulfate and vacuum concentration.Carry out purifying through column chromatography (use chloroform: the gradient of methyl alcohol 0-10% is as eluent), obtain 1.59g (79% yield) title compound:
1HNMR (CDCl
3) δ 8.89 (s, 1H), 8.64 (dd, J=4.55,1.77Hz, 2H), 7.58-7.50 (m, 2H), 7.38-7.31 (m, 3H), 7.29-7.25 (m, 1H), 3.92 (t, J=6.06Hz, 2H), 3.65 (q, J=5.64Hz, 2H), 2.01-1.90 (m, 2H); MS (ES) m/z 387,389[M+1]
+
Embodiment 23
Methylsulfonic acid 4-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
With methylsulfonic acid 4-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] (2.4g 5mmol) is dissolved in methyl alcohol (70mL) and the dense ammonium hydroxide (40mL) phenyl ester.(13.7mL, 70% the aqueous solution 100mmol), in stirred overnight at room temperature, heat 3h at 30 ℃ with mixture then to add tert-butyl hydroperoxide.Evaporate most of methyl alcohol, add entry and saturated aqueous sodium carbonate, the mixture ethyl acetate extraction.The organic extract liquid water and the salt water washing that merge are through dried over sodium sulfate and evaporation.Dry in vacuum drying oven, obtain 2.1g (90% yield) title product:
1HNMR (DMSO-d
6) δ 7.73-7.72 (m, 1H), 7.63-7.57 (m, 3H), 7.39-7.36 (m, 1H), 7.26-7.22 (m, 3H), 6.35 (br s, 2H), 3.55-3.51 (m, 2H), 3.43-3.39 (m, 2H), 3.34 (s, 3H), 1.71-1.65 (m, 2H).
Embodiment 24
Third-1-sulfonic acid 4-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
Title compound is as described in the embodiment 23, from third-1-sulfonic acid 4-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester begins to prepare 102% yield:
1HNMR (DMSO-d
6) δ 7.72 (t, J=1.88Hz, 1H), 7.63-7.56 (m, 3H), and 7.40-7.36 (m, 1H), 7.27-7.19 (m, 3H), 3.53 (t, J=5.65Hz, 2H), 3.49-3.44 (m, 2H), 3.42 (t, J=5.52Hz, 2H), and 1.86-1.77 (m, 2H), 1.72-1.65 (m, 2H), 1.02 (t, J=7.40Hz, 3H); MS (ES) m/z489,491[M-1]
-
Embodiment 25
Cyclopropyl sulfonic acid 4-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
Title compound is as described in the embodiment 23, from cyclopropyl sulfonic acid 4-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester begins to prepare 97% yield:
1HNMR (DMSO-d
6) δ 7.69 (t, J=1.88Hz, 1H), 7.63-7.58 (m, 2H), 7.57-7.53 (m, 1H), 7.40-7.36 (m, 1H), 7.26-7.23 (m, 3H), 3.54 (t, J=5.77Hz, 2H), 3.41 (t, J=5.40Hz, 2H), 3.04-2.97 (m, 1H), 1.73-1.65 (m, 2H), 1.19-1.15 (m, 2H), 1.05-0.98 (m, 2H); MS (ES) m/z 487,489[M-1]
-
Embodiment 26
8-(3-bromophenyl)-8-(4-p-methoxy-phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-6-amine also
Title compound is that from 8-(3-bromophenyl)-8-(4-p-methoxy-phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones begins to prepare 99% yield as described in the embodiment 23:
1HNMR (DMSO-d
6) δ 7.67-7.65 (m, 1H), 7.55-7.51 (m, 1H), 7.42-7.38 (m, 2H), 7.37-7.33 (m, 1H), 7.23-7.19 (m, 1H), 6.83-6.79 (m, 2H), 3.70 (s, 3H), 3.54-3.50 (m, 2H), 3.41-3.37 (m, 2H), 1.70-1.64 (m, 2H).
Embodiment 27
7-(3-bromophenyl)-7-(4-p-methoxy-phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-5-amine
Title compound is that from 7-(3-bromophenyl)-7-(4-p-methoxy-phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones begins to prepare 97% yield as described in the embodiment 23:
1HNMR (DMSO-d
6) δ 10.72 (br s, 2H), 7.70 (t, J=1.76Hz, 1H), 7.56-7.52 (m, 1H), 7.45-7.40 (m, 2H), 7.39-7.36 (m, 1H), 7.24 (t, J=7.91Hz, 1H), 6.86-6.82 (m, 2H), 4.29-4.22 (m, 2H), 3.70 (s, 3H), 3.53-3.47 (m, 2H).
Embodiment 28
Methylsulfonic acid 4-[5-amino-7-(3-bromophenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester
Title compound is as described in the embodiment 23, from methylsulfonic acid 4-[7-(3-bromophenyl)-5-sulfo--2,5,6,7-tetrahydrochysene-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester begins to prepare 99% yield:
1HNMR (DMSO-d
6) δ 10.73 (s, 1H), 7.76 (t, J=1.76Hz, 1H), 7.67-7.63 (m, 2H), 7.60-7.57 (m, 1H), 7.42-7.39 (m, 1H), 7.29-7.27 (m, 3H), 4.29 (t, J=8.91Hz, 2H), 3.52 (t, J=8.78Hz, 2H), 3.35 (s, 3H).MS(ES)m/z?447，449[M-1]
-。
Embodiment 29
Third-2-sulfonic acid 4-[5-amino-7-(3-bromophenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester
Title compound is as described in the embodiment 23, from third-2-sulfonic acid 4-[7-(3-bromophenyl)-5-sulfo--2,5,6,7-tetrahydrochysene-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester begins to prepare 106% yield:
1HNMR (DMSO-d
6) δ 7.75 (t, J=1.88Hz, 1H), 7.65-7.61 (m, 2H), 7.59-7.56 (m, 1H), 7.42-7.39 (m, 1H), 7.29-7.23 (m, 3H), 6.47 (br s, 2H), 4.29 (t, J=8.78Hz, 2H), 3.74-3.64 (m, 1H), 3.52 (t, J=8.78Hz, 2H), 1.41 (s, 3H), 1.39 (s, 3H).
Embodiment 30
8-(3-bromophenyl)-8-(pyridin-4-yl)-2,3,4,8-tetrahydrochysene-imidazo [1,5-a] pyrimidine-6-amine
With 8-(3-bromophenyl)-8-(pyridin-4-yl)-3,4,7, the 8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones (2.60g 6.7mmol) is dissolved in the methyl alcohol (90mL).Add the tert-butyl hydroperoxide aqueous solution (70%, 15mL, 100.5mmol) and ammoniacal liquor (30%, 30mL), then the mixture that obtains is spent the night in the envrionment temperature stirring.Enriched mixture is dissolved in resistates in the methylene dichloride (90mL), uses the salt water washing, through dried over sodium sulfate and vacuum concentration.Through column chromatography (use chloroform (methanol solution of 0.5% 7M ammonia): the gradient elution of methyl alcohol 0-10%) carry out purifying, obtain 1.97g (80% yield) title compound:
1HNMR (CDCl
3) δ 8.52 (d, J=6.06Hz, 2H), 7.66 (t, J=1.77Hz, 1H), 7.46-7.36 (m, 4H), 7.16 (t, J=7.96Hz, 1H), 3.72 (t, J=5.94Hz, 2H), 3.61 (ddd, J=5.43,2.65,2.53Hz, 2H), 1.92-1.82 (m, 2H); MS (ES) m/z 370,372[M+1]
+
Method A:
Embodiment 31
Methylsulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate
With methylsulfonic acid 4-[6-amino-8-(3-bromophenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] and phenyl ester (70mg, 0.15mmol), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride adducts (12mg, 0.015mmol), salt of wormwood (125mg, 0.9mmol) and 3-anisole ylboronic acid (29mg, 0.19mmol) solution in anhydrous tetrahydro furan (3mL) in microwave 130 ℃ the irradiation 2h.When being cooled to envrionment temperature, the mixture filtration is added dimethyl sulfoxide (DMSO) (800 μ L) then.With solution for vacuum concentration, remove tetrahydrofuran (THF), obtain 19mg (23% yield) title compound through preparation property HPLC purifying then:
1H NMR (CDCl
3) δ 7.85-7.82 (m, 1H), 7.70-7.66 (m, 2H), 7.58-7.54 (m, 1H), and 7.49-7.45 (m, 1H), 7.39-7.32 (m, 2H), 7.26-7.22 (m, 2H), 7.11-7.08 (m, 1H), 7.05-7.03 (m, 1H), 6.95-6.91 (m, 1H), 3.80 (s, 3H), 3.57-3.52 (m, 2H), 3.45-3.41 (m, 2H), 3.34 (s, 3H), 1.91 (s, 3H), 1.73-1.66 (m, 2H); MS (ES) m/z 491[M+1]
+
Method B:
Embodiment 32
Methylsulfonic acid 4-[6-amino-8-(3-pyrazine-2-base phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate
With methylsulfonic acid 4-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine also [1,5-a] pyrimidine-8-yl] phenyl ester (60mg, 0.13mmol), two (triphenylphosphine) palladium chloride (II) (5mg, 0.0065mmol) and 2-tributyl tinbase pyrazine (67mg, 0.18mmol) solution in anhydrous tetrahydro furan (2mL) in microwave 130 ℃ the irradiation 1h.When being cooled to envrionment temperature, mixture is filtered, add dimethyl sulfoxide (DMSO) (800 μ L) then.Vacuum concentrated solution is removed tetrahydrofuran (THF), obtains 14mg (23% yield) title compound through preparation property HPLC purifying then.
1H?NMR(CDCl
3)δ?9.12(d，J＝1.51Hz，1H)，8.72-8.69(m，1H)，8.59(d，J＝2.51Hz，1H)，8.35(t，J＝1.63Hz，1H)，7.94-7.91(m，1H)，7.73(d，J＝8.03Hz，1H)，7.69-7.65(m，2H)，7.43(t，J＝7.78Hz，1H)，7.26-7.21(m，2H)，3.56-3.53(m，2H)，3.43-3.42(m，2H)，3.34(s，3H)，1.91(s，3H)，1.73-1.66(m，2H).；MS(ES)m/z?463[M+1]
+。
Embodiment 33-72
As shown in the table, embodiment 33-72 is a synthetic described in method A (embodiment 31) or method B (embodiment 32), and yield is similar.
Embodiment 73-85
As shown in the table, embodiment 73-85 is a synthetic described in method A (embodiment 31), and yield is similar.
Embodiment 86-87
As described in following table, embodiment 86-87 is that yield is similar as synthetic as described in the method A (embodiment 31).
Embodiment 88
4-[5-amino-7-(3-bromophenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenol
With 7-(3-bromophenyl)-7-(4-hydroxy phenyl)-2,3,6,7-tetrahydrochysene-5H-imidazo [1,5-a] imidazoles-5-thioketones (0.6g, 1.55mmol) be dissolved in methyl alcohol (15mL) and ammonium hydroxide (30%, 3mL) in.Add tert-butyl hydroperoxide (4.1mL, 30mmol, 70% the aqueous solution).The mixture stirring is spent the night, evaporate most of methyl alcohol, add entry and saturated aqueous sodium carbonate, then with the mixture ethyl acetate extraction.Merge organic extract liquid, water, salt water washing, through dried over mgso, evaporation, dry in vacuum drying oven, obtain 0.4g (71% yield) title product:
1H NMR (DMSO-d
6) δ 10.73 (s, 2H), 7.70-7.68 (m, 1H), 7.55-7.52 (m, 1H), 7.38-7.34 (m, 1H), 7.31-7.27 (m, 2H), 7.23 (t, J=7.91Hz, 1H), 6.68-6.64 (m, 2H), 4.28-4.22 (m, 2H), 3.53-3.46 (m, 2H).
Embodiment 89
4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenol
With 4-[5-amino-7-(3-bromophenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenol (0.27g, 0.73mmol), cesium carbonate (0.71g, 2.2mmol), 3-chlorobenzene boric acid (0.16g, 1.02mmol) and [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride adducts (30mg, 0.04mmol) be dissolved in glycol dimethyl ether: ethanol: in the water (6:3:1), in microwave, be heated to 130 ℃ then, kept 20 minutes.Through diatomite filtration, with the ethyl acetate dilution, water and salt water washing then also concentrates through dried over mgso with mixture.Column chromatography (carrying out gradient elution as solvent with 0-10% ammonia (methanol solution of 7N)/methylene dichloride) obtains 0.115g (39% yield) title compound:
1HNMR (DMSO-d
6) δ 7.85-7.82 (m, 1H), 7.61-7.55 (m, 2H), 7.52-7.47 (m, 3H), 7.45-7.41 (m, 1H), 7.40-7.33 (m, 3H), 6.68-6.63 (m, 2H), 4.29-4.22 (m, 2H), 3.53-3.46 (m, 2H); MS (ES) m/z 401[M-1]
-
Embodiment 90
Trifluoromethanesulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.75 acetate
With 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2; 7-dihydro-3H-imidazo [1; 5-a] imidazoles-7-yl] phenol (115mg; 0.285mmol), 1,1,1-three fluoro-N-phenyl-N-[(trifluoromethyls) alkylsulfonyl] Toluidrin (98mg; 0.3mmol) and salt of wormwood (0.24g; 1.7mmol) be dissolved in the anhydrous tetrahydro furan (5mL), in microwave, be heated to 120 ℃ then, kept 12 minutes.After the cooling, add ethyl acetate and water.Organic phase is filtered, add dimethyl sulfoxide (DMSO) (2mL) then.With solution for vacuum concentration, remove ethyl acetate, obtain 36mg (21% yield) title compound through preparation property HPLC purifying then:
1HNMR (DMSO-d
6) δ 7.89-7.86 (m, 1H), 7.81-7.77 (m, 2H), 7.64-7.61 (m, 1H), 7.58-7.57 (m, 1H), and 7.55-7.49 (m, 3H), 7.48-7.40 (m, 4H), 4.31 (t, J=8.78Hz, 2H), 3.54 (t, J=8.91Hz, 2H), 1.90 (s, 2H); MS (ES) m/z 533[M-1]
-
Embodiment 91
4-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenol
Title compound is described in embodiment 88, and from 8-(3-bromophenyl)-8-(4-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones begins to prepare 98% yield:
1HNMR (DMSO-d
6) δ 10.73 (s, 2H), 7.65 (t, J=1.88Hz, 1H), and 7.54-7.50 (m, 1H), 7.36-7.32 (m, 1H), and 7.28-7.24 (m, 2H), 7.20 (t, J=7.91Hz, 1H), 6.65-6.61 (m, 2H), 3.54-3.49 (m, 2H), 3.40-3.36 (m, 2H), and 1.70-1.64 (m, 2H).
Embodiment 92
4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenol
Described in title compound such as the embodiment 89, from 4-[6-amino-8-(3-bromophenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenol begins to prepare 18% yield:
1H NMR (DMSO-d
6) δ 7.81-7.76 (m, 1H), 7.59-7.53 (m, 2H), 7.50-7.45 (m, 3H), 7.43-7.39 (m, 1H), 7.36-7.27 (m, 3H), 6.65-6.60 (m, 2H), 3.54-3.50 (m, 2H), 3.41-3.36 (m, 2H), 1.71-1.64 (m, 2H); MS (ES) m/z 415[M-1]
-
Embodiment 93
Trifluoromethanesulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate
Title compound is described in embodiment 90, and from 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenol begins to prepare 28% yield:
1HNMR (DMSO-d
6) δ 7.82 (t, J=1.76Hz, 1H), 7.78-7.74 (m, 2H), and 7.63-7.59 (m, 1H), 7.56-7.53 (m, 1H), and 7.52-7.48 (m, 3H), 7.44-7.36 (m, 4H), 3.55 (t, J=5.77Hz, 2H), 3.44-3.42 (m, 2H), 1.89 (s, 3H), and 1.72-1.67 (m, 2H); MS (ES) m/z 547[M-1]
-
Embodiment 94
1-(3-bromophenyl)-1-phenyl methylamine
(10.92g 60mmol) is added to that (24mL is in anhydrous tetrahydro furan 72mmol) (25mL) solution in bromine (phenyl) magnesium with the 3-bromobenzylcyanide under argon gas atmosphere in envrionment temperature.The mixture that obtains is stirred 4h at 60 ℃, be cooled to 0 ℃ and add anhydrous methanol (60mL) then.(5.68g 150mmol), makes the mixture that obtains reach envrionment temperature and stirs 1.5h to add sodium borohydride in three batches at 0 ℃ under argon gas atmosphere.To react cancellation by adding saturated aqueous ammonium chloride.Mixture is with the methylene dichloride dilution and separate organic phase.The water dichloromethane extraction concentrates the organic phase that merges, and obtains 17.1g (quantitative yield) title compound: MS (EI) m/z 261,263[M+1]
+
Embodiment 95
1-bromo-3-[isothiocyano (phenyl) methyl] benzene
Title compound is as described in the embodiment 9, begins to prepare from 1-(3-bromophenyl)-1-phenyl methylamine, and yield is quantitative: MS (ESI) m/z 302,304[M-1]
-
Embodiment 96
4-(3-bromophenyl)-4-phenyl-1,3-thiazoles alkane-2, the 5-dithione
Title compound is as described in the embodiment 11, from 1-bromo-3-[isothiocyano (phenyl) methyl] benzene begins to prepare, yield is quantitative: MS (ES) m/z 380,382[M+1]
+
Embodiment 97
8-(3-bromophenyl)-8-phenyl-3,4,7, the 8-imidazolidine is [1,5-a] pyrimidine-6 (2H)-thioketones also
Title compound is that from 4-(3-bromophenyl)-4-phenyl-1,3-thiazoles alkane-2, the 5-dithione begins to prepare, 90% yield: MS (ES) m/z 386,388[M+1 as described in the embodiment 13]
+
Embodiment 98
8-(3-bromophenyl)-8-phenyl-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-6-amine also
Title compound is that from 8-(3-bromophenyl)-8-phenyl-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones begins to prepare, 19% yield: MS (ESI) m/z 369,371[M+1 as described in the embodiment 23]
+
Embodiment 99
Methylsulfonic acid 3 '-(6-amino-8-phenyl-2,3,4,8-imidazolidine is [1,5-a] pyrimidine-8-yl also)-5-methoxyl biphenyl-3-base ester hydrochloride
With 8-(3-bromophenyl)-8-phenyl-2,3,4,8-imidazolidine also [1,5-a] pyrimidine-6-amine (81mg, 0.22mmol), salt of wormwood (0.18g, 1.32mmol), methylsulfonic acid 3-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl ester (100mg, 0.31mmol) and [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride adducts (18mg 0.02mmol) is dissolved in the tetrahydrofuran (THF), in microwave, be heated to 130 ℃ then, keep 4h.The reaction mixture dilute with water is used extracted with diethyl ether then.The organic layer vacuum concentration, crude product is through preparation property HPLC purifying.Resistates is used dichloromethane extraction then with the dilution of 1M sodium hydroxide.Adding hydrochloric acid (diethyl ether solution of 1M, 0.5mL), evaporating solvent obtains 28mg (24% yield) title compound then:
1H NMR (DMSO-d
6) δ 9.13 (br s, 2H), 7.76-7.70 (m, 2H), 7.55-7.47 (m, 2H), 7.43-7.36 (m, 5H), 7.23-7.17 (m, 2H), 7.00-6.94 (m, 1H), 3.86 (s, 3H), 3.83-3.77 (m, 2H), 3.43 (s, 3H), 1.91-1.83 (m, 2H); MS (ES) m/z 491[M+1]
+
Embodiment 100
1-(3-bromophenyl)-1-(3-p-methoxy-phenyl) methylamine
Title compound is as described in example 7 above, begins to prepare 89% yield from 3-bromine phenylmethylether:
1H NMR (DMSO-d
6) δ 7.63 (m, 1H), 7.38 (m, 2H), 7.28-7.16 (m, 2H), 7.01 (m, 1H), 6.94 (m, 1H), 6.76 (m, 1H), 5.05 (s, 1H), 3.73 (s, 3H), 2.33 (br s, 2H); MS (ES) m/z 293[M+1]
+
Embodiment 101
1-bromo-3-[isothiocyano (3-p-methoxy-phenyl) methyl] benzene
Title compound is as described in example 9 above, begins to prepare 93% yield from 1-(3-bromophenyl)-1-(3-p-methoxy-phenyl) methylamine:
1H NMR (CDCl
3) δ 7.46-7.42 (m, 2H), 7.32-7.19 (m, 3H), 6.90-6.81 (m, 3H), 5.91 (s, 1H), 3.80 (s, 3H).
Embodiment 102
4-(3-bromophenyl)-4-(3-p-methoxy-phenyl)-1,3-thiazoles alkane-2, the 5-dithione
Title compound is as described in example 11 above, from 1-bromo-3-[isothiocyano (3-p-methoxy-phenyl) methyl] benzene begins to prepare, yield is quantitative: MS (ES) m/z 411[M+1]
+
Embodiment 103
8-(3-bromophenyl)-8-(3-p-methoxy-phenyl)-3,4,7, the 8-imidazolidine is [1,5-a] pyrimidine-6 (2H)-thioketones also
Title compound is as described in example 13 above, and from 4-(3-bromophenyl)-4-(3-p-methoxy-phenyl)-1,3-thiazoles alkane-2, the 5-dithione begins to prepare, 68% yield: MS (ES) m/z 417[M+1]
+
Embodiment 104
8-(3-bromophenyl)-8-(3-hydroxy phenyl)-3,4,7, the 8-imidazolidine is [1,5-a] pyrimidine-6 (2H)-thioketones also
Title compound is as described in example 14 above, and from 8-(3-bromophenyl)-8-(3-p-methoxy-phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones begins to prepare, and yield is quantitative: MS (ES) m/z 403[M+1]
+
Embodiment 105
Methylsulfonic acid 3-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester
Title compound is as described in example 15 above, and from 8-(3-bromophenyl)-8-(3-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones and methylsulfonyl chloride begins to prepare, 59% yield: MS (ES) m/z 481[M+1]
+
Embodiment 106
Third-1-sulfonic acid 3-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester
Title compound is as described in example 15 above, and from 8-(3-bromophenyl)-8-(3-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones and 1-third SULPHURYL CHLORIDE begins to prepare, 34% yield: MS (ES) m/z 509[M+1]
+
Embodiment 107
Cyclopropyl sulfonic acid 3-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester
Title compound is as described in example 15 above, and from 8-(3-bromophenyl)-8-(3-hydroxy phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones and cyclopropyl SULPHURYL CHLORIDE begins to prepare, 38% yield: MS (ES) m/z 507[M+1]
+
Embodiment 108
8-(3-bromophenyl)-8-(3-p-methoxy-phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-6-amine also
Title compound is as described in example 23 above, and from 8-(3-bromophenyl)-8-(3-p-methoxy-phenyl)-3,4,7,8-imidazolidine also [1,5-a] pyrimidine-6 (2H)-thioketones begins to prepare, and yield is quantitative: MS (ES) m/z 400[M+1]
+
Embodiment 109
3-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenol
Title compound is as described in example 14 above, and from 8-(3-bromophenyl)-8-(3-p-methoxy-phenyl)-2,3,4,8-imidazolidine also [1,5-a] pyrimidine-6-amine begins to prepare, and yield is quantitative: MS (ES) m/z 386[M+1]
+
Embodiment 110
Methylsulfonic acid 3-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
Title compound is as described in example 23 above, from methylsulfonic acid 3-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester begins to prepare, yield is quantitative: MS (ES) m/z 464[M+1]
+
Embodiment 111
Third-1-sulfonic acid 3-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
Title compound is as described in example 23 above, from propane 1-sulfonic acid 3-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester begins to prepare 81% yield: MS (ES) m/z 492[M+1]
+
Embodiment 112
Cyclopropyl sulfonic acid 3-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
Title compound is as described in example 23 above, from cyclopropyl sulfonic acid 3-[8-(3-bromophenyl)-6-sulfo--2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl] phenyl ester begins to prepare 80% yield: MS (ES) m/z 490[M+1]
+
Embodiment 113
Trifluoromethanesulfonic acid 3-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also] phenyl ester
At 0 ℃ with 3-[6-amino-8-(3-bromophenyl)-2,3,4; the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] (0.83g is 2.1mmol) with 1 for phenol; 1,1-three fluoro-N-phenyl-N-[(trifluoromethyls) alkylsulfonyl] (0.77g 2.1mmol) mixes in methylene dichloride Toluidrin.(0.30mL 2.1mmol), stirs 12h with mixture at 25 ℃ then to add triethylamine.Add wet chemical and ethyl acetate and collect organic phase,, obtain 1.5g (138% yield) title compound: MS (ES) m/z518[M+1] through dried over sodium sulfate and vacuum evaporating solvent
+
Method C:
Embodiment 114
Methylsulfonic acid 3-{6-amino-8-[3 ', 5 '-two (trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester
With methylsulfonic acid 3-[6-amino-8-(3-bromophenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester (93mg 0.20mmol) is dissolved in the anhydrous dioxane (3mL), add then salt of wormwood (150mg, 1.1mmol).Fed nitrogen 5 minutes in solution, (30mg 0.04mmol), seals bottle then to add [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride adducts.Reaction mixture is heated 12h at 100 ℃.Add ethyl acetate and water, water is through dried over sodium sulfate.Vacuum evaporating solvent then carries out purifying through preparation property HPLC, obtains (6mg, 5%) title product:
1HNMR (MeOH-d
4) δ 8.17 (m, 2H), 7.94 (m, 1H), 7.71 (m, 1H), 7.66 (m, 1H), 7.59-7.53 (m, 2H), 7.48 (m, 1H), 7.43-7.26 (m, 3H), 3.76 (m, 2H), 3.57 (m, 2H), 3.20 (s, 3H), 1.96-1.88 (m, 2H); MS (ES) m/z 597[M+1]
+
Method D:
Embodiment 115
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester
With trifluoromethanesulfonic acid 3-[6-amino-8-(3-bromophenyl)-2,3,4,8-imidazolidine also [1,5-a] pyrimidine-8-yl] (103mg 0.20mmol) is dissolved in the anhydrous dioxane (3mL) phenyl ester, adds (3-chloro-phenyl-) boric acid (63mg then, 0.40mmol) and salt of wormwood (150mg, 1.1mmol).Fed nitrogen 5 minutes in solution, (30mg 0.04mmol), seals bottle then to add [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride adducts.Begin reaction in room temperature, slowly be warmed to 100 ℃ then, and continue heating 2h.Add ethyl acetate and water, water is through dried over sodium sulfate.Vacuum evaporating solvent then carries out purifying through preparation property HPLC, obtains (3mg, 3%) title product:
1HNMR (MeOH-d
4) δ 7.60 (m, 1H), 7.58-7.52 (m, 4H), 7.51-7.45 (m, 3H), 7.42-7.32 (m, 4H), 3.76 (m, 2H), 3.56 (m, 2H), 1.92 (m, 2H) .MS (ES) m/z549[M+1]
+
Embodiment 116-133
Embodiment 116-133 is as synthetic as described in embodiment 114 (method C) or the embodiment 115 (method D), and yield is similarly, sees the following form.
Embodiment 134
Uncle's N-fourth sulfinyl-3-bromophenyl-azomethine
With 3-bromo-phenyl aldehyde (3.7g, 20mmol), tertiary butyl sulfinyl amine (2.4g, 20mmol) and titanium tetraethoxide (9.1g, 40mmol) mixture in tetrahydrofuran (THF) (10mL) 65 ℃ the heating 12h.Evaporating solvent on silica gel carries out purifying through chromatogram (using the gradient of ethyl acetate/heptane (0-100%)) then, obtains 4.9g (84%) title compound.MS?m/z(ES)290[M+1]
+。
Embodiment 135
3-[amino (3-bromophenyl) methyl]-N, the N-dimethyl benzamide
With 3-iodo-N, the N-dimethyl benzamide (1.0g 3.6mmol) is dissolved in the toluene (40mL), then-40 ℃ add isopropylmagnesium chlorides (tetrahydrofuran solution of 1M, 4mL, 4mmol).Reaction mixture is stirred 1h at-40 ℃, and (1.0g, the 3.6mmol) solution in toluene (2mL) make reaction mixture be warmed to-10 ℃, keep 3h in this temperature then to add uncle's N-fourth sulfinyl-3-bromophenyl-azomethine then.By adding aqueous ammonium chloride solution with the reaction cancellation.The aqueous solution is carried out aftertreatment, uses ethyl acetate extraction then, then on silica gel, carry out purifying by chromatogram (use ethanol/methylene (0-5%) wash-out), obtain the intermediate sulfinyl amine (1.0g, 2.2mmol).Intermediate was handled 30 minutes with hydrochloric acid (diethyl ether solution of 1M, 3 equivalents) in methanol (5mL), then vacuum concentration.Crude product is distributed between ethyl acetate and wet chemical,, obtain 1.0g (63%) title compound: MS m/z (APCI) 335[M+1] through salt of wormwood drying vacuum concentration then
+
Embodiment 136
4-[amino (3-bromophenyl) methyl]-N, the N-dimethyl benzamide
Title compound is described in embodiment 135, and from 4-iodo-N, the N-dimethyl benzamide begins synthetic, 36% yield: MS m/z (APCI) 335[M+1]
+
Embodiment 137
The 3-[(3-bromophenyl) (isothiocyano) methyl]-N, the N-dimethyl benzamide
25 ℃ with thio-carbonyldiimidazole (0.39g 2.2mmol) is added to 3-[amino (3-bromophenyl) methyl of stirring in batches]-N, (1.0g is 2.2mmol) in the solution in methylene dichloride (20mL) for the N-dimethyl benzamide.After stirring 2h, solution salt water washing through dried over sodium sulfate and evaporation, obtains the 0.83g title compound, quantitative yield: MS m/z (APCI) 377[M+1]
+
Embodiment 138
The 4-[(3-bromophenyl) (isothiocyano) methyl]-N, the N-dimethyl benzamide
Title compound is described in embodiment 137, from 4-[amino (3-bromophenyl) methyl]-N, the N-dimethyl benzamide begins synthetic, quantitative yield (0.056g): MS m/z (APCI) 377[M+1]
+
Embodiment 139
3-[4-(3-bromophenyl)-2,5-dithio-1,3-thiazoles alkane-4-yl]-N, the N-dimethyl benzamide
At-78 ℃ with the 3-[(3-bromophenyl) (isothiocyano) methyl]-N, N-dimethyl benzamide (0.83g, 2.2mmol) and dithiocarbonic anhydride (0.28mL, 4.6mmol) drips of solution in anhydrous tetrahydro furan (5mL) is added to the potassium tert.-butoxide of stirring (0.34g is 3.1mmol) in the solution in anhydrous tetrahydro furan (30mL).Make mixture last 30 minutes and reach room temperature.Vacuum concentration extracts between ethyl acetate and salt solution, and through dried over sodium sulfate, vacuum-evaporation obtains 0.99g (quantitative yield) title compound: MSm/z (APCI) 453[M+1 then]
+
Embodiment 140
4-[4-(3-bromophenyl)-2,5-dithio-1,3-thiazoles alkane-4-yl]-N, the N-dimethyl benzamide
Title compound is described in embodiment 139, from the 4-[(3-bromophenyl) (isothiocyano) methyl]-N, the N-dimethyl benzamide begins synthetic, quantitative yield (0.055g): MSm/z (APCI) 453[M+1]
+
Embodiment 141
3-[8-(3-bromophenyl)-3,3-two fluoro-6-sulfo-s-2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl]-N, the N-dimethyl benzamide
With 3-[4-(3-bromophenyl)-2,5-dithio-1,3-thiazolidine-4-yl]-N, and the N-dimethyl benzamide (0.20g, 0.44mmol), 2,2 '-two fluoro-1,3-diaminopropanes hydrochloride (0.080g, 0.44mmol) and triethylamine (0.18mL 1.3mmol) mixes in ethanol (5mL), be heated to 70 ℃ then, keep 12h.With the reaction mixture vacuum concentration, resistates dilutes with ethyl acetate, at first with aqueous sodium carbonate washing, uses the salt water washing then then, through dried over sodium sulfate evaporating solvent then.On silica gel, carry out purifying, obtain 0.21g (quantitative yield) title compound through chromatogram (using ethyl acetate/heptane (0-100%) wash-out).
Embodiment 142
4-[8-(3-bromophenyl)-3,3-two fluoro-6-sulfo-s-2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl]-N, the N-dimethyl benzamide
Title compound is described in embodiment 141, from 4-[4-(3-bromophenyl)-2, and 5-dithio-1,3-thiazoles alkane-4-yl]-N, the N-dimethyl benzamide begins synthetic, quantitative yield (0.060g): MSm/z (APCI) 495[M+1]
+
Embodiment 143
3-[6-amino-8-(3-bromophenyl)-3,3-two fluoro-2,3,4,8-imidazolidine are [1,5-a] pyrimidine-8-yl also]-N, the N-dimethyl benzamide
With 3-[8-(3-bromophenyl)-3,3-two fluoro-6-sulfo-s-2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl]-N, (0.21g 0.44mmol) is dissolved in the methyl alcohol (8mL) the N-dimethyl benzamide, add ammonium hydroxide (30% the aqueous solution then, 4mL) and tert-butyl hydroperoxide (70% the aqueous solution, 1.2mL, 8.8mmol).Reaction mixture is heated 12h at 40 ℃.Vacuum concentration extracts between ethyl acetate and water, and through dried over sodium sulfate, vacuum evaporating solvent obtains 0.21g (quantitative yield) title compound then: MS m/z (APCI) 478[M+1]
+
Embodiment 144
4-[6-amino-8-(3-bromophenyl)-3,3-two fluoro-2,3,4,8-imidazolidine are [1,5-a] pyrimidine-8-yl also]-N, the N-dimethyl benzamide
Title compound is described in embodiment 143, from 4-[8-(3-bromophenyl)-3, and 3-two fluoro-6-sulfo-s-2,3,4,6,7,8-six hydrogen imidazos [1,5-a] pyrimidine-8-yl]-N, the N-dimethyl benzamide begins synthetic, quantitative yield (0.060g): MS m/z (APCI) 478[M+1]
+
Embodiment 145
3-{6-amino-3,3-two fluoro-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also }-N, the N-dimethyl benzamide
With 3-[6-amino-8-(3-bromophenyl)-3,3-two fluoro-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also]-N, N-dimethyl benzamide (0.11g, 0.24mmol) be dissolved in 1,2-glycol dimethyl ether: water: ethanol (6:3:1,3mL) in, add 2-fluoro-3-pyridyl boric acid (0.067g then, 0.48mmol) and cesium carbonate (0.23g, 0.71mmol).In solution, fed nitrogen 5 minutes.(0.020g 0.02mmol), heats reaction mixture 20 minutes at 130 ℃ under nitrogen atmosphere in microwave oven then to add [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II).Vacuum concentration, the aqueous solution carries out aftertreatment with ethyl acetate and water, and vacuum evaporating solvent is followed the purifying through preparation property HPLC then, obtains 0.030g (25%) title compound:
1H NMR (CD
3OD) δ 8.17 (m, 1H), 8.00 (m, 1H), 7.59 (m, 1H), 7.57-7.53 (m, 2H), 7.51-7.43 (m, 4H), 7.42-7.36 (m, 2H), 4.06 (m, 2H), 3.84 (m, 2H), 3.07-2.94 (m, 6H).MS?m/z(APCI)493[M+1]
+。
Embodiment 146
4-{6-amino-3,3-two fluoro-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also }-N, the N-dimethyl benzamide
Title compound is described in embodiment 145, begins synthetic, 11% yield from 2-fluoro-3-pyridyl boric acid:
1H NMR (CD
3OD) δ 8.17 (m, 1H), 8.00 (m, 1H), 7.59 (m, 1H), 7.56 (m, 1H), 7.54-7.41 (m, 6H), 7.39 (m, 1H), 4.06 (m, 2H), 3.84 (m, 2H), 3.09-2.99 (m, 6H).MS?m/z(APCI)493[M+1]
+。
Measure
With at least a in the following mensuration compound is tested:
Beta-secretase
The enzyme that is used for IGEN cracking mensuration, fluorometric assay, TR-FRET mensuration and BiaCore mensuration is described below:
The soluble part of human beta-secretase (AA 1-AA 460) is existed
Clone in the ASP2-Fc10-1-IRES-GFP-neoK mammalian expression vector.The Fc structural domain (affinity tag) of described gene and IgG1 is merged, then stable clone in HEK 293 cells.The sBACE-Fc of purifying is stored in the Tris damping fluid of pH 9.2 and has 95% purity.
The IGEN cracking is measured
Enzyme is diluted among the 43 μ g/ml in 40mM MES pH 5.0.The IGEN substrate is diluted to 12 μ M in 40mMMES pH 5.0.Compound is diluted to desired concentration in dimethyl sulfoxide (DMSO) (ultimate density of dimethyl sulfoxide (DMSO) is 5% in mensuration).Be determined in the 96 hole PCR plates (#650201) from Greiner and carry out.Dimethyl sulfoxide (DMSO) (the 3 μ L) solution and the enzyme (27 μ L) of compound are added to plate, and preincubate is 10 minutes then.Reaction starts with substrate (30 μ L).The final extent of dilution of enzyme is 20 μ g/ml; The ultimate density of substrate is 6 μ M.After 20 minutes, reaction stops by the following method: take out the reaction mixture of 10 μ L, then it is diluted among the 0.20M Tris pH 8.0 with 1:25 in room temperature (RT) reaction.Product comes quantitatively by the following method: with 50 μ L extent of dilution is that the newborn epitope antibodies (neoepitope antibody) of 1:5000 adds to the reaction mixture that 50 μ L extent of dilution are 1:25 (pearl that all antibody and streptavidin (streptavidin) apply is diluted among the PBS (comprising 0.5% BSA and 0.5% polysorbas20)).Then, add the anti-rabbit of ruthenium labelled goat (Ru-Gar) antibody that pearl (Dynabeads M-280) that the 0.2mg/mL streptavidin of 100 μ L applies and extent of dilution are 1:5000.Mixture hatched 2h under room temperature is shaken after, in Bio Veris M8 analyser, measure electrochemiluminescence (electro-chemiluminescene).Dimethyl sulphoxide control has defined 100% activity level, and utilization does not contain enzyme (using 40mM MES pH 5.0 damping fluids to replace) and defined 0% activity.
Fluorometric assay
Enzyme is diluted to 52 μ g/ml in 40mM MES pH 5.0.Substrate (Dabcyl-Edans) is diluted to 30 μ M in 40mM MES pH 5.0.Compound is diluted to desired concentration in dimethyl sulfoxide (DMSO) (ultimate density of dimethyl sulfoxide (DMSO) is 5% in mensuration).(carry out in Corning#3676) on round bottom, lower volume, non-binding property surface to be determined at Corning 384 orifice plates.Solution adds to plate in the dimethyl sulfoxide (DMSO) of 1 μ L compound with enzyme (9 μ L), and preincubate is 10 minutes then.Add substrate (10 μ L), be reflected at the room temperature lucifuge then and carried out 25 minutes.The final extent of dilution of enzyme is 23 μ g/ml; The ultimate density of substrate is 15 μ M (Km is 25 μ M).The fluorescence of product utilizes the Edans peptide scheme of mark to measure on Victor II plate reader, and excitation wavelength is 360nm, and emission wavelength is 485nm.Dimethyl sulphoxide control has defined 100% activity level, and utilization does not contain enzyme (using 40mM MES pH5.0 damping fluid to replace) and defined 0% activity.
TR-FRET measures
In reaction buffer (sodium acetate, chaps, triton x-100, EDTA pH 4.5), enzyme is diluted to 6 μ g/mL, substrate (Europium) CEVNLDAEFK (Qsy7) is diluted to 200nM.Compound is diluted to desired concentration in dimethyl sulfoxide (DMSO) (ultimate density of dimethyl sulfoxide (DMSO) is 5% in mensuration).(carry out in Corning#3676) on round bottom, lower volume, non-binding property surface to be determined at Costar 384 orifice plates.The dimethyl sulphoxide solution of enzyme (9 μ L) and 1 μ L compound is added to plate, mix, preincubate is 10 minutes then.Add substrate (10 μ L), be reflected at the room temperature lucifuge then and carried out 15 minutes.Reaction stops by adding 7 μ L sodium acetates (pH is 9).The fluorescence of product is measured on Victor II plate reader, and excitation wavelength is 340nm, and emission wavelength is 615nm.The final extent of dilution of enzyme is 2.7 μ g/ml; The ultimate density of substrate is 100nM (Km is 290nM).Dimethyl sulphoxide control has defined 100% activity level, and utilization does not contain enzyme (using reaction buffer to replace) and defined 0% activity.
The preparation of BACE Biacore sensing chip
With structure things such as peptide transition state (transition state isostere, TSI) or the peptide TSI of out of order version be connected to the surface of Biacore CM5 sensing chip, thereby on Biacore 3000 instruments, measure BACE.The surface of CM5 sensing chip has 4 different passages that can be used for the coupling peptide.Out of order peptide KFES-statin-ETIAEVENV (KFES-statine-ETIAEVENV) and passage 1 coupling, and passage 2 couplings of TSI inhibitor KTEEISEVN-statin-VAEF (KTEEISEVN-statine-VAEF) and same chip.These two kinds of peptides are dissolved in the 20mM sodium acetate (pH is 4.5) with 0.2mg/mL, and solution is centrifugal with 14K rpm then, thereby removes any particle.Carboxyl on the dextran layer activates by the following method: with 5 μ L/ minutes speed injection 0.5M N-ethyl-N '-(3-the dimethylamino-propyl)-carbodiimides and the 1:1 mixture of 0.5M N-hydroxy-succinamide, continue 7 minutes.Then, the stock solution of the control peptide speed with 5 μ L/ minutes is expelled in the passage 1, continues 7 minutes, remaining then activated carboxyl is blocked by the following method: the speed injection 1M thanomin with 5 μ L/ minutes continues 7 minutes.
BACE Biacore measures scheme
BACE is diluted to 0.5 μ M in pH is 4.5 sodium acetate buffer (electrophoretic buffer that does not contain dimethyl sulfoxide (DMSO)), measures thereby carry out BACE Biacore.The BACE of dilution is mixed with the dimethyl sulfoxide (DMSO) diluent of dimethyl sulfoxide (DMSO) or compound, and the ultimate density of dimethyl sulfoxide (DMSO) is 5%.BACE/ inhibitor mixed thing incubated at room 30 minutes, is expelled in the passage 1 and 2 of CM5 Biacore chip with 20 μ L/ minutes speed then.When BACE and chips incorporate, signal is measured with response units (RU).Produce certain signal with the TSI inhibitor bonded BACE on the passage 2.The existence of BACE inhibitor reduces described signal by combine the peptide TSI interaction that suppresses thus on BACE and the chip with BACE.With any combination of passage 1 all is nonspecific, and deducts from the response value of passage 2.Dimethyl sulphoxide control is defined as 100%, and the effect of compound is reported as inhibition per-cent with respect to dimethyl sulphoxide control.
The full raji cell assay Raji of beta-secretase
The generation of HEK293-APP695
Use the Lipofectamine transfection agents, will the encode pcDNA3.1 plasmid of cDNA of people's complete length APP695 of the scheme (Invitrogen) that provides according to manufacturers is stably transfected in the HEK-293 cell.Group is selected with the zeocin of 0.1-0.5mg/mL.Carry out limited dilution clone, thereby obtain the clone of homogeneous.The level that the clone utilizes independently developed ELISA to measure by A β secreted in APP expression levels and the conditioned medium characterizes.
The cell cultures of HEK293-APP695
The HEK293 cell (HEK293-APP695) that makes stably express people wild-type APP is at 37 ℃ of (5% CO
2) in DMEM, grow, described DMEM contains 4500g/L glucose, GlutaMAX and Sodium.alpha.-ketopropionate (being supplemented with 10% FBS, 1% non-essential amino acid and 0.1mg/mL selectivity microbiotic zeocin).
A β 40 discharges and measures
Collect the HEK293-APP695 cell during for 80-90% in fusion rate, then with 0.2 x 10
6That the concentration of cell/mL (100mL cell suspension/hole) is inoculated in 96-hole at the bottom of the black transparent is poly--plate that D-Methionin applies on.At 37 ℃ of (5% CO
2) after the night incubation, cell culture medium is replaced with the cell culture medium that contains penicillin and Streptomycin sulphate (being respectively 100U/mL and 100 μ g/mL), and it is 1% test compound that the described cell culture medium that contains penicillin and Streptomycin sulphate contains the dimethyl sulfoxide (DMSO) ultimate density.At 37 ℃ of (5% CO
2) with cellular exposure 24h in test compound.100 μ L cell culture mediums are transferred to round bottom polypropylene 96 orifice plates (assay plate), with the amount of the A β of quantitative release.Preserve Tissue Culture Plate, be used for the ATP of carrying out as described below and measure.All add the elementary detection solution (rabbit that contains 0.5 μ g/mL anti--A β 40 antibody and the biotinylated monoclonal mouse 6E10 of 0.5 μ g/mL antibody (containing among the DPBS of 0.5% BSA and 0.5% polysorbas20)) of 50 μ L to each hole of assay plate, then 4 ℃ of overnight incubation.Then, each hole is all added L level of 50 μ and is detected solution, and described solution comprises the pearl (DynabeadsM-280) of 0.5 anti-rabbit antibody of μ g/mL ruthenium labelled goat and the coating of 0.2mg/mL streptavidin.Plate was acutely shaken 1-2 hour in room temperature, and plate is measured electrochemiluminescence in Bio Veris M8 analyser then.
The cell cultures of SH-SY5Y
Make the SH-SY5Y cell at 37 ℃ of (5% CO
2) growth in containing the DMEM/F-121:1 of GlutaMAX (being supplemented with 1mM HEPES, 10%FBS and 1% non-essential amino acid).
SAPP β discharges mensuration
Collect the SH-SY5Y cell during for 80-90% in fusion rate, then with 1.5x10
6The concentration of cell/mL (100mL cell suspension/hole) is inoculated at the bottom of the black transparent in the 96 hole tissue culturing plates.At 37 ℃ of (5% CO
2) hatch 7h after, cell culture medium is replaced with the cell culture medium that 90 μ l contain penicillin and Streptomycin sulphate (being respectively 100U/mL and 100 μ g/mL), and it is 1% test compound that the described cell culture medium that contains penicillin and Streptomycin sulphate contains the dimethyl sulfoxide (DMSO) ultimate density.At 37 ℃ of (5% CO
2) with cellular exposure 18h in test compound.Use is from the sAPP β micro plate of Meso Scale Discovery (MSD), measuring the sAPP β that discharges in cell culture medium, and measures according to the scheme that manufacturers provides.In brief, 25 μ L cell culture mediums are transferred to the MSDsAPP β micro plate of blocking-up in advance.Preserve cell plate, be used for the ATP of carrying out as described below and measure.During room temperature is shaken 1 hour, catch sAPP β by the antibody of point sample in the hole of micro plate.Repeatedly after the washing, in assay plate, add the detection antibody (25 μ L/ holes, ultimate density is 1nM) of SULFO-TAG mark, then plate was hatched under room temperature is shaken 1 hour.Repeatedly after the washing, in plate, read damping fluid T (Read Buffer T) with the interpolation of 150 μ l/ holes.After room temperature kept 10 minutes, with plate at SECTOR
TMRead electrochemiluminescence in the imager.
ATP measures
As above pointed, after being used for A β 40 or sAPP beta determination, plate is used for analysis of cells toxicity from the Tissue Culture Plate transport medium, the ViaLight of total cell ATP is measured in described cytotoxicity analysis utilization
TMPlus cell proliferation/cytotoxic reagent box (Cambrex BioScience) is carried out.Measure according to the scheme that manufacturers provides.In brief, all add 50 μ L cytolysis reagent to each hole.With plate incubated at room 10 minutes.Add (reconstituted) ViaLight that 100 μ L redissolve
TMPlus ATP reagent is after 2 minutes, at Wallac Victor
2Measure luminous intensity (luminescence) in the 1420 multiple labeling counters.
HERG measures
Cell cultures
Make Chinese hamster ovary K1 (CHO) cell of expressing hERG (be described in Persson, Carlsson, Duker ， ﹠amp; Jacobson is in 2005) in the F-12Ham substratum at 37 ℃ of environment (5% CO at humidification
2) in grow to half and merge, described F-12Ham substratum contains L-glutaminate, 10% foetal calf serum (FCS) and 0.6mg/ml Totomycin (all from Sigma-Aldrich).Before the use, the 3ml equal portions liquid of the Versene 1:5000 (Invitrogen) of individual layer utilization warm in advance (37 ℃) washs.Behind this solution of sucking-off, flask was hatched 6 minutes at 37 ℃ of Versene 1:5000 with other 2ml in couveuse.Then, cell separates with at the bottom of the flask by knocking gently, then with Dulbecco phosphate buffered saline (PBS) (containing calcium (0.9mM) and magnesium (0.5mM)) (PBS of 10ml; Invitrogen) add to flask, then it is drawn onto in the 15ml centrifuge tube, centrifugal afterwards (50g, 4 minutes).Discard resulting supernatant liquor, will precipitate among the PBS that is suspended in 3ml carefully again then.The 0.5ml equal portions liquid of cell suspending liquid is taken out, then at the reader (Cedex of automatization; Innovatis) determine the number (based on the incompatible method of Trypan Blue (trypan blue exclusion)) of viable cell in, thereby available PBS adjusts the cell volume of suspension again, with the final cell concentration that obtains expecting.When relating to this parameter, quote the cell concn of this moment in the mensuration.Be used at IonWorks
TMThe CHO-Kv1.5 cell of HT last adjustment voltage excursion (voltage offset) is cultivated with identical method and is prepared, for use.
Electrophysiology
The principle and the operation of this device is described in (Schroeder, Neagle, Trezise ， ﹠amp; Worley, 2003) in.In brief, described technology is with 384 orifice plate (PatchPlate
TM) be the basis, wherein utilize and aspirate cellular localization on the duck eye that two independent fluid chamber are separated, and cell is kept thereon, in each hole, attempt to carry out record thus.In case seal, just with PatchPlate
TMSolution on the bottom side becomes a kind of solution that comprises amphotericin B.The penetrable cell patch (patch of cell membrane) that covers the hole in each hole of this solution makes the full cell patch pincers record of perforation in fact be carried out thus.
Use β-Test Ion Works
TMHT (from Essen Instrument).This device can not carry out warm to solution, therefore operates in room temperature (about 21 ℃) as described below.Container in " damping fluid " position is equipped with the PBS of 4ml, and the container in " cell " position is equipped with CHO-hERG cell suspending liquid described above.96 orifice plates (at the bottom of the V-arrangement, Greiner Bio-one) that will contain compound to be tested (for 3 times of its final test concentration) place " plate 1 " position, and with PatchPlate
TMClamp is to PatchPlate
TMThe position.Every blocking compound plate is designed 12 row, thereby can make up 10 concentration-effect curves that are linked to be by 8 points; Remaining two row occupy with the cisapride (ultimate density is 10 μ M) on vehicle (ultimate density of DMSO is 0.33%) and the maximum blocking-up concentration on the plate, vehicle is used to define establishment of base line, and the cisapride on the maximum blocking-up concentration is used to define 100% inhibition level.Then, IonWorks
TMThe jet head of HT (F head) adds to PatchPlate with the PBS of 3.5 μ l
TMEach hole, and its bottom side is with the perfusion of " inside " solution, described " inside " solution has following component (unit is mM): Potassium Gluconate (K-Gluconate) 100, KCl 40, MgCl
23.2, (all are all from Sigma-Aldrich for EGTA 3 and HEPES 5; Use 10M KOH that pH is adjusted into 7.25-7.30).After startup and deaeration, electronics head (E head) is around PatchPlate
TMMove, carry out hole test (promptly applying voltage pulse) to determine whether the hole in each hole is opened.Then, the F head is dispensed to PatchPlate with the above-mentioned cell suspending liquid of 3.5 μ l
TMEach hole in, and cell has time of 200 seconds to arrive hole in each hole, and the hole is sealed.After this, the E head circumference is around PatchPlate
TMMove, to determine resulting sealing resistance in each hole.Next, with PatchPlate
TMBottom side solution become " entering " solution, described " entering " solution has following component (unit is mM): KCl 140, EGTA 1, MgCl
21 and HEPES 20 (use 10M KOH pH is adjusted into 7.25-7.30) together with the amphotericin B (Sigma-Aldrich) of 100 μ g/ml.After lasting 9 minutes and be used for the diaphragm punching, the E head is at every turn around PatchPlate
TM48 holes move, to add the hERG current measurement value before the compound.Then, the F head 3.5 μ l solution that will come from each hole of compound plate add to PatchPlate
TM4 holes (ultimate density of DMSO in each hole is 0.33%).This realizes by the following method: move to the denseest hole of compound plate from the rarest hole of compound plate, so that the influence that any compound is left over minimizes.After hatching about 3.5 minutes, the E head circumference is around PatchPlate
TMWhole 384 holes move, to add the hERG current measurement value behind the compound.Can obtain non-cumulative concentration-effect curves by this way, if wherein reach standard for acceptance (referring to following) in the hole of enough per-cent, so the effect of the test compound of every kind of concentration is all based on the record to 1 to 4 cell.
Add before the compound and add compound after the hERG electric current cause by single voltage pulse, consisting of at-70mV of described single voltage pulse kept 20 seconds, stride with 160 milliseconds becomes-60mV (thereby leakage is estimated), become again with 100 milliseconds strides and to be-70mV, stride with 1 second becomes+40mV, stride with 2 seconds becomes-30mV, and last stride with 500 milliseconds becomes-70mV.Before adding compound and between the voltage pulse behind the interpolation compound, membrane potential is not carried out any clamp.Deduct leakage value from current value, this is based on to estimating at+caused the electric current of 10mV stride when the voltage pulse scheme begins.In one of two ways to IonWorks
TMAny voltage excursion among the HT is adjusted.When definite compound is renderd a service, (depolarisingvoltage ramp) puts on the CHO-Kv1.5 cell with depolarize voltage deflection, and record a voltage, current locus (current trace) flex point (promptly observing passage at this moment owing to the deflection scheme activates) occurs at this voltage.Before utilized identical voltage instruction in the electrophysiology of routine, to determine to occur the voltage of above-mentioned phenomenon, and find that it is-15mV (data not shown), thereby can be with this value as reference point, (offset potential) is entered into IonWorks with offset potentials
TMIn the HT software.When determining the basic electric physiological property of hERG, any skew is all adjusted by the following method: at Ion Works
TMDetermine hERG tail current counter-rotating electromotive force (reversal potential) among the HT, itself and determined value in conventional electrophysiology (82mV) are compared, then at Ion Works
TMCarry out necessary skew adjustment in the HT software.Current signal is gathered at 2.5kHz.
Initially keep 40 milliseconds of mean values (base current) of the electric current of period by adopting, and deduct described mean value, by Ion Works from the peak value of tail current response at-70mV
TMHT software from the track that deducts leakage value measure automatically scanning before and scanning after the hERG size of current.The standard for acceptance of the electric current that causes in each hole is: the sealing resistance before the scanning〉60M Ω, the hERG tail current amplitude before the scanning〉150pA, the sealing resistance after the scanning〉60M Ω.Inhibition degree to the hERG electric current is estimated by the following method: with regard to each Kong Eryan, and the hERG current value of the hERG current value after the scanning before divided by each self-scanning.
The result
The typical IC50 value of The compounds of this invention about 1 to about 10, in the scope of 000nM.The biological data of the final compound of example provides in following table 1.
Table 1
| The embodiment numbering | IC50 (nM) in TR-FRET measures |
| 31 | 156 |
| 32 | 501 |
| 33 | 397 |
| 34 | 161 |
| 35 | 463 |
| 36 | 92 |
| 37 | 1116 |
| 38 | 1155 |
| 39 | 1163 |
| 40 | 436 |
| 41 | 981 |
| 42 | 284 |
| 43 | 142 |
| 44 | 471 |
| 45 | 529 |
| 46 | 826 |
| 47 | 658 |
| 48 | 757 |
| 49 | 819 |
| 50 | 45 |
| 51 | 143 |
| 52 | 43 |
| 53 | 55 |
| 54 | 347 |
| 55 | 139 |
| 56 | 38 |
| 57 | 71 |
| 58 | 339 |
| 59 | 221 |
| 60 | 493 |
| 61 | 671 |
| 62 | 254 |
| 63 | 912 |
| 64 | 96 |
| 65 | 248 |
| 66 | 66 |
| 67 | 61 |
| 68 | 422 |
| 69 | 313 |
| 70 | 620 |
| 71 | 390 |
| 72 | 644 |
| 73 | 190 |
| 74 | 449 |
| 75 | 146 |
| 76 | 226 |
| 77 | 1530 |
| 78 | 844 |
| 79 | 436 |
| 80 | 1375 |
| 81 | 417 |
| 82 | 484 |
| 83 | 2512 |
| 84 | 2507 |
| 85 | 1031 |
| 86 | 107 |
| 87 | 57 |
| 90 | 113 |
| 98 | 727 |
| 113 | 1204 |
| 114 | 246 |
| 115 | 106 |
| 116 | 285 |
| 117 | 252 |
| 118 | 645 |
| 119 | 754 |
| 120 | 272 |
| 121 | 893 |
| 122 | 69 |
| 123 | 106 |
| 124 | 528 |
| 125 | 51 |
| 126 | 156 |
| 127 | 177 |
| 128 | 214 |
| 129 | 464 |
| 130 | 137 |
| 131 | 538 |
| 132 | 375 |
| 133 | 375 |
| 145 | 224 |
| 146 | 214 |
Claims (38)
1. the solvate of the compound or pharmaceutically acceptable salt thereof of the formula I of free alkali form, solvate or salt:
Wherein
A independently is selected from optional by one or more R
15,6 or 7 yuan of heterocycles that replace;
B independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
2Replace;
C independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
1Independently be selected from halogen, cyano group, nitro, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, NR
6R
7, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6(SO
2) R
7, SOR
6, SO
2R
6, OSO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl C
3-6Heterocyclic radical is optional to be replaced by one or more group E; Or two R
1Substituting group forms optional ring or the heterocycle that is replaced by one or more group E with the atom that they linked to each other;
R
2, R
3Or R
4Be selected from aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical, C
3-6Heterocyclic radical, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6(SO
2) R
7, SOR
6, SO
2R
6, OSO
2R
6And SO
3R
6, wherein said aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical and C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace;
R
5Independently be selected from hydrogen, cyano group, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, CONR
6R
7, CO
2R
6, COR
6, SO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace;
E independently is selected from halogen, nitro, CN, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl heterocyclic, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, NR
6R
7, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6SO
2R
7, SO
2R
6, SOR
6, OSO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl heterocyclic can be chosen wantonly by one or more substituting groups and replace, and described substituting group independently is selected from halogen, nitro, cyano group, OR
6, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy and trifluoromethoxy;
R
6And R
7Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic, or
R
6And R
7Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
R
8Independently be selected from halogen, cyano group, nitro, OR
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, NR
9R
10, CONR
9R
10, NR
9(CO) R
10, O (CO) R
9, CO
2R
9, COR
9, (SO
2) NR
9R
10, NR
9(SO
2) R
10, SO
2R
9, SOR
9, OSO
2R
9And SO
3R
9, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace; Or
Two R
8Can form optional ring or the heterocycle that is replaced by one or more group E with the atom that they linked to each other;
R
9And R
10Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic; Or
R
9And R
10Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
M=0,1 or 2;
N=0,1,2 or 3;
P=0,1,2 or 3;
Q=0,1,2 or 3;
T=0,1,2 or 3;
Wherein among n, p or the q is at least 1.
2. the compound of claim 1, wherein
A independently is selected from 5 or 6 yuan of heterocycles;
B independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
2Replace;
C independently is selected from phenyl or is selected from 5 or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
2, R
3Or R
4Independently be selected from aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical, C
3-6Heterocyclic radical, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6(SO
2) R
7, SOR
6, SO
2R
6, OSO
2R
6And SO
3R
6, wherein said aryl, heteroaryl, C
3-6Cycloalkenyl group, C
3-6Cycloalkynyl radical and C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace;
R
5Be hydrogen;
E independently is selected from halogen, nitro, CN, OR
6, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl heterocyclic, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, NR
6R
7, CONR
6R
7, NR
6(CO) R
7, O (CO) R
6, CO
2R
6, COR
6, (SO
2) NR
6R
7, NR
6SO
2R
7, SO
2R
6, SOR
6, OSO
2R
6And SO
3R
6, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical or C
0-6Alkyl heterocyclic can be chosen wantonly by one or more substituting groups and replace, and described substituting group independently is selected from halogen, nitro, cyano group, OR
6, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy and trifluoromethoxy;
R
6And R
7Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic, or
R
6And R
7Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
R
8Independently be selected from halogen, cyano group, nitro, OR
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical, C
0-6Alkyl C
3-6Heterocyclic radical, NR
9R
10, CONR
9R
10, NR
9(CO) R
10, O (CO) R
9, CO
2R
9, COR
9, (SO
2) NR
9R
10, NR
9(SO
2) R
10, SO
2R
9, SOR
9, OSO
2R
9And SO
3R
9, wherein said C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl C
3-6Heterocyclic radical can be chosen wantonly by one or more group E and replace; Or
Two R
8Can form optional ring or the heterocycle that is replaced by one or more group E with the atom that they linked to each other;
R
9And R
10Independently be selected from hydrogen, C
1-6Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
0-6Alkylaryl, C
0-6Miscellaneous alkyl aryl, C
0-6Alkyl C
3-6Cycloalkyl, C
0-6Alkyl C
3-6Cycloalkenyl group, C
0-6Alkyl C
3-6Cycloalkynyl radical and C
0-6Alkyl heterocyclic; Or
R
9And R
10Can form the heteroatomic 5 or 6 yuan of heterocycles that contain one or more N of being selected from, O and S together;
m＝0；
N=0 or 1;
P=0 or 1;
Q=0,1,2 or 3;
T=0,1,2 or 3;
Wherein among n, p or the q is at least 1.
3. claim 1 or 2 compound, wherein B independently is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by a R
2Replace.
4. claim 1 or 2 compound, wherein B independently is selected from phenyl or pyridyl, and described phenyl or pyridyl are optional by a R
2Replace.
5. each compound in the claim 1 to 4, wherein C independently is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by a R
3Replace.
6. the compound of claim 1, wherein n is 1 and R
2Be OSO
2R
6
7. the compound of claim 1, wherein B independently is selected from phenyl and pyridyl; N is 1 and R
2Be OSO
2R
6
8. the compound of claim 1, wherein R
3Be OSO
2R
6
9. the compound of claim 1, wherein C independently is selected from phenyl or 6 yuan of heteroaromatic rings; P is 1 and R
3Be OSO
2R
6
10. each compound, wherein R in the claim 6 to 9
6Be C
1-6Alkyl.
11. each compound, wherein R in the claim 6 to 9
6Be trifluoromethyl.
12. the compound of claim 1, wherein m is 0; N is 0; P is 0; And q is 1.
13. the compound of claim 1, wherein m is 0; N is 1; P is 0; And q is 0.
14. the compound of claim 1, wherein m is 0; N is 0; P is 1; And q is 0.
15. each compound in the claim 1 to 14, wherein t is 1 or 2.
16. the compound of claim 13, wherein R
8Be positioned on the C, and independently be selected from halogen, cyano group, nitro and OR
9
17. the compound of claim 16, wherein R
9Be selected from C
1-6Alkyl and trifluoromethyl.
18. the compound of claim 13, wherein R
8Be positioned on the C, and be the optional C that is replaced by one or more group E
1-6Alkyl.
19. the compound of claim 13, wherein group E is a halogen.
20. the compound of claim 1, wherein
A is selected from 5 or 6 yuan of heterocycles;
B is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by a R
2Replace;
C is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
2Or R
3Be OSO
2R
6
R
5Be hydrogen;
R
6Be C
1-6Alkyl;
R
8Be selected from halogen, cyano group, nitro and OR
9
R
9Be selected from C
1-6Alkyl and trifluoromethyl;
m＝0；
N=0 or 1;
p＝0；
Q=0,1 or 2;
T=0 or 1;
Wherein among n or the q is at least 1.
21. the compound of claim 1, wherein
A independently is selected from 5 or 6 yuan of heterocycles;
B is for choosing wantonly by a R
2The phenyl that replaces;
C independently is selected from phenyl or 6 yuan of heteroaromatic rings groups, and described phenyl or heteroaromatic rings group are optional by one or more R
3Replace;
R
2Or R
3Be OSO
2R
6
R
5Be hydrogen;
E is a halogen;
R
6Independently be selected from C
1-6Alkyl and trifluoromethyl;
R
8Independently be selected from halogen, OR
9And C
1-6Alkyl, wherein said C
1-6Alkyl is optional to be replaced by one or more group E;
R
9Independently be selected from hydrogen and C
1-6Alkyl;
m＝0；
N=0 or 1;
P=0 or 1;
q＝0；
T=0,1 or 2;
Wherein among n or the p is at least 1.
22. the compound of claim 1, wherein
A is by two R
16 yuan of heterocycles that replace;
B is by a R
2The phenyl that replaces;
C is 6 yuan of heteroaromatic rings;
R
1Be halogen;
R
2Be CONR
6R
7
R
5Be hydrogen;
R
6And R
7Be C
1-6Alkyl;
R
8Be halogen;
m＝2；
n＝1；
p＝0；
Q=0; And
T=0 or 1.
23. a compound, described compound is selected from:
Methylsulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-[6-amino-8-(3-pyrazine-2-base phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(5-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } the phenyl ester acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(5-methoxypyridine-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } the phenyl ester acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-cyanobiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(6-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.25 acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(2,6-difluoro pyridine-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.25 acetate;
Methylsulfonic acid 4-{6-amino-8-[3 '-(trifluoromethoxy) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(2 '-fluoro-3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(2 '-fluoro-5 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-ethoxybiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-nitrobiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(2 ', 5 '-dimethoxy-biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 '-cyano group-4 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(5 '-cyano group-2 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Methylsulfonic acid 4-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 4-{6-amino-8-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Methylsulfonic acid 3 '-[6-amino-8-(4-p-methoxy-phenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also]-5-methoxyl biphenyl-3-base ester acetate;
Methylsulfonic acid 3 '-[6-amino-8-(4-p-methoxy-phenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also]-5-chlordiphenyl-3-base ester acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3-pyrazine-2-base phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Third-1-sulfonic acid 4-{6-amino-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } the phenyl ester acetate;
Third-1-sulfonic acid 4-{6-amino-8-[3 '-(trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.5 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(4 '-fluoro-3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(3 '-chloro-2 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-[6-amino-8-(2 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Third-1-sulfonic acid 4-{6-amino-8-[3-(5-methoxypyridine-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-{6-amino-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-{6-amino-8-[3 '-(trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(3 '-chloro-2 '-fluorine biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.75 acetate;
Cyclopropyl sulfonic acid 4-[6-amino-8-(2 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester 0.5 acetate;
Methylsulfonic acid 3 '-[5-amino-7-(4-p-methoxy-phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl]-5-methoxyl biphenyl-3-base ester acetate;
Methylsulfonic acid 4-[5-amino-7-(3 '-methoxyl biphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[5-amino-7-(3 ', 5 '-DCBP-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.25 acetate;
Methylsulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-[5-amino-7-(3-(pyridin-3-yl) phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Methylsulfonic acid 4-{5-amino-7-[3-(2-fluorine pyridin-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.5 acetate;
Methylsulfonic acid 4-{5-amino-7-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3 '-methoxyl biphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3 ', 5 '-DCBP-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.5 acetate;
Third-2-sulfonic acid 4-[5-amino-7-(3-(pyridin-3-yl) phenyl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.75 acetate;
Third-2-sulfonic acid 4-{5-amino-7-[3-(2-fluorine pyridin-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.75 acetate;
Third-2-sulfonic acid 4-{5-amino-7-[3-(5-methoxypyridine-3-yl) phenyl]-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl } phenyl ester 0.5 acetate;
Methylsulfonic acid 3 '-(6-amino-8-(pyridin-4-yl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also)-5-chlordiphenyl-3-base ester 0.5 acetate; And
Methylsulfonic acid 3 '-(6-amino-8-(pyridin-4-yl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also)-5-methoxyl biphenyl-3-base ester 0.25 acetate.
24. a compound, described compound is selected from:
Trifluoromethanesulfonic acid 4-[5-amino-7-(3 '-chlordiphenyl-3-yl)-2,7-dihydro-3H-imidazo [1,5-a] imidazoles-7-yl] phenyl ester 0.75 acetate;
Trifluoromethanesulfonic acid 4-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] the phenyl ester acetate;
Methylsulfonic acid 3 '-(6-amino-8-phenyl-2,3,4,8-imidazolidine is [1,5-a] pyrimidine-8-yl also)-5-methoxyl biphenyl-3-base ester hydrochloride;
Methylsulfonic acid 3-{6-amino-8-[3 ', 5 '-two (trifluoromethyl) biphenyl-3-yl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 '-chlordiphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Methylsulfonic acid 3-{6-amino-8-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Methylsulfonic acid 3-[6-amino-8-(3 ', 5 '-dimethyl diphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Third-1-sulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Third-1-sulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Third-1-sulfonic acid 3-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Cyclopropyl sulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Cyclopropyl sulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 ', 5 '-DCBP-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3 '-methoxyl biphenyl-3-yl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3-(pyridin-3-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester;
Trifluoromethanesulfonic acid 3-{6-amino-8-[3-(5-chloro-2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also } phenyl ester;
Trifluoromethanesulfonic acid 3-[6-amino-8-(3-(pyrimidine-5-yl) phenyl)-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also] phenyl ester; And
Methylsulfonic acid 3 '-[6-amino-8-(3-p-methoxy-phenyl)-2,3,4,8-imidazolidine be [1,5-a] pyrimidine-8-yl also]-5-methoxyl biphenyl-3-base ester.
25. a compound, described compound is selected from:
3-{6-amino-3,3-two fluoro-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also }-N, the N-dimethyl benzamide; And
4-{6-amino-3,3-two fluoro-8-[3-(2-fluorine pyridin-3-yl) phenyl]-2,3,4, the 8-imidazolidine is [1,5-a] pyrimidine-8-yl also }-N, the N-dimethyl benzamide.
26. a pharmaceutical composition, it comprises as each compound and pharmaceutically acceptable vehicle, carrier or thinner in the claim 1 to 25 of the treatment significant quantity of activeconstituents.
27. each compound or pharmaceutically acceptable salt thereof in the claim 1 to 25, it is as medicine.
28. each compound is as the purposes that is used for the treatment of or prevents the medicine of A beta-related pathologies in the claim 1 to 25.
29. each compound is as the purposes that is used for the treatment of or prevents the medicine of A beta-related pathologies in the claim 1 to 25, wherein said A beta-related pathologies is a mongolism, the beta amyloid vascular disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment, MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, the neurodegeneration relevant with alzheimer's disease, the dementia of mixed type blood vessel origin, the dementia of sex change origin, presenile dementia, senile dementia, the dementia relevant with Parkinson's disease, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
30. each compound is used for the treatment of or prevents purposes in the medicine of A beta-related pathologies in preparation in the claim 1 to 25.
31. each compound is used for the treatment of or prevents purposes in the medicine of A beta-related pathologies in preparation in the claim 1 to 25, wherein said A beta-related pathologies is a mongolism, the beta amyloid vascular disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment, MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, the neurodegeneration relevant with alzheimer's disease, the dementia of mixed type blood vessel origin, the dementia of sex change origin, presenile dementia, senile dementia, the dementia relevant with Parkinson's disease, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
32. suppress the active method of BACE, it comprises makes described BACE contact with each compound in the claim 1 to 25.
33. the treatment or the method for preventing mammiferous A beta-related pathologies, it comprises and gives described patient with each compound in the claim 1 to 25 of treatment significant quantity.
34. the method for claim 33, wherein said A beta-related pathologies is a mongolism, the beta amyloid vascular disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment, MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, the neurodegeneration relevant with alzheimer's disease, the dementia of mixed type blood vessel origin, the dementia of sex change origin, presenile dementia, senile dementia, the dementia relevant with Parkinson's disease, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
35. the method for claim 33, wherein said Mammals is behaved.
36. the treatment or the method for preventing mammiferous A beta-related pathologies, it comprises and gives described patient with each compound and at least a cognition enhancer thing, hypermnesia medicine or anticholinesterase in the claim 1 to 25 of treatment significant quantity.
37. the method for claim 36, wherein said A beta-related pathologies is a mongolism, the beta amyloid vascular disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, the obstacle relevant with cognitive impairment, MCI (" mild cognitive impairment "), alzheimer's disease, the loss of memory, the attention deficit symptom relevant with alzheimer's disease, the neurodegeneration relevant with alzheimer's disease, the dementia of mixed type blood vessel origin, the dementia of sex change origin, presenile dementia, senile dementia, the dementia relevant with Parkinson's disease, paralysis or the sex change of cortex matrix on the carrying out property nuclear.
38. the method for claim 36, wherein said Mammals is behaved.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81372806P | 2006-06-14 | 2006-06-14 | |
| US60/813,728 | 2006-06-14 | ||
| US60/896,994 | 2007-03-26 |
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| CN101501040A true CN101501040A (en) | 2009-08-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2007800301257A Pending CN101501040A (en) | 2006-06-14 | 2007-06-12 | Amino-imidazolones and their use as a medicament for treating cognitive impairment, Alzheimer disease, neurodegeneration and dementia |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103415519A (en) * | 2011-03-01 | 2013-11-27 | 詹森药业有限公司 | 6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-ylamine derivatives useful as inhibitors of beta-secretase (bace) |
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2007
- 2007-06-12 CN CNA2007800301257A patent/CN101501040A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103415519A (en) * | 2011-03-01 | 2013-11-27 | 詹森药业有限公司 | 6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-ylamine derivatives useful as inhibitors of beta-secretase (bace) |
| CN103415519B (en) * | 2011-03-01 | 2016-03-02 | 詹森药业有限公司 | As 6,7-dihydro-pyrazol [1, the 5-a] pyrazine-4-yl amine derivatives that beta-secretase (BACE) inhibitor is useful |
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